Patent Publication Number: US-10786480-B2

Title: Combination therapy of a HIF-2-α inhibitor and an immunotherapeutic agent and uses thereof

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application is a Continuation of U.S. application Ser. No. 15/564,348, filed Oct. 4, 2017, which is a National Stage Entry of PCT/US2016/027611, filed Apr. 14, 2016, which claims the benefit of U.S. Provisional Application No. 62/149,453, filed on Apr. 17, 2015, and U.S. Provisional Application No. 62/219,039, filed on Sep. 15, 2015, each incorporated herein by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     An adequate supply of oxygen to tissues is essential in maintaining mammalian cell function and physiology. A deficiency in oxygen supply to tissues is a characteristic of a number of pathophysiologic conditions in which there is insufficient blood flow to provide adequate oxygenation, for example, ischemic disorders, cancer, and atherosclerosis. The hypoxic (low oxygen) environment of tissues activates a signaling cascade that drives the induction or repression of the transcription of a multitude of genes implicated in events such as angiogenesis (neo-vascularization), glucose metabolism, and cell survival/death. A key to this hypoxic transcriptional response lies in the transcription factors, the hypoxia-inducible factors (HIF). HIFs are disregulated in a vast array of cancers through hypoxia-dependent and independent mechanisms and expression is associated with poor patient prognosis. 
     HIFs consist of an oxygen-sensitive HIFα subunit and a constitutively expressed HIFβ subunit. When HIFs are activated, the HIFα and HIFβ subunits assemble a functional heterodimer (the a subunit heterodimerizes with the 3 subunit). Both HIFα and HIFβ have two identical structural characteristics, a basic helix-loop-helix (bHLH) and PAS domains (PAS is an acronym referring to the first proteins, PER, ARNT, SIM, in which this motif was identified). There are three human HIFα subunits (HIF-1α, HIF-2α, and HIF-3α) that are oxygen sensitive. Among the three subunits, HIF-1α is the most ubiquitously expressed and induced by low oxygen concentrations in many cell and tissue types. HIF-2α is highly similar to HIF-1α in both structure and function, but exhibits more restricted cell and tissue-specific expression, and might also be differentially regulated by nuclear translocation. HIF-3α also exhibits conservation with HIF-1α and HIF-2α in the HLH and PAS domains. HIF-1β (also referred to as ARNT—Aryl Hydrocarbon Receptor Nuclear Translocator), the dimerization partner of the HIFα subunits, is constitutively expressed in all cell types and is not regulated by oxygen concentration. 
     PD-1 (Programmed cell death protein-1) is a cell surface co-inhibitory receptor expressed mainly on T cells and B cells. PD-1 has two known ligands: PD-L1 and PD-L2. The PD-1/PD-L1 signaling axis plays an important role in the negative regulation of the immune system to prevent autoimmunity and promote self-tolerance. PD-L1 has been thought to be the principle mediator of PD-1 dependent immunosuppression. 
     PD-L1 is expressed in many human cancers and is associated with a poor prognosis for patients. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and display impaired antitumor functionality. Preclinical studies demonstrate that blockage of the interaction between PD-1 and PD-L1 can enhance T-cell function and mediate anti-tumor activity. Monoclonal antibodies targeting PD-1 or PD-L1 are under development for the treatment of cancer. One such PD-1 targeting agent, nivolumab (Opdivo, Bristol-Myers Squibb), produced complete or partial antitumor responses in multiple diseases, including non-small-cell lung cancer, melanoma and renal-cell cancer in a clinical trial, and was approved by the FDA to treat metastatic melanoma in 2014. There are at least 7 mAbs that target the PD-1/PD-L1 interaction being evaluated in clinical studies that hold promise for the immunotherapeutic treatment of various malignancies. 
     Preclinical and early clinical studies demonstrated that the combination of anti-PD-1/PD-L1 agents with other targeted agents could increase anti-tumor efficacy. Simultaneous treatment with anti-PD-1 and anti-VEGFR2 mAbs inhibited tumor growth synergistically in a preclinical murine colon cancer model. The most recent phase I clinical trial data showed that combining nivolumab with one of the current standard of care VEGFR tyrosine kinase inhibitors (TKIs), either sunitinib or pazopanib, significantly increased the overall response rate compared with the single agent alone in patients with renal cancer. 
     CTLA-4 (Cytotoxic T-lymphocyte-associated antigen 4) is a member of the immunoglobulin superfamily, which is expressed on the surface of T cells. CTLA-4 transmits an inhibitory signal to T cells by outcompeting the T-cell co-stimulatory molecule CD28 for B7 ligands (CD80 and CD86) on the surface of antigen-presenting cells with higher affinity and avidity. In preclinical studies, blockade of CTLA-4 led to a significant in T-cell proliferation and interleukin-2 production. 
     In addition to the suppression of the effector T cells, CTLA-4 also increases the function of immunosuppressive T regulatory T cells (Tregs). CTLA-4 deficiency in Tregs was shown to diminish the suppressive capacity of Tregs, and CTLA-4 blockade has been shown to deplete intratumoral Tregs in preclinical models. 
     Based on these preclinical findings, two antibodies that block CTLA-4 in humans, ipilimumab and tremelimumab, have been tested in the clinic and have demonstrated significant durable responses in a broad of spectrum of malignancies. The FDA has approved both ipilimumab and tremelimumab for the treatment of melanoma. 
     SUMMARY OF THE INVENTION 
     In view of the foregoing, there exists a need for improved methods for treating proliferative disorders. This disclosure provides compounds, compositions, and methods that address this need, and provide other advantages as well. 
     In one aspect, the present disclosure provides a method of treating a proliferative disorder in a subject in need thereof. In one embodiment, the method comprises administering to said subject a HIF-2α inhibitor and an immunotherapeutic agent. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent yield a synergistic effect in treating the proliferative disorder. In some embodiments, the proliferative disorder is a cancer condition. In some embodiments, the cancer condition is selected from the group consisting of non-small-cell lung carcinoma, melanoma, renal cell carcinoma, colorectal cancer, castration-resistant prostate cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, and a hematologic malignancy. In some embodiments, the cancer condition is renal cell carcinoma. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent together are effective in one or more of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, killing cancer cells, modulating an immune response, and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered sequentially. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered simultaneously. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent form part of the same composition. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are provided in one or more unit doses. In some embodiments, the HIF-2α inhibitor or the immunotherapeutic agent are administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally. In some embodiments, the HIF-2α inhibitor inhibits one or more biological effects selected from the group consisting of heterodimerization of HIF-2α to HIF-1β, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2α inhibitor inhibits heterodimerization of HIF-2α to HIF-1β but not heterodimerization of HIF-1α to HIF-1β. In some embodiments, the HIF-2α inhibitor binds the PAS-B domain cavity of HIF-2α. 
     In one aspect, the present invention provides a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; and 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some other embodiments of compounds of Formula I, R 1  is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R 1  is phenyl or pyridyl. In yet other embodiments, R 1  is cycloalkyl or heterocycloalkyl. Compounds of Formula I are also provided wherein R 1  is substituted with at least one substituent selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In yet other embodiments of compounds of Formula I, R 2  and R 3  are independently selected from halo, cyano and alkyl. In some further embodiments, R 3  is —(CH 2 ) n OH and n is 1, 2 or 3. In still other embodiments, n is 1. 
     In still other embodiments of compounds of Formula I, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R 4  is fluoroalkyl or alkylsulfonyl. 
     In some embodiments of compounds of Formula I, R 2  and R 3  are independently selected from halo, cyano and alkyl; and R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In another embodiment, R 3  is CH 2 OH. 
     In yet another embodiment, Z is —O—. In some embodiments, Z is —S—. In still other embodiments, Z is —N(R 8 )—. In another embodiment, Z is —C(HR 7 )—. In some embodiments, Z is absent. In some embodiments, X is N and Y is CR 6 . In another embodiment, X is CR 5  and Y is N. In yet another embodiment, X is N and Y is N. In still another embodiment, X is CR 5  and Y is CR 6 . 
     In another aspect, the invention provides a compound of Formula I-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     W 1  is N or CR 10 ; 
     R 9  is cyano, halo, alkyl or alkoxy; and 
     R 10  is hydrogen, cyano, halo, alkyl or alkoxy. 
     In another aspect, the invention provides a compound of Formula I-B: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R c  is hydrogen, cyano, halo, alkyl or alkoxy; and 
     n′ is 0, 1, 2, 3 or 4. 
     In yet another aspect, the invention provides a compound of Formula I-C: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R 11  is hydrogen, hydroxy, alkoxy or amino; 
     R 12  is hydrogen, alkyl, alkenyl or alkynyl; or R 11  and R 12  in combination form oxo or oxime; 
     each of R 13  is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R 13  is hydroxy, n is 1 or 2; or two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and 
     n is 0, 1, 2, 3 or 4. 
     In some other embodiments of compounds of Formula I-C, R 1  is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. In some embodiments, R 1  is phenyl or pyridyl. In yet other embodiments, R 1  is cycloalkyl or heterocycloalkyl. Compounds of Formula I-C are also provided wherein R 1  is substituted with at least one substituent selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In still other embodiments of compounds of Formula I-C, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In other embodiments, R 4  is fluoroalkyl or alkylsulfonyl. In some other embodiments, R 11  is hydroxy or amino. In further embodiments, R 11  is hydroxy. In yet other embodiments, R 12  is hydrogen. In yet another embodiment, R 13  is fluoro and n is 1, 2 or 3. 
     In some embodiments of compounds of Formula I-C, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11  is hydroxy or amino; and R 12  is hydrogen. In still another embodiment, R 13  is fluoro. In yet another embodiment, Z is —O—. In some embodiments, Z is —S—. In still other embodiments, Z is —N(R 8 )—. In another embodiment, Z is —C(HR 7 ). In some embodiments, Z is absent. 
     In some other embodiments of compounds of Formula I-C, R 4  is fluoroalkyl; n is 0, 1, 2 or 3; Z is —O—; R 11  is hydroxy; and R 12  is hydrogen. In still other embodiments, R 4  is sulfonyl; n is 0, 1, 2 or 3; Z is —O—; R 11  is hydroxy; and R 12  is hydrogen. In yet other embodiments, R 1  is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. In some embodiments, X is N and Y is CR 6 . In another embodiment, X is CR 5  and Y is N. In yet another embodiment, X is N and Y is N. 
     In still another aspect, the invention provides a compound of Formula I-D, I-E, I-F or I-G: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydrogen, hydroxy, alkoxy or amino. 
     In a further aspect, the invention provides a compound of Formula I-H, I-I, I-J or I-K: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydroxy or amino. 
     In yet another aspect, the invention provides a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 16  and R 17  are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R 16  and R 17  and the carbon to which they are attached form C 3 -C 8  cycloalkyl or C 5 -C 8  heterocycloalkyl; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; 
     n″ is 1 or 2; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In another aspect, the invention provides a compound of Formula II-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In still another aspect, the invention provides a compound of Formula II-B: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 15  is hydroxy or amino; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some embodiments, the present invention provides a HIF-2α inhibitor that may be a compound selected from Table 1. In some embodiments, the immunotherapeutic agent induces or enhances an immune response. In some embodiments, the immunotherapeutic agent is a PD-1 inhibitor. The PD-1 inhibitor may be nivolumab or pembrolizumab. In some embodiments, the immunotherapeutic agent is a CTLA-4 inhibitor. The CTLA-4 inhibitor may be tremelimumab or ipilimumab. In some embodiments, the immunotherapeutic agent comprises a small molecule or antibody. In some embodiments, the immunotherapeutic agent comprises an antibody. In some embodiments, the present invention provides a method of measuring a tumor size or an amount of one or more markers for the presence of the proliferative disorder before and after administering the HIF-2α inhibitor and the immunotherapeutic agent, and (b) adjusting dosage or discontinuing use of the HIF-2α inhibitor and/or the immunotherapeutic agent based on results of step (a). 
     INCORPORATION BY REFERENCE 
     All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows a synergistic effect of a treatment according to the methods of the invention on tumor growth in mice. 
         FIG. 2  depicts results of a co-immunoprecipitation assay for measuring inhibition of HIF-2α and ARNT dimerization. 
         FIG. 3  shows a synergistic effect of a treatment according to the methods of the invention on tumor growth in mice. 
         FIG. 4  depicts a 96-well plate layout of an ELISA assay. 
         FIG. 5  depicts a 96-well plate layout of a luciferase assay. 
     
    
    
     DETAILED DESCRIPTION 
     While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference. 
     As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise. 
     As used herein, “agent” or “biologically active agent” refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural nature of the agents of the present invention. 
     The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an undesired immune response as manifested in autoimmune disease. 
     The term “cell proliferation” refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal. 
     The terms “co-administration,” “administered in combination with,” and their grammatical equivalents, encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present. 
     The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. 
     As used herein, the terms “treatment”, “treating”, “palliating” and “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including, but are not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. 
     A “therapeutic effect,” as used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. 
     The term “pharmaceutically acceptable” means that a chemical entity, such as a compound, a carrier, an additive or a salt, is acceptable for being administrated to a subject. 
     The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. 
     The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions. 
     The term “selective inhibition” or “selectively inhibit” as applied to a biologically active agent refers to the agent&#39;s ability to selectively reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target. 
     The term “subject” includes, but is not limited to, humans of any age group, e.g., a pediatric subject (e.g., infant, child or adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys or rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human. 
     “Radiation therapy” or “radiation treatment” means exposing a patient, using routine methods and compositions known to the practitioner, to radiation emitters such as alpha-particle emitting radionucleotides (e.g., actinium and thorium radionuclides), low linear energy transfer (LET) radiation emitters (e.g., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation, including without limitation x-rays, gamma rays, and neutrons. 
     The term “immunotherapeutic agent” refers to any agent that induces, enhances, suppresses or otherwise modifies an immune response. This includes the administration of an active agent to, or any type of intervention or process performed on, the subject, with the objective of modifying an immune response. An immunotherapeutic agent may, for example, increase or enhance the effectiveness or potency of an existing immune response in a subject, for example, by stimulating mechanisms that enhance the endogenous host immune response or overcoming mechanisms that suppress the endogenous host immune response. 
     “Immune response” refers to the action of a cell of the immune system—including, for example, B lymphocytes, T lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, myeloid-derived suppressor cells, dendritic cells and neutrophils—and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines and complement), that results in selective targeting, binding to, damage to, destruction of, and/or elimination of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues, from the body of a subject. 
     The term “antibody” (Ab) as referred to herein includes whole antibodies and any antigen binding fragment (i.e. “antigen-binding portion”) or single chains thereof. A typical full-length antibody is a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding portion thereof. Each H chain comprises a heavy chain variable region (abbreviated herin as V H ) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, C H1 , C H2  and C H3 . Each light chain comprises a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region comprises one constant domain, C L . The V H  and V L  regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each V H  and V L  comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the Abs may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. 
     Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (K D ) of 10 −5  to 10 −11  M −1  or less. In some embodiments, an Ab that “binds specifically” to an antigen refers to an Ab that binds to the antigen and substantially identical antigens with a K D  of 10 −7  M −1  or less, preferably 10 −8  M −1  or less, even more preferably 5×10 −9  M −1  or less, and most preferably between 10 −8  M −1  and 10 −10  M −1  or less, but does not bind with such affinity to unrelated antigens. An antigen is “substantially identical” to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, preferably at least 95%, more preferably at least 97%, or even more preferably at least 99% sequence identity to the sequence of the given antigen. By way of example, an Ab that binds specifically to human PD-1 may also have cross-reactivity with PD-1 antigens from certain primate species but may not cross-react with PD-1 antigens from certain rodent species or with an antigen other than PD-1, e.g., a human PD-L1 antigen. 
     An immunoglobulin may derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include, but are not limited to, human IgG1, IgG2, IgG3 and IgG4. “Isotype” refers to the Ab class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes. The term “antibody” includes, by way of example, both naturally occuring and non-naturally occuring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic Abs; and single chain Abs. A nonhuman Ab may be humanized by recombinant methods to reduce its immunogenicity in man. Where not expressly stated, and unless the context indicates otherwise, the term “antibody” also includes an antigen-binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a sing chain Ab. 
     An “isolated antibody” refers to an Ab that is substantially free of other Abs having different antigenic specificities (e.g., an isolated Ab that binds specifically to PD-1 is substantially free of Abs that bind specifically to antigens other than PD-1). An isolated Ab that binds specifically to PD-1 may, however, have cross-reactivity to other antigens, such as PD-1 molecules from different species. Moreover, an isolated Ab may be substantially free of other cellular material and/or chemicals. 
     The term “monoclonal antibody” (“mAb”) refers to a preparation of Ab molecules of single molecular composition, i.e., Ab molecules whose primary sequences are essentially identical, and which exhibits a single binding specificity and affinity for a particular epitope. A mAb is an example of an isolated Ab. MAbs may be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art. 
     A “human” antibody (HuMAb) refers to an Ab having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the Ab contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human Abs of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody,” as used herein, is not intended to include Abs in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms “human” Abs and “fully human” Abs and are used synonymously. 
     A “humanized” antibody refers to an Ab in which some, most or all of the amino acids outside the CDR domains of a non-human Ab are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an Ab, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the Ab to bind to a particular antigen. A “humanized” Ab retains an antigenic specificity similar to that of the original Ab. 
     A “chimeric antibody” refers to an Ab in which the variable regions are derived from one species and the constant regions are derived from another species, such as an Ab in which the variable regions are derived from a mouse Ab and the constant regions are derived from a human Ab. 
     An “antigen-binding portion” of an Ab (also called an “antigen-binding fragment”) refers to one or more fragments of an Ab that retain the ability to bind specifically to the antigen bound by the whole Ab. 
     The “Programmed Death-1 (PD-1)” receptor refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term “PD-1” as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GENBANK® Accession No. U64863. 
     “Programmed Death Ligand-1 (PD-L1)” is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1. The term “PD-L1” as used herein includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GENBANK® Accession No. Q9NZQ7. 
     The terms “cytotoxic T lymphocyte-associated antigen-4,” “CTLA-4,” “CTLA4” and “CD152” are used interchangeably, and refer to an immunoinhibitory receptor belonging to the immunoglobulin (Ig) superfamily. CTLA-4 is a cell surface receptor expressed predominantly on activated T cells, and binds to two ligands, CD80 (B7-1) and CD86 (B7-2). The term “CTLA-4” as used herein includes varients, isoforms, species homologs of human CTLA-4, and analogs having at least one common epitope with CTLA-4. The complete sequence of human CTLA-4 can be found under GENBANK® Accession No. L15006. 
     A “cell surface receptor” includes, for example, molecules and complexes of molecules that are located on the surface of a cell and are capable of receiving a signal and transmitting such a signal across the plasma membrane of a cell. An example of a cell surface receptor of the present invention is the PD-1 receptor, which is located on the surface of activated B cells, activated T cells and myeloid cells, and transmits a signal that results in a decrease in tumor-infiltrating lymphocytes and a decrease in T cell proliferation. 
     A “PD-1 inhibitor” as referred to herein is meant to include any agent, including an antibody or small molecule, that blocks or inhibits the PD-1 pathway. A PD-1 inhibitor may, for example, block or inhibit an interaction between PD-1/PD-L1, PD-1/PD-L2 and/or PD-L1/CD80. A PD-1 inhibitor includes any compound able to directly or indirectly affect the regulation of PD-1 by reducing, for example, the expression of PD-1, PD-L1 or PD-L2, or a PD-1 activity. 
     A “CTLA-4 inhibitor” as referred to herein is meant to include any agent, including an antibody or small molecule, that blocks or inhibits the CTLA-4 pathway. A CTLA-4 inhibitor may, for example, block or inhibit an interaction between CTLA-4/CD80 and/or CTLA-4/CD86. A CTLA-4 inhibitor includes any compound able to directly or indirectly affect the regulation of CTLA-4 by reducing, for example, the expression of CTLA-4, CD80 or CD86, or a CTLA-4 activity. 
     A “B7 inhibitor” as referred to herein is meant to include any agent, including an antibody or small molecule, that blocks or inhibits an interaction between a B7 protein and a receptor. “B7 protein” includes members of the B7 family, including CD80 (B7-1), CD86 (B7-2), PD-L1 (B7-H1) and PD-L2 (B7-DC). Receptors of B7 proteins include PD-1, CTLA-4 and CD28. A B7 inhibitor may, for example, block or inhibit an interaction between PD-1/PD-L1, PD-1/PD-L2, PD-L1/CD80, CTLA-4/CD80 and/or CTLA-4/CD86. 
     “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. 
     The term “in vivo” refers to an event that takes place in a subject&#39;s body. 
     The term “in vitro” refers to an event that takes place outside of a subject&#39;s body. For example, an in vitro assay encompasses any assay run outside of a subject&#39;s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed. 
     The term “HIF-2α” refers to a monomeric protein that contains several conserved structured domains: basic helix-loop-helix (bHLH), and two Per-ARNT-Sim (PAS) domains designated PAS-A and PAS-B, in addition to C-terminal regulatory regions. “HIF-2α” is also alternatively known by several other names in the scientific literature, including Endothelial PAS Domain Protein 1 (EPAS1), HIF2A, PASD2, HIF-2-Alpha, HIF2-Alpha, HLF, Hypoxia-Inducible Factor 2-Alpha, HIF-1alpha-Like Factor, and MOP2. As a member of the bHLH/PAS family of transcription factors, “HIF-2α” forms an active heterodimeric transcription factor complex by binding to the ARNT (also known as HIF-1β) protein through non-covalent interactions. 
     The term “scintillation proximity assay” (SPA) refers to a homogeneous assay in which light is emitted when a radiolabeled ligand is brought into close proximity to a radiosensitive bead. The assay typically contains a target protein that contains a tag (e.g., His Tag, Glutathione S-transferase Tag). The tag on the protein is used to bind the target protein to the scintillation bead. Radio-labeled ligand (e.g., labeled with tritium) that binds to the protein is now in close proximity to the bead, and when the radio-label (e.g., tritium) decays, the high energy particle hits the bead resulting in the emission of light that is detected by a detector, such as photomultiplier tube or CCD camera. When unlabeled ligands or compounds that bind to the protein are used in the assay, they displace the radio-labeled ligand, resulting in loss of signal. For a general reference describing the assay, see Park, et al.  Analytical Biochemistry  269: 94-104, 1999. 
     “HIF-2α activity” as used herein has its ordinary meaning in the art. HIF-2α activity, for example, includes activation of gene transcription mediated by HIF-2α. 
     The term “inhibiting HIF-2α activity”, as used herein, refers to slowing, reducing, altering, as well as completely eliminating and/or preventing HIF-2α activity. 
     “Combination therapy” and “co-therapy” means the administration of a first active agent and at least a second, different active agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of the at least two active agents. The beneficial effect of the combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). Combination therapy is not intended to encompass the administration of two or more different therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily results in a combination therapy of the invention. Combination therapy includes administration of at least two different therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at a different time, as well as administration of at least two different therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in separate capsules for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The two different therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the second therapeutic agent of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not critical, unless otherwise stated. Combination therapy also includes the administration of the different therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or physical therapy). Where a combination therapy comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks. 
     The term “simultaneous” or “simultaneously” as applied to administering more than one pharmaceutically active ingredient (e.g., a HIF-2α inhibitor and an immunotherapeutic agent) refers to administering the more than one ingredient at the same time, or at two different time points that are separated by no more than 2 hours. The term “sequentially” as applied to administering more than one pharmaceutically active ingredient (e.g., a HIF-2α inhibitor and an immunotherapeutic agent) refers to administering the more than one ingredient at two different time points that are separated by more than 2 hours, e.g., about 5 hours, 8 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or even longer. 
     As used herein, the term “neoplastic condition” refers to the presence of cells possessing abnormal growth characteristics, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, perturbed oncogenic signaling, or certain characteristic morphological features. 
     A “sub-therapeutic amount” of an agent or therapy is an amount less than the effective amount for that agent or therapy, but when combined with an effective or sub-therapeutic amount of another agent or therapy can produce a result desired by the physician, due to, for example, synergy in the resulting efficacious effects, or reduced side effects. 
     A “synergistic” or “synergizing” effect can be such that the one or more effects of the combination compositions are greater than the one or more effects of each component alone at a comparable dosing level, or they can be greater than the predicted sum of the effects of all of the components at a comparable dosing level, assuming that each component acts independently. The synergistic effect can be about, or greater than about 1, 2, 3, 5, 10, 20, 30, 50, 75, 100, 110, 120, 150, 200, 250, 350, or 500% or even more than the effect on a subject with one of the components alone, or the additive effects as measured when each of the components when administered individually. The effect can be any of the measurable effects described herein. 
     An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition. One class of anti-cancer agents comprises chemotherapeutic agents. “Chemotherapy” means the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, inhalation, or in the form of a suppository. 
     “Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule. 
     The term “heterodimerization” as used herein refers to the complex formed by the non-covalent binding of HIF-2α to HIF-10 (ARNT). Heterodimerization of HIF-2α to HIF-10 (ARNT) is required for HIF-2α DNA binding and transcriptional activity and is mediated by the HLH and PAS-B domains. Transcriptional activity following heterodimerization of HIF-2a to HIF-1β (ARNT) can affect four groups of target genes including angiogenic factors, glucose transporters and glycolytic enzymes, survival factors, and invasion factors. 
     The term “HIF-2α PAS-B domain cavity” refers to an internal cavity within the PAS-B domain of HIF2α. The crystal structure of the PAS-B domain can contain a large (approximately 290 A) cavity in its core. However, the amino acid side chains in the solution structure are dynamic. For example, those side chains can tend to intrude more deeply in the core, and can shrink the cavity to 1 or 2 smaller cavities or can even expand the cavity. The cavity is lined by amino acid residues comprising PHE-244, SER-246, HIS-248, MET-252, PHE-254, ALA-277, PHE-280, TYR-281, MET-289, SER-292, HIS-293, LEU-296, VAL-302, VAL-303, SER-304, TYR-307, MET-309, LEU-319, THR-321, GLN-322, GLY-323, ILE-337, CYS-339, and ASN-341 of HIF-2α PAS-B domain. The numbering system is from the known structures reported in the RCSB Protein Data Bank with PDB code 3H7W. Other numbering systems in the PDB could define the same amino acids, expressed above, that line the cavity. 
     As described herein “a biological marker”, or “a biomarker”, generally refers to a measurable indicator of some biological state or condition. Biological markers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. 
     The terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. 
     “Controlled release” refers to a drug-containing formulation or unit dose form thereof from which release of the drug is not immediate, i.e., with a controlled release formulation, administration does not result in immediate release of all of the drug administered into an absorption pool. The term is used interchangeably with “nonimmediate release” as defined in  Remington: The Science and Practice of Pharmacy, Nineteenth Ed.  (Easton, Pa.: Mack Publishing Company, 1995). In general, controlled release formulations include sustained release and delayed release formulations. 
     “Sustained release” and “extended release” refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and typically, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. 
     “Delayed release” refers to a drug formulation that, following administration to a patient, provides a measurable time delay before drug is released from the formulation into the patient&#39;s body. 
     “Dosage form” means any form of a pharmaceutical composition for administration to a subject (typically a human or animal of veterinary interest suffering from a disease or condition to be treated). “Dose” refers to an amount of active agent. “Unit dosage form” refers to a dosage form that contains a fixed amount of active agent. A single tablet or capsule is a unit dosage form. Multiple unit dosage forms can be administered to provide a therapeutically effective dose. A dosage form can include a combination of dosage forms. 
     The term “alkyl” refers to a straight or branched hydrocarbon chain radical comprising carbon and hydrogen atoms, containing no unsaturation, and having from one to ten carbon atoms (e.g., C 1 -C 10  alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, it is a C 1 -C 4  alkyl group. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and the like. The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl, (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “fluoroalkyl” refers to an alkyl group substituted with one or more fluorine atoms. In some embodiments, it is a C 1 -C 4  alkyl group substituted with one or more fluorine atoms. Typical fluoroalkyl groups include, but are in no way limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     The term “alkenyl” refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C 2 -C 10  alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkenyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C 2 -C 8  alkenyl). In other embodiments, an alkenyl comprises two to five carbon atoms (i.e., C 2 -C 5  alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “alkynyl” refers to a straight or branched hydrocarbon chain radical group comprising carbon and hydrogen atoms, containing at least one triple bond, and having from two to ten carbon atoms (i.e., C 2 -C 10  alkynyl). In some embodiments, an alkynyl group may contain one or more double bonds. Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range; e.g., “2 to 10 carbon atoms” means that the alkynyl group may contain 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C 2 -C 8  alkynyl). In other embodiments, an alkynyl has two to five carbon atoms (i.e., C 2 -C 5  alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “aromatic” or “aryl” refers to an aromatic radical with six to ten ring atoms (i.e., C 6 -C 10  aromatic or C 6 -C 10  aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical wherein the arylalkyl moiety is attached via the alkyl portion of the moiety. Aryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl, respectively. 
     The term “heteroaryl” or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aromatic radical (i.e., C 5 -C 18  heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range; e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical, e.g., nitrogen or sulfur, is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. Examples of monocylic heteroaryls include, but are not limited to, imidazolyl, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, thiazolyl, furanyl and thienyl. 
     Substituted heteroaryl also includes ring systems substituted with one or more oxide substituents, such as pyridinyl N-oxides. 
     “Heteroarylalkyl” refers to a moiety having a heteroaryl moiety, as described herein, connected to an alkyl moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkyl group. Heteroaryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl, respectively. 
     The term “acyl” refers to a —C(═O)R radical, wherein R is alkyl, cycloalkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, which are as described herein. The R group is attached to the parent structure through the carbonyl functionality. In some embodiments, it is a C 1 -C 10  acyl radical which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyl group plus the carbonyl carbon of acyl, i.e. ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “halo”, “halide”, or alternatively, “halogen” means fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” refer to haloalkyl and haloalkoxy groups, respectively, in which the halo is fluoro. Examples of fluoroalkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , and —CF 2 CF 3 . The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group. 
     The term “cyano” refers to a —CN radical. 
     The term “alkoxy” refers to an —O-alkyl radical, including from wherein alkyl is as described herein and contains 1 to 10 carbon atoms (i.e., C 1 -C 10  alkoxy) of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In some embodiments, it is a C 1 -C 4  alkoxy group. Unless stated otherwise specifically in the specification, an alkoxy moiety may be substituted by one or more of the substituents described as suitable substituents for an alkyl radical. 
     The term “sp 3  hybridized carbon” refers to a carbon atom that is bonded to four other atoms. sp 3  hybridization results from the combination of the s orbital and all three p orbitals in the second energy level of carbon. It results in four equivalent orbitals and the geometric arrangement of those four orbitals is tetrahedral. 
     The term “sulfonyl” refers to a —S(═O) 2 R a  radical, wherein R a  is selected from the group consisting of alkyl, amino, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Unless stated otherwise specifically in the specification, the R a  group may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical. 
     The term “sulfoximinyl” refers to a —S(═O)(═NR a )R b  radical, wherein R a  is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, cyano, carbamoyl, acyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon) and R b  is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Unless stated otherwise specifically in the specification, the R a  and R b  groups may be substituted by one or more of the substituents described as suitable substituents for an alkyl, an aryl or a heteroaryl radical. 
     “Sulfonamide,” “sulfonamidyl” or “sulfonamido” refers to a —S(═O) 2 N(R a ) 2  radical, wherein each R a  is selected independently from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl. The R a  groups in —N(R a ) 2  of the —S(═O) 2 —N(R a ) 2  radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6-, or 7-membered ring. In some embodiments, it is a C 1 -C 10  sulfonamido, wherein each R a  in sulfonamido contains 1 carbon, 2 carbons, 3 carbons or 4 carbons total. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl and heteroaryl, respectively. 
     The term “fluoroalkylsulfonyl” refers to a —S(═O) 2 R a  radical, wherein R a  is fluoroalkyl. In some embodiments, R a  is C 1 -C 4  alkyl, substituted with one or more fluorines. 
     The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical that contains carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (e.g., C 3 -C 10  cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range; e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon ring atoms, 4 carbon ring atoms, 5 carbon ring atoms, etc., up to and including 10 carbon ring atoms. In some embodiments, it is a C 3 -C 8  cycloalkyl radical. In some embodiments, it is a C 3 -C 5  cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbomyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “heterocyclyl” or “heterocycloalkyl” refers to a stable 3- to 18-membered nonaromatic ring (e.g., C 3 -C 18  heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range; e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. In some embodiments, it is a C 5 -C 10  heterocycloalkyl. In some embodiments, it is a C 4 -C 10  heterocycloalkyl. In some embodiments, it is a C 3 -C 10  heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, may optionally be quaternized. The heterocycloalkyl radical may be partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, 6,7-dihydro-5H-cyclopenta[b]pyridine, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected form oxygen, sulfur and nitrogen and is not aromatic. 
     The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals, which respectively have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range, which refers to the chain length in total, may be given. For example, C 3 -C 4  heteroalkyl has a chain length of 3-4 atoms. For example, a —CH 2 OCH 2 CH 3  radical is referred to as a “C 4  heteroalkyl”, which includes the heteroatom in the atom chain length description. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl may be a substituted alkyl. The same definition applies to heteroalkenyl or heteroalkynyl. Unless otherwise stated in the specification, a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “amino” or “amine” refers to a —N(R a ) 2  radical group, where each R a  is independently hydrogen, alkyl, heteroalkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(R a ) 2  group has two R a  other than hydrogen, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, 7- or 8-membered ring. For example, —N(R a ) 2  is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “substituted amino” also refers to N-oxides of the group N(R a ) 2  as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation. 
     The term “acyloxy” refers to a RC(═O)O— radical wherein R is alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl, which are as described herein. In some embodiments, it is a C 1 -C 4  acyloxy radical, which refers to the total number of chain or ring atoms of the alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e., the other ring or chain atoms plus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the “R” of an acyloxy group is optionally substituted by one or more of the following substituents: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     The term “amide” or “amido” refers to a chemical moiety with formula —C(═O)N(R a ) 2  or —NR a C(═O)R a , wherein each of R a  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl. Two R a s may optionally be taken together with the nitrogen to which it is attached to form a 4-10 membered ring. In some embodiments, it is a C 1 -C 4  amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound having an amine or a carboxylic acid moiety, thereby forming a prodrug. Any amine, hydroxy or carboxyl side chain on the compounds described herein can be amidified. The procedures and specific groups to make such amides are known to those of skilled in the art and can readily be found in reference sources such as Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5 th  Ed., Wiley, New York, N.Y., 2014, which is incorporated herein by reference in its entirety. 
     “Carboxaldehyde” refers to a —C(═O)H radical. 
     “Carboxyl” refers to a —C(═O)OH radical. 
     “Ester” refers to a chemical radical of formula —C(═O)OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be esterified. The procedures and specific groups to make such esters are known to those skilled in the art and can readily be found in reference sources such as Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5 th  Ed., Wiley, New York, N.Y., 2014, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, thioxo, trimethylsilanyl, —OR a , —SR a , —OC(═O)R a , —OC(═O)OR a , —OC(═O)N(R a ) 2 , —N(R a ) 2 , —C(═O)OR a , —C(═O)R a , —C(═O)N(R a ) 2 , —N(R a )C(═O)OR a , —N(R a )C(═O)N(R a ) 2 , —N(R a )C(NR a )N(R a ) 2 , —N(R a )C(═O)R a , —N(R a )S(═O) t R a  (where t is 1 or 2), —N(R a )S(═O) t N(R a ) 2  (where t is 1 or 2), —S(═O) t R a  (where t is 1 or 2), —S(═O) t N(R a ) 2  (where t is 1 or 2), —PO 3 (R a ) 2 , —OPO 3 WY (where W and Y are independently hydrogen, methyl, ethyl, alkyl, lithium, sodium or potassium) or —OPO 3 Z (where Z is calcium, magnesium or iron), wherein each R a  is independently hydrogen, alkyl, fluoroalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl. 
     “Imino” refers to a ═N—R a  radical, wherein R a  is hydrogen, alkyl, heteroalkyl, cycloalkyl, cyano, aryl, heterocycloalkyl or heteroaryl. 
     “Isocyanato” refers to a —NCO radical. 
     “Isothiocyanato” refers to a —NCS radical. 
     “Mercaptyl” refers to an —S(alkyl) or —SH radical. 
     “Methylene” refers to a ═CH 2  radical. 
     “Hydroxy” refers to a —OH radical. 
     “Oxa” refers to a —O— radical. 
     “Oxo” refers to a ═O radical. 
     “Nitro” refers to a —NO 2  radical. 
     “Oxime” refers to a ═N(—OR) radical, where R is hydrogen or alkyl. 
     “Sulfinyl” refers to a —S(═O)R radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heterocycloalkyl (bonded through a ring carbon). In some embodiments, R is fluoroalkyl. 
     “Sulfoxyl” refers to a —S(═O) 2 OH radical. 
     “Sulfonate” refers to a —S(═O) 2 OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl (bonded through a ring carbon) and heteroalkyl (bonded through a ring carbon). The R group is optionally substituted by one or more of the substituents described for alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, respectively. 
     “Thiocyanato” refers to a —CNS radical. 
     “Thioxo” refers to a ═S radical. 
     “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. 
     “Substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, heteroalkyl, cycloalkyl, aralkl, heterocycloalkyl, aryl, carbohydrate, carbonate, heteroaryl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups and the protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may have a halide substituted at one or more ring carbons, and the like. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5 th  Ed., Wiley, New York, N.Y., 2014. 
     The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and includes instances where the event or circumstance occurs and instances in which it does not. For example, “alkyl optionally substituted with” encompasses both “alkyl” and “alkyl” substituted with groups as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns which would be deemed unacceptable by one of ordinary skill in the art. 
     Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form,” “polymorph,” and “novel form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. 
     The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. For example, hydrogen has three naturally occurring isotopes, denoted  1 H (protium),  2 H (deuterium), and  3 H (tritium). Protium is the most abundant isotope in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. See Pleiss and Voger,  Synthesis and Applications of Isotopically Labeled Compounds , Vol. 7, Wiley, ISBN-10: 0471495018, published on Mar. 14, 2001. 
     “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(+)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R—S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined. 
     Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans-form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well. 
     The term “enantiomeric excess,” as used herein, is the percent excess of one enantiomer compared to that of the other enantiomer in a mixture, and can be calculated using the following equation: enantiomeric excess=((R−S)/(R+S))×100=% (R*)−% (S*), wherein R and S are the number of moles of each enantiomer in the mixture, and R* and S* are the respective mole fractions of the enantiomers in the mixture. For example, for a mixture with 87% R enantiomer and 13% S enantiomer, the enantiomeric excess is 74%. 
     “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. 
     “Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5 th  Ed., Wiley, New York, N.Y., 2014. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected. 
     “Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that the present chemical entities encompass the present chemical entities and solvates of the compound, as well as mixtures thereof. 
     “Solvent,” “organic solvent,” and “inert solvent” each means a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert organic solvents. Unless specified to the contrary, for each gram of the limiting reagent, one cc (or mL) of solvent constitutes a volume equivalent. 
     Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used. 
     When desired, the (R)- and (S)-isomers of the compounds of the present invention, if present, may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diasteroisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enatiomer to the other by asymmetric transformation. 
     The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts. 
     When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. 
     Abbreviations used herein have their conventional meaning within the chemical and biological arts. 
     The following abbreviations and terms have the indicated meanings throughout: 
     DAST=Diethylaminosulfur trifluoride 
     DCM=Dichloromethane 
     MTBE=Methyl t-butyl ether 
     HATU=O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate 
     NBS=N-Bromosuccinimide 
     NMP=N-Methyl-2-pyrrolidone 
     e.e. or ee=Enantiomeric excess 
     PPTS=Pyridinium p-toluenesulfonate 
     TLC=Thin Layer Chromatography 
     DMAP=4-Dimethylaminopyridine 
     DMF=N,N-Dimethylformamide 
     When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration. In addition, such certain small molecules include Z- and E-forms (or cis- and trans-forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule. 
     When “ ” is drawn across a bond, it denotes where a bond disconnection or attachment occurs. For example, in the chemical structure shown below, 
                         
R a  is attached to the para position of a fluorophenyl ring through a single bond. When R a  is phenyl, it can also be drawn as
 
     
       
         
         
             
             
         
       
     
     The waved line “ ” means a bond with undefined stereochemistry. For example, 
                         
represents a mixture of B
 
     
       
         
         
             
             
         
       
     
     When a bond is drawn across a ring, it means substitution at a non-specific ring atom or position. For example, in the structure shown below, 
                         
R b  may be attached to any one of the —CH 2 — in the five-membered ring.
 
     When a bold bond “ ” appears two or more times in the same chemical structure, a mixture of the two cis isomers of the compound is described. For example, 
                         
represents a mixture of the two isomers
 
     
       
         
         
             
             
         
       
     
     In one aspect, the present invention provides a method for treating a proliferative disorder in a subject in need thereof, comprising administering to said subject a HIF-2α inhibitor and an immunotherapeutic agent. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered sequentially or simultaneously. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are more effective in treating the proliferative disorder than either agent alone. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent yield a synergistic effect in treating the proliferative disorder. The synergistic effect may be a therapeutic effect that is greater than either agent used alone in comparable amounts under comparable conditions. The synergistic effect may be a therapeutic effect that is greater than results expected by adding the effects of each agent alone. In some embodiments, the proliferative disorder is a cancer condition. In some further embodiments, said cancer condition is a cancer selected from the group consisting of lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, breast cancer, ovarian cancer, renal cell carcinoma, prostate cancer, neuroendocrine cancer, gastric cancer, bladder cancer and colon cancer. In another embodiment, the cancer condition is renal cell carcinoma. In still another embodiment, the cancer condition is a cancer selected from the group consisting of non-small-cell lung carcinoma, melanoma, renal cell carcinoma, colorectal cancer, castration-resistant prostate cancer, hepatocellular carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, ovary, gastrointestinal tract and breast, and a hematologic malignancy. 
     In a further embodiment, the present invention provides a method of treating a cancer condition, wherein the HIF-2α inhibitor and the immunotherapeutic agent together are effective in one or more of inhibiting proliferation of cancer cells, inhibiting metastasis of cancer cells, killing cancer cells, modulating an immune response and reducing severity or incidence of symptoms associated with the presence of cancer cells. In some other embodiments, said method comprises administering to the cancer cells simultaneously or sequentially a therapeutically effective amount of a combination of a HIF-2α inhibitor and an immunotherapeutic agent. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo. 
     In some embodiments, the present invention provides a method of treating a von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof a HIF-2α inhibitor and an immunotherapeutic agent. VHL disease is an autosomal dominant syndrome that not only predisposes patients to kidney cancer (˜70% lifetime risk), but also to hemangioblastomas, pheochromocytoma and pancreatic neuroendocrine tumors. VHL disease results in tumors with constitutively active HIF-α proteins with the majority of these dependent on HIF-2α activity (Maher, et al.  Eur. J. Hum. Genet.  19: 617-623, 2011). HIF-2α has been linked to cancers of the retina, adrenal gland and pancreas through both VHL disease and activating mutations. Recently, gain-of-function HIF-2α mutations have been identified in erythrocytosis and paraganglioma with polycythemia (Zhuang, et al.  NEJM  367: 922-930, 2012; Percy, et al.  NEJM  358: 162-168, 2008; and Percy, et al.  Am. J. Hematol.  87: 439-442, 2012). Notably, a number of known HIF-2α target gene products (e.g., VEGF, PDGF, and cyclin D1) have been shown to play pivotal roles in cancers derived from kidney, liver, colon, lung, and brain. In fact, therapies targeted against one of the key HIF-2α regulated gene products, VEGF, have been approved for the treatment of these cancers. 
     In practicing any of the discussed methods, a HIF-2α inhibitor and an immunotherapeutic agent can be administered sequentially, wherein the two agents are introduced into a subject at two different time points. The two time points can be separated by more than 2 hours, 1 or more days, 1 or more weeks, 1 or more months, or according to any intermittent regimen schedule disclosed herein. 
     In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered simultaneously. The two agents may form part of the same composition, or the two agents may be provided in one or more unit doses. 
     In some other embodiments, the HIF-2α inhibitor or the immunotherapeutic agent are administered parenterally, orally, intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, or intrathecally. 
     As used herein, a therapeutically effective amount of a combination of a HIF-2α inhibitor and an immunotherapeutic agent refers to a combination of a HIF-2α inhibitor and an immunotherapeutic agent, wherein the combination is sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a HIF-2α inhibitor and an immunotherapeutic agent in combination for treating an intended disease condition. The individual components of the combination, though present in sub-therapeutic amounts, synergistically yield an efficacious effect and/or reduced a side effect in an intended application. 
     The amount of the HIF-2α inhibitor and the immunotherapeutic agent administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. 
     Measuring an immune response and/or the inhibition of biological effects of HIF-2a can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples. 
     A subject being treated with a HIF-2α inhibitor and an immunotherapeutic agent may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject&#39;s physiological response to treatment. For example, if inhibition of a biological effect of HIF-2α inhibition is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. Alternatively, the treatment regimen may be adjusted with respect to an immune response. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound or compounds in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound or compounds in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a HIF-2α inhibitor and an immunotherapeutic agent is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators. 
     In one embodiment, an immunotherapeutic agent may comprise a PD-1 inhibitor. In another embodiment, an immunotherapeutic agent may comprise a CTLA-4 inhibitor. In still another embodiment, an immunotherapeutic agent may comprise a B7 inhibitor. 
     Exemplary PD-1 inhibitors: A PD-1 inhibitor suitable for use in the subject methods can be selected from a variety of types of molecules. For example, the PD-1 inhibitor can be a biological or chemical compound, such as an organic or inorganic molecule, peptide, peptide mimetic, antibody or an antigen-binding fragment of an antibody. Some exemplary classes of agents suitable for use in the subject methods are detailed in the sections below. A PD-1 inhibitor for use in the present invention can be any PD-1 inhibitor that is known in the art, and can include any entity that, upon administration to a patient, results in inhibition of the PD-1 pathway in the patient. A PD-1 inhibitor can inhibit PD-1 by any biochemical mechanism, including disruption of any one or more of PD-1/PD-L1, PD-1/PD-L2 and PD-L1/CD80 interactions. 
     In some embodiments, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect, the PD-1 ligand binding partners are PD-L1 and/or PD-L2. In another embodiment, a PD-1 inhibitor is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, PD-L1 binding partners are PD-1 and/or CD80. In another embodiment, the PD-1 inhibitor is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, a PD-L2 binding partner is PD-1. The inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein or oligopeptide. 
     In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some further embodiments, the anti-PD-1 antibody is capable of inhibiting binding between PD-1 and PD-L1. In another embodiment, the anti-PD-1 antibody is capable of inhibiting binding between PD-1 and PD-L2. In some embodiments, the PD-1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and CD80. In some embodiments, the PD-1 inhibitor is an anti-PD-L2 antibody. In some further embodiments, the anti-PD-L2 antibody is capable of inhibiting binding between PD-1 and PD-L2. In yet another embodiment, the PD-1 inhibitor is nivolumab or pembrolizumab. 
     Inhibition of the PD-1 pathway can enhance the immune response to cancerous cells in a patient. The interaction between PD-1 and PD-L1 impairs T cell response as manifested by a decrease in tumor-infiltrating lymphocytes (TILs) and a decrease in T-cell receptor mediated proliferation, resulting in T cell anergy, exhaustion or apoptosis, and immune evasion by the cancerous cells. This immune suppresion can be reversed by inhibiting the local interaction between PD-L1 and PD-1 using a PD-1 inhibitor, including, for example, an anti-PD-1 and/or an anti-PD-L1 Ab. A PD-1 inhibitor may improve or restore antitumor T-cell functions. 
     Anti-PD-1 antibodies suitable for use in the invention can be generated using methods well known in the art. Exemplary PD-1 inhibitors include, but are not limited to: nivolumab (BMS936558), pembrolizumab (MK-3475), pidilizumab (CT-011), AMP-224, AMP-514, BMS-936559, RG7446 (MPDL3280A), MDX-1106 (Medarex Inc.), MSB0010718C, MEDI4736, and HenGrui mAB005 (WO 15/085847). Further PD-1 antibodies and other PD-1 inhibitors include those described in WO 04/056875, WO 06/121168, WO 07/005874, WO 08/156712, WO 09/014708, WO 09/114335, WO 09/101611, WO 10/036959, WO 10/089411, WO 10/027827, WO 10/077634, WO 11/066342, WO 12/145493, WO 13/019906, WO 13/181452, WO 14/022758, WO 14/100079, WO 14/206107, WO 15/036394, WO 15/085847, WO 15/112900, WO 15/112805, WO 15/112800, WO 15/109124, WO 15/061668, WO 15/048520, WO 15/044900, WO 15/036927, WO 15/035606; U.S. Pub. No. 2015/0071910; and U.S. Pat. Nos. 7,488,802; 7,521,051; 7,595,048; 7,722,868; 7,794,710; 8,008,449; 8,354,509; 8,383,796; 8,652,465; and 8,735,553; all of which are incorporated herein by reference. Some anti-PD-1 antibodies are commercially available, for example from ABCAM® (AB137132), BIOLEGEND® (EH12.2H7, RMP1-14) and AFFYMETRIX EBIOSCIENCE (J105, J116, M1H4). 
     Exemplary CTLA-4 Inhibitors: 
     A CTLA-4 inhibitor suitable for use in the subject methods can be selected from a variety of types of molecules. For example, the CTLA-4 inhibitor can be a biological or chemical compound, such as an organic or inorganic molecule, peptide, peptide mimetic, antibody or an antigen-binding fragment of an antibody. Some exemplary classes of agents suitable for use in the subject methods are detailed in the sections below. A CTLA-4 inhibitor for use in the present invention can be any CTLA-4 inhibitor that is known in the art, and can include any entity that, upon administration to a patient, results in inhibition of the CTLA-4 pathway in the patient. A CTLA-4 inhibitor can inhibit CTLA-4 by any biochemical mechanism, including disruption of either one or both of CTLA-4/CD80 and CTLA-4/CD86 interactions. 
     In some embodiments, the CTLA-4 inhibitor is a molecule that inhibits the binding of CTLA-4 to its ligand binding partners. In a specific aspect, the CTLA-4 ligand binding partners are CD80 and/or CD86. In another embodiment, a CTLA-4 inhibitor is a molecule that inhibits the binding of CD80 to its binding partners. In a specific aspect, a CD80 binding partner is CTLA-4. In another embodiment, the CTLA-4 inhibitor is a molecule that inhibits the binding of CD86 to its binding partners. In a specific aspect, a CD86 binding partner is CTLA-4. The inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein or oligopeptide. 
     In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. In some further embodiments, the anti-CTLA-4 antibody is capable of inhibiting binding between CTLA-4 and CD80. In another embodiment, the anti-CTLA-4 antibody is capable of inhibiting binding between CTLA-4 and CD86. In some embodiments, the CTLA-4 inhibitor is an anti-CD80 antibody. In some embodiments, the anti-CD80 antibody is capable of inhibiting binding between CTLA-4 and CD80. In some embodiments, the CTLA-4 inhibitor is an anti-CD86 antibody. In some further embodiments, the anti-CD86 antibody is capable of inhibiting binding between CTLA-4 and CD86. In yet another embodiment, the CTLA-4 inhibitor is tremelimumab or ipilimumab. 
     Inhibition of the CTLA-4 pathway can enhance the immune response to cancerous cells in a patient. The interaction between CTLA-4 and one of its natural ligands, CD80 and CD86, delivers a negative regulatory signal to T cells. This immune suppresion can be reversed by inhibiting the local interaction between CD80 or CD86 and CTLA-4 using a CTLA-4 inhibitor, including, for example, an anti-CTLA-4 Ab, anti-CD80 Ab or an anti-CD86 Ab. A CTLA-4 inhibitor may improve or restore antitumor T-cell functions. 
     Anti-CTLA-4 antibodies suitable for use in the invention can be generated using methods well known in the art. Exemplary CTLA-4 inhibitors include but are not limited to tremelimumab and ipilimumab (also known as 10D1 or MDX-010). Further CTLA-4 antibodies and other CTLA-4 inhibitors include those described in WO 98/042752, WO 00/037504, WO 01/014424 and WO 04/035607; U.S. Pub. Nos. 2002/0039581, 2002/086014 and 2005/0201994; U.S. Pat. Nos. 5,811,097; 5,855,887; 5,977,318; 6,051,227; 6,207,156; 6,682,736; 6,984,720; 7,109,003; 7,132,281; 7,605,238; 8,143,379; 8,318,916; 8,435,516; 8,784,815; and 8,883,984; EP Pat. No. 1212422; Hurwitz et al., PNAS 1998, 95(17): 10067-10071; Camacho et al., J Clin Oncology 2004, 22(145): abstract no. 2505 (antibody CP-675206); and Mokyr, et al., Cancer Research 1998, 58:5301-5304; all of which are incorporated herein by reference. 
     Exemplary HIF-2α Inhibitors: 
     A HIF-2α inhibitor suitable for use in the subject methods can be selected from a variety of types of molecules. For example, the HIF-2α inhibitor can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, peptide, peptide mimetic, protein (e.g. antibody), liposome, or a polynucleotide (e.g. small interfering RNA, microRNA, anti-sense, aptamer, ribozyme, or triple helix). Some exemplary classes of chemical compounds suitable for use in the subject methods are detailed in the sections below. A HIF-2α inhibitor for use in the present invention can be any HIF-2α inhibitor that is known in the art, and can include any chemical entity that, upon administration to a patient, results in inhibition of HIF-2α in the patient. 
     In general, a HIF-2α inhibitor is a compound that inhibits one or more biological effects of HIF-2α. Examples of biological effects of HIF-2α include, but are not limited to, heterodimerization of HIF-2α to HIF-10, HIF-2α target gene expression, VEGF gene expression, and VEGF protein secretion. In some embodiments, the HIF-2α inhibitor is selective for HIF-2α, such that the inhibitor inhibits heterodimerization of HIF-2α to HIF-10 but not heterodimerization of HIF-1a to HIF-10. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. 
     Hypoxia-inducible factors (HIFs), like HIF-2α, are transcription factors that respond to changes in available oxygen in the cellular environment (e.g. a decrease in oxygen, or hypoxia). The HIF signaling cascade mediates the effects of hypoxia, the state of low oxygen concentration, on the cell. Hypoxia often keeps cells from differentiating. However, hypoxia promotes the formation of blood vessels, and is important for the formation of a vascular system in embryos, and cancer tumors. The hypoxia in wounds also promotes the migration of keratinocytes and the restoration of the epithelium. A HIF-2α inhibitor of the present disclosure may be administered in an amount effective in reducing any one or more of such effects of HIF-2α activity. 
     HIF-2α activity can be inhibited by inhibiting heterodimerization of HIF-2α to HIF-10 (ARNT), such as with inhibitor compounds disclosed herein. A variety of methods for measuring HIF-2α dimerization are available. In some embodiments, the HIF-2α inhibitor binds the PAS-B domain cavity of HIF-2α. 
     Inhibition of heterodimerization of HIF-2α to HIF-10 (ARNT) may also be determined by a reduction in HIF-2α target gene mRNA expression. mRNA quantitation can be performed using real-time PCR technology. (Wong, et al, “Real-time PCR for mRNA quantitation”, 2005. BioTechniques 39, 1: 1-1.). Yet another method for determining inhibition of heterodimerization of HIF-2α to HIF1β (ARNT) is by co-immunoprecipitation. 
     As described herein, HIF-2α is a transcription factor that plays important roles in regulating expression of target genes. Non-limiting examples of HIF-2α target gene include HMOX1, SFTPA1, CXCR4, PAI1, BDNF, hTERT, ATP7A, and VEGF. For instance, HIF-2a is an activator of VEGF. Further non-limiting examples of HIF-2α target genes include HMOX1, EPO, CXCR4, PAI1, CCND1, CLUT1, IL6, and VEGF. A HIF-2α inhibitor of the present disclosure may be administered in an amount effective in reducing expression of any one or more of genes induced by HIF-2α activity. A variety of methods is available for the detection of gene expression levels, and includes the detection of gene transcription products (polynucleotides) and translation products (polypeptides). For example, gene expression can be detected and quantified at the DNA, RNA or mRNA level. Various methods that have been used to quantify mRNA include in situ hybridization techniques, fluorescent in situ hybridization techniques, reporter genes, RNase protection assays, Northern blotting, reverse transcription (RT)-PCR, SAGE, DNA microarray, tiling array, and RNA-seq. Examples of methods for the detection of polynucleotides include, but are not limited to selective colorimetric detection of polynucleotides based on the distance-dependent optical properties of gold nanoparticles, and solution phase detection of polynucleotides using interacting fluorescent labels and competitive hybridization. Examples for the detection of proteins include, but are not limited to microscopy and protein immunostaining, protein immunoprecipitation, immunoelectrophoresis, western blot, BCA assay, spectrophotometry, mass spectrophotometry and enzyme assay. 
     In some embodiments, inhibition of HIF-2α is characterized by a decrease in VEGF gene expression. The decrease may be measured by any of a variety of methods, such as those described herein. As a further example, the mRNA expression level of VEGF can be measured by quantitative PCR (QT-PCR), microarray, RNA-seq and nanostring. As another example, an ELISA assay can be used to measure the level VEGF protein secretion. 
     In one aspect, the invention provides a compound which is an inhibitor of HIF-2a of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; and 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In one aspect, the invention provides a compound which is an inhibitor of HIF-2α of Formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is nitro, carboxaldehyde, carboxyl, ester, amido, cyano, halo, sulfonyl, alkyl, alkenyl, alkynyl or heteroalkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, carboxaldehyde, carboxylic acid, oxime, ester, amido or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; and 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some embodiments, for a compound of Formula I, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl. In some further embodiments, R 1  is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 1  is bicyclic heteroaryl. In a further embodiment, the bicyclic heteroaryl is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 1  is pyridyl N-oxide. In a further embodiment, the pyridyl N-oxide is substituted with one or more substituents selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 1  is 
                         
wherein the aryl ring may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is 
                         
wherein W 1  is N or CR 10 , R 9  is cyano, halo, alkyl or alkoxy, and R 10  is hydrogen, cyano, halo, alkyl or alkoxy. In a further embodiment, R 9  is cyano, halo, C 1 -C 4  alkyl or C 1 -C 4  alkoxy, and R 10  is hydrogen, cyano, halo, C 1 -C 4  alkyl or C 1 -C 4  alkoxy.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, cyano and oxo.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In some embodiments, R 2  is fluoro, chloro, bromo or iodo. In some embodiments, R 2  is fluoroalkyl. In some further embodiments, R 2  is —CH 2 F, —CHF 2  or —CF 3 . In another embodiment, R 2  is hydrogen. In some other embodiments, R 2  is heteroalkyl, alkenyl or alkynyl. 
     In some embodiments, R 3  is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2  and R 3  taken together form a cyclic moiety. In a further embodiment, R 3  is halo, cyano or alkyl. In yet a further embodiment, R 3  is —(CH 2 ) n OH, wherein n is 1, 2 or 3. In still a further embodiment, R 3  is —CH 2 OH. 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following: 
                         
wherein the carbocycle formed by linking R 2  and R 3  may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2  and R 3 . In some embodiments, the substituent(s) is C 3 -C 5  cycloalkyl or C 3 -C 5  heterocycloalkyl. In other embodiments, the substituent is oxo.
 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 4  is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4  is fluoroalkyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . In still a further embodiment, R a  is methyl, optionally substituted with one or more fluorines. 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 3  is hydrogen, R 4  is —S(═O) 2 R a  or —S(═O)(═NR b )R c , wherein R a  is fluoroalkyl, R b  is hydrogen, cyano or alkyl and R c  is alkyl. In a further embodiment, R 1  is selected from the group consisting of 
                         
wherein W 1  is N or CR 10 , R 9  is cyano, halo, alkyl or alkoxy, and R 10  is hydrogen, cyano, halo, alkyl or alkoxy; and
 
                         
may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the alkyl is C 1 -C 4  alkyl. In another further embodiment, the alkoxy is C 1 -C 4  alkoxy.
 
     In some embodiments, each of R 2  and R 3  is independently alkyl and R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. 
     In some embodiments, R 3  is —CH 2 OH. In a further embodiment, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl and R 5  is hydrogen. In still a further embodiment, R 2  is cyano, halo or alkyl. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl; R 2  is nitro, halo, cyano or alkyl; R 3  is halo, cyano or alkyl; R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . In still a further embodiment, R 5  is hydrogen. 
     In some embodiments, R 1  is bicyclic heteroaryl; R 2  is nitro, halo, cyano or alkyl; R 3  is halo, cyano or alkyl; R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R 5  is hydrogen. 
     In some embodiments, R 1  is phenyl, monocyclic heteroaryl or bicyclic heteroaryl; R 2  is halo, cyano or alkyl; R 3  is halo, cyano or alkyl; R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R 5  is hydrogen. 
     In some embodiments, R 2  and R 3  together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon; R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; and R 5  is hydrogen. In a further embodiment, R 1  is phenyl or monocyclic heteroaryl. In another further embodiment, R 1  is bicyclic heteroaryl. 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In another aspect, the invention provides a compound of Formula I-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     W 1  is N or CR 10 ; 
     R 9  is cyano, halo, alkyl or alkoxy; and 
     R 10  is hydrogen, cyano, halo, alkyl or alkoxy. 
     In another aspect, the invention provides a compound of Formula I-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     W 1  is N or CR 10 ; 
     R 9  is cyano, halo, alkyl or alkoxy; and 
     R 10  is hydrogen, cyano, halo, alkyl or alkoxy. 
     In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In some embodiments, R 2  is fluoro, chloro, bromo or iodo. In some embodiments, R 2  is fluoroalkyl. In some further embodiments, R 2  is —CH 2 F, —CHF 2  or —CF 3 . 
     In some embodiments, R 3  is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2  and R 3  taken together form a cyclic moiety. In a further embodiment, R 3  is halo, cyano or alkyl. In yet a further embodiment, R 3  is —(CH 2 ) n OH, wherein n is 1, 2 or 3. In still a further embodiment, R 3  is —CH 2 OH. 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following: 
                         
wherein the carbocycle formed by linking R and R may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2  and R 3 . In some embodiments, the substituent(s) is C 3 -C 5  cycloalkyl or C 3 -C 5  heterocycloalkyl. In other embodiments, the substituent is oxo.
 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 4  is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4  is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . In still a further embodiment, R a  is methyl, optionally substituted with one or more fluorines. 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 9  is cyano, halo, C 1 -C 4  alkyl or C 1 -C 4  alkoxy. 
     In some embodiments, R 10  is hydrogen, cyano, halo, C 1 -C 4  alkyl or C 1 -C 4  alkoxy. 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon and R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. 
     In some embodiments, R 3  is —CH 2 OH and R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 5  is hydrogen. In still a further embodiment, R 2  is cyano, halo or alkyl. 
     In some embodiments, R 2  is halo, cyano or alkyl; R 3  is CH 2 OH; R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR)—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In another aspect, the invention provides a compound of Formula I-B: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R c  is hydrogen, cyano, halo, alkyl or alkoxy; and 
     n′ is 0, 1, 2, 3 or 4. 
     In another aspect, the invention provides a compound of Formula I-B: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 2  is nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; 
     R 3  is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, amino, oxime or acyl; or R 2  and R 3  taken together form a cyclic moiety; 
     R 4  is nitro, halo, cyano, alkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R c  is hydrogen, cyano, halo, alkyl or alkoxy; and 
     n′ is 0, 1, 2, 3 or 4. 
     In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In some embodiments, R 2  is fluoro, chloro, bromo or iodo. In some embodiments, R 2  is fluoroalkyl. In some further embodiments, R 2  is —CH 2 F, —CHF 2  or —CF 3 . 
     In some embodiments, R 3  is hydrogen, halo, cyano, alkyl, alkenyl, heteroalkyl or acyl; or R 2  and R 3  taken together form a cyclic moiety. In a further embodiment, R 3  is halo, cyano or alkyl. In yet a further embodiment, R 3  is —(CH 2 ) n OH, wherein n is 1, 2 or 3. 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon. Representative compounds with the carbocycle include, but are not limited to, the following: 
                         
wherein the carbocycle formed by linking R 2  and R 3  may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In yet other embodiments, the substituent(s) is cycloalkyl or heterocycloalkyl and shares one or more ring atoms with the carbocycle formed by linking R 2  and R 3 . In some embodiments, the substituent(s) is C 3 -C 5  cycloalkyl or C 3 -C 5  heterocycloalkyl. In other embodiments, the substituent is oxo.
 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered heterocycle, including, but not limited to, a lactone or lactol, wherein said heterocycle may be optionally substituted with fluoro, chloro, hydroxy, alkyl or heteroalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. 
     In some embodiments, R 3  is hydrogen, R 4  is is —S(═O) 2 R a  or —S(═O)(═NR b )R d , wherein R a  is fluoroalkyl, R b  is hydrogen, cyano or alkyl and R d  is alkyl. 
     In some embodiments, R 4  is halo, cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In some embodiments, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In some embodiments, R 4  is fluoroalkyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . In still a further embodiment, R a  is methyl, optionally substituted with one or more fluorines. 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 —N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In a further embodiment, both R a s are hydrogen. In another further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 2  and R 3  taken together with the atoms to which they are attached form a 5- or 6-membered carbocycle with at least one sp 3  hybridized carbon and R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl. In a further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 3  is —CH 2 OH and R 4  is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl. In a further embodiment, R 5  is hydrogen. In still a further embodiment, R 2  is cyano, halo or alkyl. 
     In some embodiments, R 2  is halo, cyano or alkyl; R 3  is CH 2 OH; R 4  is fluoroalkyl, sulfonamidyl, sulfonyl, sulfinyl or sulfoximinyl. In a further embodiment, R 4  is selected from the group consisting of —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR)—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In some embodiments, R c  is cyano, halo, C 1 -C 4  alkyl or C 1 -C 4  alkoxy. 
     In yet another aspect, the invention provides a compound of Formula I-C: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R 11  is hydrogen, hydroxy, alkoxy or amino; 
     R 12  is hydrogen, alkyl, alkenyl or alkynyl; or R 11  and R 12  in combination form oxo or oxime; 
     each of R 13  is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R 13  is hydroxy, n is 1 or 2; or two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and 
     n is 0, 1, 2, 3 or 4. 
     In yet another aspect, the invention provides a compound of Formula I-C: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; 
     R 11  is hydrogen, halo, hydroxy, alkoxy or amino; 
     R 12  is hydrogen, alkyl, alkenyl or alkynyl; or R 11  and R 12  in combination form oxo or oxime; 
     each of R 13  is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl, with the proviso that when R 13  is hydroxy, n is 1 or 2; or two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and 
     n is 0, 1, 2, 3 or 4. 
     In some embodiments, for a compound of Formula I-C, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, acyl and cyano. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl. In some further embodiments, R 1  is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1  is 
                         
wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R 1  is
 
                         
wherein W 1  is N or CR 10 , R 9  is cyano, halo, alkyl or alkoxy, and R 10  is hydrogen, cyano, halo, alkyl or alkoxy.
 
     In some embodiments, R 1  is bicyclic heteroaryl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, cyano and oxo.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R 4  is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . In still a further embodiment, R a  is methyl, optionally substituted with one or more fluorines. 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In another further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen or alkyl. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen or alkyl. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen or alkyl. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen or alkyl. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 11  is hydroxy or amino. In a further embodiment, R 11  is hydroxy. In another further embodiment, R 11  is amino. 
     In some embodiments, R 12  is hydrogen. In some other embodiments, R 12  is alkyl or alkenyl. 
     In some embodiments, R 13  is fluoro. In a further embodiment, n is 1, 2 or 3. In a further embodiment, two R 13 s in combination form oxo, oxime or methylene. In still further embodiments, two R 13 s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety. 
     In some embodiments, R 1  is monocyclic aryl or monocyclic heteroaryl and R 11  is hydroxy or amino. In a further embodiment, R 13  is fluoro. In still a further embodiment, n is 1, 2 or 3. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl, R 11  is hydroxy or amino, R 13  is fluoro, n is 1, 2 or 3, and R 5  is hydrogen. 
     In some embodiments, R 1  is bicyclic heteroaryl and R 11  is hydroxy or amino. In a further embodiment, R 13  is fluoro. In still a further embodiment, n is 1, 2 or 3. 
     In some embodiments, R 1  is bicyclic heteroaryl, R 11  is hydroxy or amino, R 13  is fluoro, n is 1, 2 or 3, and R 5  is hydrogen. 
     In some embodiments, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl, and R 11  is hydroxy or amino. In a further embodiment, R 12  is hydrogen. In another further embodiment, R 13  is fluoro. In still a further embodiment, n is 1, 2 or 3. 
     In some embodiments, R 4  is cyano, fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl, sulfoximinyl or fluoroalkylsulfonyl; R 11  is hydroxy or amino; R 13  is fluoro; n is 1, 2 or 3; and R 5  is hydrogen. In a further embodiment, R 12  is hydrogen. 
     In some embodiments R 11  is hydroxy or amino and R 12  is hydrogen. In a further embodiment, R 13  is fluoro. In still a further embodiment, n is 1, 2 or 3. 
     In some embodiments R 11  is hydroxy or amino, R 12  is hydrogen, R 13  is fluoro, n is 1, 2 or 3, and R 5  is hydrogen. In a further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 4  is fluoroalkyl; n is 0, 1, 2 or 3; Z is —O—; R 11  is hydroxy; and R 12  is hydrogen. 
     In some embodiments, R 4  is sulfonyl or fluoroalkylsulfonyl; n is 0, 1, 2 or 3; Z is —O—; R 11  is hydroxy; and R 12  is hydrogen. 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR)—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In still another aspect, the invention provides a compound of Formula I-D, I-E, I-F or I-G: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )—, or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydrogen, hydroxy, alkoxy or amino. 
     In still another aspect, the invention provides a compound of Formula I-D, I-E, I-F or I-G: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydrogen, halo, hydroxy, alkoxy or amino. 
     In some embodiments, for a compound of Formula I-D, I-E, I-F, or I-G, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl. 
     In some embodiments, R 1  is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R 1  is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1  is 
                         
wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R 1  is
 
                         
wherein W 1  is N or CR 10 , R 9  is cyano, halo, alkyl or alkoxy, and R 10  is hydrogen, cyano, halo, alkyl or alkoxy.
 
     In some embodiments, R 1  is bicyclic heteroaryl having at least one N atom. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, cyano and oxo.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In some embodiments, R 4  is fluoroalkyl, sulfonamidyl, sulfinyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In another further embodiment, both R a s are hydrogen. In a further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen or alkyl. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen or alkyl. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen or alkyl. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen or alkyl. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 11  is hydroxy. In another further embodiment, R 11  is amino. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl and R 11  is hydroxy or amino. 
     In some embodiments, R 1  is bicyclic heteroaryl and R 11  is hydroxy or amino. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 5  is alkyl. In still a further embodiment, R 5  is C 1 -C 4  alkyl. 
     In some embodiments R 1  is bicyclic heteroaryl and R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is bicyclic heteroaryl; R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11  is hydroxy or amino; and X is CR 5  or N; and R 5  is hydrogen. In a further embodiment, R 11  is hydroxy. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is phenyl or monocyclic heteroaryl and R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is phenyl or monocyclic heteroaryl; R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11  is hydroxy or amino; and X is CR 5  or N; and R 5  is hydrogen. In a further embodiment, R 11  is hydroxy. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In a further aspect, the invention provides a compound of Formula I-H, I-I, I-J or I-K: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydroxy or amino. 
     In a further aspect, the invention provides a compound of Formula I-H, I-I, I-J or I-K: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     X is CR 5  or N; 
     Y is CR 6  or N; 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
     R 4  is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; 
     R 5 , R 6 , R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; and 
     R 11  is hydroxy or amino. 
     In some embodiments, for a compound of Formula I-H, I-I, I-J, or I-K, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl. 
     In some embodiments, R 1  is monocyclic aryl or monocyclic heteroaryl. In some further embodiments, R 1  is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano. In a further embodiment, R 1  is 
                         
wherein the aryl ring is optionally substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In another further embodiment, R 1  is
 
                         
wherein W 1  is N or CR 10 , R 9  is cyano, halo, alkyl or alkoxy, and R 10  is hydrogen, cyano, halo, alkyl or alkoxy.
 
     In some embodiments, R 1  is bicyclic heteroaryl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted with one or more substituents described for cycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, cyano and oxo.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, R 4  is fluoroalkyl. In yet another embodiment, R 4  is sulfonyl. In still another embodiment, R 4  is alkylsulfonyl. 
     In some embodiments, R 4  is —S(═O) 2 R a , wherein R a  is alkyl or cycloalkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . In still a further embodiment, R a  is methyl, optionally substituted with one or more fluorines. 
     In some embodiments, R 4  is —S(═O)(═NR b )R a , wherein R a  is alkyl or cycloalkyl and R b  is hydrogen, cyano or alkyl. In a further embodiment, R a  is C 1 -C 4  alkyl, optionally substituted with one or more fluorines. Suitable examples of fluorine-substituted C 1 -C 4  alkyl include, but are not limited to, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 F, —CHFCH 3  and —CF 2 CH 3 . 
     In some embodiments, R 4  is —S(═O) 2 N(R a ) 2 , wherein each R a  is independently hydrogen, alkyl, heteroalkyl, cycloalkyl or heterocycloalkyl, and at least one R a  is hydrogen. In another further embodiment, both R a s are hydrogen. In a further embodiment, one R a  is hydrogen and the other R a  is C 1 -C 4  alkyl. 
     In some embodiments, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, R 5  is hydrogen or alkyl. In some other embodiments, R 5  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 5  is methyl. 
     In some embodiments, R 6  is hydrogen or alkyl. In some other embodiments, R 6  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 6  is methyl. 
     In some embodiments, R 7  is hydrogen or alkyl. In some other embodiments, R 7  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 7  is methyl. 
     In some embodiments, R 8  is hydrogen or alkyl. In some other embodiments, R 8  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy. In a further embodiment, R 8  is methyl. 
     In some embodiments, R 11  is hydroxy. In another further embodiment, R 11  is amino. 
     In some embodiments, R 1  is phenyl or monocyclic heteroaryl and R 11  is hydroxy or amino. 
     In some embodiments, R 1  is bicyclic heteroaryl and R 11  is hydroxy or amino. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 5  is alkyl. In still a further embodiment, R 5  is C 1 -C 4  alkyl. 
     In some embodiments R 1  is bicyclic heteroaryl and R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is bicyclic heteroaryl; R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11  is hydroxy or amino; and X is CR 5  or N; and R 5  is hydrogen. In a further embodiment, R 11  is hydroxy. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is phenyl or monocyclic heteroaryl and R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. In a further embodiment, X is CR 5  and R 5  is hydrogen. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments R 1  is phenyl or monocyclic heteroaryl; R 4  is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R 11  is hydroxy or amino; and X is CR 5  or N; and R 5  is hydrogen. In a further embodiment, R 11  is hydroxy. In another further embodiment, R 4  is selected from the group consisting of —CN, —CF 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 CH 2 F, —S(═O) 2 CHF 2 , —S(═O) 2 CF 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)(═NH)CH 3 , —S(═O)(═NH)CH 2 F, —S(═O)(═NH)CHF 2 , —S(═O)(═NH)CF 3 , —S(═O)(═N—CN)CH 3 , —S(═O)(═N—CN)CH 2 F, —S(═O)(═N—CN)CHF 2  and —S(═O)(═N—CN)CF 3 . 
     In some embodiments, X is N and Y is CR 6 . In other embodiments, X is CR 5  and Y is N. In still other embodiments, X is N and Y is N. In yet other embodiments, X is CR 5  and Y is CR 6 . 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR)—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In some embodiments, a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or even higher. In some embodiments, a compound of any one of Formulae I-H-I-K may have an enantiomeric excess of about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% or about 99%. 
     In yet another aspect, the invention provides a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 16  and R 17  are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R 16  and R 17  and the carbon to which they are attached form C 3 -C 8  cycloalkyl or C 5 -C 8  heterocycloalkyl; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; 
     n″ is 1 or 2; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In yet another aspect, the invention provides a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 16  and R 17  are independently selected from the group consisting of hydrogen, halo, alkyl, heteroalkyl and cycloalkyl; or R 16  and R 17  and the carbon to which they are attached form C 3 -C 8  cycloalkyl or C 5 -C 8  heterocycloalkyl; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; 
     n″ is 1 or 2; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some embodiments, for a compound of Formula II, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, acyl and cyano. 
     In some embodiments, R 1  is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 1  is phenyl. In another further embodiment, R 1  is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl. 
     In some embodiments, R 1  is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. 
     In some embodiments, R 1  is 
                         
wherein each of R e  is independently hydrogen or C 1 -C 4  alkyl, or two R e s and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of R f  is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n′″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 2  is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2  is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In a further embodiment, R 2  is fluoroalkyl. In a still further embodiment, R 2  is C 1 -C 4  fluoroalkyl. Exemplary C 1 -C 4  fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3  and the like. 
     In some embodiments, R 14  is hydrogen or deuterium. In some embodiments, R 14  is alkyl. In a further embodiment, R 14  is C 1 -C 4  alkyl. 
     In some embodiments, R 15  is hydroxy or amino. In some embodiments, R 15  is hydroxy. In some embodiments, R 15  is amino. In a further embodiment, R 15  is NH 2 . 
     In some embodiments, each of R 16  and R 17  is independently hydrogen or fluoro. In some embodiments, each of R 16  and R 17  is hydrogen. In some embodiments, each of R 16  and R 17  is fluoro. In some embodiments, at least one of R 16  and R 17  is fluoro. 
     In some embodiments, R 18  is O, N—CN, or NH. In some embodiments, R 18  is O. In some embodiments, R 18  is NH. In some embodiments, R 18  is N—CN. 
     In some embodiments, R 14  is hydrogen and R 15  is hydroxy or amino. In some further embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 2  is cyano, halo or alkyl. In a still further embodiment, R 16  and R 17  are fluoro. 
     In some embodiments, R 15  is hydroxy or amino and R 2  is cyano, halo or alkyl. In a further embodiment, R 2  is fluoroalkyl. In a still further embodiment, at least one R 16  and R 17  is fluoro. In a yet still further embodiment, n″ is 1. 
     In some embodiments, R 18  is O or NH and R 14  is hydrogen. In some further embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 2  is cyano, halo or alkyl. In a still further embodiment, at least one of R 16  and R 17  is fluoro. 
     In some embodiments, n″ is 1. In some further embodiments, R 15  is hydroxy or amino and R 16  and R 17  are fluoro. In a further embodiment, R 1  is aryl or heteroaryl. In a still further embodiment, R 1  is phenyl or pyridyl, optionally substituted with one or more substituents selected from the group consisting of halo, alkoxy, cyano and alkyl. 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In another aspect, the invention provides a compound of Formula II-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In another aspect, the invention provides a compound of Formula II-A: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 14  is hydrogen, deuterium or alkyl; 
     R 15  is hydrogen, hydroxy or amino; or R 14  and R 15  in combination form oxo or methylene; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some embodiments, for a compound of Formula II-A, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, acyl and cyano. 
     In some embodiments, R 1  is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 1  is phenyl. In another further embodiment, R 1  is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl. 
     In some embodiments, R 1  is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. 
     In some embodiments, R 1  is 
                         
wherein each of R e  is independently hydrogen or C 1 -C 4  alkyl, or two R e s and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of R f  is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n′″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 2  is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2  is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In a further embodiment, R 2  is fluoroalkyl. In a still further embodiment, R 2  is C 1 -C 4  fluoroalkyl. Exemplary C 1 -C 4  fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3  and the like. 
     In some embodiments, R 14  is hydrogen or deuterium. In some embodiments, R 14  is alkyl. In a further embodiment, R 14  is C 1 -C 4  alkyl. 
     In some embodiments, R 15  is hydroxy or amino. In some embodiments, R 15  is hydroxy. In some embodiments, R 15  is amino. In a further embodiment, R 15  is NH 2 . 
     In some embodiments, R 18  is O, N—CN, or NH. In some embodiments, R 18  is O. In some embodiments, R 18  is NH. In some embodiments, R 18  is N—CN. 
     In some embodiments, R 18  is O or NH and R 14  is hydrogen. In some further embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 2  is cyano, halo or alkyl. In a still further embodiment, at least one of R 16  and R 17  is fluoro. 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In still another aspect, the invention provides a compound of Formula II-B: 
                         
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 
     Z is —O—, —S—, —C(HR 7 )—, —N(R 8 )— or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 15  is hydroxy or amino; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In still another aspect, the invention provides a compound of Formula II-B: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
     Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR 7 )—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent; 
     R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; 
     R 2  is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, nitro, carboxaldehyde, carboxylic acid, ester, amido, cyano, halo or sulfonyl; 
     R 15  is hydroxy or amino; 
     R 18  is O or NR 19 , wherein R 19  is selected from the group consisting of hydrogen, alkyl and cyano; and 
     R 7  and R 8  are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy. 
     In some embodiments, for a compound of Formula II-B, R 1  is further selected from alkyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, acyl and cyano. 
     In some embodiments, R 1  is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is heterocycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is cycloalkyl, aryl or heteroaryl. In some embodiments, R 1  is aryl or heteroaryl. In a further embodiment, R 1  is phenyl. In another further embodiment, R 1  is pyridyl. In a still further embodiment, the phenyl or pyridyl is substituted with at least one substituent selected from the group consisting of halo, alkoxy, cyano and alkyl. 
     In some embodiments, R 1  is selected from the group consisting of cyclobutyl, cyclohexyl, tetrahydrofuranyl and tetrahydropyranyl. 
     In some embodiments, R 1  is 
                         
wherein each of R e  is independently hydrogen or C 1 -C 4  alkyl, or two R e s and the carbon atom to which they are attached form a 4- to 8-membered cyclic moiety; each of R f  is independently selected from the group consisting of halo, alkoxy, cyano and alkyl; and n′″ is 0, 1, 2, 3 or 4. In some further embodiments, the 4- to 8-membered cyclic moiety is an all carbon or heterocyclic ring system.
 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
and the rings specified for R 1  may optionally be substituted by one or more substituents described for aryl and heteroaryl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 1  is cycloalkyl. In other embodiments, R 1  is heterocycloalkyl. In a further embodiment, R 1  is C 3 -C 6  cycloalkyl or C 3 -C 6  heterocycloalkyl. In yet a further embodiment, R 1  is cyclobutyl. In some embodiments, said cycloalkyl, cyclobutyl or heterocycloalkyl may optionally be substituted with one or more substituents described for cycloalkyl or heterocycloalkyl. In a further embodiment, the substituent(s) is selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the substituent(s) is at least one fluoro. 
     In some embodiments, R 1  is acyl or cyano. In a further embodiment, R 1  is acetyl. 
     In some embodiments, R 1  is alkyl. In a further embodiment, the alkyl is substituted with at least one substituent(s) selected from the group consisting of halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano. In another further embodiment, the alkyl is substituted with at least one fluoro. In some embodiments, R 1  is heteroalkyl. 
     In some embodiments, R 1  is selected from the group consisting of: 
                         
wherein each of the members may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy. In a further embodiment, the substituent(s) is selected from the group consisting of fluoro, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and cyano.
 
     In some embodiments, R 2  is nitro, cyano, halo, alkyl, heteroalkyl, alkynyl or alkenyl. In some embodiments, R 2  is cyano, halo, alkyl, heteroalkyl or alkynyl. In some embodiments, R 2  is cyano, halo or alkyl. In some embodiments, R 2  is halo or alkyl. In a further embodiment, R 2  is fluoroalkyl. In a still further embodiment, R 2  is C 1 -C 4  fluoroalkyl. Exemplary C 1 -C 4  fluoroalkyl includes, but is not limited to, —CH 2 F, —CHF 2 , —CF 2 CH 3  and the like. 
     In some embodiments, R 15  is hydroxy. In some embodiments, R 15  is amino. In a further embodiment, R 15  is NH 2 . 
     In some embodiments, R 18  is O, N—CN, or NH. In some embodiments, R 18  is O. In some embodiments, R 18  is NH. In some embodiments, R 18  is N—CN. 
     In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —S(O 2 )N(R 8 )—, —C(O)—, —C(O)O—, —C(HR 7 )—, —N(R 8 )—, —C(O)N(R 8 )—, alkylene, alkenylene, alkynylene, heteroalkylene, or absent. In some embodiments, Z is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, —C(HR)—, —N(R 8 )—, C 1 -C 3  alkylene, C 1 -C 3  heteroalkylene, C 1 -C 3  alkenylene or absent. In some embodiments, Z is —O—. In other embodiments, Z is —S—. In further embodiments, Z is —C(HR 7 )—. In yet other embodiments, Z is —N(R 8 ). In some embodiments, Z is absent. 
     In some embodiments, a compound of Formula II-B may have an enantiomeric excess of at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least about 99%. In a further embodiment, the compound has an enantiomeric excess of at least about 90%. 
     In another aspect, the present disclosure provides a compound or pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the compounds given in Table 1. 
     The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Schemes 1-27, the steps in some cases may be performed in a different order than the order shown in Schemes 1-27. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. 
     Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from −10° C. to 200° C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about −10° C. to about 110° C. over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours. 
     In general, compounds of the invention may be prepared by the following reaction schemes: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 1-9 can be prepared according to steps outlined in Scheme 1. The synthesis starts with phenol 1-1. Reaction of 1-1 with chloride 1-2 (wherein R g  and R h  are independently alkyl) provides intermediate 1-3. The reaction may be carried out in a suitable organic solvent in the presence of a base. Suitable bases for the reaction include, but are not limited to, organic bases, for example, triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and inorganic bases, for example, sodium hydroxide, cesium carbonate, cesium bicarbonate, sodium carbonate, and potassium carbonate. A compound of Formula 1-3 is then subjected to a rearrangement reaction to give a compound of Formula 1-4. Elevated temperature may be needed for the rearrangement to occur. The temperature may be in a range of 100° C. to 300° C. In some embodiments, the temperature is in a range of 180° C. to 240° C. Hydrolysis of a compound of Formula 1-4 provides thiophenol 1-5, which is alkylated to provide a compound if Formula 1-6. A variety of alkyl groups may be introduced in Step D. In some embodiments, R a  is a C 1 -C 4  alkyl. In a further embodiment, R a  is a C 1 -C 4  fluoroalkyl. Oxidation of a compound of Formula 1-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3  catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Ketone 1-7 is then reduced to give alcohol 1-8, which then undergoes a nucleophilic aromatic substitution (SNAr) reaction with a suitable substrate R 1 OH to give a compound of Formula 1-9. Temperatures for carrying out the SNAr reaction may depend on the reactivity of both R 1 OH and/or compound 1-8. The reaction may be carried out in a temperature range from about room temperature to 200° C. In some embodiments, the temperature range is from room temperature to 60° C. In some other embodiments, the temperature range is from 60° C. to 100° C. In some other embodiments, the temperature range is from 100° C. to 200° C. 
     
       
         
         
             
             
         
       
     
     In some other embodiments, a compound of Formula 1-9 can be prepared asymmetrically to give a compound of Formula 2-2 (Scheme 2). For example, direct asymmetric reduction of ketone 1-7 (Step A) may be accomplished chemically or enzymatically. For a recent review on enzymatic reduction of ketones, see Moore, et al.  Acc. Chem. Res.  40: 1412-1419, 2007. Examples of chemical asymmetric reduction of ketones include, but are not limited to, Corey-Bakshi-Shibata (CBS) reduction, asymmetric hydrogenation and asymmetric transfer hydrogenation. In some embodiments, the asymmetric transfer hydrogenation is catalyzed by ruthenium. For examples of methods and catalysts for ruthenium catalyzed transfer hydrogenation, see U.S. Pat. Nos. 6,184,381 and 6,887,820. Exemplary catalysts for asymmetric transfer hydrogenation include, but are not limited to, the following (shown as the R, R configuration): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The asymmetric transfer hydrogenation may be carried out at or below room temperature. In some embodiments, the asymmetric transfer hydrogenation is carried out at about 4° C. The alcohol product may have an enantiomeric excess of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, or even higher. It is well understood by one skilled in the art that changing the catalyst configuration will lead to a product with the opposite configuration. Chiral alcohol 2-1 can be coupled with a suitable substrate, for example, a phenol, to give a compound of Formula 2-2 without significant loss of enantiomeric excess. The loss of enantiomeric excess (ee) in the coupling step for 2-2 may be less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6% or less than about 8%. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 3-6 may be prepared according to Scheme 3. The ketone in 1-7 is protected as a ketal to give a compound of Formula 3-1, wherein each of R i  and R j  is independently an alkyl group. In addition, R i  and R j  may optionally be connected to form a cyclic ketal. Exemplary structures of ketal 3-1 include, but are not limited to, the following: 
     
       
         
         
             
             
         
       
     
     A compound of Formula 3-1 and a suitable R 1 OH may undergo a nucleophilic aromatic substitution reaction (SNAr) to give biaryl ether 3-2. As described in Step G of Scheme 1, the reaction temperature of the SNAr reaction may depend on the reactivity of the aryl halide (i.e. compound 3-1) and/or R 1 OH. Ketone 3-3, resulting from the deprotection of ketal 3-2, is condensed with an amine to form imine 3-4, wherein R k  is alkyl. The imine functional group in a compound of Formula 3-4 may exist as a mixture of E and Z isomers. Fluorination of 3-4 can be accomplished with a fluorinating reagent, for example, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate, to give difluoroketone 3-5 after acid hydrolysis. Finally, reduction of ketone 3-5 with a hydride donor gives a compound of Formula 3-6. 
     
       
         
         
             
             
         
       
     
     A compound of Formula 4-1 (Scheme 4) can be prepared asymmetrically following the general procedure described above in Scheme 2. In some embodiments, the asymmetric reduction gives a compound of Formula 4-1 with an enantiomeric excess of at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or even higher. The enantiomeric excess of a compound of Formula 2-2 or 4-1 may be determined by chiral HPLC or Mosher ester analysis. For determination of ee with Mosher ester, see Hoye, et al.  Natural Protocol,  2: 2451, 2007. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 4-1 may be prepared according to Scheme 5. Ketone 5-1 is fluorinated to give monofluoroketone 5-2, which is then converted to a silylenol ether, e.g., TBS enol ether 5-3. Other silyl protecting groups may also be used, for example, triisopropylsilyl or diphenyl-t-butylsilyl. The resulting enol ether is further fluorinated to give difluoroketone 5-4, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 5-5. Protection of the hydroxy moiety, followed by SNAr reaction and deprotection of the alcohol, provides a compound of Formula 4-1. 
     
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 3-6 can be prepared according to Scheme 6. Treatment of aryl halide 3-1 with a hydroxide source gives phenol 6-1. Suitable hydroxide sources include, but are not limited to, sodium hydroxide and potassium hydroxide. Suitable solvents for the reaction include, but are not limited to, DMSO, DMA, DMF and EtOH. Phenol 6-1 can react with a suitable halide via an SNAr reaction to give ether 3-2, which can be converted to a compound of Formula 3-6 as described in Scheme 3. 
     
       
         
         
             
             
         
       
     
     Compounds of Formulae 7-3 and 7-4 may be prepared according to Scheme 7. For example, condensation of NH 2 R k  with difluoroketone 7-1, wherein R a  is aryl, heteroaryl, alkyl, heteroalkyl, heterocycle, or cycloalkyl, gives intermediate 7-2. In some embodiments, R k  is a chiral auxiliary. Exemplary chiral auxiliaries include, but are not limited to: 
                         
and enantiomers thereof. Hydride reduction of intermediate 7-2 yields 7-3. At this stage, the chiral auxiliary may be cleaved under appropriate conditions, e.g., hydrogenation or acid treatment, to give chiral secondary amine 7-4. In some other embodiments, when a compound of Formula 7-3 is desirable and R k  is not hydrogen, asymmetric hydrogenation or asymmetric transfer hydrogenation is applied on intermediate 7-2 to give a compound of Formula 7-3. For a review on asymmetric hydrogenation and asymmetric transfer hydrogenation, see Iwao Ojima ed.  Catalytic Asymmetric Synthesis , Wiley-VCH, Inc., 2000, ISBN 0-471-29805-0.
 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 8-2 can be prepared according to Scheme 8. For example, ketone 3-3 is monofluorinated to give a monofluoroketone of Formula 8-1. The monofluorination can be achieved with a variety of fluorinating reagents, e.g., N-Fluoro-O-benzenedisulfonimide, acetyl hypofluorite, Accufluor®, Selectfluor®, Selectfluor® II, or N-fluorobenzenesulfonimide, in the presence or absence of a base. A compound of Formula 8-1 is reduced to give a compound of Formula 8-2. In some cases, the reduction is highly diastereoselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% diastereoselectivity. In some cases, the reduction is highly enantioselective to give a compound of Formula 8-2 with greater than 80%, greater than 82%, greater than 84%, greater than 86%, greater than 88%, greater than 90%, greater than 92%, greater than 94%, greater than 96% or even greater than 96% enantioselectivity. Reduction conditions to achieve high enantioselectivity include, but are not limited to, asymmetric transfer hydrogenation and enzymatic reduction as described herein. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 9-6 may be prepared according to Scheme 9, wherein R 13  is hydrogen, alkyl or fluoro. The hydroxy group of compound 9-1 may be protected, for example, with an acyl or methoxymethyl ether (MOM) group, to give a compound of Formula 9-2. Benzylic bromination in Step B may be carried out with a bromide source, e.g., N-bromosuccinimide, in the presence of a radical initiator, e.g., 2,2′-azobis(2-methylpropionitrile) (AIBN) or benzyol peroxide. The bromide of compound 9-3 can be replaced with a hydroxy group in a solvent comprising water in the presence of a silver salt, e.g., Ag 2 CO 3  or AgClO 4  or AgBF 4 . Finally, fluorination of a compound of Formula 9-4 followed by deprotection gives a compound of Formula 9-6. In some cases, direct benzylic oxidation may be used for converting a compound of Formula 9-2 to a compound of Formula 9-4, thus bypassing an intermediate bromination step. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 10-7 can be prepared according to Scheme 10. For example, a compound of Formula 10-3 may be prepared from a compound of Formula 3-2 following a similar sequence as outlined in Scheme 9. Further functional group manipulations lead to a compound of Formula 10-7. 
     
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 10-3 can be deprotected to give diketone 11-1, which is fluorinated to give difluorodiketone 11-2. Asymmetric reduction of 11-2 provides diol 11-3. In some embodiments, a fluorination step is performed to give a compound of Formula 10-7. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 10-7 may be prepared according to Scheme 12. For example, difluoroketone 12-2 is reduced to give hydroxyketone 12-3. The reduction maybe enantioselective under transfer hydrogenation conditions with a Ru-catalysis as described herein. One of the aryl fluorines may be selectively displaced with an alkyl thiol to give a compound of Formula 12-4. Oxidation, fluorination, nucleophilic aromatic substitution (SNAr) and asymmetric reduction give a compound of Formula 10-7. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 13-4 can be prepared according to Scheme 13. An aryl sulfide of Formula 13-1 is treated with H 2 N—R b  and an oxidant, e.g., diacetoxyiodobenzene or dipivaloyloxyiodobenzene, in a suitable solvent, such as acetonitrile, to obtain aryl sulfinimide 13-2. In some embodiments, wherein R a  is fluoroalkyl, the addition of rhodium(II) acetate or Rh 2 (esp) 2  catalyst along with magnesium oxide is helpful in Step A. Oxidation of aryl sulfinimide 13-2 to substituted sulfoximine 13-3 may be accomplished with catalytic ruthenium(III) chloride and sodium periodate in a suitable solvent, such as a mixture of water, acetonitrile, and carbon tetrachloride. Substituted sulfoximine 13-3 is then manipulated similarly as described in Schemes 3 and 4 to afford sulfoximines of Formula 13-4 as a diastereomeric mixture. The diastereomers may be separated by column chromatography. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 14-10 can be prepared according to steps outlined in Scheme 14, wherein R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; R 2  is halo, cyano, alkyl, alkenyl or alkynyl; and R 16  and R 17  are fluoro or alkyl, or R 16  and R 17  and the carbon to which they are attached form C 3 -C 8  cycloalkyl or C 5 -C 8  heterocycloalkyl. The synthesis commences with compounds of Formula 14-1. Orthoiodination of 14-1 provides compound 14-2. The reaction may be carried out in a suitable organic solvent in the presence of iodine and a palladium catalyst at an elevated temperature, if needed. After esterification of 14-2, the resulting ester 14-3 may undergo a transition-metal catalyzed coupling reaction with a thioate, e.g., potassium ethanethioate or sodium ethanethioate, to give compounds of Formula 14-4. Suitable transition-metal catalysts include, but are not limited to, Pd(PPh 3 ) 4 , Pd 2 (dba) 3  chloroform complex or Pd(OAc) 2 , in the presence or absence of a suitable ligand. Hydrolysis of a compound of Formula 14-4 followed by alkylation of the resulting thiophenol intermediate with an alkyl halide, e.g., methyl iodide, gives a compound of Formula 14-5. The hydrolysis and alkylation may be carried out in a one-pot procedure without purification. In some embodiments, this is carried out by treating a compound of Formula 14-4 with a carbonate base in a suitable solvent at or near room temperature for a period ranging from 0.1 to 24 hours, followed by addition of an alkyl halide. Carbonate bases include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate and cesium bicarbonate. Oxidation of a compound of Formula 14-5 to give a compound of Formula 14-6 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3  catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA), and oxidation with Oxone®. A compound of Formula 14-6 is then subjected to a nucleophilic aromatic substitution (SNAr) reaction with R 1 OH (wherein R 1  is alkyl, aryl or heteroaryl) to give a compound of Formula 14-7. Temperature for carrying out the SNAr reaction may depend on the reactivity of both R 1 OH and/or a compound of Formula 14-6. The reaction may be carried out at a temperature ranging from −10° C. to 200° C. In some embodiments, the temperature range is from 30° C. to 120° C. In some other embodiments, the temperature range is from 0° C. to room temperature. Cyclization of a compound of Formula 14-7 may be effected with a base, e.g., sodium hydride, in a suitable solvent to yield a compound of Formula 14-8. After the cyclization, a variety of R 16  and R 17  groups may be introduced. In some embodiments, a compound of Formula 14-8 is difluorinated to give a compound of Formula 14-9, formed by treatment with a fluorinating agent, e.g., 1-(chloromethyl)-4-fluoro-1,4-diazo niabicyclo[2.2.2]octane ditetrafluoroborate (Selectfluor®), in the presence of suitable base, e.g., sodium carbonate. Reduction of a compound of Formula 14-9 yields a compound of Formula 14-10. In some embodiments, the reduction is carried out with a hydride, e.g., sodium borohydride and sodium triacetoxyborohydride, to give a racemic mixture. In some embodiments, an asymmetric reduction is carried out as described above (see Scheme 2) to give an enantiomer having an enantiomeric excess as disclosed herein. 
     
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 14-8 may be prepared according to Scheme 15. For example, lithiation of a compound of Formula 15-1 followed by trapping of the resulting lithio intermediate with a suitable electrophile gives a compound of Formula 15-2. In some embodiments, the electrophile is N,N-dimethylformamide and R 2  is —CHO. In a further embodiment, —CHO is converted to —CHF 2  through addition of a fluorinating reagent, e.g., diethylaminosulfur trifluoride. One of the fluorines in a compound of Formula 15-2 may be selectively displaced with a thiomethoxide, e.g., sodium thiomethoxide, to give compounds of Formula 15-3. The reaction temperature may be in a range of −50 to 40° C. In some embodiments, the temperature is at or about 0° C. Oxidation of a compound of Formula 15-3, followed by SNAr reaction with R 1 OH and base-mediated cyclization provides a compound of Formula 14-8. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 16-6 may be prepared according to Scheme 16. Oxidation of a compound of Formula 15-3 gives a compound of Formula 16-1. The oxidation may be accomplished with Oxone® or mCPBA. The amount of oxidant used for the oxidation may be about 1.5 equivalent, about 1.4 equivalent, about 1.3 equivalent, about 1.2 equivalent, about 1.1 equivalent or about 1.0 equivalent. SNAr reaction of a compound of Formula 16-1 with R 1 OH (wherein R 1  is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl) in the presence of a base gives a compound of Formula 16-2. At this stage, a sulfoximine moiety may be installed to give a compound of Formula 16-3 through a transition-metal catalyzed insertion of a suitable nitrogen donor. Suitable transition-metal catalysts include, but are not limited to, copper and rhodium catalysts, e.g., bis(rhodium(α,α,α′,α′-tetramethyl-1,3-benezenedipropionic acid)) and dirhodium tetraacetate. Suitable nitrogen donors include, but are not limited to, PhI=NNs, cyanamide, and fluoroalkylamides, e.g., trifluoromethyl acetamide. Cyclization of a compound of Formula 16-3 to give a compound of Formula 16-4 may be achieved with a base, e.g., sodium hydride, at about room temperature. Finally, reduction of a compound of Formula 16-5 as outlined in Scheme 14 provides a compound of Formula 16-6. A compound of Formula 16-6 may exist as a mixture of diastereomers and/or enantiomers. Diastereomers may be separated by conventional column chromatography, while enantiomers may be separated by chiral column chromatography. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 17-5 can be prepared according to Scheme 17. Reaction of a compound of Formula 15-3 with cyanamide in the presence of an oxidant, e.g., (diacetoxyiodo)benzene, affords a compound of Formula 15-1. Further oxidation of a compound of Formula 15-1 provides a compound of Formula 15-2, which undergoes SNAr reaction, cyclization and reduction to give a compound of Formula 17-5. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In some embodiments, compounds of Formula 18-8a and 18-8b may be prepared according to Scheme 18. For example, pyridine 18-1 may be converted to alkylaryl derivative 18-2 in Step A, wherein R 4  is, for example, trifluoromethyl. The ketone may be converted to protected enol ether 18-3, then fluorinated to give fluoroketal 18-4. Treatment of a compound of Formula 18-4 with a suitable hydroxide source as described in Scheme 6 gives a mixture of phenols 18-5a and 18-5b. The phenols can undergo an SNAr reaction with a suitable halide to give aryl ethers of Formulae 18-6a and 18-6b, which may be deprotected to give the resultant ketones. In some embodiments, a compound of Formula 18-7 is reduced with a hydride source to give a racemic mixture. In other embodiments, an asymmetric reduction is carried out as described in Scheme 2, affording alcohols 18-8a and 18-8b, separable by methods known to one skilled in the art, such as, for example, conventional column chromatography. 
     
       
         
         
             
             
         
       
     
     Alternatively, a compound of Formula 18-8a can be prepared according to Scheme 19. For example, conversion of a compound of Formula 19-1 to a phenol is followed by coupling to form an aryl ether and deprotection to give a ketone of Formula 18-7b as described above. Ketone 18-7b is converted to silyl enol ether 19-5 using a suitable silyl protecting group, including, for example, tert-butyldimethylsilyl, triisopropylsilyl or diphenyl-t-butylsilyl. The resulting silyl enol ether is fluorinated to give fluoroketone 18-7a, which undergoes an asymmetric reduction, such as asymmetric transfer hydrogenation as described herein, to give chiral alcohol 18-8a. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     A compound of Formula 20-9 can be prepared following the general procedure outlined in Scheme 20, wherein the aryl fluoride of a compound of Formula 20-1 is displaced with an alkyl thiol to give 20-2. Formation of benzaldehyde 20-3 may be followed by, for example, a Wittig reaction, to give alkene 20-4, which is reduced to an alkane of Formula 20-5 under suitable conditions. In some embodiments, a Dieckmann condensation reaction is followed by a decarboxylation to give ketone 20-6. Oxidation of a compound of Formula 20-6 to give a compound of Formula 20-7 may be accomplished by a variety of methods known in the art, including, but not limited to, RuCl 3  catalyzed oxidation in the presence of NaIO 4 , oxidation with m-chloroperoxybenzoic acid (mCPBA) and oxidation with Oxone®. Protection of the ketone, for example, as the cyclic ketal (20-8) is followed by the general procedure outlined in Scheme 19 to give a compound of Formula 20-9. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 21-7 may be prepared according to Scheme 21. Formation of a chloropyridine of Formula 21-2 may be followed by an SNAr reaction with a suitable alcohol of formula R 1 OH as described above to give a compound of Formula 21-3. Aryl bromide 21-3 may undergo a transition-metal catalyzed coupling reaction with a thioate to give a compound of Formula 21-4, analogously to the procedure detailed in Scheme 14. Hydrolysis, alkylation with a suitable alkyl halide and oxidation affords a compound of Formula 21-7. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a ketone of Formula 22-1 may be reduced to give 22-2, optionally with high enantioselectivity using asymmetric transfer hydrogenation or enzymatic reduction conditions as described herein. A compound of Formula 22-2 and a suitable coupling partner, including, but not limited to, a boronic acid of formula R 1 B(OH) 2 , may undergo a coupling reaction to give a compound of Formula 22-3. 
     
       
         
         
             
             
         
       
     
     In some embodiments, R 1  can be coupled to a compound of Formula 23-1 or 23-4 via a reaction scheme represented generally in Scheme 23. In some embodiments, wherein Z is —N(R 8 ), an aryl halide of Formula 23-1 is coupled to a suitably substituted amine, i.e. NHR 1 R 8 , via a Buchwald-Hartwig amination to give a compound of Formula 23-2. In a further embodiment, Step A is a cross coupling reaction, including, but not limited to, a Stille, Negishi or Suzuki reaction, wherein an aryl halide of Formula 23-1 is combined with an appropriate reactant containing R 1  and a suitable catalyst to afford a compound of Formula 23-3. In other embodiments, a compound of Formula 23-4 undergoes an SNAr reaction and a subsequent deprotection to give a compound of Formula 23-3. R 1  in a compound of Formula 23-5 may be, for example, morpholine, wherein a C—N bond connects said morpholine to the aryl ring. In still other embodiments, Z is —S—, and R 1 S— is attached to a compound of Formula 23-1 via an SNAr reaction to give a compound of Formula 23-6. 
     
       
         
         
             
             
         
       
     
     In some additional embodiments, a compound of Formula 24-2 can be prepared according to steps outlined in Scheme 24. A compound of Formula 12-6 is prepared via an asymmetric variation of the sequence presented in Scheme 12, then reacted with an amine, i.e. (3S)-3-piperidinol hydrochloride, to give a compound of Formula 24-1. Asymmetric reduction as described above gives a compound of Formula 24-2. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 25-3 or 25-4 may be prepared according to steps outlined in Scheme 25. For example, 25-2 may be prepared via a cross coupling reaction, i.e., a Suzuki reaction with a boronic acid of formula R 1 B(OH) 2 . Hydride reduction of 25-2 gives a mixture of alcohols 25-3 and unsaturated alcohol 25-4. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 26-5 can be synthesized according to Scheme 26. For example, treatment of compound 26-1 with base can provides difluoroalkene 26-2. The amount of base may be about 1 equivalent to avoid byproduct formation. The olefin in 26-2 may be hydrogenated to give a compound of Formula 26-3 with cis difluoro configuration. At this stage, an alkoxy group can be introduced by displacement of the aryl fluoride in 26-3 by an alcohol in the presence of a base. Finally, deprotection followed by reduction of the resulting ketone provides a compound of Formula 26-5. Intermediate 26-3 may be separated, for example, by chiral column chromatography, to give both enantiomers, each of which can be functionalized as outlined in Scheme 26 to provide either enantiomer of a compound of Formula 26-5. 
     
       
         
         
             
             
         
       
     
     In some embodiments, a compound of Formula 27-6 may be synthesized according to Scheme 27. For example, alkylation of compound 27-1 provides a compound of Formula 27-2, wherein R 1  is alkyl, cycloalkyl, or heterocycloalkyl. A compound of Formula 27-2 can be selectively iodinated to give aryl iodide 27-3. A compound of Formula 27-3 can be difluorinated as previously described. Installation of a CF 3  group followed by asymmetric reduction provides a compound of Formula 27-6. 
     In some other embodiments, a compound of a formula given in Table 1 is synthesized according to one of the general routes outlined in Schemes 1-27, Examples 1-35 or by methods generally known in the art. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 No. 
                 Structure 
                 m/z 
                   1 H NMR Data 
               
               
                   
               
             
            
               
                  1 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 7.00-6.89 (m, 3H), 6.73-6.71 (m, 1H), 6.35 (t, 1H), 5.66-5.65 (m, 1H), 3.19- 3.13 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40 (m, 1H), 2.30-2.24 (m, 1H) 
               
               
                   
               
               
                  2 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 6.96 (d, 1H), 6.73-6.68 (m, 1H), 6.62- 6.61 (m, 2H), 6.36 (t, 1H), 5.66-5.65 (m, 1H), 3.22-3.10 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.40 (m, 1H), 2.29-2.24 (m, 1H) 
               
               
                   
               
               
                  3 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376, 378 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.49 (s, 1H), 8.36 (s, 1H), 7.81 (d, 1H), 7.44-7.43 (m, 1H), 6.89 (d, 1H), 6.36 (t, 1H), 5.67-5.66 (m, 1H), 3.23-3.16 (m, 2H), 2.99-2.92 (m, 1H), 2.51-2.42 (m, 1H), 2.32-2.25 (m, 1H) 
               
               
                   
               
               
                  4 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.76 (s, 1H), 8.66 (s, 1H), 7.86 (d, 1H), 7.65-7.64 (m, 1H), 6.93 (d, 1H), 6.38 (t, 1H), 5.71-5.65 (m, 1H), 3.20-3.16 (m, 2H), 2.96-2.90 (m, 1H), 2.50-2.42 (m, 1H), 2.37-2.24 (m, 1H) 
               
               
                   
               
               
                  5 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.41 (s, 1H), 8.32 (s, 1H), 7.82 (d, 1H), 7.22-7.17 (m, 1H), 6.92 (d, 1H), 6.37 (t, 1H), 5.70-5.60 (m, 1H), 3.23-3.18 (m, 2H), 2.99-2.97 (m, 1H), 2.54-2.40 (m, 1H), 2.34-2.22 (m, 1H) 
               
               
                   
               
               
                  6 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433 (M − H + 46) 
                 (400 MHz, CDCl 3 ): δ 7.77 (d, 1H), 6.91 (d, 1H), 6.54-6.50 (m, 1H), 6.42- 6.38 (m, 2H), 6.39 (t, 1H), 5.67-5.63 (m, 1H), 3.80 (s, 3H), 3.23-3.15 (m, 2H), 2.99-2.92 (m, 1H), 2.50-2.45 (m, 1H), 2.30-2.23 (m, 1H) 
               
               
                   
               
               
                  7 
                                   
                    
 
                 7a, 429, 431 (M + Na) 7b, 429, 431 (M + Na) 
                 7a: (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 7.01-6.98 (m, 1H), 6.91-6.89 (m, 2H), 6.75-6.71 (m, 1H), 6.34 (t, 1H), 5.58-5.53 (m, 1H), 3.48-3.40 (m, 1H), 3.22 (d, 1H), 2.66-2.59 (m, 1), 1.98- 1.93 (m, 1H), 1.46 (d, 3H) 7b: (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 7.01-6.97 (m, 1H), 6.92 (d, 1H), 6.89-6.88 (m, 1H), 6.73-6.69 (m, 1H), 6.38 (t, 1H), 5.70-5.67 (m, 1H), 3.71- 3.64 (m, 1H), 3.25 (d, 1H), 2.47-2.41 (m, 1H), 2.14-2.06 (m, 1H), 1.36 (d, 3H) 
               
               
                   
               
               
                  8 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429, 431 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H), 6.94- 6.92 (m, 1H), 6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.50 (d, 1H), 3.61-3.43 (m, 2H), 3.24 (s, 1H) 
               
               
                   
               
               
                  9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H), 7.01 (d, 1H), 6.80-6.73 (m, 1H), 6.70- 6.63 (m, 2H), 6.43 (t, 1H), 5.50 (m, 1H), 3.60-3.43 (m, 2H), 3.30 (d, 1H) 
               
               
                   
               
               
                  10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375, 377 (M − OH) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H), 7.04-7.00 (m, 1H), 6.97-6.95 (m, 1H), 6.84-6.77 (m, 2H), 6.18 (t, 1H), 5.58- 5.53 (m, 1H), 3.59-3.50 (m, 1H), 3.34-3.26 (m, 1H), 2.60-2.50 (m, 1H), 2.31 (d, 1H), 2.21-2.13 (m, 1H) 
               
               
                   
               
               
                  11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H), 7.33-7.29 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.00 (d, 1H), 6.43 (t, 1H), 5.51 (d, 1H), 3.60-3.43 (m, 2H), 3.30 (br s, 1H) 
               
               
                   
               
               
                  12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 451 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H), 6.97 (d, 1H), 6.82-6.55 (m, 4H), 5.76- 5.64 (m, 1H), 5.35-5.26 (m, 2H), 3.54-3.44 (m, 2H), 3.31-3.18 (m, 1H), 3.06-2.96 (m, 2H) 
               
               
                   
               
               
                  13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 451 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.0 (d, 1H), 7.33-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 6.92 (d, 1H), 6.62 (m, 1H), 3.58-3.49 (m, 2H), 3.34-3.20 (m, 1H), 1.84-1.82 (m, 3H) 
               
               
                   
               
               
                  14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 364 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.9 (d, 1H), 6.97 (d, 1H), 6.73-6.67 (m 1H), 6.64- 6.58 (m, 1H), 5.83-5.79 (m, 1H), 6.57-6.53 (m, 1H), 4.22 (d, 1H), 3.20- 3.10 (m, 1H), 2.95-2.85 (m, 2H), 2.60-2.50 (m, 1H), 2.25-2.16 (m, 1H) 
               
               
                   
               
               
                  15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H), 7.33-6.98 (m, 4H), 6.44 (t, 1H), 5.51 (d, 1H), 3.61-3.45 (m, 2H) 
               
               
                   
               
               
                  16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437/439 (M − H) + 46 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 7.00-6.98 (m, 1H), 6.94 (d, 1H), 6.89- 6.88 (m, 1H), 6.74-6.71 (m, 1H), 6.35 (t, 1H), 5.67-5.65 (m, 1H), 3.21-3.13 (m, 2H), 2.96-2.89 (m, 1H), 2.50-2.41 (m, 1H), 2.30-2.23 (m, 1H) 
               
               
                   
               
               
                  17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M + H) 
                   
               
               
                   
               
               
                  18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391, 393 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.15 (d, 1H), 7.14 (d, 1H), 7.12 (t, 1H), 7.07-7.04 (m, 1H), 6.96-6.93 (m, 1H), 6.80-6.76 (m, 1H), 3.23-3.20 (m, 2H), 2.90-2.87 (m, 2H) 
               
               
                   
               
               
                  19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 6.92 (d, 1H), 6.72-6.67 (m, 1H), 6.62 (t, 1H), 6.63-6.59 (m, 2H), 4.96-4.94 (m, 1H), 3.18-3.10 (m, 1H), 2.99-2.92 (m, 1H), 2.51-2.41 (m, 1H), 2.30-2.00 (m, 3H) 
               
               
                   
               
               
                  20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.76 (d, 1H), 6.87 (d, 1H), 6.69-6.63 (m, 1H), 6.60- 6.55 (m, 2H), 6.18 (t, 1H), 3.37 (t, 2H), 2.93 (t, 2H), 2.20-2.17 (m, 2H) 
               
               
                   
               
               
                  21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.88 (d, 1H), 7.47-7.45 (m, 1H), 6.93-6.90 (m, 2H), 6.71-6.60 (m, 3H), 6.22 (t, 1H), 3.49- 3.48 (m, 1H) 
               
               
                   
               
               
                  22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 (M − H + 46) 
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H), 6.90 (d, 1H), 6.72-6.66 (m, 1H), 6.64- 6.57 (m, 2H), 6.19 (t, 1H), 4.85-4.81 (m, 1H), 3.60-3.44 (m, 3H), 3.21-2.99 (m, 2H) 
               
               
                   
               
               
                  23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 (M − H + 46) 
                 (400 MHz, CDCl 3 ): δ 7.83 (d, 1H), 6.98 (d, 1H), 6.74-6.69 (m, 1H), 6.64- 6.62 (m, 2H), 6.36 (t, 1H), 5.37 (brs, 1H), 4.65-4.63 (m, 1H), 3.45-3.39 (m, 2H), 2.92-2.88 (m, 1H) 
               
               
                   
               
               
                  24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.77 (d, 1H), 6.90 (d, 1H), 6.71-6.65 (m, 1H), 6.62- 6.36 (m, 2H), 6.23 (t, 1H), 3.94-3.71 (m, 3H), 2.97-2.89 (m, 2H), 2.84 (s, 1H), 2.40-2.22 (m, 2H) 
               
               
                   
               
               
                  25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410, 412 (M + H) 
                 (400 MHz, CDCl 3 ) δ 8.55-8.54 (m, 1H), 8.40-8.39 (m, 1H), 7.91 (d, 1H), 7.52-7.49 (m, 1H), 6.93 (d, 1H), 6.44 (t, 1H), 5.53-5.49 (m, 1H), 3.64-3.48 (m, 2H), 3.35 (d, 1H) 
               
               
                   
               
               
                  26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 473, 475 (M − H + 46) 
                 (400 MHz, CDCl 3 ): δ 7.86 (d, 1H), 7.26-7.22 (m, 2H), 7.05-6.95 (m, 1H), 6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H), 3.58-3.51 (m, 2H), 3.26 (brd s, 1H) 
               
               
                   
               
               
                  27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.82 (s, 1H), 8.71 (s, 1H), 7.95 (d, 1H), 7.73-7.71 (m, 1H), 6.95 (d, 1H), 6.44 (t, 1H), 5.55-5.50 (m, 1H), 3.60-3.51 (m, 2H), 3.29 (d, 1H) 
               
               
                   
               
               
                  28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412, 414 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.27 (d, 1H), 7.17-7.14 (m, 1H), 7.03-7.02 (m, 1H), 6.97 (d, 1H), 6.88-6.85 (m, 1H) 
               
               
                   
               
               
                  29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403/405 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.31 (d, 1H), 7.44-7.41 (m, 1H), 7.32-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.97 (d, 1H) 
               
               
                   
               
               
                  30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385, 387 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.28 (d, 1H), 7.42-7.40 (m, 1H), 7.31-7.26 (m, 1H), 7.22-7.19 (m, 1H), 6.97 (d, 1H), 6.45 (t, 1H) 
               
               
                   
               
               
                  31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 374 
                 (400 MHz, CDCl 3 ): δ 8.14 (d, 1H), 7.67-7.61 (m, 2H), 7.48-7.47 (m, 1H), 6.80 (d, 1H), 6.24 (t, 1H), 2.98 (s, 3H) 
               
               
                   
               
               
                  32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − 1] 374 
                 (400 MHz, CDCl 3 ): δ 8.15 (d, 1H), 7.12-7.08 (m, 1H), 7.01-6.99 (m, 1H), 6.89 (d, 1H), 6.85-6.81 (m, 1H), 6.24 (t, 1H), 2.97 (s, 3H) 
               
               
                   
               
               
                  33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 365 
                 (400 MHz, CDCl 3 ): δ 8.20 (d, 1H), 7.39-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.20-7.16 (m, 1H), 6.90 (d, 1H), 6.26 (t, 1H), 2.90 (s, 3H) 
               
               
                   
               
               
                  34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 358 
                 (400 MHz, CDCl 3 ): δ 8.15 (d, 1H), 6.91 (d, 1H), 6.85-6.79 (m, 1H), 6.77- 6.70 (m, 2H), 6.24 (t, 1H), 2.97 (s, 3H) 
               
               
                   
               
               
                  35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 391 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H), 7.13-7.05 (m, 1H), 7.04-6.95 (m, 2H), 6.89-6.85 (m, 1H), 6.26 (t 1H), 5.60 (s, 2H) 
               
               
                   
               
               
                  36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 419 
                 (400 MHz, CDCl 3 ): δ 8.29 (d, 1H), 7.13-7.09 (m, 1H), 7.02 (t, 1H), 7.01- 6.99 (m, 1H), 6.96 (d, 1H), 6.86-6.82 (m, 1H), 4.11 (s, 2H), 2.34 (s, 6H) 
               
               
                   
               
               
                  37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 358 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H), 7.07-7.03 (m, 1H), 7.01 (d, 1H), 6.96- 6.94 (m, 1H), 6.81-6.77 (m, 1H), 6.15 (t, 1H), 2.68 (s, 3H) 
               
               
                   
               
               
                  38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 18] 413 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H), 7.24 (d, 1H), 7.12-7.08 (m, 1H), 6.96- 6.94 (m, 1H), 6.81-6.77 (m, 1H), 6.41 (t, 1H) 
               
               
                   
               
               
                  39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 18] 404 
                 (400 MHz, CDCl 3 ): δ 8.09 (d, 1H), 7.37-7.34 (m, 1H), 7.29 (d, 1H), 7.22- 7.21 (m, 1H), 7.14-7.10 (m, 1H), 6.43 (t, 1H) 
               
               
                   
               
               
                  40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 18] 386 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H), 7.68-7.62 (m, 2H), 7.45-7.43 (m, 1H), 7.40-7.36 (m, 1H), 7.17 (d, 1H), 6.41 (t, 1H) 
               
               
                   
               
               
                  41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 445 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H), 7.06 (d, 1H), 7.04-7.01 (m, 1H), 6.91- 6.88 (m, 1H), 6.76-6.71 (m, 1H), 6.47 (t, 1H), 5.21 (d, 2H), 2.69 (t, 1H) 
               
               
                   
               
               
                  42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 436 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H), 7.28-7.25 (m, 1H), 7.15-7.12 (m, 2H), 7.07-7.03 (m, 1H), 6.50 (t, 1H), 5.21 (d, 2H), 2.70 (t, 1H) 
               
               
                   
               
               
                  43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 418 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H), 7.59-7.56 (m, 1H), 7.38-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.00 (d, 1H), 6.48 (t, 1H), 5.22 (d, 2H), 2.71 (t, 1H) 
               
               
                   
               
               
                  44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 445 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H), 7.06 (d, 1H), 7.04-7.01 (m, 1H), 6.91- 6.88 (m, 1H), 6.76-6.71 (m, 1H), 6.47 (t, 1H), 5.21 (d, 2H), 2.69 (t, 1H) 
               
               
                   
               
               
                  45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 451 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H), 7.67 (s, 1H), 7.12-7.03 (m, 4H), 6.93 (s, 1H), 6.77 (br d, 1H), 5.92 (t, 1H), 5.76 (d, 2H) 
               
               
                   
               
               
                  46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 463 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H), 7.07 (d, 1H), 7.06-7.03 (m, 1H), 6.93- 6.91 (m, 1H), 6.78-6.74 (m, 1H), 6.42 (t, 1H), 5.26 (d, 2H) 
               
               
                   
               
               
                  47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 482 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.05-7.01 (m, 2H), 6.90-6.89 (m, 1H), 6.75-6.71 (m, 1H), 6.67 (s, 1H), 6.43 (t, 1H), 4.50 (br s, 2H) 3.40-3.30 (m, 2H) 
               
               
                   
               
               
                  48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 484 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.07 (t, 2H), 7.03-6.99 (m, 2H), 6.89- 6.87 (m, 1H), 6.74-6.70 (m, 1H), 4.40 (s, 2H), 4.05-3.98 (m, 2H) 3.48-3.40 (m, 2H), 2.89-2.81 (m, 1H), 1.97-1.90 (m, 2H), 1.52-1.41 (m, 3H) 
               
               
                   
               
               
                  49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 484 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.09 (t, 2H), 7.03-7.00 (m, 2H), 6.89- 6.88 (m, 1H), 6.74-6.70 (m, 1H), 4.40 (s, 2H), 3.94-3.89 (m, 1H) 3.78-3.71 (m, 1H), 3.56-3.49 (m, 1H), 3.39-3.33 (m, 1H), 2.86-2.79 (m, 1H), 2.06-1.97 (m, 1H), 1.80-1.72 (m, 1H), 1.66-1.46 (m, 3H) 
               
               
                   
               
               
                  50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 338 
                 (400 MHz, CDCl 3 ): δ 8.20 (d, 1H), 7.08-7.04 (m, 1H), 6.96-6.94 (m, 1H), 6.87 (d, 1H), 6.81-6.77 (m, 1H), 3.12 (s, 3H), 2.97 (s, 3H) 
               
               
                   
               
               
                  51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 329 
                 (400 MHz, CDCl 3 ): δ 8.25 (d, 1H), 7.33-7.30 (m, 1H), 7.22-7.20 (m, 1H), 7.16-7.12 (m, 1H), 6.93-6.89 (m, 1H), 3.13 (s, 3H), 2.98 (s, 3H) 
               
               
                   
               
               
                  52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 322 
                 (400 MHz, CDCl 3 ): δ 8.20 (d, 1H), 6.91-6.88 (m, 1H), 6.81-6.75 (m, 1H), 6.72-6.65 (m, 2H), 3.12 (s, 3H), 2.97 (s, 3H) 
               
               
                   
               
               
                  53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 363 
                 (400 MHz, CDCl 3 ): δ 8.18 (br d, 1H), 7.26 (t, 1H), 7.01-6.97 (m, 1H), 6.89- 6.84 (m, 2H), 6.71-6.67 (m, 1H), 3.15 (s, 3H), 2.95 (t, 3H) 
               
               
                   
               
               
                  54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 425 
                 (400 MHz, CDCl 3 ): δ 8.21 (d, 1H), 7.31 (t, 1H), 7.03-6.98 (m, 2H), 6.89- 6.87 (m, 1H), 6.74-6.70 (m, 1H), 5.27 (d, 2H), 3.30 (s, 3H), 2.96-2.91 (m, 1H) 
               
               
                   
               
               
                  55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 393 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H), 6.95 (d, 1H), 6.76-6.70 (m, 1H), 6.66- 6.60 (m, 2H), 5.65-5.60 (m, 1H), 3.25-3.15 (m, 2H), 3.00-2.92 (m, 1H) 2.47-2.28 (m, 2H) 
               
               
                   
               
               
                  56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 455 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H), 7.03-6.99 (m, 1H), 6.93 (d, 1H), 6.92- 6.90 (m, 1H), 6.75-6.71 (m, 1H), 5.65-5.61 (m, 1H), 3.24-3.15 (m, 2H), 3.01-2.92 (m, 1H) 2.47-2.28 (m, 2H) 
               
               
                   
               
               
                  57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 446 
                 (400 MHz, CDCl 3 ): δ 7.88 (d, 1H), 7.28-7.25 (m, 2H), 7.19-7.17 (m, 1H), 7.09-7.05 (m, 1H), 6.96 (d, 1H), 5.66- 5.62 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.90 (m, 1H) 2.47-2.29 (m, 2H) 
               
               
                   
               
               
                  58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 329 
                 (400 MHz, CDCl 3 ): δ 7.53-7.49 (m, 1H), 6.98-6.95 (m, 1H), 6.62-6.55 (m, 1H), 6.53-6.46 (m, 2H), 5.53 (br s, 1H), 3.11-3.01 (m, 1H), 2.84-2.76 (m, 1H), 2.41-2.31 (m, 1H) 2.25-2.18 (m, 1H), 2.04 (br s, 1H) 
               
               
                   
               
               
                  59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 403 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 6.97 (d, 1H), 6.70-6.64 (m, 1H), 6.61- 6.55 (m, 2H), 5.70-5.66 (m, 1H), 5.41-5.14 (m, 2H), 3.29 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.42 (m, 1H) 2.27-2.19 (m, 1H) 
               
               
                   
               
               
                  60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 403 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 6.97 (d, 1H), 6.70-6.64 (m, 1H), 6.61- 6.55 (m, 2H), 5.70-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.83 (m, 1H), 2.51-2.42 (m, 1H) 2.27-2.19 (m, 1H) 
               
               
                   
               
               
                  61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 419 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H), 6.97-6.93 (m, 2H), 6.87-6.85 (m, 1H), 6.71-6.67 (m, 1H), 5.71-5.66 (m, 1H), 5.42-5.13 (m, 2H), 3.30 (d, 1H), 3.18- 3.09 (m, 1H), 2.92-2.84 (m, 1H), 2.51-2.41 (m, 1H) 2.28-2.19 (m, 1H) 
               
               
                   
               
               
                  62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 410 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H), 7.23-7.19 (m, 2H), 7.13-7.11 (m, 1H), 7.04-7.00 (m, 1H), 6.98 (d, 1H), 5.72- 5.67 (m, 1H), 5.44-5.12 (m, 2H), 3.29 (d, 1H), 3.16-3.07 (m, 1H), 2.90-2.81 (m, 1H), 2.52-2.42 (m, 1H), 2.29-2.20 (m, 1H) 
               
               
                   
               
               
                  63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 446 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H), 7.30-7.26 (m, 1H), 7.20-7.19 (m, 1H), 7.10-7.07 (m, 1H), 7.00 (d, 1H), 5.59- 5.13 (m, 3H), 3.58-3.38 (m, 1H) 
               
               
                   
               
               
                  64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 439 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H), 7.01 (d, 1H), 6.77-6.71 (m, 1H), 6.67- 6.60 (m, 2H), 5.58-5.12 (m, 3H), 3.58-3.38 (m, 3H) 
               
               
                   
               
               
                  65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 455 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H), 7.03-7.00 (m, 1H), 6.98 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 5.58-5.12 (m, 3H), 3.59-3.39 (m, 3H) 
               
               
                   
               
               
                  66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 286 
                 (400 MHz, CDCl 3 ): δ 7.55-7.52 (m, 1H), 6.90 (d, 1H), 6.65-6.60 (m, 1H), 6.55-6.49 (m, 2H), 5.56-5.51 (m, 1H), 3.08-3.00 (m, 1H), 2.80-2.71 (m, 1H), 2.68-2.64 (m, 1H) 2.60-2.50 (m, 1H), 2.17-2.08 (m, 1H) 
               
               
                   
               
               
                  67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 368 
                 (400 MHz, CDCl 3 ): δ 7.62 (d, 1H), 6.94 (d, 1H), 6.72-6.67 (m, 1H), 6.61- 6.54 (m, 2H), 5.36-5.30 (m, 1H), 3.54-3.30 (m, 2H), 3.13-3.10 (m, 1H) 
               
               
                   
               
               
                  68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 372 
                 (400 MHz, CDCl 3 ): δ 7.87 (d, 1H), 7.25-7.22 (m, 1H), 7.15-7.13 (m, 1H), 7.08-6.97 (m, 2H), 5.86-5.80 (m, 1H), 3.51 (s, 3H), 3.19-3.06 (m, 2H), 2.95- 2.78 (m, 1H), 2.65-2.55 (m, 1H), 2.27-2.14 (m, 1H) 
               
               
                   
               
               
                  69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414, 416, 418 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.34 (d, 1H), 7.96 (m, 1H), 7.08 (d, 1H), 6.99 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 6.16 (t, 1H), 3.35 (br s, 1H) 
               
               
                   
               
               
                  70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428, 430, 432 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.26 (d, 1H), 7.87 (m, 1H), 7.07 (d, 1H), 6.98 (m, 1H), 6.86 (m, 1H), 6.70 (m, 1H), 6.22 (t, 1H), 2.98 (s, 3H) 
               
               
                   
               
               
                  71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 430, 432, 434 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.42 (d, 1H), 8.03 (m, 1H), 7.07 (d, 1H), 7.01 (m, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 3.65 (br s, 1H) 
               
               
                   
               
               
                  72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377, 379 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.47 (d, 1H), 8.23 (m, 1H), 7.12 (m, 1H), 7.07 (d, 1H), 7.00 (m, 1H), 6.84 (m, 1H), 3.74 (br s, 1H) 
               
               
                   
               
               
                  73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.50 (d, 1H), 8.28 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.20 (m, 1H), 7.09 (d, 1H), 3.78 (br s, 1H) 
               
               
                   
               
               
                  74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 462, 464, 466 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H), 7.04-6.99 (m, 2H), 6.90 (m, 1H), 6.73 (m, 1H), 6.48 (t, 1H), 5.25 (d, 2H), 2.69 (t, 1H) 
               
               
                   
               
               
                  75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 464, 466, 468 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.33 (d, 1H), 7.03 (m, 1H), 6.98 (d, 1H), 6.90 (m, 1H), 6.74 (m, 1H), 3.88 (br s, 1H) 
               
               
                   
               
               
                  76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441, 443, 445 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H), 7.36 (d, 1H), 7.03 (m, 1H), 6.87 (m, 1H), 6.72 (m, 1H), 6.33 (t, 1H) 
               
               
                   
               
               
                  77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 432, 434 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H), 7.42 (d, 1H), 7.28 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.36 (t, 1H) 
               
               
                   
               
               
                  78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.86 (d, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.97 (d, 1H), 6.37 (t, 1H), 5.69-5.65 (m, 1H), 3.21-3.11 (m, 2H), 2.92 (m, 1H), 2.51-2.41 (m, 1H), 2.32-2.23 (m, 1H) 
               
               
                   
               
               
                  79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.16 (d, 1H), 7.43 (m, 1H), 7.34-7.32 (m, 1H), 7.24-7.21 (m, 1H), 7.06 (d, 1H), 2.79 (s, 3H) 
               
               
                   
               
               
                  80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 453, 455 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.11 (d, 1H), 7.28-7.23 (m, 1H), 7.15-7.13 (m, 1H), 7.09 (d, 1H), 7.05 (m, 1H), 6.50 (t, 1H), 5.25 (d, 2H), 2.69 (t, 1H) 
               
               
                   
               
               
                  81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 435, 437 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H), 7.59-7.56 (m, 2H), 7.39-7.37 (m, 1H), 7.36-7.31 (m, 1H), 6.95 (d, 1H), 6.48 (t, 1H), 5.26 (d, 2H), 2.70 (t, 1H) 
               
               
                   
               
               
                  82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457, 459, 461 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H), 7.28 (d, 1H), 6.96 (m, 1H), 6.83-6.81 (m, 1H), 6.66 (m, 1H), 6.58 (m, 1H), 4.04 (t, 3H) 
               
               
                   
               
               
                  83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 488, 490, 492 [MH +  − C 4 H 8 ] 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.02 (m, 1H), 6.99 (d, 1H), 6.90-6.88 (m, 1H), 6.73 (m, 1H), 6.62 (br t, 1H), 5.22 (br s, 1H), 4.95 (d, 2H), 1.45 (s, 9H) 
               
               
                   
               
               
                  84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393, 395 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H), 7.11 (m, 1H), 7.04-6.99 (m, 2H), 6.87 (m, 1H), 6.26 (t, 1H), 5.61 (d, 2H) 
               
               
                   
               
               
                  85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 444, 446, 448 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.02 (m, 1H), 6.97 (d, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 6.66 (t, 1H), 4.45 (br s, 2H) 
               
               
                   
               
               
                  86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 486, 488, 490 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.03 (m, 1H), 6.99 (d, 1H), 6.90 (m, 1H), 6.74 (m, 1H), 6.66 (t, 1H), 6.11 (br s, 1H), 5.05 (d, 2H), 2.00 (s, 3H) 
               
               
                   
               
               
                  87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379, 381 (M + H − 16) 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H), 7.02 (d, 1H), 7.00 (m, 1H), 6.90-6.88 (m, 1H), 6.75-6.71 (m, 1H), 6.46 (t, 1H), 5.18 (d, 2H), 5.01 (d, 2H), 3.01 (t, 1H), 2.76 (t, 1H) 
               
               
                   
               
               
                  88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377, 379 (M + H − 16) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H), 7.03 (m, 1H), 6.97-6.94 (m, 2H), 6.80 (m, 1H), 6.67 (m, 1H), 6.20 (t, 1H), 5.57 (m, 1H), 5.39 (d, 1H), 3.33 (d, 1H) 
               
               
                   
               
               
                  89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 478, 480 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H), 7.63-7.55 (m, 2H), 7.41-7.38 (m, 1H), 7.28 (m, 1H), 6.90 (d, 1H), 6.47 (t, 1H), 5.26 (d, 2H), 2.73 (t, 1H) 
               
               
                   
               
               
                  90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339, 341 (M + H − 16) 
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H), 6.95 (d, 1H), 6.93 (m, 1H), 6.84-6.82 (m, 1H), 6.66 (m, 1H), 5.68 (m, 1H), 3.64 (d, 1H), 3.20 (s, 3H), 3.15-3.06 (m, 1H), 2.83 (m, 1H), 2.53-2.43 (m, 1H), 2.27-2.18 (m, 1H) 
               
               
                   
               
               
                  91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353, 355 (M − OH) 
                 (400 MHz, CDCl 3 ): δ 7.74 (d, 1H), 6.95-6.92 (m, 2H), 6.84-6.82 (m, 1H), 6.66 (m, 1H), 5.65-5.60 (m, 1H), 3.70 (d, 1H), 3.35-3.19 (m, 2H), 3.15-3.06 (m, 1H), 2.83 (m, 1H), 2.49-2.39 (m, 1H), 2.27-2.19 (m, 1H), 1.34 (t, 3H) 
               
               
                   
               
               
                  92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393, 395 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.29-8.25 (m, 1H), 7.27-7.23 (m, 1H), 7.22 (t, 1H), 7.10-7.06 (m, 1H), 6.93-6.91 (m, 1H), 6.76 (m, 1H), 3.35 (s, 3H) 
               
               
                   
               
               
                  93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.29-8.25 (m, 1H), 7.29-7.25 (m, 1H), 7.22 (t, 1H), 6.80 (tt, 1H), 6.69-6.63 (m, 2H), 3.35 (s, 3H) 
               
               
                   
               
               
                  94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.34-8.30 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.25 (m, 1H), 7.21 (t, 1H), 7.21-7.18 (m, 1H), 7.11 (m, 1H), 3.36 (s, 3H) 
               
               
                   
               
               
                  95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H), 7.17 (m, 1H), 7.05-7.03 (m, 1H), 6.97 (m, 1H), 6.95 (d, 1H), 5.44-5.39 (m, 1H), 3.72 (m, 1H), 3.25 (s, 3H), 3.04- 2.95 (m, 1H), 2.58-2.47 (m, 1H), 2.29-2.22 (m, 1H), 2.16-2.03 (m, 1H), 1.91-1.73 (m, 2H) 
               
               
                   
               
               
                  96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H), 6.94 (d, 1H), 6.93-6.90 (m, 1H), 6.74- 6.73 (m, 1H), 6.61-6.57 (m, 1H) 
               
               
                   
               
               
                  97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.68 (d, 1H), 6.99-6.94 (m, 2H), 6.85-6.84 (m, 1H), 6.71-6.67 (m, 1H) 
               
               
                   
               
               
                  98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 456, 458 
                 (400 MHz, CDCl 3 ): δ 8.12 (d, 1H), 7.18 (d, 1H), 7.14-7.11 (m, 1H), 6.97- 6.96 (m, 1H), 6.82-6.79 (m, 1H) 
               
               
                   
               
               
                  99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH 4 ) 448 
                 (400 MHz, CDCl 3 ): δ 8.12 (d, 1H), 7.69-7.63 (m, 2H), 7.46-7.45 (m, 1H), 7.41-7.38 (m, 1H), 7.11 (d, 1H) 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH 4 ) 466 
                 (400 MHz, CDCl 3 ): δ 8.17 (d, 1H), 7.39-7.36 (m, 1H), 7.24-7.23 (m, 1H), 7.22 (d, 1H), 7.16-7.13 (m, 1H) 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 10.31 (s, 1H), 7.99 (d, 1H), 7.10 (d, 1H), 7.10-7.07 (m, 1H), 6.96-6.94 (m, 1H), 6.81-6.77 (m, 1H) 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.77 (d, 1H), 7.16 (d, 1H), 7.00-6.97 (m, 1H), 6.83- 6.82 (m, 1H), 6.70-6.67 (m, 1H), 5.43 (s, 2H) 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 475, 477 
                 (400 MHz, CDCl 3 ): δ 8.11 (d, 1H), 7.06-7.03 (m, 1H), 6.95 (d, 1H), 6.92- 6.91 (m, 1H), 6.77-6.74 (m, 1H), 5.88 (m, 1H), 3.38 (d, 1H), 1.81 (d, 3H) 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 474.8/476.7 
                 (400 MHz, CDCl 3 ): δ 7.97-7.94 (m, 1H), 7.10-7.07 (m, 1H), 7.01 (d, 1H), 6.80-6.77 (m, 1H), 2.71 (s, 3H) 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 424, 426 
                 (400 MHz, CDCl 3 ): δ 8.35 (d, 1H), 7.84 (brd s, 1H), 7.26 (d, 1H), 7.15- 7.12 (m, 1H), 7.04-7.03 (m, 1H), 6.89-6.86 (m, 1H) 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 492, 494 
                 (400 MHz, CDCl 3 ): δ 7.95-7.94 (m, 1H), 7.09-7.06 (m, 1H), 7.01 (d, 1H), 6.96-6.95 (m, 1H), 6.80-6.77 (m, 1H), 2.70 (s, 3H) 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 476, 478 
                 (400 MHz, CDCl 3 ): δ 8.39 (s, 1H), 8.07 (d, 1H), 7.07 (d, 1H), 7.07-7.04 (m, 1H), 6.94-6.93 (m, 1H), 6.79-6.76 (m, 1H) 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 506, 508 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H), 7.06-7.03 (m, 1H), 6.98 (d, 1H), 6.93- 6.92 (m, 1H), 6.78-6.74 (m, 1H), 4.32 (s, 2H), 3.72 (t, 2H), 2.97 (t, 2H) 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 476, 478 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H), 7.05-7.02 (m, 1H), 6.97 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.25 (s, 2H), 2.57 (s, 3H) 
               
               
                   
               
               
                 110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 552, 554 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H), 7.39-7.31 (m, 4H), 7.28-7.23 (m, 1H), 7.05-7.02 (m, 1H), 6.94 (d, 1H), 6.91- 6.89 (m, 1H), 6.75-6.72 (m, 1H), 4.30 (s, 2H), 3.96 (s, 2H). 
               
               
                   
               
               
                 111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH 4 ) 431, 433 
                 (400 MHz, CDCl 3 ): δ 8.08 (d, 1H), 7.23 (d, 1H), 7.14-7.11 (m, 1H), 6.98- 6.96 (m, 1H), 6.83-6.79 (m, 1H) 
               
               
                   
               
               
                 112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 10.43 (s, 1H), 7.96 (d, 1H), 7.15 (d, 1H), 7.09-7.07 (m, 1H), 6.95-6.94 (m, 1H), 6.80-6.77 (m, 1H) 
               
               
                   
               
               
                 113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 432, 434 
                 (400 MHz, CDCl 3 ): δ 8.02 (d, 1H),  7.05-7.02 (m, 1H), 7.01 (d, 1H), 6.91- 6.90 (m, 1H), 6.76-6.72 (m, 1H), 4.22 (s, 2H), 2.56 (s, 3H) 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 464, 466 
                 (400 MHz, CDCl 3 ): δ 8.02 (d, 1H),  7.06-7.03 (m, 1H), 7.01 (d, 1H), 6.92 (m, 1H), 6.77-6.73 (m, 1H), 4.64 (t, 1H), 4.52 (t, 1H), 4.34 (s, 2H), 3.11- 3.09 (m, 1H), 3.04-3.02 (m, 1H) 
               
               
                   
               
               
                 115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 376, 378 
                 (400 MHz, CDCl 3 ): δ 8.50-8.49 (m,  1H), 8.36-8.35 (m, 1H), 7.89 (d, 1H), 7.43 (t, 1H), 6.93 (d, 1H), 5.62-5.58 (m, 1H), 3.62-3.40 (m, 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 431 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.30 (d, 1H), 7.93 (m, 1H), 7.08-7.02 (m, 2H), 6.93-6.91 (m, 1H), 6.78-6.74 (m, 1H) 
               
               
                   
               
               
                 117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                   
               
               
                   
               
               
                 118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 422 (M − H) 
                   
               
               
                   
               
               
                 119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.35 (d, 1H),  8.13 (m, 1H), 7.16-7.13 (m, 1H), 7.11 (d, 1H), 7.03-7.01 (m, 1H), 6.88-6.85 (m, 1H) 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 (M − H) 
                   
               
               
                   
               
               
                 121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.58 (d, 1H),  8.10-8.07 (m, 1H), 7.14 (d, 1H), 7.03-7.00 (m, 1H), 6.91-6.90 (m, 1H), 6.77-6.73 (m, 1H), 3.94 (s, 3H) 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M − H) 
                   
               
               
                   
               
               
                 123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.35-8.34 (m, 1H),  8.09-8.05 (m, 1H), 7.17-6.90 (m, 4H), 6.82-6.78 (m, 1H) 
               
               
                   
               
               
                 125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 396 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.95 (d, 1H),  8.07-8.04 (m, 1H), 7.21 (br s, 1H), 7.15-7.12 (m, 1H), 7.05 (d, 1H), 7.02-7.01 (m, 1H), 6.86-6.83 (m, 1H), 6.01 (br s, 1H) 
               
               
                   
               
               
                 126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.96 (d, 1H),  7.84 (m, 1H), 7.02-6.98 (m, 2H), 6.88-6.87 (m, 1H), 6.73-6.69 (m, 1H), 3.74-3.60 (m, 2H), 2.91-2.87 (m, 2H), 1.97-1.90 (m, 2H), 1.40-1.37 (m, 1H) 
               
               
                   
               
               
                 127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.02 (d, 1H),  7.86 (m, 1H), 7.02-6.99 (m, 2H), 6.89-6.87 (m, 1H), 6.74-6.70 (m, 1H), 3.98-3.93 (m, 2H), 3.06 (t, 2H), 1.50-1.47 (m, 1H) 
               
               
                   
               
               
                 128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M − H) 
                   
               
               
                   
               
               
                 129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.39-8.38 (m, 1H),  7.98-7.95 (m, 1H), 7.15 (d, 1H), 7.08-7.05 (m, 1H), 6.95-6.94 (m, 1H), 6.80-6.77 (m, 1H) 
               
               
                   
               
               
                 130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.18 (d, 1H),  7.83-7.80 (m, 1H), 7.07 (d, 1H), 6.97-6.94 (m, 1H), 6.82-6.81 (m, 1H), 6.70-6.64 (m, 2H), 6.54-6.50 (m, 1H), 6.13-6.11 (m, 1H) 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.26 (d, 1H),  7.89-7.87 (m, 1H), 7.07 (d, 1H), 7.04-7.00 (m, 1H), 6.90-6.89 (m, 1H), 6.75-6.72 (m, 1H), 6.21 (t, 1H) 
               
               
                   
               
               
                 132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.30 (d, 1H),  7.95-7.93 (m, 1H), 7.27-7.25 (m, 1H), 7.15-7.13 (m, 2H), 7.06-7.03 (m, 1H), 6.24 (t, 1H) 
               
               
                   
               
               
                 133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.34 (d, 1H),  8.15-8.12 (m, 1H), 7.40-7.37 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 1H), 7.10 (d, 1H), 6.26 (t, 1H) 
               
               
                   
               
               
                 134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.34 (d, 1H),  8.15-8.12 (m, 1H), 7.40-7.37 (m, 1H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 1H), 7.10 (d, 1H), 6.26 (t, 1H) 
               
               
                   
               
               
                 135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.86 (d, 1H),  7.80-7.77 (m, 1H), 7.01 (d, 1H), 6.98-6.95 (m, 1H), 6.84-6.83 (m, 1H), 6.69-6.65 (m, 1H), 6.19 (t, 1H), 2.39 (s, 3H) 
               
               
                   
               
               
                 136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 340 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.85-7.82 (m, 1H), 7.23-7.20 (m, 1H), 7.11-7.09 (m, 1H), 7.04 (d, 1H), 7.03-6.98 (m, 1H), 6.21 (t, 1H), 2.39 (s, 3H) 
               
               
                   
               
               
                 137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.25 (d, 1H),  7.89-7.86 (m, 1H), 7.09 (d, 1H), 7.00-6.97 (m, 1H), 6.87-6.86 (m, 1H), 6.72-6.69 (m, 1H), 5.17 (d, 2H) 
               
               
                   
               
               
                 138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M − H) 
                   
               
               
                   
               
               
                 139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370  (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 8.29-8.28 (m,  1H), 8.09-8.06 (m, 1H), 7.10-7.06 (m, 2H), 6.97-6.96 (m, 1H), 6.83-6.79 (m, 1H), 3.10 (s, 3H) 
               
               
                   
               
               
                 140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 445 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H),  7.03-7.00 (m, 1H), 6.94 (d, 1H), 6.87-6.86 (m, 1H), 6.72-6.68 (m, 1H), 2.52 (s, 3H) 
               
               
                   
               
               
                 141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 438 (M + H) 
                   
               
               
                   
               
               
                 142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 412 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H),  7.26-7.23 (m, 1H), 7.12-7.11 (m, 1H), 7.03-6.99 (m, 1H), 6.97 (d, 1H), 4.62 (d, 2H), 2.49 (s, 3H), 1.96-1.91 (m, 1H) 
               
               
                   
               
               
                 143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H),  7.03-7.00 (m, 1H), 6.90 (d, 1H), 6.88-6.86 (m, 1H), 6.72-6.69 (m, 1H), 2.47 (s, 3H) 
               
               
                   
               
               
                 144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 392 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.05 (m, 1H),  7.29-7.26 (m, 1H), 7.14 (s, 1H), 7.05-7.02 (m, 1H), 6.94-6.91 (m, 1H), 2.46 (s, 3H) 
               
               
                   
               
               
                 145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 (M − H) 
                 (400 MHz, CDCl 3 ): δ 10.62 (s, 1H),  7.97 (d, 1H), 7.30-7.27 (m, 1H), 7.16-7.15 (m, 1H), 7.10 (d, 1H), 7.07-7.03 (m, 1 H), 2.40 (s, 3H) 
               
               
                   
               
               
                 146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 434 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.26-7.23 (m, 1H), 7.12-7.11 (m, 1H), 7.03-6.99 (m, 2H), 4.99 (d, 2H), 2.50 (s, 3H) 
               
               
                   
               
               
                 147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 442 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.02 (s, 1H),  7.99 (d, 1H), 7.28-7.25 (m, 1H), 7.16-7.15 (m, 1H), 7.07-7.05 (m, 1H), 6.98 (d, 1H), 6.03 (d, 1H), 3.85 (s, 3H), 2.34 (s, 3H) 
               
               
                   
               
               
                 148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 458 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.02 (s, 1H),  7.99 (d, 1H), 7.28-7.25 (m, 1H), 7.16-7.15 (m, 1H), 7.07-7.03 (m, 1H), 6.98 (d, 1H), 6.02 (d, 1H), 4.31 (q, 2H), 2.34 (s, 3H), 1.36 (t, 3H) 
               
               
                   
               
               
                 149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 519 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.79 (d, 1H), 7.39-7.29 (m, 5H), 7.27-7.24 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.03 (m, 1H), 6.97 (d, 1H), 6.06-6.02 (m, 2H), 4.60 (d, 2H), 2.33 (s, 3H) 
               
               
                   
               
               
                 150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 454 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.47 (d, 1H),  8.05 (d, 1H), 7.98 (d, 1H), 7.31-7.27 (m, 1H), 7.19-7.18 (m, 1H), 7.10- 7.07 (m, 1H), 7.01 (d, 1H), 6.72 (d, 1H), 2.42 (s, 3H) 
               
               
                   
               
               
                 151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 468 (M + H) 
                 (400 MHz, CDCl3): δ 8.03 (d, 1H),  7.85 (d, 1H), 7.30-7.27 (m, 1H), 7.18-7.17 (m, 1H), 7.09-7.05 (m, 1H), 6.99 (d, 1H), 6.62 (d, 1H), 2.63 (s, 3H), 2.40 (s, 3H) 
               
               
                   
               
               
                 152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.32 (d, 1H),  7.38-7.35 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.15 (m, 1H), 6.97 (d, 1H), 3.30 (s, 3H) 
               
               
                   
               
               
                 153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 396 (M − H) 
                 (400 MHz, CDCl3): δ 8.01 (d, 1H),  7.22 (d, 1H), 7.09-7.05 (m, 1H), 6.94-6.92 (m, 1H), 6.80-6.77 (m, 1H) 
               
               
                   
               
               
                 154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.44-7.40 (m,  1H), 7.33 (m, 1H), 7.15 (d, 1H), 6.91-6.88 (m, 1H) 6.74-6.73 (m, 1H), 6.62-6.58 (m, 1H), 3.95-3.91 (m, 2H), 3.44-3.40 (m, 2H), 1.71-1.69 (m, 1H) 
               
               
                   
               
               
                 155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.26-7.24 (m, 1H), 7.17-7.15 (m, 1H), 7.06-7.03 (m, 1H), 6.97 (d, 1H), 6.37 (t, 3H), 5.68-5.65 (m, 1H), 3.20-3.11 (m, 2H), 2.94-2.87 (m, 1H), 2.51-2.41 (m, 1H), 2.31-2.25 (m, 1H) 
               
               
                   
               
               
                 156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H),  7.56-7.54 (m, 2H), 7.39-7.30 (m, 2H), 6.88-6.84 (m, 1H), 6.38 (t, 1H), 5.68-5.66 (m, 1H), 3.22-3.13 (m, 2H), 2.98-2.90 (m, 1H), 2.50-2.41 (m, 1H), 2.32-2.22 (m, 1H) 
               
               
                   
               
               
                 157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 (M + HCO 2   − ) 
                   
               
               
                   
               
               
                 158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 473 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.06-7.03 (m, 1H), 6.99 (d, 1H), 6.94-6.93 (m, 1H), 6.78-6.75 (m, 1H), 6.43 (t, 1H), 5.52-5.48 (m, 1H), 3.64-3.43 (m, 2H), 3.29 (s, 1H) 
               
               
                   
               
               
                 159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.01 (d, 1H), 6.74-6.68 (m, 1H), 6.62-6.58 (m, 2H) 5.61-5.57 (m, 1H), 3.54-3.40 (m, 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90-7.87 (m,  1H), 7.01-6.97 (m, 2H), 6.88-6.87 (m, 1H), 6.73-6.69 (m, 1H), 5.61-5.57 (m, 1H), 3.57-3.37 (m, 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 421 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.01 (d, 1H), 6.74-6.68 (m, 1H), 6.62-6.58 (m, 2H), 5.61-5.57 (m, 1H), 3.54-3.40 (m, 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 (M + HCO 2   − ) 
                   
               
               
                   
               
               
                 163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 164 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.93-7.91 (m, 1H),  7.25-7.22 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.02 (m, 1H), 6.96 (d, 1H), 4.97-4.93 (m, 1H), 3.55-3.37 (m, 2H), 3.32 (s, 3H) 
               
               
                   
               
               
                 165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.93-7.91 (m,  1H), 7.25-7.22 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.02 (m, 1H), 6.96 (d, 1H), 4.97-4.93 (m, 1H), 3.55-3.37 (m, 2H), 3.32 (s, 3H) 
               
               
                   
               
               
                 166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46]: 442 
                 (400 MHz, CDCl 3 ) δ 7.87 (d, 1H),  7.38 (br s, 1H), 7.16 (br d, 1H), 6.88 (d, 1H), 5.58-5.12 (m, 3H), 3.59-3.44 (m, 3H) 
               
               
                   
               
               
                 167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46]: 462 
                 (400 MHz, CDCl 3 ) δ 7.92 (d, 1H),  7.36-7.33 (m, 1H), 7.32-7.27 (m, 1H), 6.97 (d, 1H), 5.58-5.12 (m, 3H), 3.62- 3.38 (m, 3H) 
               
               
                   
               
               
                 168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46]: 429 
                 (400 MHz, CDCl 3 ) δ 8.01 (d, 1H),  7.09 (d, 1H), 6.77-6.67 (m, 1H), 6.64- 6.61 (m, 2H), 6.47 (t, 1H), 5.21 (d, 2H), 2.70 (t, 1H) 
               
               
                   
               
               
                 169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.30 (d, 1H),  7.89 (d, 1H), 7.54 (d, 1H), 7.26 (s, 1H), 6.99 (m, 2H) 
               
               
                   
               
               
                 170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.30 (s, 1H),  7.88 (d, 1H), 7.21-7.31 (m, 3H), 6.90 (d, 1H) 
               
               
                   
               
               
                 171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, d 6 -DMSO): δ 8.40 (d,  1H), 8.02 (d, 1H), 7.45 (d, 1H), 7.35 (t, 1H), 7.20 (d, 1H), 6.95 (d, 1H), 2.13 (s, 3H) 
               
               
                   
               
               
                 172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.30 (d, 1H),  7.93 (d, 1H), 7.31 (d, 1H), 7.04 (m, 3H) 
               
               
                   
               
               
                 173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.26 (d, 1H),  7.81 (d, 1H), 6.95 (s, 1H), 6.91 (d, 1H), 6.74 (s, 2H), 2.35 (s, 6H) 
               
               
                   
               
               
                 174 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.29 (d, 1H),  7.84 (d, 1H), 7.22-7.27 (m, 2H), 7.06 (s, 1H), 6.78 (d, 1H), 2.16 (s, 3H) 
               
               
                   
               
               
                 175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, d 6 -DMSO): δ 8.40 (s, 1H),  8.03 (d, 1H), 7.58 (m, 2H), 7.23 (m, 1H), 7.11 (d, 1H) 
               
               
                   
               
               
                 176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, d 6 -DMSO): δ 8.30 (s, 1H),  7.88 (d, 1H), 7.27-7.32 (m, 1H), 7.08- 7.14 (m, 2H), 6.85 (d, 1H) 
               
               
                   
               
               
                 177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.29 (d, 1H),  7.87 (m, 1H), 7.06 (d, 1H), 7.02 (d, 1H), 6.94 (d, 1H), 6.77 (m, 1H), 4.75 (d, 2H), 1.83 (t, 1H) 
               
               
                   
               
               
                 178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.18 (d, 1H),  7.38-7.35 (m, 1H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (d, 1H), 6.56-6.47 (m, 1H), 6.22 (t, 1H), 2.08-2.06 (m, 1H) 
               
               
                   
               
               
                 179 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.13 (d, 1H),  7.08-7.05 (m, 1H), 6.95-6.93 (m, 2H), 6.79-6.76 (m, 1H) 
               
               
                   
               
               
                 180 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359, 361 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.33 (d, 1H),  7.09 (m, 1H), 6.97-6.95 (m, 1H), 6.94 (d, 1H), 6.81 (m, 1H), 3.32 (s, 3H), 2.94 (br s, 1H) 
               
               
                   
               
               
                 181 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359, 361 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H),  7.23 (m, 1H), 7.12-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.07 (d, 1H), 5.54- 5.49 (m, 1H), 3.68 (m, 1H), 3.26 (s, 3H), 3.20 (m, 1H), 2.97-2.86 (m, 1H), 2.63-2.45 (m, 1H), 2.35-2.25 (m, 1H) 
               
               
                   
               
               
                 182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 410/412 
                   
               
               
                   
               
               
                 183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 478 mCi 
                   
               
               
                   
               
               
                 184 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 394 
                 (400 MHz, CDCl 3 ): δ 8.47 (d, 1H),  8.35 (d, 1H), 7.82 (d, 1H), 7.45 (t, 1H), 6.88 (d, 1H), 5.64-5.59 (m, 1H), 3.30-3.15 (m, 2H), 3.02-2.93 (m, 1H) 2.46-2.26 (m, 2H) 
               
               
                   
               
               
                 185 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] 436 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.35-7.31 (m, 1H), 7.26-7.23 (m, 1H), 7.15-7.11 (m, 1H), 6.99 (d, 1H), 5.46- 5.39 (m, 1H), 3.63-3.41 (m, 2H), 3.36 (d, 1H) 
               
               
                   
               
               
                 186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 430 
                 (400 MHz, CDCl 3 ): δ 8.55 (d, 1H),  8.40 (d, 1H), 7.91 (d, 1H), 7.52 (t, 1H), 6.94 (d, 1H), 5.46-5.40 (m, 1H), 3.85 (d, 1H), 3.66-3.47 (m, 2H) 
               
               
                   
               
               
                 187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 394 
                 (400 MHz, CDCl 3 ): δ 8.51 (d, 1H),  8.37 (d, 1H), 7.90 (d, 1H), 7.48 (t, 1H), 6.93 (d, 1H), 5.61-5.11 (m, 3H), 3.94 (d, 1H), 3.62-3.42 (m, 2H) 
               
               
                   
               
               
                 188 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + 46] 457   
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  6.94 (d, 1H), 6.82-6.71 (m, 2H), 5.59- 5.11 (m, 3H), 3.59-3.38 (m, 3H) 
               
               
                   
               
               
                 189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 365 
                 (400 MHz, CDCl 3 ): δ 7.88-7.80 (m,  1H), 6.97 (d, 1H), 6.72-6.65 (m, 1H), 6.63-6.55 (m, 2H), 5.83-5.76 (m, 1H), 3.57 (s, 1H), 3.51 (s, 3H), 3.18-3.07 (m, 1H), 2.93-2.79 (m, 1H), 2.60-2.47 (m, 1H), 2.23-2.11 (m, 1H) 
               
               
                   
               
               
                 190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 340 
                 (400 MHz, CDCl 3 ): δ 7.89-7.81 (m,  1H), 6.99-6.94 (m, 1H), 6.66-6.60 (m, 1H), 6.57-6.51 (m, 2H), 5.66-5.59 (m, 1H), 3.28 (s, 3H), 3.24 (s, 1H), 3.15- 3.01 (m, 1H), 2.87-2.71 (m, 1H), 2.55-2.41 (m, 1H), 2.27-2.13 (m, 1H) 
               
               
                   
               
               
                 191 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 401 
                 (400 MHz, CDCl 3 ): δ 7.98-7.91 (m,  1H), 7.04-7.01 (m, 1H), 6.80-6.73 (m, 1H), 6.69-6.61 (m, 2H), 5.73-5.63 (m, 1H), 3.60 (s, 1H), 3.58-3.40 (m, 5H) 
               
               
                   
               
               
                 192 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 376 
                 (400 MHz, CDCl 3 ): δ 7.96-7.89 (m,  1H), 7.03-6.98 (m, 1H), 6.73-6.66 (m, 1H), 6.63-6.55 (m, 2H), 5.62-5.56 (m, 1H), 5.47-5.41 (m, 1H), 3.57-3.30 (m, 2H), 3.28 (s, 3H) 3.24-2.88 (m, 1H) 
               
               
                   
               
               
                 193 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ) δ 8.18 (d, 1H),  7.41-7.39 (m, 1H), 7.30-7.26 (m, 1H), 7.13-7.05 (m, 2H), 6.91 (t, 1H), 3.67 (t, 2H) 
               
               
                   
               
               
                 194 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H): 517, 519 
                 (400 MHz, CDCl 3 ) δ 7.86 (d, 1H),  7.37-7.35 (m, 1H), 7.25-7.21 (m, 1H), 7.08-7.04 (m, 1H), 6.86 (d, 1H), 6.41 (t, 1H), 5.51-5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.25 (d, 1H) 
               
               
                   
               
               
                 195 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ) δ 8.16 (d, 1H),  7.32 (q, 1H), 7.13 (d, 1H), 7.06-7.02 (m, 1H), 6.93-6.91 (m, 1H), 6.90 (t, 1H), 3.67 (t, 2H) 
               
               
                   
               
               
                 196 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H) 457 
                 (400 MHz, CDCl 3 ) δ 7.86 (d, 1H),  7.30-7.24 (m, 1H), 7.02-6.97 (m, 1H), 6.89-6.86 (m, 2H), 6.41 (t, 1H), 5.51- 5.47 (m, 1H), 3.63-3.47 (m, 2H), 3.27 (d, 1H) 
               
               
                   
               
               
                 197 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ) δ 8.14 (d, 1H),  7.15-7.05 (m, 2H), 6.99-6.91 (m, 2H), 6.92 (t, 1H), 3.67 (t, 2H), 2.33 (m, 3H) 
               
               
                   
               
               
                 198 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H) 453 
                 (400 MHz, CDCl 3 ) δ 7.82 (d, 1H),  7.09 (t, 1H), 6.93-6.88 (m, 2H), 6.82 (d, 1H), 6.40 (t, 1H), 5.48 (m, 1H), 3.63-3.48 (m, 2H), 3.25 (d, 1H), 2.31 (m, 3H) 
               
               
                   
               
               
                 199 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ) δ 8.20 (d, 1H),  7.47-7.38 (m, 3H), 7.11 (d, 1H), 6.92 (t, 1H), 3.68 (t, 2H) 
               
               
                   
               
               
                 200 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H) 464 
                 (400 MHz, CDCl 3 ) δ 7.89 (d, 1H),  7.41-7.32 (m, 3H), 6.85 (d, 1H), 6.43 (t, 1H), 5.57-5.48 (m, 1H), 3.59-3.49 (m, 2H), 3.29 (d, 1H) 
               
               
                   
               
               
                 201 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H) 401 
                 (400 MHz, CDCl 3 ) δ 8.31 (s, 1H),  8.28 (s, 1H), 7.94 (d, 1H), 7.33 (d, 1H), 5.61-5.58 (m, 1H), 3.57 (d, 1H), 3.51-3.28 (m, 2H), 3.24 (s, 3H), 2.44 (s, 3H) 
               
               
                   
               
               
                 202 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCOOH − H) 428 
                 (400 MHz, CDCl 3 ) δ 7.95 (d, 1H),  7.28-7.26 (m, 1H), 7.18 (brd s, 1H), 7.08-7.03 (m, 2H), 6.64-6.47 (m, 1H), 6.34 (t, 1H), 3.23-3.14 (m, 1H), 3.04- 2.95 (m, 1H), 2.57-2.42 (m, 2H) 
               
               
                   
               
               
                 203 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ) δ 7.78-7.75 (m,  1H), 7.05-7.02 (m, 1H), 7.00-6.98 (m, 1H), 6.93-6.92 (m, 1H), 6.78-6.75 (m, 1H) 
               
               
                   
               
               
                 204 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 350, 352, 354 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.71 (d, 1H),  7.38 (t, 1H), 7.31-7.26 (m, 1H), 7.14 (t, 1H), 7.03-7.00 (m, 1H), 6.91 (d, 1H) 
               
               
                   
               
               
                 205 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  7.18 (d, 1H), 7.09 (s, 1H), 6.98 (m, 2H), 5.65 (m, 1H), 3.69 (d, 1H), 3.29 (m, 2H), 3.08 (m, 1H), 2.83 (m, 1H), 2.45 (m, 1H), 2.24 (m, 1H), 1.36 (t, 3H) 
               
               
                   
               
               
                 206 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 442 (M + HCO2) 
                 (400 MHz, CDCl 3 ): δ 7.86 (m, 1H),  7.27-7.24 (m, 1H), 7.16-7.14 (m, 1H), 7.07-7.04 (m, 1H), 6.99 (d, 1H), 5.55-5.51 (m, 1H), 3.61-3.27 (m, 5H), 1.35 (t, 3H) 
               
               
                   
               
               
                 207 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.32-7.28 (m, 1H), 7.22-7.19 (m, 1H), 7.12-7.07 (m, 1H), 6.94 (d, 1H), 6.83 (t, 1H), 4.91 (d, 1H), 3.60-3.40 (m, 2H), 1.91 (br s, 2H) 
               
               
                   
               
               
                 208 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.73 (d, 1H),  7.18 (d, 1H), 7.08 (s, 1H), 6.95 (m, 2H), 5.62 (m, 1H), 4.02 (m, 1H), 3.77 (s, 1H), 3.07 (m, 1H), 2.81 (m, 1H), 2.61 (m, 2H), 2.45 (m 1H), 2.26 (m, 3H), 2.06 (m, 2H) 
               
               
                   
               
               
                 209 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 468 (M + HCO2) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H),  7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.06-7.03 (m, 1H), 6.96 (d, 1H), 5.50-5.45 (m, 1H), 3.70 (d, 1H), 3.55-3.34 (m, 2H), 2.67-2.50 (m, 2H), 2.29-2.17 (m, 2H), 2.08-2.01 (m, 2H) 
               
               
                   
               
               
                 210 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.24 (d, 1H), 7.13 (br s, 1H), 7.05- 7.01 (m, 1H), 6.99 (d, 1H), 5.31 (d, 1H), 3.78 (s, 3H), 3.53-3.32 (m, 2H), 3.19 (s, 3H) 
               
               
                   
               
               
                 211 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 354 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.75 (d, 1H),  6.94 (d, 1H), 6.65-6.60 (m, 1H), 6.54- 6.52 (m, 2H), 5.77-5.71 (m, 1H), 5.02-4.95 (m, 1H), 3.23-3.18 (m, 1H), 3.12-3.04 (m, 1H), 2.84-2.70 (m, 1H), 2.65 (d, 3H), 2.57-2.47 (m, 1H), 2.19- 2.11 (m, 1H) 
               
               
                   
               
               
                 212 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.77 (d, 1H),  7.05-7.26 (m, 4H), 6.75 (d, 1H), 5.62 (m, 1H), 3.17-3.30 (m, 2H), 2.98-3.07 (m, 1H), 2.40-2.47 (m, 1H), 2.28-2.37 (m, 1H) 
               
               
                   
               
               
                 213 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.22-7.25 (m,  1H), 7.08 and 7.12 (m 1H), 6.98-7.04 (m, 1H), 6.80 (s, 1H), 5.58 and 5.78 (m, 1H), 3.69 (d, 1H), 3.20 and 3.23 (s, 3H), 3.08-3.47 (m, 2H), 2.68 (s, 3H) 
               
               
                   
               
               
                 214 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, d 6 -DMSO): 7.87 (d, 1H),  7.51-7.64 (m, 2H), 7.11-7.16 (m, 1H), 6.96 (d, 1H), 5.51 (m, 1H), 5.30 (d, 1H), 3.04-3.31 (m, 1H), 2.87-2.95 (m, 1H), 2.11-2.30 (m, 1H), 1.99-2.09 (m, 1H) 
               
               
                   
               
               
                 215 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): 7.92 (d, 1H), 7.27  (m, 2H), 7.08 (d, 1H), 6.99 (d, 1H), 5.63 (dd, 1H), 4.92 (d, 1H), 4.65 (d, 1H), 3.34-3.49 (m, 2H), 3.21 (s, 1H) 
               
               
                   
               
               
                 216 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl3): 7.83 (d. 1H),  7.26-7.38 (m, 3H), 6.81 (d, 1H), 5.64 (dd, 1H), 3.16-3.25 (m, 2H), 3.00-3.04 (m 1H), 2.34-2.42 (m, 2H) 
               
               
                   
               
               
                 217 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): 7.88 (d, 1H), 7.17  (d, 1H), 7.09 (s, 1H), 7.06 (m, 2H), 5.07 (d, 1H), 3.20 (m, 5H), 2.60 (d, 1H), 1.18-1.32 (m, 2H), 0.68-0.87 (m, 2H) 
               
               
                   
               
               
                 218 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl3): 7.80 (d, 1H),  7.18-7.23 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, 1H), 5.63 (m 1H), 3.16-3.29 (m, 2H), 2.96-3.05 (m 1H), 2.29-2.46 (m, 2H) 
               
               
                   
               
               
                 219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, d6-DMSO): δ 7.85 (d,  1H), 7.67 (m, 1H), 7.46 (d, 1H), 6.85 (d, 1H), 5.38 (dd, 1H), 3.40-3.49 (m, 2H), 3.40 (s, 3H) 
               
               
                   
               
               
                 220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 445, 447 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.28-7.22 (m, 2H), 7.02 (d, 1H), 6.87 (d, 1H), 5.43-5.39 (m, 1H), 3.64-3.47 (m, 2H), 3.26 (d, 1H) 
               
               
                   
               
               
                 222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 392 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H),  7.19-7.17 (m, 1H), 7.08 (s, 1H), 7.00-6.97 (m, 2H), 5.71-5.68 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12- 3.04 (m, 1H), 2.84-2.76 (m, 1H), 2.52-2.43 (m, 1H), 2.27-2.19 (m, 1H) 
               
               
                   
               
               
                 223 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2 −) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 224 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.87 (d, 1H),  7.40 (s, 1H), 7.36 (s, 1H), 7.08 (d, 1H), 5.42-5.38 (m, 1H), 3.94 (s, 3H), 3.59-3.52 (m, 2H), 3.21 (d, 1H) 
               
               
                   
               
               
                 225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.82 (d, 1H),  8.70 (d, 1H), 7.95 (d, 1H), 7.71-7.69 (m, 1H), 6.94 (d, 1H), 5.64-5.59 (m, 1H), 5.46-5.31 (m, 1H), 3.36-3.27 (m, 2H), 3.19 (d, 1H) 
               
               
                   
               
               
                 226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H) 3.56-3.35 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 436 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.42-7.30 (m, 3H), 6.86 (d, 1H), 5.42 (dd, 1H), 3.58-3.47 (m, 2H), 3.32 (d, 1H) 
               
               
                   
               
               
                 229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 432 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.26-7.24 (m, 1H), 7.15 (s, 1H), 7.06-7.03 (m, 1H), 7.01 (d, 1H), 3.56-3.35 (m, 3H) 
               
               
                   
               
               
                 230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.19-7.08 (m, 4H), 6.83 (d, 1H), 5.42 (dd, 1H) 3.65-3.49 (m, 2H), 3.25 (dd, 1H) 
               
               
                   
               
               
                 231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.21-7.20 (m, 1H), 7.12-7.11 (m, 1H), 7.03-6.98 (m, 2H), 5.71-5.65 (m, 1H), 5.46-5.33 (m, 1H), 3.66 (dd, 1H), 3.31 (s, 3H), 3.27-3.05 (m, 2H) 
               
               
                   
               
               
                 232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.21-7.20 (m, 1H), 7.12-7.11 (m, 1H), 7.03-6.98 (m, 2H), 5.71-5.65 (m, 1H), 5.46-5.33 (m, 1H), 3.66 (dd, 1H), 3.31 (s, 3H), 3.27-3.05 (m, 2H) 
               
               
                   
               
               
                 233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.88 (d, 1H),  7.32-7.25 (m, 1H), 7.03-6.98 (m, 1H), 6.91-6.86 (m, 2H), 5.42 (dd, 1H), 3.64-3.47 (m, 2H), 3.22 (d, 1H) 
               
               
                   
               
               
                 234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 444 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.52-7.51 (m, 1H), 7.32-7.31 (m, 1H), 7.25-7.24 (m, 1H), 6.98 (d, 1H), 5.62-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.84 (d, 1H),  8.73 (d, 1H), 7.96 (d, 1H), 7.75-7.74 (m, 1H), 6.95 (d, 1H), 5.45 (dd, 1H), 3.64-3.48 (m, 2H), 3.31 (d, 1H) 
               
               
                   
               
               
                 236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + NH4) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.62-7.57 (m, 2H), 7.42 (s, 1H), 7.39- 7.34 (m, 1H), 6.90 (d, 1H), 6.44 (t, 1H), 5.51 (dd, 1H), 5.63-5.45 (m, 2H), 3.37 (d, 1H) 
               
               
                   
               
               
                 237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 435 
                 (400 MHz, CDCl 3 ): δ 10.35 (br s,  1H), 8.14 (s, 1H), 7.82 (d, 1H), 7.61 (d, 1H), 7.51 (d, 1H), 7.21-7.17 (m, 1H), 6.82 (d, 1H), 5.44 (d, 1H), 3.70- 3.57 (m, 2H), 3.40 (br s, 1H) 
               
               
                   
               
               
                 239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + formic acid] 459 
                 (400 MHz, CDCl 3 ): δ 7.78 (d, 1H),  7.68 (d, 1H), 7.44 (d, 1H), 7.37 (t, 1H), 7.23 (d, 1H), 7.00 (d, 1H), 6.71 (d, 1H), 5.73-5.68 (m, 1H), 5.38-5.12 (m, 2H), 3.37-3.33 (m, 1H), 3.32-3.22 (m, 1H) 3.07-2.99 (m, 1H), 2.56-2.46 (m, 1H), 2.35-2.24 (m, 1H) 
               
               
                   
               
               
                 240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 408 
                 (400 MHz, CD 3 OD): δ 8.01 (d, 1H),  7.54-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.40-7.36 (m, 1H), 7.20-7.14 (m, 1H), 5.56 (d, 1H), 3.78-3.61 (m, 1H), 3.62 (s, 3H), 3.55-3.47 (m, 1H) 
               
               
                   
               
               
                 241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + 1] 453 
                 (400 MHz, CDCl 3 ): δ 10.55 (br s,  1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.16- 7.10 (m, 1H), 6.86 (d, 1H), 6.83-6.78 (m, 1H), 5.46 (d, 1H), 3.72-3.59 (m, 2H), 3.34 (br s, 1H) 
               
               
                   
               
               
                 242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + formic acid] 459 
                 (400 MHz, CDCl 3 ): δ 7.83-7.76 (m,  2H), 7.47 (d, 1H), 7.40 (t, 1H), 7.21- 7.19 (m, 1H), 7.05 (d, 1H), 6.76 (d, 1H), 5.61-5.11 (m, 3H), 3.71-3.57 (m, 2H), 3.30 (br s, 1H) 
               
               
                   
               
               
                 243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 435 
                 (400 MHz, CDCl 3 ): δ 10.45 (br s,  1H), 7.93 (s, 1H), 7.84 (d, 1H), 7.48- 7.41 (m, 2H), 6.92 (d, 1H), 6.86 (dd, 1H), 5.46 (d, 1H), 3.72-3.59 (m, 2H), 3.44 (br s, 1H) 
               
               
                   
               
               
                 244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 453 
                 (400 MHz, CDCl 3 ): δ 10.35 (br s,  1H), 7.96 (s, 1H), 7.84 (d, 1H), 7.47- 7.43 (m, 1H), 7.39-7.33 (m, 1H), 6.81 (dd, 1H), 5.46 (d, 1H), 3.74-3.59 (m, 2H), 3.36 (br s, 1H) 
               
               
                   
               
               
                 245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 408 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.32-7.28 (m, 1H), 7.22-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.02 (d, 1H), 5.67 (d, 1H), 4.22 (br s, 1H), 3.65 (s, 3H), 3.60-3.40 (m, 2H) 
               
               
                   
               
               
                 246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 435 
                 (400 MHz, CDCl 3 ): δ 8.15 (d, 1H),  7.82 (d, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 6.99 (d, 1H), 6.88-6.81 (m, 2H), 5.43 (d, 1H), 3.76-3.63 (m, 2H), 3.51 (br s, 1H) 
               
               
                   
               
               
                 247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 385 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27-7.23 (m, 1H), 7.16-7.13 (m, 1H), 7.07-6.98 (m, 2H), 3.56-3.34 (m, 3H), 3.24 (s, 3H) 
               
               
                   
               
               
                 248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 402, 404 
                 (400 MHz, CDCl 3 ): δ 7.70 (d, 1H),  7.20-7.15 (m, 1H), 7.10-7.08 (m, 1H), 7.02 (dt, 1H), 6.86 (d, 1H), 3.50 (t, 2H) 
               
               
                   
               
               
                 249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH 4 ) 397 
                 (400 MHz, CDCl 3 ): δ 7.83 (d, 1H),  7.60 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.94 (d, 1H), 6.65 (t, 1H), 5.72- 5.68 (m, 1H), 3.64 (br d, 1H), 3.22 (s, 3H), 3.14-3.04 (m, 1H), 2.81 (ddd, 1H), 2.54-2.43 (m, 1H), 2.28-2.19 (m, 1H) 
               
               
                   
               
               
                 250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.27-7.24 (m, 1H), 7.16 (br s, 1H), 7.06 (d, 1H), 7.00 (d, 1H), 5.62 (d, 1H), 4.00-4.16 (m, 2H), 3.30-3.74 (m, 4H) 
               
               
                   
               
               
                 251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 392 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.82 (d, 1H),  6.97 (d, 1H), 6.69 (t, 1H), 6.64-6.54 (m, 2H), 5.62 (d, 1H), 5.04-4.96 (m, 1H), 3.50-3.30 (m, 2H), 2.64 (d, 3H) 
               
               
                   
               
               
                 252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.26-7.20 (m, 1H), 7.12 (br s, 1H), 7.04-6.96 (m, 2H), 5.74-5.66 (m, 1H), 5.28 (br s, 2H), 3.50-3.32 (m, 2H) 
               
               
                   
               
               
                 253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.67 (s, 1H),  8.58 (s, 1H), 7.85 (d, 1H), 7.58 (s, 1H), 6.89 (d, 1H), 5.54 (d, 2H), 3.50- 3.24 (m, 2H) 
               
               
                   
               
               
                 254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.25-7.18 (m, 1H), 7.13 (brs, 1H), 7.08-6.92 (m, 2H), 5.68-5.56 (m, 1H), 5.05 (br s, 1H), 3.58-3.30 (m, 2H), 2.65 (s, 3H) 
               
               
                   
               
               
                 255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 322 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.06 (d, 1H),  6.97-6.93 (m, 1H), 6.85-6.83 (m, 1H), 6.69-6.66 (m, 1H), 3.37 (d, 1H), 3.20- 3.12 (m, 1H), 2.93-2.85 (m, 1H), 2.52-2.43 (m, 1H), 2.32-2.25 (m, 1H) 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  6.98 (d, 1H), 6.72-6.60 (m, 1H), 6.62- 6.52 (m, 2H), 5.72-5.64 (m, 1H), 5.29 (br s, 2H), 3.56-3.34 (m, 2H) 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 340 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.82 (d, 1H),  6.95 (d, 1H), 6.62 (t, 1H), 6.55-6.50 (m, 2H), 5.84-5.80 (m, 1H), 5.34 (br s, 2H), 3.11-3.03 (m, 1H), 2.83-2.75 (m, 1H), 2.61-2.52 (m, 1H), 2.19-2.10 (m, 1H) 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 399 
                 (400 MHz, CDCl 3 ): δ 7.96 (d, 1H),  7.27-7.22 (m, 1H), 7.18-7.15 (m, 1H), 7.07-7.03 (m, 1H), 6.97 (d, 1H), 5.59 (d, 1H), 4.59 (s, 1H), 3.89 (s, 1H), 3.18 (dt, 1H), 2.96 (ddd, 1H), 2.43- 2.27 (m, 2H) 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 399 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.25-7.21 (m, 1H), 7.17-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.96 (d, 1H), 5.78- 5.73 (m, 1H), 3.96-3.93 (m, 1H), 3.73 (s, 1H), 3.13 (dt, 1H), 2.87 (ddd, 1H), 2.52-2.41 (m, 1H), 2.31-2.23 (m, 1H) 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 446, 448 
                 (400 MHz, CDCl 3 ): δ 8.17 (s, 1H),  8.03 (s, 1H), 7.99 (d, 1H), 7.11 (d, 1H), 7.08 (s, 1H), 5.44 (dd, 1H), 3.64- 3.42 (m, 3H) 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 471 
                 (400 MHz, CDCl 3 ): δ 7.95-7.87 (m,  2H), 6.95 (d, 1H), 6.77 (dd, 1H), 5.46 (d, 1H), 3.66-3.58 (m, 2H), 3.25 (m, 1H) 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 453 
                 (400 MHz, CDCl 3 ): δ 7.91-7.88 (m,  2H), 7.12 (d, 1H), 7.03 (d, 1H), 6.66 (d, 1H), 6.46 (d, 1H), 3.66-3.56 (m, 2H), 3.26 (br s, 1H) 
               
               
                   
               
               
                 263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 435 
                 (400 MHz, CDCl 3 ): δ 7.92 (s, 1H),  7.84 (d, 1H), 7.48-7.42 (m, 2H), 6.92 (d, 1H), 6.86 (d, 1H), 5.46 (d, 1H), 3.68-3.59 (m, 2H), 3.28 (br s, 1H) 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 453 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.84 (d, 1H), 7.13 (t, 1H), 6.81 (d, 1H), 6.86 (d, 1H), 5.46 (d, 1H), 3.68- 3.69 (m, 2H), 3.29 (br s, 1H) 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.30-7.28 (m, 1H), 7.19 (br s, 1H), 7.10-7.06 (m, 1H), 6.92 (d, 1H), 5.44-5.26 (m, 1H), 4.93 (t, 1H), 3.40-3.24 (m, 2H), 1.95 (br s, 2H) 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 453 
                 (400 MHz, CDCl 3 ): δ 7.96 (s, 1H),  7.83 (d, 1H), 7.36 (t, 1H), 6.81 (d, 1H), 6.68 (d, 1H), 5.47 (d, 1H), 3.74- 3.65 (m, 2H), 3.28 (br s, 1H) 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 435 
                 (400 MHz, CDCl 3 ): δ 8.32 (s, 1H),  8.23 (s, 1H), 8.03 (d, 1H), 7.23 (s, 1H), 7.13 (d, 1H), 5.46 (dd, 1H), 3.64-3.42 (m, 2H), 3.25 (d, 1H) 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.30-7.28 (m, 1H), 7.22 (br s, 1H), 7.12-7.08 (m, 1H), 6.95 (d, 1H), 5.25-5.12 (m, 1H), 4.95 (d, 1H), 3.52-3.46 (m, 1H), 3.29-3.18 (m, 1H), 1.73 (br s, 2H) 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398/400 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 8.23-8.21 (m,  1H), 7.35-7.32 (m, 1H), 7.26-7.24 (m, 1H), 7.23-7.21 (m, 1H), 7.14-7.10 (m, 1H), 3.97-3.78 (m, 2H), 3.43 (s, 3H) 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 417/419 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.95-7.91 (m,  1H), 7.26-7.23 (m, 1H), 7.14-7.13 (m, 1H), 7.06-7.00 (m, 2H), 5.80-5.78 (m, 0.5H), 5.65-5.61 (m, 0.5H), 3.81-3.55 (m, 3.5H), 3.25 (s, 1.5H), 3.24 (s, 1.5H) 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.87 (d, 1H),  7.23-7.21 (m, 1H), 7.13-7.12 (m, 1H), 7.05-7.00 (m, 2H), 5.62-5.56 (m, 1H), 5.44-5.29 (m, 1H), 3.66 (dd, 1H), 3.49-3.35 (m, 1H), 3.20 (s, 3H), 3.17-3.06 (m, 1H) 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 368 
                 (400 MHz, CDCl 3 ): δ 7.84-7.80 (m,  1H), 7.19-7.16 (m, 1H), 7.10 (d, 1H), 7.08-7.06 (m, 1H), 7.00-6.96 (m, 1H), 5.40 (d, 1H), 4.48-4.36 (m, 1H), 3.49- 3.27 (m, 2H), 2.93 (s, 3H) 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + formate − H] 418 
                 (400 MHz, CDCl 3 ): δ 7.63 (d, 1H),  7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 7.03-6.97 (m, 2H), 5.29 (d, 1H), 3.51- 3.28 (m, 2H), 2.76 (br s, 1H) 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 401 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.28-7.25 (m, 1H), 7.17-7.15 (m, 1H), 7.06 (dt, 1H), 7.00 (d, 1H), 5.62-5.56 (m, 1H), 5.37 (dd, 1H), 5.24 (dd, 1H), 4.26 (d, 1H), 3.57-3.34 (m, 2H), 3.20 (br d, 1H) 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 401 
                 (400 MHz, CDCl 3 ): δ 7.96 (d, 1H),  7.28-7.25 (m, 1H), 7.18-7.16 (m, 1H), 7.06 (dt, 1H), 7.01 (d, 1H), 5.42 (dd, 1H), 5.27 (dd, 1H), 5.15 (dd, 1H), 5.04-5.02 (m, 1H), 3.62-3.38 (m, 2H), 3.33 (br s, 1H) 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 408 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H),  7.30 (ddd, 1H), 7.21-7.19 (m, 1H), 7.09 (dt, 1H), 6.99 (d, 1H), 5.92 (dd, 1H), 5.76-5.69 (m, 1H), 5.65 (dd, 1H), 5.55-5.37 (m, 1H), 3.43-3.18 (m, 2H), 3.22 (dd, 1H) 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 408 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H),  7.31 (ddd, 1H), 7.24-7.22 (m, 1H), 7.11 (dt, 1H), 7.00 (d, 1H), 6.27 (dd, 1H), 5.75-5.69 (m, 1H), 5.55 (dd, 1H), 5.56-5.39 (m, 1H), 3.45-3.22 (m, 2H), 3.12 (t, 1H) 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + Cl − ) 551, 553 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.27-7.23 (m, 1H), 7.17-7.13 (m, 1H), 7.07 (dt, 1H), 7.02 (d, 1H), 5.54 (dd, 1H), 5.49-5.41 (m, 1H), 5.12 (br d, 1H), 3.33 (br s, 1H), 2.73-2.64 (m, 1H), 2.22 (d, 1H), 1.35 (s, 9H) 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 417 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.31 (ddd, 1H), 7.26-7.24 (m, 1H), 7.16 (dt, 1H), 6.94 (d, 1H), 5.53 (d, 1H), 4.59 (d, 1H), 2.69-2.61 (m, 1H), 2.35-1.95 (m, 4H) 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 369, 371 
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  6.98 (ddd, 1H), 6.91 (d, 1H), 6.91- 6.89 (m, 1H), 6.74 (dt, 1H), 5.97 (t, 1H), 5.68 (dt, 1H), 5.41 (t, 1H), 3.75 (d, 1H), 3.26-3.17 (m, 1H), 3.20 (s, 3H), 2.91-2.84 (m, 1H) 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 387, 389 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  6.95 (ddd, 1H), 6.92 (d, 1H), 6.88- 6.85 (m, 1H), 6.70 (dt, 1H), 5.65 (d, 1H), 4.24-4.06 (br m, 1H), 4.08 (dd, 1H), 3.88 (dd, 1H), 364-359 (m, 1H), 3.26 (s, 3H), 2.69 (ddd, 1H), 2.66-2.48 (br m, 1H), 2.12 (d, 1H) 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 390 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.27 (ddd, 1H), 7.20-7.18 (m, 1H), 7.08 (dt, 1H), 7.00 (d, 1H), 5.98 (dd, 1H), 5.80-5.75 (m, 1H), 5.49 (dd, 1H), 3.17 (dt, 1H), 2.94 (ddd, 1H), 2.86 (d, 1H), 2.62-2.51 (m, 1H), 2.29- 2.20 (m, 1H) 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 390 
                 (400 MHz, CDCl 3 ): δ 7.91 (d, 1H),  7.27 (ddd, 1H), 7.19-7.16 (m, 1H), 7.06 (dt, 1H), 6.98 (d, 1H), 5.85-5.79 (m, 1H), 5.72 (dd, 1H), 5.61 (dd, 1H), 3.15 (ddd, 1H), 2.97 (d, 1H), 2.89 (ddd, 1H), 2.62-2.52 (m, 1H), 2.27- 2.18 (m, 1H) 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 479 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H),  7.30 (ddd, 1H), 7.22-7.19 (m, 1H), 7.10 (dt, 1H), 7.01 (d, 1H), 5.97 (dd, 1H), 5.70 (dd, 1H), 5.60 (dd, 1H), 3.68 (d, 1H), 3.61-3.39 (m, 2H), 3.23 (s, 3H) 
               
               
                   
               
               
                 285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 426 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.34 (ddd, 1H), 7.25-7.22 (m, 1H), 7.12 (dt, 1H), 7.01 (d, 1H), 5.75 (dd, 1H), 5.71-5.65 (m, 1H), 5.61 (dd, 1H), 3.64-3.45 (m, 2H), 3.14 (dd, 1H) 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 426 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H),  7.34 (ddd, 1H), 7.26-7.24 (m, 1H), 7.14 (dt, 1H), 7.02 (d, 1H), 6.02 (dd, 1H), 5.65-5.59 (m, 1H), 5.54 (dd, 1H), 3.66-3.48 (m, 2H), 3.30 (dd, 1H) 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 392 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.83 (d, 1H),  7.19-7.16 (m, 1H), 7.09-7.07 (m, 1H), 7.01-6.96 (m, 2H), 5.71-5.67 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.02 (m, 1H), 2.84-2.75 (m, 1H), 2.52-2.42 (m, 1H), 2.27-2.18 (m, 1H) 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 8.08 (d, 1H),  7.29-7.23 (m, 1H), 7.19 (brs, 1H), 7.15-7.08 (m, 1H), 7.02 (d, 1H), 5.78- 5.70 (m, 1H), 3.89 (d, 1H), 3.23 (s, 3H), 3.17-3.02 (m, 1H), 2.80-2.64 (m, 1H) 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.13 (d, 1H),  7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09- 5.91 (m, 1H), 5.87-5.80 (m, 1H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H) 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H), 7.34-7.30 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.94 (d, 1H), 4.85 (d, 1H), 3.65-3.41 (m, 2H) 
               
               
                   
               
               
                 291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 481 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.35-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.14-7.10 (m, 1H), 6.95 (d, 1H), 4.59 (d, 1H), 3.77-3.52 (m, 2H), 3.42 (t, 2H), 3.06 (t, 2H) 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 8.14-8.11 (m,  1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.12 (m, 1H), 7.05 (d, 1H), 5.91-5.75 (m, 1H), 5.71-5.65 (m, 1H), 3.39 (d, 1H), 3.25 (s, 3H) 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 8.10-8.07 (m,  1H), 7.32-7.28 (m, 1H), 7.23-7.20 (m, 1H), 7.15-7.10 (m, 1H), 7.02 (d, 1H), 6.07-5.90 (m, 1H), 5.87-5.80 (m, 1H), 3.95 (d, 1H), 3.26 (s, 3H) 
               
               
                   
               
               
                 294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.09-8.06 (m,  1H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 1H), 7.10-7.07 (m, 1H), 7.04 (d, 1H), 6.30-6.12 (m, 1H), 5.96-5.89 (m, 1H), 5.46-5.27 (m, 1H), 3.53-3.51 (m, 1H), 3.27 (s, 3H) 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 8.04-8.01 (m,  1H), 7.25-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.11-7.06 (m, 1H), 7.00 (d, 1H), 6.09-5.79 (m, 1H), 5.69-5.61 (m, 1H), 3.54 (d, 1H), 3.23 (s, 3H), 2.94-2.80 (m, 1H), 2.52-2.41 (m, 1H) 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H),  7.26-7.22 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.07 (m, 1H), 7.05 (d, 1H), 5.76- 5.70 (m, 1H), 5.30-5.24 (m, 1H), 5.18-5.01 (m, 1H), 3.29 (s, 3H) 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H),  7.34-7.30 (m, 1H), 7.25-7.22 (m, 1H), 7.23 (t, J = 54 Hz, 1H), 7.14-7.10 (m, 1H), 7.00 (d, 1H), 5.71-5.63 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39 (m, 0.5H), 3.59 (t, 1H), 3.46-3.18 (m, 2H) 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.22-7.19 (m, 1H), 7.12-7.09 (m, 1H), 7.03-6.98 (m, 2H), 5.29-5.23 (m, 1H), 3.57-3.53 (m, 1H), 3.26-3.04 (m, 2H), 3.19 (s, 3H), 1.70 (d, J = 22 Hz, 3H) 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H),  7.34-7.30 (m, 1H), 7.23-7.21 (m, 1H), 7.13-7.09 (m, 1H), 7.01 (t, J = 53 Hz, 1H), 6.99 (d, 1H), 5.73-5.66 (m, 1H), 5.56-5.52 (m, 0.5H), 5.43-5.39 (m, 0.5H), 3.45-3.34 (m, 1H), 3.35-3.19 (m, 2H) 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.21-7.19 (m, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 6.98 (d, 1H), 5.40-5.35 (m, 1H), 3.79-3.77 (m, 1H), 3.36-3.27 (m, 1H), 3.32 (s, 3H), 2.95-2.84 (m, 1H), 1.70 (d, 3H) 
               
               
                   
               
               
                 301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H),  7.19-7.15 (m, 1H), 7.07-7.06 (m, 1H), 6.98 (d, 1H), 6.97 (dt, 1H), 5.46-5.43 (m, 1H), 3.12 (s, 3H), 3.08 (d, 1H), 2.97-2.91 (m, 1H), 2.68-2.53 (m, 2H), 1.25 (d, 3H) 
               
               
                   
               
               
                 302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, J = 8.7  Hz, 0.5H), 7.95 (d, J = 8.7 Hz, 0.5H), 7.29-7.25 (m, 1H), 7.19-7.16 (m, 1H), 7.10-7.05 (m, 1H), 7.01 (d, 1H), 5.78- 5.69 (m, 1H), 5.54-5.50 (m, 0.5H), 5.40-5.37 (m, 0.5H), 3.50 (d, J = 42 Hz, 3H), 3.39-3.11 (m, 3H) 
               
               
                   
               
               
                 303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] = 357 
                 (400 MHz, CDCl 3 ): δ 8.72 (s, 1H),  8.64 (s, 1H), 7.64 (d, 1H), 7.59-7.57 (m, 1H), 6.97 (d, 1H), 5.33-5.28 (m, 1H), 3.55-3.32 (m, 2H), 2.86-2.82 (m, 1H) 
               
               
                   
               
               
                 304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437, 439 (M + H + ) 
                 (400 MHz, CDCl 3 ): δ 7.88 (d, 1H),  7.17-7.13 (m, 1H), 7.04-7.02 (m, 1H), 6.98 (d, 1H), 6.77-6.74 (m, 1H), 5.61-5.56 (m, 1H), 3.57-3.36 (m 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 437 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.32 (ddd, 1H), 7.24-7.22 (m, 1H), 7.12 (dt, 1H), 6.99 (d, 1H), 5.35 (dd, 1H), 4.73-4.71 (m, 1H), 3.97 (br s, 1H), 3.63-3.46 (m, 2H) 
               
               
                   
               
               
                 306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 437 
                 (400 MHz, CDCl 3 ): δ 8.07 (d, 1H),  7.30 (ddd, 1H), 7.23-7.21 (m, 1H), 7.11 (dt, 1H), 6.98 (d, 1H), 5.59 (ddd, 1H), 3.97 (d, 1H), 3.81 (br s, 1H), 3.61-3.39 (m, 2H) 
               
               
                   
               
               
                 307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 477 
                 (400 MHz, CDCl 3 ): δ 7.99 (d, 1H),  7.30 (ddd, 1H), 7.23-7.20 (m, 1H), 7.10 (dt, 1H), 6.98 (d, 1H), 6.04-5.93 (m, 1H), 5.35-5.28 (m, 2H), 5.21 (dq, 1H), 4.87 (br s, 1H), 4.16-4.09 (m, 1H), 4.04-3.96 (m, 1H), 3.61-3.44 (m, 2H) 
               
               
                   
               
               
                 308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 477 
                 (400 MHz, CDCl 3 ): δ 8.04 (d, 1H),  7.29 (ddd, 1H), 7.21-7.19 (m, 1H), 7.09 (dt, 1H), 6.97 (d, 1H), 5.98 (ddt, 1H), 5.58 (dd, 1H), 5.34 (dq, 1H), 5.19 (dq, 1H), 4.13-4.05 (m, 1H), 4.03-3.95 (m, 1H), 3.59-3.33 (m, 3H) 
               
               
                   
               
               
                 309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 414 
                 (400 MHz, CDCl 3 ): δ 8.49 (d, 1H),  8.37 (d, 1H), 7.93 (d, 1H), 7.26 (dt, 1H), 6.95 (d, 1H), 5.44 (dd, 1H), 3.67-3.48 (m, 2H), 3.42 (d, 1H). 
               
               
                   
               
               
                 310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 430 
                 (400 MHz, CDCl 3 ): δ 8.11-8.08 (m,  1H), 8.01-7.97 (m, 2H), 7.14 (d, 1H), 6.90 (dt, 1H), 5.43 (dd, 1H), 3.95 (d, 1H), 3.62-3.41 (m, 2H) 
               
               
                   
               
               
                 311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H),  7.27-7.25 (m, 1H), 7.20-7.18 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (d, 1H), 5.81- 5.74 (m, 1H), 5.43-5.36 (m, 1H), 3.81 (d, 1H), 3.25 (s, 3H), 2.71 (m, 1H) 
               
               
                   
               
               
                 312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H),  7.29-7.20 (m, 2H), 7.15-7.10 (m, 1H), 7.05 (d, 1H), 5.63-5.57 (m, 1H), 5.22- 5.15 (m, 1H), 3.53-3.48 (m, 1H), 3.24 (s, 3H), 2.73 (d, 1H) 
               
               
                   
               
               
                 313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.75-8.72 (m,  1H), 8.66-8.64 (m, 1H), 7.92 (d, 1H), 7.61-7.59 (m, 1H), 6.95 (d, 1H), 5.73- 5.65 (m, 1H), 5.51-5.47 (m, 0.5H), 5.38-5.34 (m, 0.5H), 3.71-3.68 (m, 1H), 3.36-3.38 (m, 2H), 3.31 (s, 3H) 
               
               
                   
               
               
                 314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 420 
                 (400 MHz, CDCl 3 ): δ 8.83 (d, 1H),  8.72 (d, 1H), 8.02 (d, 1H), 7.73 (dd, 1H), 6.95 (d, 1H), 5.35 (dd, 1H), 4.73-4.70 (m s, 1H), 3.99 (br s, 1H), 3.67-3.49 (m, 2H) 
               
               
                   
               
               
                 315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 420 
                 (400 MHz, CDCl 3 ): δ 8.82 (d, 1H),  8.71 (d, 1H), 8.08 (d, 1H), 7.72 (dd, 1H), 6.93 (d, 1H), 5.63-5.57 (m, 1H), 3.97 (d, 1H), 3.82 (br s, 1H), 3.65- 3.43 (m, 2H) 
               
               
                   
               
               
                 316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 426 
                 (400 MHz, CD 3 OD): δ 8.21 (dd, 1H),  7.59-7.56 (m, 1H), 7.54-7.53 (m, 1H), 7.46 (dt, 1H), 7.25 (d, 1H), 6.00 (dd, 1H), 5.60-5.56 (m, 1H), 3.64 (s, 3H) 
               
               
                   
               
               
                 317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 426 
                 (400 MHz, CDCl 3 ): δ 8.23-8.20 (m,  1H), 7.38-7.34 (m, 1H), 7.30-7.28 (m, 1H), 7.21-7.17 (m, 1H), 7.09 (d, 1H), 5.90 (dd, 1H), 5.71-5.66 (m, 1H), 3.90-3.88 (m, 1H), 3.64 (s, 3H) 
               
               
                   
               
               
                 318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 426 
                 (400 MHz, CDCl 3 ): δ 8.13 (dd, 1H),  7.37-7.33 (m, 1H), 7.28-7.27 (m, 1H), 7.19-7.15 (m, 1H), 7.05 (d, 1H), 6.08-5.84 (m, 2H), 4.08 (d, 1H), 3.54 (s, 3H) 
               
               
                   
               
               
                 319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 409 
                 (400 MHz, CD 3 COCD 3 ): δ 8.95 (d,  1H), 8.94 (d, 1H), 8.34-8.32 (m, 1H), 8.23-8.20 (m, 1H), 7.45 (d, 1H), 6.43- 6.40 (m, 1H), 6.15 (dd, 1H), 5.72-5.66 (m, 1H), 3.69 (s, 3H) 
               
               
                   
               
               
                 320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 409 
                 (400 MHz, CD 3 COCD 3 ): δ 8.96-8.95  (m, 1H), 8.94-8.92 (m, 1H), 8.34-8.32 (m, 1H), 8.24-8.20 (m, 1H), 7.44-7.41 (m, 1H), 6.51-6.31 (m, 2H), 5.90-5.83 (m, 1H), 3.81 (s, 3H) 
               
               
                   
               
               
                 321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 409 
                 (400 MHz, CD 3 COCD 3 ): δ 8.97-8.96  (m, 1H), 8.96-8.94 (m, 1H), 8.35 (dd, 1H), 8.25 (dd, 1H), 7.45 (d, 1H), 6.50 (brs, 1H), 6.16 (dd, 1H), 5.68-5.30 (m, 1H), 3.80 (s, 3H) 
               
               
                   
               
               
                 322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 409 
                 (400 MHz, CD 3 COCD 3 ): δ 8.95-8.94  (m, 1H), 8.94-8.92 (m, 1H), 8.33 (dd, 1H), 8.19 (dd, 1H), 7.41 (d, 1H), 6.50-6.28 (m, 2H), 5.90-5.85 (m, 1H), 3.70 (s, 3H) 
               
               
                   
               
               
                 323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418, 420 (M + H) 
                 (400 MHz, CD 3 COCD 3 ): δ 8.65-8.63  (m, 1H), 8.60-8.59 (m, 1H), 8.15-8.12 (m, 1H), 8.02-8.00 (m, 1H), 7.60-7.57 (m, 1H), 3.86-3.79 (m, 2H), 3.39 (s, 3H) 
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420, 422 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.61-8.59 (m,  1H), 8.41-8.39 (m, 1H), 7.91-7.87 (d, 1H), 7.61-7.58 (m, 1H), 6.95-6.9′ (d, 1H), 5.63-5.57 (m, 1H), 3.61-3.40 (m, 3H), 3.23 (s, 3H) 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.76-8.75 (m,  1H), 8.67-8.66 (m, 1H), 7.95 (d, 1H), 7.70-7.68 (m, 1H), 6.98 (d, 1H), 5.60 (d, 1H), 3.57-3.35 (m, 3H), 3.22 (s, 3H) 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402, 404 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.57-8.56 (m,  1H), 8.39-8.38 (m, 1H), 7.88 (d, 1H), 7.56-7.54 (m, 1H), 6.91 (d, 1H), 5.72- 5.65 (m, 1H), 5.51-5.47 (m, 0.5H), 5.38-5.34 (m, 0.5H), 3.71-3.69 (m, 1H), 3.38-3.09 (m, 3H), 3.29 (s, 3H) 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.10-8.06 (m,  1H), 7.44-7.32 (m, 3H), 6.91 (d, 1H), 5.95-5.91 (m, 0.5H), 5.81-5.78 (m, 0.5H), 5.70-5.64 (m, 1H), 4.00-3.97 (m, 1H), 3.24 (s, 3H) 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420, 422 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.63-8.61 (m, 1H), 8.45-8.43 (m, 1H), 8.11-8.07 (m, 1H), 7.66-7.64 (m, 1H), 6.96 (d, 1H), 6.13-6.11 (m, 0.5H), 5.99-5.97 (m, 0.5H), 5.86-5.82 (m, 1H), 5.24-5.04 (m, 1H), 3.30 (s, 3H), 3.03-3.00 (m, 1H) 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.49-8.47 (m,  1H), 8.39-8.37 (m, 1H), 8.11-8.07 (m, 1H), 7.29-7.25 (m, 1H), 7.00 (d, 1H), 5.96-5.93 (m, 0.5H), 5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.65-3.63 (m, 1H), 3.24 (s, 3H) 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.49-8.46 (m,  1H), 8.39-8.36 (m, 1H), 8.08-8.04 (m, 1H), 8.28-8.24 (m, 1H), 6.98 (d, 1H), 6.12-6.08 (m, 0.5H), 5.99-5.95 (m, 0.5H), 5.88-5.81 (m, 1H), 4.10-4.06 (m, 1H), 3.26 (s, 3H) 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394, 396 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.56-8.55 (m,  1H), 8.44-8.43 (m, 1H), 8.11-8.08 (m, 1H), 7.54-7.52 (m, 1H), 6.99 (d, 1H), 5.96-5.92 (m, 0.5H), 5.83-5.79 (m, 0.5H), 5.71-5.65 (m, 1H), 3.66-3.64 (m, 1H), 3.25 (s, 3H) 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394, 396 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.56-8.54 (m,  1H), 8.43-8.41 (m, 1H), 8.08-8.04 (m, 1H), 7.52-7.50 (m, 1H), 6.96 (d, 1H), 6.12-6.08 (m, 0.5H), 5.98-5.94 (m, 0.5H), 5.88-5.81 (m, 1H), 4.02-3.99 (m, 1H), 3.26 (s, 3H) 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 (M + H) 
                 (400 MHz, CD 3 COCD 3 ): δ 8.88-8.86  (m, 1H), 8.82-8.80 (m, 1H), 8.13-8.08 (m, 2H), 7.33 (d, 1H), 6.21-6.18 (m, 0.5H), 6.07-6.04 (m, 0.5H), 5.83-5.79 (m, 1H), 5.36-5.29 (m, 0.5H), 5.25- 5.16 (m, 0.5H), 5.07-5.04 (m, 1H), 3.33 (s, 3H) 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 365 (M − H) 
                 (400 MHz, CD 3 OD): δ 7.87 (d, 1H),  7.42-7.35 (m, 1H), 7.26-7.13 (m, 2H), 7.08 (d, 1H), 5.63-5.51 (m, 1H), 5.40- 5.18 (m, 1H), 3.20-3.15 (m, 2H) 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.04 (d, 1H),  7.45-7.41 (m, 1H), 7.31-7.29 (m, 1H), 7.26-7.21 (m, 1H), 7.18 (d, 1H), 6.30- 6.11 (m, 1H), 5.80 (t, 1H), 5.37-5.17 (m, 1H) 
               
               
                   
               
               
                 336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 (M − H) 
                   
               
               
                   
               
               
                 337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.00 (d, 1H),  7.44-7.41 (m, 1H), 7.35-7.32 (m, 1H), 7.29-7.24 (m, 1H), 7.14 (d, 1H), 5.46 (d, 1H), 5.06 (d, 1H) 
               
               
                   
               
               
                 338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.03-8.00 (m,  1H), 7.24-7.20 (m, 1H), 7.17-7.15 (m, 1H), 7.08-7.04 (m, 1H), 6.96 (d, 1H), 5.82-5.65 (m, 1H), 5.54-5.48 (m, 1H) 
               
               
                   
               
               
                 339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.09-8.05 (m,  1H), 7.50-7.46 (m, 1H), 7.39-7.38 (m, 1H), 7.33-7.29 (m, 1H), 7.14 (d, 1H), 6.19-6.02 (m, 1H), 5.72-5.65 (m, 1H) 
               
               
                   
               
               
                 340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.81 (d, 1H),  8.73 (d, 1H), 8.11-8.07 (m, 1H), 8.06- 8.04 (m, 1H), 7.18 (d, 1H), 6.04-5.86 (m, 1H), 5.57-5.51 (m, 1H) 
               
               
                   
               
               
                 341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M − H) 
                 (400 MHz, CD 3 OD): δ 8.43 (d, 1H),  8.35 (d, 1H), 8.10-8.06 (m, 1H), 7.59- 7.54 (m, 1H), 7.15 (d, 1H), 6.03-5.85 (m, 1H), 5.56-5.50 (m, 1H) 
               
               
                   
               
               
                 342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 385 
                 (400 MHz, CDCl 3 ): δ 8.82 (d, 1H),  8.74 (d, 1H), 8.14 (dd, 1H), 7.74 (dd, 1H), 7.02 (d, 1H), 5.87 (dd, 1H), 5.73-5.66 (m, 1H), 3.58 (d, 1H), 3.26 (s, 3H) 
               
               
                   
               
               
                 343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 385 
                 (400 MHz, (CD 3 ) 2 CO): δ 8.89 (dd,  1H), 8.86 (d, 1H), 8.21 (dd, 1H), 8.11 (dd, 1H), 7.36 (d, 1H), 6.36 (ddd, 1H), 6.10 (d, 1H), 5.87-5.80 (m, 1H), 3.31 (s, 3H) 
               
               
                   
               
               
                 344 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 403 
                 (400 MHz, CDCl 3 ): δ 8.84 (d, 1H),  8.75 (d, 1H), 8.15 (dd, 1H), 7.77 (dd, 1H), 7.02 (d, 1H), 5.83 (dd, 1H), 5.68-5.62 (m, 1H), 5.43 (dd, 1H), 5.31 (dd, 1H), 3.43 (dd, 1H) 
               
               
                   
               
               
                 345 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 403 
                 (400 MHz, (CD 3 ) 2 CO): δ 8.93 (dd,  1H), 8.90 (dd, 1H), 8.26 (dd, 1H), 8.13 (dd, 1H), 7.38 (d, 1H), 6.39 (ddd, 1H), 5.73 (dd, 1H), 5.80 (ddd, 1H), 5.61 (dd, 1H) 
               
               
                   
               
               
                 346 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 401 
                 (400 MHz, CDCl 3 ): δ 8.14 (dd, 1H),  7.30 (ddd, 1H), 7.24-7.22 (m, 1H), 7.14 (dt, 1H), 6.98 (d, 1H), 5.77 (dd, 1H), 5.10-5.01 (m, 1H), 3.45 (s, 3H), 1.82 (br d, 2H) 
               
               
                   
               
               
                 347 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.86 (d, 1H),  7.27 (d, 1H), 7.27-7.24 (m, 1H), 7.13- 7.11 (m, 1H), 7.04-7.00 (m, 1H), 5.41-5.37 (m, 1H), 3.06 (d, 1H) 
               
               
                   
               
               
                 348 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352, 354 (M − H) 
                 (CDCl 3 , 400 MHz) δ 7.89 (d, 1H),  7.13 (d, 1H), 7.09-7.06 (m, 1H), 6.96-6.94 (m, 1H), 6.80 (dt, 1H), 5.78-5.74 (m, 1H), 3.91 (dd, 1H), 3.65 (dd, 1H), 3.41 (d, 1H) 
               
               
                   
               
               
                 349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.10-7.06 (m, 1H), 5.69-5.65 (m, 1H), 3.23 (d, 1H) 
               
               
                   
               
               
                 350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391, 393, 395 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.70 (d, 1H),  7.10 (d, 1H), 6.93 (ddd, 1H), 6.78- 6.76 (m, 1H), 6.63 (dt, 1H), 3.62-3.58 (m, 2H), 3.42-3.37 (m, 2H) 
               
               
                   
               
               
                 351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 336, 338 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.87 (d, 1H),  7.06 (dt, 1H), 7.03 (d, 1H), 6.94-6.92 (m, 1H), 6.78 (dt, 1H), 3.66-3.61 (m, 2H), 3.60-3.55 (m, 2H) 
               
               
                   
               
               
                 352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424, 426, 428 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.72 (d, 1H),  7.19 (d, 1H), 6.98-6.94 (ddd, 1H), 6.82-6.80 (m, 1H), 6.67 (dt, 1H), 5.60 (td, 1H), 3.80 (dd, 1H), 3.68 (dd, 1H), 2.89 (d, 1H) 
               
               
                   
               
               
                 353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352, 354 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.13 (d, 1H), 7.07 (ddd, 1H), 6.97- 6.94 (m, 1H), 6.80 (dt, 1H), 5.79-5.72 (m, 1H), 3.91 (dd, 1H), 3.64 (dd, 1H), 3.57 (br d, 1H) 
               
               
                   
               
               
                 354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.50 (d, 1H), 7.06 (ddd, 1H), 6.89- 6.86 (m, 1H), 6.73 (dt, 1H) 
               
               
                   
               
               
                 355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425, 427, 429 (M − OH) 
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H),  7.22 (d, 1H), 7.01 (dt, 1H), 6.87-6.85 (m, 1H), 6.71 (dt, 1H), 5.38 (d, 1H), 2.98 (br s, 1H) 
               
               
                   
               
               
                 356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388, 390 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.19 (d, 1H), 7.12 (ddd, 1H), 6.99- 6.97 (m, 1H), 6.83 (dt, 1H), 5.58-5.51 (m, 1H), 3.51 (br d, 1H) 
               
               
                   
               
               
                 357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397, 399 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.76 (d, 1H),  7.26 (d, 1H), 7.01 (ddd, 1H), 6.87- 6.85 (m, 1H), 6.71 (dt, 1H), 5.44 (dd, 1H), 2.94 (d, 1H) 
               
               
                   
               
               
                 358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 364, 366 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H),  7.36 (dd, 1H), 7.20 (ddd, 1H), 6.99 (ddd, 1H), 6.89-6.86 (m, 1H), 6.71 (dt, 1H), 4.73-4.61 (m, 1H), 1.79 (br d, 2H) 
               
               
                   
               
               
                 359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377, 379 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.70 (d, 1H),  7.16 (d, 1H), 6.95 (ddd, 1H), 6.80- 6.78 (m, 1H), 6.64 (dt, 1H), 5.30 (dd, 1H), 2.72 (dd, 1H), 2.43 (s, 3H) 
               
               
                   
               
               
                 360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 431, 433 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H),  7.29 (d, 1H), 7.04 (ddd, 1H), 6.91- 6.89 (m, 1H), 6.74 (dt, 1H), 5.58 (d, 1H), 3.16 (br s, 1H) 
               
               
                   
               
               
                 361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377, 379 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.22 (t, 1H), 7.14 (dt, 1H), 7.01 (ddd, 1H), 6.87-6.85 (m, 1H), 6.71 (dt, 1H), 5.90-5.85 (m, 1H), 3.77 (ddd, 1H), 3.67 (dd, 1H), 2.87 (t, 1H) 
               
               
                   
               
               
                 362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363, 365 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H),  7.27-7.23 (m, 2H), 7.01 (dt, 1H), 6.90-6.88 (m, 1H), 6.72 (dt, 1H), 5.35 (q, 1H), 2.79 (dd, 1H) 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 378, 380 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H),  7.22 (t, 1H), 7.06 (dt, 1H), 7.00 (dt, 1H), 6.87-6.84 (m, 1H), 6.70 (dt, 1H), 5.16-5.03 (br s, 1H), 3.75 (dd, 1H), 3.49 (dd, 1H), 2.20-1.97 (br s, 2H) 
               
               
                   
               
               
                 364 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413, 415 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.25 (t, 1H), 7.21-7.17 (m, 1H), 7.06 (ddd, 1H), 6.92-6.89 (m, 1H), 6.75 (dt, 1H), 5.67 (dd, 1H), 3.10 (dd, 1H) 
               
               
                   
               
               
                 365 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.28 (dd, 1H), 7.18-7.14 (m, 1H), 6.76 (tt, 1H), 6.67-6.60 (m, 2H), 4.98 (dt, 1H), 2.01 (br d, 2H) 
               
               
                   
               
               
                 366 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.87 (d, 1H),  7.44 (dd, 1H), 7.15 (d, 1H), 6.73 (tt, 1H), 6.64-6.57 (m, 2H), 5.58 (dd, 1H), 5.17-5.07 (m, 1H), 2.02-1.93 (m, 2H) 
               
               
                   
               
               
                 367 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H),  7.22 (t, 1H), 7.10-7.06 (m, 1H), 6.72 (tt, 1H), 6.63-6.56 (m, 2H), 5.14-5.07 (m, 1H), 3.75 (dd, 1H), 3.49 (dd, 1H), 2.12-2.04 (m, 2H) 
               
               
                   
               
               
                 368 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.25 (t, 1H), 7.23-7.19 (m, 1H), 6.78 (tt, 1H), 6.68-6.61 (m, 2H), 5.67 (dd, 1H), 3.09 (dd, 1H) 
               
               
                   
               
               
                 369 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.29 (t, 1H), 7.19 (d, 1H), 6.74 (tt, 1H), 6.65-6.58 (m, 2H), 5.87-5.80 (m, 1H), 5.66 (dd, 1H), 2.98 (ddd, 1H) 
               
               
                   
               
               
                 370 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.25 (t, 1H), 7.16 (dt, 1H), 6.73 (tt, 1H), 6.63-6.56 (m, 1H), 5.90-5.86 (m, 1H), 5.90-5.85 (m, 1H), 3.78 (ddd, 1H), 3.67 (dd, 1H), 2.89 (t, 1H) 
               
               
                   
               
               
                 371 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414, 416 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.95-7.92 (m,  1H), 7.25 (t, 1H), 7.21-7.17 (m, 1H), 7.06 (ddd, 1H), 6.92-6.89 (m, 1H), 6.75 (dt, 1H), 3.07 (d, 1H) 
               
               
                   
               
               
                 372 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.31-7.27 (m, 1H), 7.30 (dd, 1H), 7.19-7.14 (m, 2H), 7.07 (dt, 1H), 5.00-4.92 (m, 1H), 2.03 (d, 2H) 
               
               
                   
               
               
                 373 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 (M + H) 
                 (400 MHz, CDCl 3 ): δ 11.26-11.22 (m,  1H), 8.09 (dd, 1H), 8.06 (d, 1H), 7.04 (d, 1H), 7.27-7.23 (m, 1H), 7.15-7.13 (m, 1H), 7.06 (dt, 1H), 5.87 (dd, 1H) 
               
               
                   
               
               
                 374 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.28-7.25 (m, 1H), 7.20 (t, 1H), 7.17- 7.13 (m, 2H), 7.04 (dt, 1H), 5.90-5.85 (m, 1H), 3.79 (dd, 1H), 3.69 (dd, 1H), 2.93 (t, 1H) 
               
               
                   
               
               
                 375 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.31 (ddd, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.08 (dt, 1H), 5.66 (dd, 1H), 3.23 (d, 1H) 
               
               
                   
               
               
                 376 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426, 428 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.78 (d, 1H),  7.18 (d, 1H), 6.72 (tt, 1H), 6.63-6.54 (m, 2H), 4.70 (dt, 1H), 1.92 (d, 2H) 
               
               
                   
               
               
                 377 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426, 428 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.88 (d, 1H),  7.22 (d, 1H), 6.71 (tt, 1H), 6.62-6.55 (m, 2H), 5.31 (dd, 1H), 3.43 (br s, 1H), 3.03 (d, 1H) 
               
               
                   
               
               
                 378 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426, 428 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H),  7.22 (d, 1H), 6.70 (tt, 1H), 6.61-6.54 (m, 2H), 5.35 (t, 1H), 3.75 (br s, 1H), 3.27 (d, 1H) 
               
               
                   
               
               
                 379 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 484, 486 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.75 (d, 1H),  7.16 (d, 1H), 6.71 (tt, 1H), 6.62-6.55 (m, 2H), 4.60 (dd, 1H), 3.55 (t, 2H), 3.35 (s, 3H), 3.21-3.06 (m, 2H), 2.10- 2.03 (m, 1H) 
               
               
                   
               
               
                 380 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.31 (ddd, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.08 (dt, 1H), 5.66 (dd, 1H), 3.23 (d, 1H) 
               
               
                   
               
               
                 381 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398, 400 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.55 (d, 1H),  8.38 (d, 1H), 7.96 (d, 1H), 7.46 (t, 1H), 7.29 (t, 1H), 7.16-7.13 (m, 1H), 5.67 (dd, 1H), 3.24 (dd, 1H) 
               
               
                   
               
               
                 382 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 463 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.91 (d, 1H),  7.39 (t, 1H), 7.29-7.24 (m, 1H), 7.19- 7.14 (m, 2H), 7.05 (dt, 1H), 4.94-4.87 (m, 1H), 3.53 (t, 2H), 3.37 (s, 3H), 3.17-3.07 (m, 2H), 2.28-2.20 (m, 1H) 
               
               
                   
               
               
                 383 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M + H) 
                 (400 MHz, CD 3 OD): δ 8.81 (d, 1H),  8.71 (d, 1H), 8.08 (d, 1H), 8.04 (dd, 1H), 7.42 (d, 1H), 7.38 (t, 1H), 5.69 (d, 1H) 
               
               
                   
               
               
                 384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.31-7.27 (m, 1H), 7.30 (dd, 1H), 7.19-7.14 (m, 2H), 7.07 (dt, 1H), 5.01-4.91 (dd, 1H), 2.06-1.99 (m, 2H) 
               
               
                   
               
               
                 385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, (CD 3 ) 2 SO): δ 8.79 (s, 2H),  8.27 (d, 1H), 7.78-7.73 (m, 1H), 7.72 (t, 1H), 7.55-7.47 (m, 3H) 
               
               
                   
               
               
                 386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.08 (dt, 1H), 3.12 (s, 1H) 
               
               
                   
               
               
                 387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.30 (d, 1H), 7.31-7.27 (m, 1H), 7.19- 7.14 (m, 2H), 7.08 (dt, 1H), 5.02-4.89 (m, 1H), 2.12-1.92 (m, 2H) 
               
               
                   
               
               
                 388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.29-7.25 (m, 1H), 7.19 (d, 1H), 7.16- 7.14 (m, 1H), 7.06-7.01 (m, 1H), 5.75 (d, 2H), 5.58 (br d, 1H), 3.30-3.22 (m, 1H) 
               
               
                   
               
               
                 389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22- 7.18 (m, 2H), 7.08 (dt, 1H), 3.12 (s, 1H) 
               
               
                   
               
               
                 390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M + NH 4 ) 
                 (400 MHz, CD 3 CN): δ 8.02 (d, 1H),  7.27 (d, 1H), 7.01-6.87 (m, 3H), 5.88- 5.73 (m, 2H), 4.91 (d, 1H) 
               
               
                   
               
               
                 391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.13 (d, 1H),  7.67 (t, 1H), 7.53 (d, 1H), 7.43 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 2.45 (s, 3H) 
               
               
                   
               
               
                 392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.91 (d, 1H),  7.41 (s, 1H), 7.27 (t, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 7.10 (d, 1H), 5.71- 5.64 (m, 1H), 3.04 (br d, 1H), 2.44 (s, 3H) 
               
               
                   
               
               
                 393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 467, 469 (M + H2O + NH4) 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H),  7.55 (d, 1H), 7.30 (d, 1H), 7.13 (s, 1H), 7.07-7.02 (m, 1H) 
               
               
                   
               
               
                 394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.01 (d, 1H),  7.28 (t, 1H), 7.21 (d, 1H), 6.83-6.76 (m, 1H), 6.69-6.63 (m, 2H), 6.03-5.97 (m, 1H), 4.20 (dd, 1H), 3.88 (dd, 1H), 3.15-3.11 (m, 1H) 
               
               
                   
               
               
                 395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.26 (t, 1H), 7.21 (d, 1H), 6.83-6.76 (m, 1H), 6.70-6.63 (m, 2H), 5.99 (t, 1H), 4.08-4.02 (m, 1H), 3.98 (dd, 1H), 3.20-3.15 (m, 1H) 
               
               
                   
               
               
                 396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H),  7.17 (t, 1H), 7.12 (d, 1H), 6.74-6.67 (m, 1H), 6.62-6.55 (m, 2H), 5.80-5.74 (m, 1H), 3.80 (dd, 1H), 3.75-3.69 (m, 2H), 3.41-3.34 (m, 1H) 
               
               
                   
               
               
                 397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.07-8.00 (m,  1H), 7.42-7.13 (m, 2H), 6.87-6.80 (m, 1H), 6.73-6.66 (m, 2H), 5.83-5.76 (m, 1H), 3.78-3.66 (m, 1H) 
               
               
                   
               
               
                 398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.02 (d, 1H),  7.22 (t, 1H), 7.19 (d, 1H), 6.79-6.72 (m, 1H), 6.66-6.59 (m, 2H), 5.60 (t, 1H), 3.39 (br s, 1H), 3.12 (d, 1H) 
               
               
                   
               
               
                 399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.95 (d, 1H),  7.23 (t, 1H), 7.19 (d, 1H), 6.79-6.72 (m, 1H), 6.66-6.59 (m, 2H), 5.64 (t, 1H), 3.68 (br s, 1H), 3.33 (d, 1H) 
               
               
                   
               
               
                 400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M + H) 
                 (400 MHz, CD 3 OD): δ 7.99 (d, 1H),  7.57 (d, 1H), 7.26 (t, 1H), 5.57-5.52 (m, 1H), 4.95-4.88 (m, 1H), 3.98-3.91 (m, 2H), 3.67-3.60 (m, 2H), 2.32-2.03 (m, 2H), 1.86-1.76 (m, 2H) 
               
               
                   
               
               
                 401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.90 (d, 1H),  7.29 (t, 1H), 7.16 (d, 1H), 6.76 (tt, 1H), 6.67-6.60 (m, 2H), 5.02-4.93 (m, 1H), 2.01 (br d, 2H) 
               
               
                   
               
               
                 402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 8.08 (d, 1H),  7.31 (t, 1H), 7.10 (d, 1H), 6.71 (tt, 1H), 6.61-6.54 (m, 2H), 5.52-5.48 (m, 1H), 4.05 (td, 1H), 3.32 (ddd, 1H), 2.84-2.74 (m, 1H), 2.73-2.64 (m, 2H) 
               
               
                   
               
               
                 403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441, 443, 445 (M − H) 
                 (CDCl 3 , 400 MHz) δ: 7.80 (d, 1H),  7.22 (d, 1H), 7.02-7.00 (m, 1H), 6.87-6.86 (m, 1H), 6.72 (dt, 1H), 5.38 (d, 1H) 
               
               
                   
               
               
                 404 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 475, 477, 479 (M + HCO2−) 
                 (CDCl 3 , 400 MHz) δ: 8.00 (d, 1H),  7.46 (d, 1H), 6.99-6.96 (m, 1H), 6.81-6.80 (m, 1H), 6.67 (dt, 1H), 2.08-2.04 (m, 2H), 1.96-1.93 (m, 2H) 
               
               
                   
               
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 441, 443, 445 (M − H) 
                 (CDCl 3 , 400 MHz): δ 7.80 (d, 1H),  7.22 (d, 1H), 7.02-7.00 (m, 1H), 6.87-6.86 (m, 1H), 6.72 (dt, 1H), 5.38 (d, 1H) 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 479, 481, 483 (M + HCO 2   − ) 
                 (CDCl 3 , 400 MHz): δ 7.73 (dd, 1H),  7.16 (d, 1H), 6.98-6.95 (m, 1H), 6.83-6.82 (m, 1H), 6.66 (dt, 1H), 1.65 (s, 3H), 1.40 (s, 3H) 
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352, 354 (M − H) 
                 (CDCl 3 , 400 MHz): δ 7.89 (d, 1H),  7.13 (d, 1H), 7.09-7.06 (m, 1H), 6.96-6.94 (m, 1H), 6.80 (dt, 1H), 5.78-5.74 (m, 1H), 3.91 (dd, 1H), 3.65 (dd, 1H), 3.41 (d, 1H) 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380, 382 (M − H) 
                 (CDCl 3 , 400 MHz): δ 7.91 (d, 1H),  7.10-7.06 (m, 2H), 6.97-6.96 (m, 1H), 6.81 (dt, 1H), 1.55 (s, 3H), 1.49 (s, 3H) 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.27-7.23 (m, 2H), 7.15 (s, 1H), 7.04 (d, 1H), 5.46 (dd, 1H), 3.69 (s, 1H), 3.13 (d, 1H) 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.28-7.25 (m, 1H), 7.23 (d, 1H), 7.16- 7.14 (m, 1H), 7.05 (dt, 1H), 5.43 (d, 1H), 5.19 (d, 2H), 3.27 (s, 1H) 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394 (M + NH 4 ) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.46-7.10 (m, 7H), 5.61 (d, 1H), 5.26 (s, 2H), 3.00 (s, 1H) 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407, 409 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.89-7.81 (m,  1H), 7.31-7.26 (m, 1H), 6.78 (t, 1H), 6.65 (d, 2H), 5.59-5.51 (m, 1H), 4.60- 4.38 (br s, 1H) 
               
               
                   
               
               
                 413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.72 (d, 1H),  7.21 (d, 1H), 6.71-6.64 (m, 1H), 6.57- 6.52 (m, 2H), 5.60 (t, 1H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 1H), 2.88 (d, 1H) 
               
               
                   
               
               
                 414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.15 (d, 1H), 6.83-6.76 (m, 1H), 6.71- 6.67 (m, 2H), 5.78-5.74 (m, 1H), 3.94-3.89 (m, 1H), 3.67-3.63 (m, 1H), 3.27-3.24 (m, 1H) 
               
               
                   
               
               
                 415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.77 (d, 1H),  7.25 (d, 1H), 7.22-7.19 (m, 1H), 7.06- 7.05 (m, 1H), 6.99-6.96 (m, 1H), 5.62-5.59 (m, 1H), 3.85-3.80 (m, 1H), 3.71-3.69 (m, 1H), 2.90 (d, 1H) 
               
               
                   
               
               
                 416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.35-7.31 (m, 1H), 7.24-7.22 (m, 1H), 7.16 (d, 1H), 7.16-7.12 (m, 1H), 5.80- 5.73 (m, 1H), 3.96-3.90 (m, 1H), 3.68-3.63 (m, 1H), 3.48-3.46 (m, 1H) 
               
               
                   
               
               
                 417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.24 (d, 1H),  7.89-7.86 (dd, 1H), 7.11 (d, 1H), 6.70-6.65 (m, 1H), 6.59-6.51 (m, 2H), 3.10 (s, 2H) 
               
               
                   
               
               
                 418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.72 (d, 1H),  7.20 (d, 1H), 6.70-6.65 (m, 1H), 6.58- 6.52 (m, 2H), 5.62-5.58 (m, 1H), 3.83-3.78 (m, 1H), 3.71-3.67 (m, 1H), 2.93 (d, 1H) 
               
               
                   
               
               
                 419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.66 (d, 1H),  7.40-7.35 (m, 1H), 7.10 (d, 1H), 6.97- 6.93 (m, 1H), 6.83-6.76 (m, 2H), 5.62-5.59 (m, 1H), 3.82-3.77 (m, 1H), 3.70-3.66 (m, 1H), 2.96 (d, 1H) 
               
               
                   
               
               
                 420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3  + CD 3 OD): δ 8.69  (d, 1H), 8.61-8.60 (d, 1H), 7.79 (d, 1H), 7.55-7.54 (m, 1H), 7.29 (d, 1H), 5.57 (d, 1H), 3.84-3.79 (m, 1H), 3.70- 3.66 (m, 1H) 
               
               
                   
               
               
                 421 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.50 (s, 1H),  8.33 (s, 1H), 7.81 (d, 1H), 7.41-7.40 (m, 1H), 7.19 (d, 1H), 5.41-5.37 (m, 1H), 3.45-3.40 (m, 1H) 
               
               
                   
               
               
                 422 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.83 (d, 1H),  7.48-7.42 (m, 1H), 7.08-7.03 (m, 1H), 7.06 (d, 1H), 6.94-6.87 (m, 2H), 5.78- 5.73 (m, 1H), 3.93-3.88 (m, 1H), 3.66-3.62 (m, 1H), 3.56 (d, 1H) 
               
               
                   
               
               
                 423 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.43 (d, 1H),  8.29 (d, 1H), 7.82 (d, 1H), 7.21 (d, 1H), 7.18-7.14 (dt, 1H), 5.41-5.37 (m, 1H), 3.29-3.28 (m, 1H) 
               
               
                   
               
               
                 424 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.76 (s, 1H),  8.64 (d, 1H), 7.87 (d, 1H), 7.59-7.58 (m, 1H), 7.27 (d, 1H), 5.42-5.36 (m, 1H), 3.36-3.32 (m, 1H) 
               
               
                   
               
               
                 425 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407 (M + HCOOH − H) 
                 (400 MHz, CDCl 3 ): δ 7.81 (d, 1H),  7.28 (d, 1H), 7.24-7.21 (m, 1H), 6.76- 6.70 (1H), 6.65-6.95 (m, 2H), 2.80 (m, 1H), 1.75 (m, 3H) 
               
               
                   
               
               
                 426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 437, 439 (M − H) 
                 (400 MHz, CDCl 3 ) δ 7.75 (d, 1H),  7.17 (d, 1H), 6.56-6.51 (m, 1H), 6.42- 6.37 (m, 2H), 5.42-5.35 (m, 1H), 3.80 (s, 3H), 2.99-2.95 (m, 1H) 
               
               
                   
               
               
                 427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 (M − H) 
                 (400 MHz, CDCl 3 ) δ 7.92 (d, 1H),  7.17 (d, 1H), 6.64-6.60 (m, 1H), 6.50- 6.45 (m, 2H), 6.57-6.51 (m, 1H), 3.82 (s, 3H), 3.80-3.74 (m, 1H) 
               
               
                   
               
               
                 428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.38-8.36 (m,  1H), 8.14 (d, 1H), 7.72 (d, 1H), 7.24- 7.22 (m, 1H), 7.01 (d, 1H), 5.41-5.37 (m, 1H), 4.14-4.08 (m, 1H), 2.40 (s, 3H) 
               
               
                   
               
               
                 429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.26-8.23 (m,  1H), 7.95-7.93 (m, 1H), 7.73 (d, 1H), 7.06 (d, 1H), 6.95-6.92 (m, 1H), 5.42- 5.35 (m, 1H), 4.03-3.97 (m, 1H), 3.88 (s, 3H) 
               
               
                   
               
               
                 430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.80 (d, 1H),  7.59-7.54 (m, 2H), 7.37-7.35 (m, 1H), 7.32-7.27 (m, 1H), 7.15 (d, 1H), 5.42- 5.37 (m, 1H), 3.11 (d, 1H) 
               
               
                   
               
               
                 431 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388, 390 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.82 (d, 1H),  7.32 (d, 1H), 7.25-7.23 (m, 1H), 7.12- 7.10 (m, 1H), 7.03-7.00 (dt, 1H), 5.44 (d, 1H), 3.39-3.25 (m, 1H) 
               
               
                   
               
               
                 432 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.50 (d, 1H),  8.33 (d, 1H), 7.78 (d, 1H), 7.41-7.40 (m, 1H), 7.22 (d, 1H), 5.47-5.42 (m, 1H), 3.45 (d, 1H) 
               
               
                   
               
               
                 433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 430 (M + HCOOH − H) 
                 (400 MHz, CDCl 3 ): δ 7.62 (d, 1H),  7.32 (d, 1H), 7.21-7.18 (m, 1H), 7.08- 7.06 (m, 1H), 6.97-6.93 (m, 1H), 5.47-5.43 (m, 1H), 4.02 (s, 3H), 3.10- 3.08 (m, 1H) 
               
               
                   
               
               
                 434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418 (M + HCOOH − H) 
                 (400 MHz, CDCl 3 ): δ 7.72 (d, 1H),  7.44-7.40 (m, 1H), 7.25-7.22 (m, 1H), 7.13-7.10 (m, 1H), 7.05-7.01 (m, 1H), 5.51 (d, 1H) 
               
               
                   
               
               
                 435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.62-7.57 (m, 2H), 7.42-7.40 (m, 1H), 7.35-7.31 (m, 1H), 7.28 (t, J = 53 Hz, 1H), 7.11 (d, 1H), 5.69-5.65 (m, 1H), 3.33-3.32 (m, 1H) 
               
               
                   
               
               
                 436 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3  + CD 3 OD): δ 7.80  (d, 1H), 7.23-7.15 (m, 1H), 7.20 (t, 1H), 7.02 (d, 1H), 6.94-6.88 (m, 1H), 6.80-6.75 (m, 1H), 5.50 (d, 1H) 
               
               
                   
               
               
                 437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3  + CD 3 OD): δ 7.83  (d, 1H), 7.33-7.23 (m, 3H), 7.18 (t, 1H), 7.01 (d, 1H), 5.51-5.48 (m, 1H) 
               
               
                   
               
               
                 438 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.24 (d, 1H), 7.21 (t, 1H), 5.63-5.58 (m, 1H), 4.23 (q, 2H), 2.94-2.89 (m, 1H), 1.51 (t, 3H) 
               
               
                   
               
               
                 439 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.26 (t, 1H), 7.21 (d, 1H), 5.63-5.59 (m, 1H), 4.01-3.98 (m, 2H), 2.95-2.92 (m, 1H), 1.37-1.27 (m, 1H), 0.74-0.70 (m, 2H), 0.42-0.38 (m, 2H) 
               
               
                   
               
               
                 440 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.85 (d, 1H),  7.78 (d, 1H), 7.50 (d, 1H), 7.47 (t, 1H), 7.42 (t, 1H), 7.17 (dd, 1H), 7.05 (dd, 1H), 6.96 (d, 1H), 5.73-5.67 (m, 1H), 3.20-3.13 (br s, 1H) 
               
               
                   
               
               
                 441 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.17 (s, 1H),  7.83 (d, 1H), 7.72 (d, 1H), 7.42 (t, 1H), 7.22 (t, 1H), 7.12-7.07 (m, 2H), 5.69 (d, 1H) 
               
               
                   
               
               
                 442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.95-7.90 (d,  1H), 7.65 (t, 1H), 7.25-7.22 (m, 1H), 7.22-7.18 (d, 1H), 7.13-7.11 (m, 1H), 7.08-7.04 (m, 1H), 3.73 (brd s, 1H), 1.91-1.88 (m, 3H) 
               
               
                   
               
               
                 443 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.20 (d, 1H), 6.87-6.81 (m, 1H), 6.76- 6.69 (m, 2H), 5.55 (dd, 1H) 
               
               
                   
               
               
                 444 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439, 441 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.78 (d, 1H),  7.16 (d, 1H), 6.75-6.69 (m, 1H), 6.62- 6.54 (m, 2H), 3.04-2.98 (m, 1H), 1.95 (d, 3H) 
               
               
                   
               
               
                 445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 472 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.03 (d, 1H),  7.57 (t, 1H), 7.37 (d, 1H), 7.29-7.25 (m, 1H), 7.17-7.14 (m, 1H), 7.08 (dt, 1H), 5.40-5.10 (m, 1H) 
               
               
                   
               
               
                 446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.13 (d, 1H), 6.83 (tt, 1H), 6.75-6.68 (m, 2H), 3.54 (s, 1H), 1.97 (d, 3H) 
               
               
                   
               
               
                 447 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 457, 459 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  7.27 (d, 1H), 6.72 (tt, 1H), 6.62-6.55 (m, 2H), 4.71 (s, 1H), 4.16 (d, 1H), 3.83 (d, 1H) 
               
               
                   
               
               
                 448 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.26 (d, 1H), 6.83 (tt, 1H), 6.76-6.69 (m, 2H), 4.26 (br s, 1H), 4.18 (d, 1H), 3.81 (d, 1H) 
               
               
                   
               
               
                 449 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 464, 466 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H),  7.30 (d, 1H), 7.27-7.24 (m, 1H), 7.12- 7.10 (m, 1H), 7.00 (dt, 1H), 4.63 (s, 1H), 4.18 (d, 1H), 3.85 (d, 1H) 
               
               
                   
               
               
                 450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.99 (d, 1H),  7.38-7.34 (m, 1H), 7.29-7.24 (m, 2H), 7.20-7.16 (dt, 1H), 4.75 (br s, 1H), 4.20 (d, 1H), 3.82 (d, 1H) 
               
               
                   
               
               
                 451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H) 
               
               
                   
               
               
                 452 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  7.27-7.24 (m, 1H), 7.21 (t, 1H), 7.16- 7.11 (m, 2H), 7.06-7.02 (m, 1H), 5.34 (br s, 1H), 3.66-3.58 (m, 1H), 3.13 (br s, 1H), 1.55 (d, 3H) 
               
               
                   
               
               
                 453 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M + NH 4   + ) 
                 (400 MHz, DMSO-d6): δ 7.99 (d,  1H), 7.75-7.71 (m, 1H), 7.52-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.36 (d, 1H), 7.29 (t, 1H), 6.23 (d, 1H), 5.52 (t, 1H), 3.76-3.68 (m, 1H), 1.35 (d, 3H) 
               
               
                   
               
               
                 454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 347 (M + NH 4   + ) 
                 (400 MHz, CDCl 3 ): δ 7.84 (d, 1H),  7.31 (t, 1H), 7.09 (d, 1H), 5.87-5.79 (m, 1H), 4.17-4.04 (m, 2H), 3.75-3.68 (m, 1H), 3.65-3.59 (m, 1H), 2.91-2.84 (m, 1H), 1.54-1.48 (m, 2H), 1.22-1.14 (m, 2H) 
               
               
                   
               
               
                 455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 (M + HCO 2   − ) 
                 (400 MHz, CDCl 3 ): δ 7.86 (d, 1H),  7.19 (t, 1H), 7.14 (d, 1H), 5.47 (d, 1H), 4.15-4.03 (m, 2H), 3.15 (s, 1H), 1.47-1.39 (m, 2H), 1.19-1.12 (m, 2H) 
               
               
                   
               
               
                 456 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 316 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.18 (d, 1H), 4.81 (m, 1H), 3.18 (s, 1H), 1.92 (d, 3H), 1.48 (t, 6H) 
               
               
                   
               
               
                 457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H) 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 393 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.98 (d, 1H),  7.39-7.35 (m, 1H), 7.27-7.25 (m, 1H), 7.17 (dt, 1H), 7.13 (d, 1H), 3.27 (d, 1H), 1.99 (d, 3H) 
               
               
                   
               
               
                 459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 410 (M + HCO2−) 
                 (400 MHz, (CD 3 ) 2 CO): δ 8.23 (d,  1H), 7.74 (d, 1H), 7.57 (d, 2H), 7.48- 7.36 (m, 3H), 6.54 (d, 1H), 5.54 (s, 2H), 1.86 (d, 3H) 
               
               
                   
               
               
                 460 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 (M − H) 
                 (400 MHz, CDCl 3 ): δ 8.00 (d, 1H),  7.39-7.35 (m, 1H), 7.26-7.24 (m, 1H), 7.18-7.13 (m, 2H), 6.12 (ddd, 1H), 5.86 (d, 1H), 5.73 (d, 1H), 3.45 (d, 1H) 
               
               
                   
               
               
                 461 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 364 (M − H) 
                 (400 MHz, CDCl 3 ): δ 7.97 (d, 1H),  7.02 (d, 1H), 4.90-4.81 (m, 1H), 3.29- 3.17 (m, 2H), 3.10 (d, 1H), 3.02-2.87 (m, 2H), 1.93 (d, 3H) 
               
               
                   
               
               
                 462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 486, 488, 490 (M + H) 
                 (400 MHz, (CD 3 ) 2 SO): δ 8.15 (d, 1H),  7.48 (d, 1H), 7.47 (ddd, 1H), 7.29- 7.27 (m, 1H), 7.18 (dt, 1H), 5.04 (d, 1H) 
               
               
                   
               
               
                 463 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 342 (M − H) 
                 (400 MHz, (CD 3 ) 2 CO): δ 7.99 (d,  1H), 7.66-7.61 (m, 2H), 7.56 (dt, 1H), 7.42 (d, 1H), 5.03 (br s, 1H), 3.95 (dd, 1H), 3.48 (dd, 1H), 2.40 (br s, 2H) 
               
               
                   
               
               
                 464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 (M + H) 
                 (400 MHz, (CD 3 ) 2 CO): δ 8.20 (d,  1H), 7.62 (ddd, 1H), 7.55-7.53 (m, 1H), 7.45 (dt, 1H), 7.39 (d, 1H), 5.14- 5.04 (m, 1H), 2.42 (br d, 2H) 
               
               
                   
               
               
                 465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 328 
                 (400 MHz, CDCl 3 ): δ 8.04 (s, 1H),  5.46-5.26 (m, 2H), 4.89-4.79 (m, 1H), 3.36-3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H) 
               
               
                   
               
               
                 466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 310 
                 (400 MHz, CDCl 3 ): δ 7.98 (s, 1H),  5.59-5.54 (m, 1H), 4.88-4.79 (m, 1H), 3.24-3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H), 2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H) 
               
               
                   
               
               
                 467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 357 
                 (400 MHz, CDCl 3 ): δ 8.33 (s, 1H),  7.22 (ddd, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd, 1H), 3.11 (ddd, 1H), 2.67 (dd, 1H) 
               
               
                   
               
               
                 468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 367 
                 (400 MHz, CDCl 3 ): δ 8.27 (s, 1H),  7.25 (ddd, 1H), 7.14 (m, 1H), 7.03 (dt, 1H), 5.69 (dt, 1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34 (s, 3H), 3.31- 3.24 (m, 1H), 3.09 (ddd, 1H) 
               
               
                   
               
               
                 469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 326/328 (M + H) 
                   
               
               
                   
               
               
                 470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.49 (s, 1H),  6.80-6.71 (m, 3H), 6.19 (t, 1H), 3.36 (t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H) 
               
               
                   
               
               
                 471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 341 
                 (400 MHz, CDCl 3 ): δ 8.65 (s, 1H),  7.53-7.48 (m, 2H), 7.40 (ddd, 1H), 5.56-5.48 (m, 1H), 5.35 (ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd, 1H), 2.65 (dd, 1H) 
               
               
                   
               
               
                 472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339 (M + H) 
                   
               
               
                   
               
               
                 473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 302 (M + H) 
                   
               
               
                   
               
               
                 474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 284 (M + H) 
                   
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 338 (M + H) 
                   
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 338 (M + H) 
                   
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 333 (M + H) 
                   
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 310 (M + H) 
                   
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 340 (M + H) 
                   
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCO 2   − ) 445 
                 (400 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.52 (d, 1H), 5.40 (dd, 1H), 4.33-4.28 (m, 1H), 3.59 (ddd, 1H), 3.49 (t, 1H), 3.22-3.13 (m, 2H), 1.97-1.82 (m, 4H), 1.75-1.58 (m, 3H), 1.46 (dd, 1H), 1.42-1.37 (m, 1H) 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − OH) 381 
                 (400 MHz, CDCl 3 ): δ 7.93 (d, 1H),  7.50 (d, 1H), 5.91-5.88 (m, 1H), 5.39 (dd, 1H), 4.49-4.43 (m, 1H), 3.64 (ddd, 1H), 3.39 (t, 1H), 3.18 (dd, 1H), 2.49-2.39 (m, 1H), 2.22-2.11 (m, 1H), 2.09-1.92 (m, 2H), 1.81-1.59 (m, 3H) 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCO 2   − ) 445 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.56 (ddd, 1H), 3.42 (t, 1H), 3.20 (dd, 1H), 2.67 (tt, 1H), 2.17-2.08 (m, 2H), 2.01-1.94 (m, 1H), 1.82-1.75 (m, 1H), 1.60-1.42 (m, 3H), 1.40-1.27 (m, 2H) 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + HCO 2   − ) 445 
                 (400 MHz, CDCl 3 ): δ 7.94 (d, 1H),  7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.58 (ddd, 1H), 3.40 (t, 1H), 3.18 (d, 1H), 2.67 (tt, 1H), 2.16-2.06 (m, 2H), 2.02-1.95 (m, 1H), 1.86-1.78 (m, 1H), 1.58-1.28 (m, 5H) 
               
               
                   
               
               
                 484 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 366 (M + H) 
                   
               
               
                   
               
               
                 485 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 411/413 
                   
               
               
                   
               
               
                 486 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 420 
                   
               
               
                   
               
               
                 487 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 377 
                   
               
               
                   
               
               
                 488 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 420 
                   
               
               
                   
               
               
                 489 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 435 
                   
               
               
                   
               
               
                 490 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 388 
                   
               
               
                   
               
               
                 491 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + Na) 449 
                   
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + Na) 422 
                   
               
               
                   
               
               
                 493 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 453/455 (M + HCO 2   − ) 
                   
               
               
                   
               
               
                 494 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 346 (M − H) 
                   
               
               
                   
               
               
                 495 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 309 (M − H) 
                   
               
               
                   
               
               
                 496 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 (M − H) 
                   
               
               
                   
               
               
                 497 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 320 (M − H) 
                   
               
               
                   
               
               
                 498 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 (M − H) 
                   
               
               
                   
               
               
                 499 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 337 (M − H) 
                   
               
               
                   
               
               
                 500 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M − H) 
                   
               
               
                   
               
               
                 501 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 356 (M − H) 
                   
               
               
                   
               
               
                 502 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381 (M − H) 
                   
               
               
                   
               
               
                 503 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 (M − H) 
                   
               
               
                   
               
               
                 504 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 408 (M − H) 
                   
               
               
                   
               
               
                 505 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M − H) 
                   
               
               
                   
               
               
                 506 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 392 (M − H) 
                   
               
               
                   
               
               
                 507 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   1 HNMR (300 MHz, CDCl 3 ): δ 7.83  (d, 1H), 7.30 (d, 1H), 6.77 (m, 2H), 6.67 (m, 1H), 6.10 (s, 1H), 5.36 (m, 1H), 3.45 (m, 1H), 3.27 (m, 2H). 
               
               
                   
               
               
                 508 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 361 (M − H) 
                   
               
               
                   
               
               
                 509 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 397 (M − H) 
                   
               
               
                   
               
               
                 510 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M − H) 
                   
               
               
                   
               
               
                 511 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 (M − H) 
                   
               
               
                   
               
               
                 512 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   1 HNMR (300 MHz, CDCl 3 ): δ 8.76  (d, 1H), 6.97 (d, 1H), 5.62 (m, 1H), 3.29 (m, 1H), 3.09 (m, 1H), 3.05 (m, 1H), 2.36 (m, 2H), 1.98 (m, 1H), 1.17 (m, 2H), 0.85 (m, 2H). 
               
               
                   
               
               
                 513 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 341 (M − H) 
                   
               
               
                   
               
               
                 514 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 294 (M − H) 
                   
               
               
                   
               
               
                 515 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 307 (M − H) 
                   
               
               
                   
               
               
                 516 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 329 (M − H) 
                   
               
               
                   
               
               
                 517 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343 (M − H) 
                   
               
               
                   
               
               
                 518 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 322 (M − H) 
                   
               
               
                   
               
               
                 519 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 214 (M + H) 
                   
               
               
                   
               
               
                 520 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 (M − H) 
                   
               
               
                   
               
               
                 521 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375 (M − H) 
                   
               
               
                   
               
               
                 522 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323 (M − H) 
                   
               
               
                   
               
               
                 523 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 322 (M − H) 
                   
               
               
                   
               
               
                 524 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323 (M − H) 
                   
               
               
                   
               
               
                 525 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 323 (M − H) 
                   
               
               
                   
               
               
                 526 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 (M + H) 
                   
               
               
                   
               
               
                 527 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 (M + H) 
                   
               
               
                   
               
               
                 528 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  7.29 (d, 1H), 7.07-7.00 (m, 2H), 6.78 (d, 1H), 6.33 (t, 1H), 5.40 (d, 1H), 4.66 (d, 2H), 4.64-4.58 (m, 1H), 3.38- 3.24 (m, 2H), 3.14 (t, 1H) 
               
               
                   
               
               
                 529 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  7.40 (s, 1H), 6.80 (d, 1H), 6.46-6.20 (m, 3H), 5.39 (d, 1H), 4.64 (t, 1H), 4.47 (d, 2H), 3.46-3.24 (m, 2H), 3.14 (t, 1H) 
               
               
                   
               
               
                 530 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.79 (d, 1H),  7.28 (d, 1H), 7.01-6.94 (m, 3H), 6.35 (t, 1H), 5.38 (d, 1H), 4.61 (m, 2H), 3.70-3.58 (m, 1H), 3.52-3.44 (m, 1H), 3.23 (br s, 1H), 3.00 (s, 3H) 
               
               
                   
               
               
                 531 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  392 
                   
               
               
                   
               
               
                 532 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  343 
                   
               
               
                   
               
               
                 533 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.00 (dd, 1H),  7.84 (dd, 1H), 5.41 (dd, 1H), 5.00- 4.93 (m, 1H), 3.83 (ddd, 1H), 3.72- 3.43 (m, 4H) 
               
               
                   
               
               
                 534 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  382 
                   
               
               
                   
               
               
                 535 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  382 
                   
               
               
                   
               
               
                 536 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  382 
                   
               
               
                   
               
               
                 537 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  331 
                   
               
               
                   
               
               
                 538 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  406 
                   
               
               
                   
               
               
                 539 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  395 
                   
               
               
                   
               
               
                 540 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  428/430 
                   
               
               
                   
               
               
                 541 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  425 
                   
               
               
                   
               
               
                 542 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  444 
                   
               
               
                   
               
               
                 543 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − OH] +  409 
                   
               
               
                   
               
               
                 544 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Cl] −  463/465 
                   
               
               
                   
               
               
                 545 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Cl] −  463/465 
                   
               
               
                   
               
               
                 546 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  444 
                   
               
               
                   
               
               
                 547 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Cl] −  463/465 
                   
               
               
                   
               
               
                 548 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  446 
                   
               
               
                   
               
               
                 549 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  446 
                   
               
               
                   
               
               
                 550 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  446 
                   
               
               
                   
               
               
                 551 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − OH] +  409 
                   
               
               
                   
               
               
                 552 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  446 
                   
               
               
                   
               
               
                 553 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  366 
                   
               
               
                   
               
               
                 554 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  310 
                   
               
               
                   
               
               
                 555 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  346 
                   
               
               
                   
               
               
                 556 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  346 
                   
               
               
                   
               
               
                 557 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  454 
                   
               
               
                   
               
               
                 558 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  380 
                   
               
               
                   
               
               
                 559 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  383 
                   
               
               
                   
               
               
                 560 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  369 
                   
               
               
                   
               
               
                 561 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  369 
                   
               
               
                   
               
               
                 562 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  397 
                   
               
               
                   
               
               
                 563 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  436/438 
                   
               
               
                   
               
               
                 564 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  393 
                   
               
               
                   
               
               
                 565 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  436/438 
                   
               
               
                   
               
               
                 566 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  383 
                   
               
               
                   
               
               
                 567 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  434 
                   
               
               
                   
               
               
                 568 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  419 
                   
               
               
                   
               
               
                 569 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  402 
                   
               
               
                   
               
               
                 570 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  405 
                   
               
               
                   
               
               
                 571 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 381 
                   
               
               
                   
               
               
                 572 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 407 
                   
               
               
                   
               
               
                 573 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 405 
                   
               
               
                   
               
               
                 574 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M + H) 
                   
               
               
                   
               
               
                 575 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M + H) 
                   
               
               
                   
               
               
                 576 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 391 
                   
               
               
                   
               
               
                 577 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH4) 372 
                   
               
               
                   
               
               
                 578 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH4) 390 
                   
               
               
                   
               
               
                 579 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + formate] 363 
                   
               
               
                   
               
               
                 580 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] 332 
                   
               
               
                   
               
               
                 581 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.33 (d, 1H),  7.88-7.84 (m, 1H), 7.04 (d, 1H), 5.82 (dd, 1H), 4.67 (dt, 2H), 4.33-4.24 (m, 2H), 2.32-2.20 (m, 2H) 
               
               
                   
               
               
                 582 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.80-7.77 (m,  1H), 7.05 (d, 1H), 5.74 (dd, 1H), 5.25-5.20 (m, 1H), 4.66 (dt, 2H), 4.33-4.22 (m, 2H), 2.52 (d, 1H), 2.32- 2.19 (m, 2H) 
               
               
                   
               
               
                 583 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.87 (d, 1H),  6.95 (d, 1H), 5.58 (d, 1H), 4.08 (m, 2H), 2.06-3.17 (m, 2H), 2.84-2.94 (m, 1H), 2.37 (m, 1H), 2.27 (m, 1H), 1.86 (m, 2H), 1.07 (t, 3H) 
               
               
                   
               
               
                 584 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 (M − H) 
                   
               
               
                   
               
               
                 585 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 337 (M + H) 
                   
               
               
                   
               
               
                 586 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 587 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 588 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.90 (d, 1H),  6.97 (d, 1H), 5.58 (m, 1H), 3.97 (s, 3H), 3.17 (m, 1H), 3.12 (m, 1H), 2.87 (m, 1H), 2.37 (m, 1H), 2.27 (m, 1H). 
               
               
                   
               
               
                 589 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.86 (d, 1H),  6.94 (d, 1H), 5.58 (m, 1H), 4.20 (m, 2H), 3.17 (m, 1H), 3.09 (m, 1H), 2.89 (m, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 1.47 (t, 3H). 
               
               
                   
               
               
                 590 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 331 (M − H) 
                   
               
               
                   
               
               
                 591 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 (M − H) 
                   
               
               
                   
               
               
                 592 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.85 (d, 1H),  6.94 (d, 1H), 5.57 (m, 1H), 4.72 (m, 1H), 3.18 (m, 1H), 3.11 (m, 1H), 2.86 (m, 1H), 2.35 (m, 1H), 2.25 (m, 1H), 1.41 (d, 6H). 
               
               
                   
               
               
                 593 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 (M − H) 
                   
               
               
                   
               
               
                 594 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 595 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375 (M − H) 
                   
               
               
                   
               
               
                 596 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CD 3 OD): δ 7.89 (d, 1H),  7.28 (d, 1H), 5.44 (m, 1H), 5.27 (m, 1H), 5.14 (d, 1H), 3.77-3.96 (m, 4H), 2.93 (m, 1H), 2.76 (m, 1H), 2.29 (m, 1H), 2.15 (m, 1H), 1.97 (m, 2H). 
               
               
                   
               
               
                 597 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.85 (d, 1H),  6.92 (d, 1H), 5.57 (m, 1H), 3.96 (m, 2H), 3.17 (m, 1H), 3.08 (m, 1H), 2.94 (m, 1H), 2.36 (m, 1H), 2.26 (m, 1H), 1.28 (m, 1H), 0.68 (m, 2H), 0.39 (m, 2H). 
               
               
                   
               
               
                 598 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 (M − H) 
                   
               
               
                   
               
               
                 599 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.87 (d, 1H), 6.99 (d, 1H), 5.57 (m, 1H), 4.27 (m, 2H), 3.80 (m, 2H), 3.45 (s, 3H), 3.15 (m, 1H), 3.11 (m, 1H), 2.93 (m, 1H), 2.36 (m, 1H), 2.27 (m, 1H) 
               
               
                   
               
               
                 600 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 (M + NH 4 ) 
                   
               
               
                   
               
               
                 601 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.82 (d, 1H), 6.79 (d, 1H), 5.57 (m, 1H), 4.78 (m, 1H), 3.17 (m, 1H), 3.09 (m, 1H), 2.89 (m, 1H), 2.50 (m, 2H), 2.20-2.28 (m, 4H), 1.77 (m, 1H), 1.55 (m, 1H). 
               
               
                   
               
               
                 602 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 (M − H) 
                   
               
               
                   
               
               
                 603 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.85 (d, 1H),  6.95 (d, 1H), 5.56 (m, 1H), 4.91 (m, 1H), 3.18 (m, 1H), 3.10 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 2.25 (m, 1H), 1.56-1.99 (m, 8H). 
               
               
                   
               
               
                 604 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M − H) 
                   
               
               
                   
               
               
                 605 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 (M − H) 
                   
               
               
                   
               
               
                 606 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.92 (d, 1H),  7.04 (d, 1H), 5.36 (d, 1H), 4.60 (m, 1H), 3.46 (m, 1H), 3.39 (m, 1H), 3.14 (m, 2H), 2.80 (m, 2H), 2.05 (m, 2H), 1.76 (m, 2H), 1.55 (m, 4H) 
               
               
                   
               
               
                 607 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 (M + H) 
                   
               
               
                   
               
               
                 608 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 609 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.90 (d, 1H),  6.94 (d, 1H), 5.60 (m, 1H), 4.04 (m, 2H), 3.20 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H) 
               
               
                   
               
               
                 610 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M − H) 
                   
               
               
                   
               
               
                 611 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.90 (d, 1H),  6.94 (d, 1H), 5.60 (m, 1H), 4.04 (m, 2H), 3.20 (m, 1H), 3.15 (m, 1H), 2.98 (m, 1H), 2.40 (m, 1H), 2.31 (m, 1H), 1.54 (s, 3H), 1.53 (s, 3H) 
               
               
                   
               
               
                 612 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M + H) 
                   
               
               
                   
               
               
                 613 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 614 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363 (M + H) 
                   
               
               
                   
               
               
                 615 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 616 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 382 (M + NH 4   + ) 
                   
               
               
                   
               
               
                 617 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 (M − H) 
                   
               
               
                   
               
               
                 618 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415 (M − H) 
                   
               
               
                   
               
               
                 619 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 620 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 398 (M + H) 
                   
               
               
                   
               
               
                 621 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 622 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) 
                   
               
               
                   
               
               
                 623 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 415 (M − H) 
                   
               
               
                   
               
               
                 624 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 625 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 (M + NH 4 ) 
                   
               
               
                   
               
               
                 626 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 627 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 444 (M + H) 
                   
               
               
                   
               
               
                 628 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 480 (M + H) 
                   
               
               
                   
               
               
                 629 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 430 (M + H) 
                   
               
               
                   
               
               
                 630 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 466 (M + H) 
                   
               
               
                   
               
               
                 631 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439 (M + H) 
                   
               
               
                   
               
               
                 632 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M + H) 
                   
               
               
                   
               
               
                 633 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M + H) 
                   
               
               
                   
               
               
                 634 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 416 (M + H) 
                   
               
               
                   
               
               
                 635 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 (M + H) 
                   
               
               
                   
               
               
                 636 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 (M + H) 
                   
               
               
                   
               
               
                 637 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 440 (M + H) 
                   
               
               
                   
               
               
                 638 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 (M + H) 
                   
               
               
                   
               
               
                 639 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 640 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 (M − H) 
                   
               
               
                   
               
               
                 641 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 (M + H) 
                   
               
               
                   
               
               
                 642 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.93 (d, 1H),  6.94 (d, 1H), 5.35 (m, 1H), 4.96 (m, 1H), 3.38-3.47 (m, 3H), 2.82-2.92 (m, 3H), 2.52 (m, 1H), 2.43 (m 1H), 2.42 (s, 3H), 2.04 (m 1H) 
               
               
                   
               
               
                 643 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 (M + H) 
                   
               
               
                   
               
               
                 644 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 433 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 645 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 (M − H) 
                   
               
               
                   
               
               
                 646 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 647 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418 (M + H) 
                   
               
               
                   
               
               
                 648 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 7.92 (d, 1H),  6.87 (d, 1H), 5.36 (m, 1H), 4.93 (m, 1H), 3.80 (s, 3H), 3.44-3.60 (m, 2H), 3.22 (m, 1H), 1.71 (d, 3H) 
               
               
                   
               
               
                 649 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 (M − H) 
                   
               
               
                   
               
               
                 650 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376 (M + H) 
                   
               
               
                   
               
               
                 651 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.31 (m, 1H),  7.17 (d, 1H), 6.82 (d, 1H), 6.09 (t, 1H), 5.15 (m, 1H), 4.20 (m, 2H), 3.45 (m, 1H), 3.27 (m, 1H), 2.27 (m, 1H) 
               
               
                   
               
               
                 652 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 313 (M − H + HCOOH) 
                   
               
               
                   
               
               
                 653 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.56 (d, 1H),  7.17 (d, 1H), 5.13 (m, 1H), 3.56 (m, 2H), 2.50 (s, 1H) 
               
               
                   
               
               
                 654 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 (M − H) 
                   
               
               
                   
               
               
                 655 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 (M − H) 
                   
               
               
                   
               
               
                 656 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 (M − H) 
                   
               
               
                   
               
               
                 657 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 (M − H) 
                   
               
               
                   
               
               
                 658 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 442 (M + HCO 2   − ) 
                   
               
               
                   
               
               
                 659 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 660 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 (M − H) 
                   
               
               
                   
               
               
                 661 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424 (M + HCO 2   − ) 
                   
               
               
                   
               
               
                 662 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 265 (M − OH) 
                   
               
               
                   
               
               
                 663 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH4) 426 
                   
               
               
                   
               
               
                 664 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − H) 421 
                   
               
               
                   
               
               
                 665 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 410 
                   
               
               
                   
               
               
                 666 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.15 (s, 1H),  6.12 (t, 1H), 4.96-4.87 (1H), 4.22- 4.09 (2H), 3.62-3.50 (2H), 2.49 (1H) 
               
               
                   
               
               
                 667 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M − OH) 467 
                   
               
               
                   
               
               
                 668 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + NH4) 330 
                   
               
               
                   
               
               
                 669 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 350 
                   
               
               
                   
               
               
                 670 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.63 (d, 1H),  7.25 (d, 1H), 6.62 (t, 1H), 5.30-5.25 (m, 1H), 3.58-3.37 (m, 2H), 2.54-2.51 (m, 1H) 
               
               
                   
               
               
                 671 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.59 (d, 1H),  7.18 (d, 1H), 6.60 (t, 1H), 5.40-5.23 (m, 2H), 3.40-3.12 (m, 2H), 2.55-2.51 (m, 1H) 
               
               
                   
               
               
                 672 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 (M + H) 358 
                   
               
               
                   
               
               
                 673 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − OH] +  229 
                   
               
               
                   
               
               
                 674 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  284 
                   
               
               
                   
               
               
                 675 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  445 
                   
               
               
                   
               
               
                 676 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  360 
                   
               
               
                   
               
               
                 677 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  382 
                   
               
               
                   
               
               
                 678 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] +  346 
                   
               
               
                   
               
               
                 679 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.62 (d, 1H),  6.63 (d, 1H), 4.94 (dd, 1H), 3.81 (s, 3H), 3.46-3.38 (m, 2H), 2.43-2.40 (m, 1H) 
               
               
                   
               
               
                 680 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  289 
                   
               
               
                   
               
               
                 681 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.64 (d, 1H),  6.61 (d, 1H), 6.07 (tt, 1H), 4.94 (d, 1H), 4.19 (td, 2H), 3.50-3.42 (m, 2H), 2.41 (brs, 1H) 
               
               
                   
               
               
                 682 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.59 (d, 1H),  6.61 (d, 1H), 4.98-4.91 (m, 1H), 3.92 (td, 2H), 3.48-3.39 (m, 2H), 2.40 (brs, 1H), 1.84-1.76 (m, 2H), 1.02 (t, 3H) 
               
               
                   
               
               
                 683 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.58 (d, 1H),  6.57 (d, 1H), 5.26 (dq, 1H), 5.06-5.01 (m, 1H), 3.91 (t, 2H), 3.21 (dd, 2H), 2.42-2.38 (m, 1H), 1.84-1.74 (m, 2H), 1.03 (t, 3H) 
               
               
                   
               
               
                 684 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  317 
                   
               
               
                   
               
               
                 685 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH4] −  251 
                   
               
               
                   
               
               
                 686 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  363 
                   
               
               
                   
               
               
                 687 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.42 (d, 1H),  6.73 (d, 1H), 6.07 (tt, 1H), 5.08 (d, 1H), 4.23-4.17 (m, 2H), 3.54-3.35 (m, 2H), 2.49 (brs, 1H) 
               
               
                   
               
               
                 688 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  276 
                   
               
               
                   
               
               
                 689 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.78 (d, 1H),  7.09 (d, 1H), 6.17 (tt, 1H), 5.79 (dd, 1H), 5.24-5.18 (m, 1H), 4.42-4.31 (m, 2H), 2.47-2.44 (m, 1H) 
               
               
                   
               
               
                 690 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.74 (d, 1H),  7.05 (d, 1H), 6.16 (tt, 1H), 6.02 (dd, 1H), 5.54-5.48 (m, 1H), 4.35 (td, 2H), 2.68 (brd, 1H) 
               
               
                   
               
               
                 691 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  290 
                   
               
               
                   
               
               
                 692 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  310 
                   
               
               
                   
               
               
                 693 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  286 
                   
               
               
                   
               
               
                 694 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  343 
                   
               
               
                   
               
               
                 695 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  317 
                   
               
               
                   
               
               
                 696 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.56 (d, 1H),  6.84 (d, 1H), 6.11 (tt, 1H), 5.38-5.22 (m, 2H), 4.26 (td, 2H), 3.33-3.07 (m, 2H), 2.52-2.48 (m, 1H) 
               
               
                   
               
               
                 697 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.56 (d, 1H),  6.87 (d, 1H), 6.12 (tt, 1H), 5.49-5.22 (m, 2H), 4.31-4.23 (m, 2H), 3.48-3.06 (m, 2H), 2.48 (brs, 1H) 
               
               
                   
               
               
                 698 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.62 (d, 1H),  7.61 (s, 1H), 6.81 (d, 1H), 6.13 (tt, 1H), 4.28 (td, 2H), 3.09-2.97 (m, 4H) 
               
               
                   
               
               
                 699 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  381 
                   
               
               
                   
               
               
                 700 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  344 
                   
               
               
                   
               
               
                 701 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H + HCOOH] −  377 
                   
               
               
                   
               
               
                 702 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  328 
                   
               
               
                   
               
               
                 703 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  310 
                   
               
               
                   
               
               
                 704 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  320 
                   
               
               
                   
               
               
                 705 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  312 
                   
               
               
                   
               
               
                 706 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363 (M − H) −   
                   
               
               
                   
               
               
                 707 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 472 (M + HCO 2 ) −   
                   
               
               
                   
               
               
                 708 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 491 (M + HCO 2 ) −   
                   
               
               
                   
               
               
                 709 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M − H) −   
                   
               
               
                   
               
               
                 710 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 373 (M − H) −   
                   
               
               
                   
               
               
                 711 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M − H) −   
                   
               
               
                   
               
               
                 712 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 (M − H) −   
                   
               
               
                   
               
               
                 713 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M − H) −   
                   
               
               
                   
               
               
                 714 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) −   
                   
               
               
                   
               
               
                 715 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) −   
                   
               
               
                   
               
               
                 716 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 (M − H) −   
                   
               
               
                   
               
               
                 717 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 (M − H) −   
                   
               
               
                   
               
               
                 718 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 (M − H) −   
                   
               
               
                   
               
               
                 719 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 416 (M + H) +   
                   
               
               
                   
               
               
                 720 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 416 (M + H) +   
                   
               
               
                   
               
               
                 721 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 495 (M + HCO 2 ) −   
                   
               
               
                   
               
               
                 722 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 (M + H − CO 2  − C 4 H 8 ) +   
                   
               
               
                   
               
               
                 723 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 451 (M − H) −   
                   
               
               
                   
               
               
                 724 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 (M + H) +   
                   
               
               
                   
               
               
                 725 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 430 (M + H) +   
                   
               
               
                   
               
               
                 726 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 510 (M + HCO 2 ) −   
                   
               
               
                   
               
               
                 727 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407 (M − H) −   
                   
               
               
                   
               
               
                 728 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407 (M − H) 
                   
               
               
                   
               
               
                 729 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439 (M + H) +   
                   
               
               
                   
               
               
                 730 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) −   
                   
               
               
                   
               
               
                 731 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 (M − H) −   
                   
               
               
                   
               
               
                 732 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 439 (M + H) +   
                   
               
               
                   
               
               
                 733 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 436 (M + H) +   
                   
               
               
                   
               
               
                 734 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M + H) +   
                   
               
               
                   
               
               
                 735 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353 (M + H) +   
                   
               
               
                   
               
               
                 736 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M + H) +   
                   
               
               
                   
               
               
                 737 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M + H) +   
                   
               
               
                   
               
               
                 738 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 353 (M + H) +   
                   
               
               
                   
               
               
                 739 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 (M + Na) +   
                   
               
               
                   
               
               
                 740 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 355 (M + H) +   
                   
               
               
                   
               
               
                 741 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 (M + H) +   
                   
               
               
                   
               
               
                 742 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 (M + NH 4 ) +   
                   
               
               
                   
               
               
                 743 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 (M + NH 4 ) +   
                   
               
               
                   
               
               
                 744 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  420 
                   
               
               
                   
               
               
                 745 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  384 
                   
               
               
                   
               
               
                 746 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  404 
                   
               
               
                   
               
               
                 747 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  422 
                   
               
               
                   
               
               
                 748 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  429 
                   
               
               
                   
               
               
                 749 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  445 
                   
               
               
                   
               
               
                 750 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  408 
                   
               
               
                   
               
               
                 751 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  382 
                   
               
               
                   
               
               
                 752 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  381 
                   
               
               
                   
               
               
                 753 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  354 
                   
               
               
                   
               
               
                 754 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                   
               
               
                   
               
               
                 755 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  364 
                   
               
               
                   
               
               
                 756 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  390 
                   
               
               
                   
               
               
                 757 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  407 
                 (400 MHz, CDCl 3 ): δ 8.09 (d, 1H), 7.07 (d, 1H), 5.82-5.66 (m, 1H), 5.61-5.57 (m, 1H), 4.73 (m, 1H), 3.41 (d, 1H), 3.20 (s, 3H), 2.87 (m, 1H), 2.17- 1.80 (m, 8H) 
               
               
                   
               
               
                 758 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  407 
                 (400 MHz, CDCl 3 ): δ 8.07 (dd, 1H),  7.04 (d, 1H), 5.85-5.70 (m, 1H), 5.62- 5.58 (m, 1H), 4.65 (m, 1H), 3.25 (d, 1H), 3.20 (s, 3H), 2.76-2.74 (m, 1H), 2.12-1.55 (m, 8H) 
               
               
                   
               
               
                 759 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  404 
                   
               
               
                   
               
               
                 760 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                 (400 MHz, CDCl 3 ): δ 8.10 (dd, 1H), 6.86 (d, 1H), 5.82-5.66 (m, 1H), 5.61- 5.58 (m, 1H), 5.17-5.14 (m, 1H), 3.32-3.29 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 2.99-2.93 (m, 2H), 2.76-2.70 (m, 2H) 
               
               
                   
               
               
                 761 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                 (400 MHz, CDCl 3 ): δ 8.08 (dd, 1H), 6.84 (d, 1H), 5.85-5.69 (m, 1H), 5.62- 5.58 (m, 1H), 4.86-4.79 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 3.07-3.00 (m, 2H), 2.96-2.87 (m, 1H), 2.76-2.66 (m, 2H) 
               
               
                   
               
               
                 762 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  378 
                   
               
               
                   
               
               
                 763 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  397 
                 (400 MHz, CDCl 3 ): δ 8.06 (dd, 1H), 6.90 (d, 1H), 5.85-5.70 (m, 1H), 5.59- 5.56 (m, 1H), 5.39-5.32 (m, 2H), 4.79-4.76 (m, 1H), 3.24 (d, 1H), 3.20 (s, 3H), 2.83-2.74 (m, 3H), 2.63-2.55 (m, 2H) 
               
               
                   
               
               
                 764 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                 (400 MHz, CDCl 3 ): δ 8.10 (dd, 1H), 7.09 (d, 1H), 5.91-5.76 (m, 1H), 5.58- 5.55 (m, 1H), 4.48-4.44 (m, 1H), 4.14-4.10 (m, 1H), 3.41 (d, 1H), 3.20 (s, 3H), 1.94-1.91 (m, 1H), 1.81-1.76 (m, 1H), 1.46-1.41 (m, 1H), 1.20-1.18 (m, 1H) 
               
               
                   
               
               
                 765 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                 (400 MHz, CDCl 3 ): δ 8.12 (dd, 1H), 7.10 (d, 1H), 5.91-5.75 (m, 1H), 5.62- 5.58 (m, 1H), 4.39-4.29 (m, 2H), 3.26 (d, 1H), 3.21 (s, 3H), 1.90-1.86 (m, 1H), 1.79-1.76 (m, 1H), 1.45-1.39 (m, 1H), 1.26-1.22 (m, 1H) 
               
               
                   
               
               
                 766 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  393 
                 (400 MHz, CDCl 3 ): δ 8.10 (dd, 1H),  6.88 (d, 1H), 5.82-5.66 (m, 1H), 5.61- 5.58 (m, 1H), 5.08-5.02 (m, 1H), 3.29 (d, 1H), 3.20 (s, 3H), 3.19-3.14 (m, 2H), 2.42-2.32 (m, 2H), 1.65 (s, 3H) 
               
               
                   
               
               
                 767 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  393 
                 (400 MHz, CDCl 3 ): δ 8.05 (d, 1H),  6.81 (d, 1H), 5.87-5.71 (m, 1H), 5.61- 5.58 (m, 1H), 4.97-4.91 (m, 1H), 3.25 (d, 1H), 3.20 (s, 3H), 2.92-2.76 (m, 2H), 2.74-2.70 (m, 2H), 1.65 (s, 3H) 
               
               
                   
               
               
                 768 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  390 
                 (400 MHz, CDCl 3 ): δ 8.11 (dd, 1H),  7.07 (d, 1H), 5.85-5.69 (m, 1H), 5.62- 5.58 (m, 1H), 4.36-4.32 (m, 1H), 4.21-4.17 (m, 1H), 3.27 (d, 1H), 3.20 (s, 3H), 2.18-2.10 (m, 1H), 1.72-1.67 (m, 2H), 1.41-1.33 (m, 1H) 
               
               
                   
               
               
                 769 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  390 
                 (400 MHz, CDCl 3 ): δ 8.11 (dd, 1H),  7.06 (d, 1H), 5.87-5.72 (m, 1H), 5.61- 5.57 (m, 1H), 4.25-4.23 (m, 2H), 3.27 (d, 1H), 3.20 (s, 3H), 2.22-2.10 (m, 1H), 1.73-1.70 (m, 2H), 1.39-1.36 (m, 1H) 
               
               
                   
               
               
                 770 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  379 
                 (400 MHz, CDCl 3 ): δ 8.10 (dd, 1H),  7.02 (d, 1H), 5.83-5.67 (m, 1H), 5.61- 5.58 (m, 1H), 4.25-4.22 (m, 1H), 4.14-4.09 (m, 1H), 3.32-3.29 (m, 1H), 3.21 (s, 3H), 2.06-2.04 (m, 1H), 1.59- 1.55 (m, 1H), 1.47-1.44 (m, 1H), 1.28-1.25 (m, 1H) 
               
               
                   
               
               
                 771 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  418 
                   
               
               
                   
               
               
                 772 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  393 
                   
               
               
                   
               
               
                 773 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  340 
                   
               
               
                   
               
               
                 774 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  378 
                   
               
               
                   
               
               
                 775 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  366 
                   
               
               
                   
               
               
                 776 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  260 
                   
               
               
                   
               
               
                 777 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  296 
                   
               
               
                   
               
               
                 778 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  310 
                   
               
               
                   
               
               
                 779 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  336 
                   
               
               
                   
               
               
                 780 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  408 
                   
               
               
                   
               
               
                 781 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  372 
                   
               
               
                   
               
               
                 782 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 7.89 (d, 1H),  6.98 (d, 1H), 6.55 (t, J = 54 Hz, 1H), 5.41 (d, 1H), 4.68 (m, 1H), 3.98-3.88 (m, 2H), 3.66-3.54 (m, 2H), 3.48-3.26 (m, 2H), 1.87-1.74 (m, 2H), 1.62-1.51 (m, 2H) 
               
               
                   
               
               
                 783 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  402 
                   
               
               
                   
               
               
                 784 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  392 
                   
               
               
                   
               
               
                 785 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  406 
                   
               
               
                   
               
               
                 786 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  415 
                   
               
               
                   
               
               
                 787 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  415 
                   
               
               
                   
               
               
                 788 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  429 
                   
               
               
                   
               
               
                 789 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  429 
                   
               
               
                   
               
               
                 790 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  429 
                   
               
               
                   
               
               
                 791 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + HCl − H] −  508 
                   
               
               
                   
               
               
                 792 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  374 
                   
               
               
                   
               
               
                 793 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  469 
                   
               
               
                   
               
               
                 794 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  411 
                   
               
               
                   
               
               
                 795 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  411 
                   
               
               
                   
               
               
                 796 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  384 
                   
               
               
                   
               
               
                 797 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 (M + H) 
                   
               
               
                   
               
               
                 798 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  404 
                   
               
               
                   
               
               
                 799 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  354 
                   
               
               
                   
               
               
                 800 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + NH 4 ] +  350 
                   
               
               
                   
               
               
                 801 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 8.25 (d, 1H),  7.27 (d, 1H), 4.18 (t, 2H), 3.50 (t, 2H), 1.94 (m, 2H), 1.11 (t, 3H) 
               
               
                   
               
               
                 802 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (300 MHz, CDCl 3 ): δ 8.23 (d, 1H),  7.25 (d, 1H), 4.83 (m, 1H), 3.47 (t, 2H), 1.48 (d, 6H) 
               
               
                   
               
               
                 803 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 804 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                   
               
               
                   
               
               
                 805 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.21 (d, 1H),  7.40 (d, 1H), 4.88-4.83 (m, 1H), 3.67- 3.39 (m, 7H), 1.43 (d, 3H) 
               
               
                   
               
               
                 806 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                   
                 (400 MHz, CDCl 3 ): δ 8.13 (d, 1H),  7.34 (d, 1H), 4.82-4.76 (m, 1H), 3.60- 3.31 (m, 7H), 1.36 (d, 3H) 
               
               
                   
               
               
                 807 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405/407 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.38 (d, 1H), 7.37-  7.36 (m, 1H), 7.30 (ddd, 1H), 7.24 (dt, 1H), 6.09 (dddd, 1H), 6.00 (dddd, 1H) 
               
               
                   
               
               
                 808 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403/405 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.36 (d, 1H), 7.37-  7.35 (m, 1H), 7.29 (ddd, 1H), 7.25 (dt, 1H), 5.86 (dd, 1H), 5.11 (ddd, 1H), 2.73 (d, 1H) 
               
               
                   
               
               
                 809 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.75 (d, 1H), 7.39-  7.37 (m, 1H), 7.34 (ddd, 1H), 7.29-7.25 (m, 1H), 6.25 (ddd, 1H), 5.94-5.87 (m, 1H), 5.44 (ddd, 1H), 3.66-3.58 (m, 1H), 3.29 (s, 3H) 
               
               
                   
               
               
                 810 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.60-8.59 (m, 1H),  7.35-7.33 (m, 1H), 7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.51 (dtd, 1H), 3.76 (dd, 1H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H) 
               
               
                   
               
               
                 811 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.80 (d, 1H), 7.40-  7.38 (m, 1H), 7.36 (ddd, 1H), 7.28 (dt, 1H), 5.88 (dd, 1H), 5.66-5.60 (m, 1H), 3.52 (dd, 1H), 3.28 (s, 3H) 
               
               
                   
               
               
                 812 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.77 (d, 1H), 7.39-  7.37 (m, 1H), 7.35 (ddd, 1H), 7.27 (dt, 1H), 6.00 (dd, 1H), 5.83 (tdd, 1H), 3.97 (d, 1H), 3.29 (s, 3H) 
               
               
                   
               
               
                 813 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 7.28  (ddd, 1H), 7.20-7.18 (m, 1H), 7.09 (dt, 1H), 5.92 (dt, 1H), 5.53-5.46 (m, 1H), 5.19 (ddt, 1H), 2.66 (ddd, 1H) 
               
               
                   
               
               
                 814 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 298 (M + H) 
                   
               
               
                   
               
               
                 815 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 298 (M + H) 
                   
               
               
                   
               
               
                 816 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 280 (M + H) 
                   
               
               
                   
               
               
                 817 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 280 (M + H) 
                   
               
               
                   
               
               
                 818 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 302 (M + H) 
                   
               
               
                   
               
               
                 819 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 349 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.52-8.51 (m, 1H),  7.33 (ddd, 1H), 7.29 (ddd, 1H), 7.23 (dt, 1H), 5.71-5.66 (m, 1H), 3.64 (d, 1H), 3.26-3.17 (m, 1H), 3.22 (s, 3H), 2.99- 2.90 (ddd, 1H), 2.66-2.56 (m, 1H), 2.32- 2.22 (m, 1H) 
               
               
                   
               
               
                 820 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 367 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.60-8.59 (m, 1H),  7.35-7.33 (m, 1H), 7.31 (ddd, 1H), 7.24 (dt, 1H), 5.63 (ddd, 1H), 5.52 (dtd, 1H), 3.76 (dd, 1H), 3.47-3.35 (m, 1H), 3.31 (s, 3H), 3.29-3.15 (m, 1H) 
               
               
                   
               
               
                 821 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 310 (M + H) 
                   
               
               
                   
               
               
                 822 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 310 (M + H) 
                   
               
               
                   
               
               
                 823 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.29-8.27 (m, 1H),  7.34-7.32 (m, 1H), 7.26 (ddd, 1H), 7.22 (dt, 1H), 5.57-5.10 (m, 1H), 3.22 (dt, 1H), 2.96 (ddd, 1H), 2.56-2.45 (m, 1H), 2.33-2.25 (m, 1H), 2.22-2.18 (m, 1H) 
               
               
                   
               
               
                 824 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.36-8.34 (m, 1H),  7.35-7.32 (m, 1H), 7.28 (ddd, 1H), 7.23 (dt, 1H), 5.53-5.35 (m, 2H), 3.40 (ddd, 1H), 3.22 (ddd, 1H), 2.73-2.68 (m, 1H) 
               
               
                   
               
               
                 825 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 358 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.79 (dd, 1H), 8.71  (d, 1H), 8.41 (s, 1H), 7.67 (dd, 1H), 5.94 (dt, 1H), 5.53-5.46 (m, 1H), 5.21 (ddt, 1H), 2.73 (ddd, 1H) 
               
               
                   
               
               
                 826 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 298 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.68 (s, 1H), 7.55-  7.45 (m, 3H), 7.44-7.40 (m, 2H), 5.54- 5.46 (m, 1H), 5.31 (ddt, 1H), 3.46 (ddd, 1H), 3.24 (ddd, 1H), 2.61 (dd, 1H) 
               
               
                   
               
               
                 827 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 334 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.65 (s, 1H), 6.99-  6.91 (m, 3H), 5.54-5.47 (m, 1H), 5.33 (ddt, 1H), 3.44 (ddd, 1H), 3.23 (ddd, 1H), 2.63 (dd, 1H) 
               
               
                   
               
               
                 828 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 346 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.24 (s, 1H), 5.95  (ddd, 1H), 5.47-5.41 (m, 1H), 5.07 (ddt, 1H), 4.97-4.88 (m, 1H), 3.30-3.15 (m, 2H), 2.99-2.79 (m, 2H), 2.54-2.49 (m, 1H) 
               
               
                   
               
               
                 829 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 315 (M + H) 
                 (400 MHz, DMSO-d 6 ): δ 8.30 (s, 1H),  6.26 (tt, 1H), 6.15 (ddd, 1H), 4.55 (td, 2H), 3.46-3.32 (m, 1H), 3.13 (ddd, 1H) 
               
               
                   
               
               
                 830 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 324 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.14 (s, 1H), 6.10  (tt, 1H), 5.58-5.30 (m, 1H), 4.39-4.24 (m, 2H), 3.10 (dt, 1H), 2.87 (ddd, 1H), 2.37- 2.27 (m, 1H), 2.20-2.12 (m, 1H), 1.90- 1.86 (m, 1H), 1.47-1.39 (m, 2H), 1.27- 1.21 (m, 2H) 
               
               
                   
               
               
                 831 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351 (M + H) 
                   
               
               
                   
               
               
                 832 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 351 (M + H) 
                 (400 MHz, CDCl 3 ): δ 8.75 (d, 1H), 8.65-  8.62 (m, 1H), 6.17 (tt, 1H), 5.83 (dd, 1H), 4.83-4.64 (m, 2H) 
               
               
                   
               
               
                 833 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 340 (M + H) 
                 (400 MHz, CDCl 3 ): δ 7.43-7.41 (m, 1H),  7.33 (dt, 1H), 7.33-7.29 (m, 1H), 5.67- 5.62 (m, 1H), 3.36-3.26 (m, 1H), 3.05 (ddd, 1H), 2.63-2.53 (m, 1H), 2.40-2.30 (m, 2H) 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the invention provides a combination treatment comprising a HIF-2α inhibitor, which can be a compound as provided herein, and an immunotherapeutic agent also as provided herein. In some embodiments, the immunotherapeutic agent is nivolumab (BMS936558), pembrolizumab (MK-3475), pidilizumab (CT-011), AMP-224, AMP-514, BMS-936559, RG7446 (MPDL3280A), MDX-1106 (Medarex Inc.), MSB0010718C, MEDI4736, tremelimumab or ipilimumab. In some embodiments, the HIF-2α inhibitor is a compound of Formula I, I-A, I-B, I-C, I-D, I-E, I-F, I-G, I-H, I-I, I-J, I-K, Formula II, II-A, II-B or a compound in Table 1, and the immunotherapeutic agent is a PD-1 inhibitor or a CTLA-4 inhibitor. For example, the HIF-2a inhibitor is a compound of Formula I-C, wherein: X is CR 5 ; Y is CR 6 ; Z is —O—; R 1  is phenyl, optionally substituted with one or more substituents selected from the group consisting of fluoro and cyano; R 4  is sulfonyl; R 11  is hydroxy; R 12  is hydrogen; R 13  is fluoro; n=1 or 2; and R 5  and R 6  are hydrogen; and the immunotherapeutic agent is an agent that inhibits the PD-1 pathway and enhances an immune response to cancerous cells in a patient. In a further embodiment, the PD-1 inhibitor is an antibody or a small molecule. In another embodiment, the immunotherapeutic agent is an agent that inhibits the CTLA-4 pathway and enhances an immune response to cancerous cells in a patient. In some embodiments, the CTLA-4 inhibitor is an antibody or a small molecule. In another embodiment, the immunotherapeutic agent is an agent that inhibits a B7 protein and enhances an immune response to cancerous cells in patient. 
     In some other embodiments, the subject methods are useful for treating a disease condition associated with HIF-2, PD-1, CTLA-4 and/or a B7 protein. Any disease condition characterized by an abnormal activity or expression level of HIF-2α can be an intended disease condition. In some embodiments, the disease condition is a proliferative disorder, such as described herein, including but not limited to cancer. A role of HIF-2α in tumorigenesis and tumor progression has been implicated in many human cancers. Constitutively active HIF-2α may be the result of defective VHL or a low concentration of oxygen in a cancer cell. Rapidly growing tumors are normally hypoxic due to poor vascularization, a condition that activates HIF-2α in support of tumor cell survival and proliferation. Constitutive activation of HIF-2α is emerging as a common theme in diverse human cancers, consequently agents that target HIF-2α have therapeutic value. 
     In still other embodiments, any disease condition in which cells of the afflicted subject express PD-L1 can be an intended disease condition. The subject methods are particularly suitable for treating a subject having a disorder that can be treated by potentiating a T-cell mediated immune response. In some embodiments, the disorder is a proliferative disorder, such as described herein, including but not limited to cancer. 
     Where desired, the subject to be treated is tested prior to treatment using a diagnostic assay to determine the sensitivity of tumor cells to a HIF-2α inhibitor or an immunotherapeutic agent. Any method known in the art that can determine the sensitivity of the tumor cells of a subject to a HIF-2α inhibitor or an immunotherapeutic agent can be employed. In one embodiment, when the subject is identified as one whose tumor cells are predicted to have high sensitivity to a HIF-2α inhibitor as a single agent, but may also display enhanced sensitivity in the presence of a PD-1 inhibitor based on the results of a diagnostic assay, the subject is administered a therapeutically effective amount of a combination of a HIF-2α inhibitor and a PD-1 inhibitor. In another embodiment, when detection of PD-L1 expression in a tumor of the subject predicts for efficacy of a PD-1 inhibitor as a single agent, but may also display enhanced sensitivity in the presence of a HIF-2α inhibitor based on the results of a diagnostic assay, the subject is administered a therapeutically effective amount of a combination of a HIF-2α inhibitor and a PD-1 inhibitor. In another embodiment, when detection of CTLA-4 expression in a tumor of the subject predicts for efficacy of a CTLA-4 inhibitor as a single agent, but may also display enhanced sensitivity in the presence of a HIF-2α inhibitor based on the results of a diagnostic assay, the subject is administered a therapeutically effective amount of a combination of a HIF-2α inhibitor and a CTLA-4 inhibitor. In these methods, one or more additional anti-cancer agents or treatments can be co-administered simultaneously or sequentially with the HIF-2α inhibitor and the immunotherapeutic agent, as judged to be appropriate by the administering physician given the prediction of the likely responsiveness of the subject to the combination of HIF-2α inhibitor and immunotherapeutic agent, in combination with any additional circumstances pertaining to the individual subject. 
     The data presented in the Examples herein demonstrate that the anti-tumor effects of a combination of a HIF-2α inhibitor and a PD-1 inhibitor are superior to the anti-tumor effects of either inhibitor by itself. As such, the subject method is particularly useful for treating a proliferative disorder, such as a neoplastic condition. Non-limiting examples of such conditions include but are not limited to acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, adamantinoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancers, AIDS-related lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anal cancer, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, appendix cancer, astrocytoma, atypical teratoid rhabdoid tumor, basal cell carcinoma, basal-like carcinoma, B-cell leukemia, B-cell lymphoma, bellini duct carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, bone tumor, brain stem glioma, brain tumor, breast cancer, brenner tumor, bronchial tumor, bronchioloalveolar carcinoma, brown tumor, Burkitt&#39;s lymphoma, carcinoid tumor, carcinoma, carcinosarcoma, Castleman&#39;s disease, central nervous system embryonal tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cholangiocarcinoma, chondroma, chondrosarcoma, chordoma, choriocarcinoma, choroid plexus papilloma, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, clear cell renal cell carcinoma, clear-cell tumor, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, dermoid cyst, desmoplastic small round cell tumor, diffuse large B cell lymphoma, dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, endometrial cancer, endometrial uterine cancer, endometrioid tumor, enteropathy-associated T-cell lymphoma, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, esophageal cancer, esthesioneuroblastoma, Ewing&#39;s sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, extramammary Paget&#39;s disease, fallopian tube cancer, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, gallbladder cancer, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, germinoma, gestational choriocarcinoma, gestational trophoblastic tumor, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma, gonadoblastoma, granulosa cell tumor, hairy cell leukemia, head and neck cancer, heart cancer, hemangioblastoma, hemangiopericytoma, hemangiosarcoma, hematological malignancy, hepatocellular carcinoma, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, hypopharyngeal cancer, hypothalamic glioma, inflammatory breast cancer, intraocular melanoma, islet cell carcinoma, juvenile myelomonocytic leukemia, Kaposi&#39;s sarcoma, kidney cancer, klatskin tumor, krukenberg tumor, laryngeal cancer, lentigo maligna melanoma, leukemia, lip and oral cavity cancer, liposarcoma, lung cancer, luteoma, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoid leukemia, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, malignant glioma, malignant mesothelioma, malignant peripheral nerve sheath tumor, malignant rhabdoid tumor, malignant triton tumor, malt lymphoma, mantle cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, mediastinal tumor, medullary thyroid cancer, medulloblastoma, medulloepithelioma, melanoma, meningioma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, metastatic urothelial carcinoma, mixed mullerian tumor, monocytic leukemia, mouth cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic disease, myeloid leukemia, myeloid sarcoma, myeloproliferative disease, myxoma, nasal cavity cancer, nasopharyngeal cancer, neoplasm, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, nonmelanoma skin cancer, non-small cell lung cancer, ocular oncology, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancoast tumor, pancreatic cancer, papillary thyroid cancer, papillomatosis, paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, perivascular epithelioid cell tumor, pharyngeal cancer, pheochromocytoma, pineal parenchymal tumor of intermediate differentiation, pineoblastoma, pituicytoma, pituitary adenoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, polyembryoma, precursor T-lymphoblastic lymphoma, primitive neuroectodermal tumor, prostate cancer, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter&#39;s transformation, sacrococcygeal teratoma, salivary gland cancer, sarcoma, schwannomatosis, sebaceous gland carcinoma, secondary neoplasm, seminoma, serous tumor, Sertoli-Leydig cell tumor, sex cord-stromal tumor, sezary syndrome, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, small cell lung cancer, small cell lymphoma, small intestine cancer, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, stomach cancer, superficial spreading melanoma, supratentorial primitive neuroectodermal tumor, surface epithelial-stromal tumor, synovial sarcoma, T-cell acute lymphoblastic leukemia, T-cell large granular lymphocyte leukemia, T-cell leukemia, T-cell lymphoma, T-cell prolymphocytic leukemia, teratoma, terminal lymphatic cancer, testicular cancer, thecoma, throat cancer, thymic carcinoma, thymoma, thyroid cancer, transitional cell cancer of renal pelvis and ureter, transitional cell carcinoma, urachal cancer, urethral cancer, urogenital neoplasm, uterine sarcoma, uveal melanoma, vaginal cancer, verner morrison syndrome, verrucous carcinoma, visual pathway glioma, vulvar cancer, Waldenstrom&#39;s macroglobulinemia, Warthin&#39;s tumor, Wilms&#39; tumor or any combination thereof. 
     In some embodiments, the methods comprising administering a HIF-2α inhibitor and an immunotherapeutic agent described herein are applied to the treatment of cancers of the adrenal glands, blood, bone marrow, brain, breast, cervix, colon, head and neck, kidney, liver, lung, ovary, pancreas, plasma cells, rectum, retina, skin, spine, throat, or any combination thereof. 
     Certain embodiments contemplate a human subject such as a subject that has been diagnosed as having or being at risk for developing or acquiring a proliferative disorder condition. Certain other embodiments contemplate a non-human subject, for example a non-human primate such as a macaque, chimpanzee, gorilla, vervet, orangutan, baboon or other non-human primate, including such non-human subjects that can be known to the art as preclinical models. Certain other embodiments contemplate a non-human subject that is a mammal, for example, a mouse, rat, rabbit, pig, sheep, horse, bovine, goat, gerbil, hamster, guinea pig or other mammal. There are also contemplated other embodiments in which the subject or biological source can be a non-mammalian vertebrate, for example, another higher vertebrate, or an avian, amphibian or reptilian species, or another subject or biological source. In certain embodiments of the present invention, a transgenic animal is utilized. A transgenic animal is a non-human animal in which one or more of the cells of the animal includes a nucleic acid that is non-endogenous (i.e., heterologous) and is present as an extrachromosomal element in a portion of its cell or stably integrated into its germ line DNA (i.e., in the genomic sequence of most or all of its cells). 
     Therapeutic Efficacy: 
     In some embodiments, therapeutic efficacy is measured based on an effect of treating a proliferative disorder, such as cancer. In general, therapeutic efficacy of the methods and compositions of the invention, with regard to the treatment of a proliferative disorder (e.g. cancer, whether benign or malignant), may be measured by the degree to which the methods and compositions promote inhibition of tumor cell proliferation, the inhibition of tumor vascularization, the eradication of tumor cells, the reduction in the rate of growth of a tumor, and/or a reduction in the size of at least one tumor. Several parameters to be considered in the determination of therapeutic efficacy are discussed herein. The proper combination of parameters for a particular situation can be established by the clinician. The progress of the inventive method in treating cancer (e.g., reducing tumor size or eradicating cancerous cells) can be ascertained using any suitable method, such as those methods currently used in the clinic to track tumor size and cancer progress. The primary efficacy parameter used to evaluate the treatment of cancer by the inventive method and compositions preferably is a reduction in the size of a tumor. Tumor size can be figured using any suitable technique, such as measurement of dimensions, or estimation of tumor volume using available computer software, such as FreeFlight software developed at Wake Forest University that enables accurate estimation of tumor volume. Tumor size can be determined by tumor visualization using, for example, CT, ultrasound, SPECT, spiral CT, MRI, photographs, and the like. In embodiments where a tumor is surgically resected after completion of the therapeutic period, the presence of tumor tissue and tumor size can be determined by gross analysis of the tissue to be resected, and/or by pathological analysis of the resected tissue. 
     In some desirable embodiments, the growth of a tumor is stabilized (i.e., one or more tumors do not increase more than 1%, 5%, 10%, 15%, or 20% in size, and/or do not metastasize) as a result of the inventive method and compositions. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months. In some embodiments, a tumor is stabilized for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. Preferably, the inventive method reduces the size of a tumor at least about 5% (e.g., at least about 10%, 15%, 20%, or 25%). More preferably, tumor size is reduced at least about 30% (e.g., at least about 35%, 40%, 45%, 50%, 55%, 60%, or 65%). Even more preferably, tumor size is reduced at least about 70% (e.g., at least about 75%, 80%, 85%, 90%, or 95%). Most preferably, the tumor is completely eliminated, or reduced below a level of detection. In some embodiments, a subject remains tumor free (e.g. in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months following treatment. In some embodiments, a subject remains tumor free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years after treatment. 
     In some embodiments, the efficacy of the inventive method in reducing tumor size can be determined by measuring the percentage of necrotic (i.e., dead) tissue of a surgically resected tumor following completion of the therapeutic period. In some further embodiments, a treatment is therapeutically effective if the necrosis percentage of the resected tissue is greater than about 20% (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), more preferably about 90% or greater (e.g., about 90%, 95%, or 100%). Most preferably, the necrosis percentage of the resected tissue is 100%, that is, no tumor tissue is present or detectable. 
     The efficacy of the inventive method can be determined by a number of secondary parameters. Examples of secondary parameters include, but are not limited to, detection of new tumors, detection of tumor antigens or markers (e.g., CEA, PSA, or CA-125), biopsy, surgical downstaging (i.e., conversion of the surgical stage of a tumor from unresectable to resectable), PET scans, survival, disease progression-free survival, time to disease progression, quality of life assessments such as the Clinical Benefit Response Assessment, and the like, all of which can point to the overall progression (or regression) of cancer in a human. Biopsy is particularly useful in detecting the eradication of cancerous cells within a tissue. Radioimmunodetection (RAID) is used to locate and stage tumors using serum levels of markers (antigens) produced by and/or associated with tumors (“tumor markers” or “tumor-associated antigens”), and can be useful as a pre-treatment diagnostic predicate, a post-treatment diagnostic indicator of recurrence, and a post-treatment indicator of therapeutic efficacy. Examples of tumor markers or tumor-associated antigens that can be evaluated as indicators of therapeutic efficacy include, but are not limited to, carcinembryonic antigen (CEA), prostate-specific antigen (PSA), CA-125, CA19-9, ganglioside molecules (e.g., GM2, GD2, and GD3), MART-1, heat shock proteins (e.g., gp96), sialyl Tn (STn), tyrosinase, MUC-1, HER-2/neu, c-erb-B2, KSA, PSMA, p53, RAS, EGF-R, VEGF, MAGE, and gp100. Other tumor-associated antigens are known in the art. RAID technology in combination with endoscopic detection systems also can efficiently distinguish small tumors from surrounding tissue (see, for example, U.S. Pat. No. 4,932,412). 
     In additional desirable embodiments, the treatment of cancer in a human patient in accordance with the inventive method is evidenced by one or more of the following results: (a) the complete disappearance of a tumor (i.e., a complete response), (b) about a 25% to about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before treatment, (c) at least about a 50% reduction in the size of a tumor for at least four weeks after completion of the therapeutic period as compared to the size of the tumor before the therapeutic period, and (d) at least a 2% decrease (e.g., about a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% decrease) in a specific tumor-associated antigen level at about 4-12 weeks after completion of the therapeutic period as compared to the tumor-associated antigen level before the therapeutic period. While at least a 2% decrease in a tumor-associated antigen level is preferred, any decrease in the tumor-associated antigen level is evidence of treatment of a cancer in a patient by the inventive method. For example, with respect to unresectable, locally advanced pancreatic cancer, treatment can be evidenced by at least a 10% decrease in the CA19-9 tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CA19-9 level before the therapeutic period. Similarly, with respect to locally advanced rectal cancer, treatment can be evidenced by at least a 10% decrease in the CEA tumor-associated antigen level at 4-12 weeks after completion of the therapeutic period as compared to the CEA level before the therapeutic period. 
     With respect to quality of life assessments, such as the Clinical Benefit Response Criteria, the therapeutic benefit of the treatment in accordance with the invention can be evidenced in terms of pain intensity, analgesic consumption, and/or the Kamofsky Performance Scale score. The treatment of cancer in a human patient alternatively, or in addition, is evidenced by (a) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in pain intensity reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment, as compared to the pain intensity reported by the patient before treatment, (b) at least a 50% decrease (e.g., at least a 60%, 70%, 80%, 90%, or 100% decrease) in analgesic consumption reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of treatment as compared to the analgesic consumption reported by the patient before treatment, and/or (c) at least a 20 point increase (e.g., at least a 30 point, 50 point, 70 point, or 90 point increase) in the Kamofsky Performance Scale score reported by a patient, such as for any consecutive four week period in the 12 weeks after completion of the therapeutic period as compared to the Kamofsky Performance Scale score reported by the patient before the therapeutic period. 
     In some cases, conventional response criteria may not adequately assess the activity of immunotherapeutic agents (i.e., a PD-1 inhibitor) because progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic failure. Accordingly, to properly evaluate immunotherapeutic agents, long-term effects on the target disease may also be captured. In this regard, systemic immune-related response criteria (irRC) that make allowances for an early increase in tumor burden and/or the appearance of new lesions, and which seek to enhance the characterization of immune-related response patterns, have been proposed (see e.g. Wolchok et al., 2009). 
     The treatment of a proliferative disorder (e.g. cancer, whether benign or malignant) in a human patient desirably is evidenced by one or more (in any combination) of the foregoing results, although alternative or additional results of the referenced tests and/or other tests can evidence treatment efficacy. 
     In some embodiments, tumor size is reduced as a result of the inventive method preferably without significant adverse events in the subject. Adverse events are categorized or “graded” by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI), with Grade 0 representing minimal adverse side effects and Grade 4 representing the most severe adverse events. Desirably, the inventive method is associated with minimal adverse events, e.g. Grade 0, Grade 1, or Grade 2 adverse events, as graded by the CTEP/NCI. However, as discussed herein, reduction of tumor size, although preferred, is not required in that the actual size of tumor may not shrink despite the eradication of tumor cells. Eradication of cancerous cells is sufficient to realize a therapeutic effect. Likewise, any reduction in tumor size is sufficient to realize a therapeutic effect. 
     Detection, monitoring and rating of various cancers in a human are further described in Cancer Facts and Figures 2001, American Cancer Society, New York, N.Y., and International Patent Application WO 01/24684. Accordingly, a clinician can use standard tests to determine the efficacy of the various embodiments of the inventive method in treating cancer. However, in addition to tumor size and spread, the clinician also may consider quality of life and survival of the patient in evaluating efficacy of treatment. 
     In some embodiments, administration of a HIF-2α inhibitor and an immunotherapeutic agent provides improved therapeutic efficacy over treatment with either agent alone. Improved efficacy may be measured using any method known in the art, including but not limited to those described herein. In some embodiments, the improved therapeutic efficacy is an improvement of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 95%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 1000% or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival). Improved efficacy may also be expressed as fold improvement, such as at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 1000-fold, 10000-fold or more, using an appropriate measure (e.g. tumor size reduction, duration of tumor size stability, duration of time free from metastatic events, duration of disease-free survival). 
     In some other embodiments, the subject method further comprises measuring a tumor size or an amount of one or more markers for the presence of the proliferative disorder before and after administering the HIF-2α inhibitor and the immunotherapeutic agent, and adjusting dosage or discontinuing use of the HIF-2α inhibitor and/or the immunotherapeutic agent based on results of said measuring. 
     Pharmaceutical Compositions: 
     The invention provides, in one aspect, a combination treatment comprising administering to a subject a HIF-2α inhibitor and an immunotherapeutic agent. The HIF-2α inhibitor can be any HIF-2α inhibitor described herein, either alone or in combination with one or more other such HIF-2α inhibitors. The immunotherapeutic agent can be any immunotherapeutic agent described herein, either alone or in combination with one or more other immunotherapeutic agents. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered sequentially. In some further embodiments, the immunotherapeutic agent is administered after administration of the HIF-2α inhibitor. In still further embodiments, the HIF-2α inhibitor is administered after administration of the immunotherapeutic agent. In the sequential administration protocol, a HIF-2α inhibitor and an immunotherapeutic agent may be administered a few hours apart, a few days apart, a few weeks apart, or a few months apart. In some other embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are administered simultaneously. In a further embodiment, the HIF-2α inhibitor and the immunotherapeutic agent form part of the same composition. In still a further embodiment, the HIF-2α inhibitor and the immunotherapeutic agent are provided in one or more unit doses. In some embodiments, a composition comprising both a HIF-2α inhibitor and an immunotherapeutic agent releases the majority of the immunotherapeutic agent (e.g. at least 60%, 70%, 80%, 85%, 90%, 95%, 99%, or more) as an active compound after the release of the majority of the HIF-2α inhibitor (e.g. at least 60%, 70%, 80%, 85%, 90%, 95%, 99%, or more) as an active compound. In some embodiments, a composition comprising both a HIF-2α inhibitor and an immunotherapeutic agent releases the majority of the HIF-2a inhibitor (e.g. at least 60%, 70%, 80%, 85%, 90%, 95%, 99%, or more) as an active compound after the release of the majority of the immunotherapeutic agent (e.g. at least 60%, 70%, 80%, 85%, 90%, 95%, 99%, or more) as an active compound. 
     In some embodiments, a HIF-2α inhibitor and/or an immunotherapeutic agent is administered to a subject more than once. In some embodiments, a HIF-2α inhibitor is administered one or more times (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or more) every 1, 2, 3, 4, 5, 6, 7, or more days (e.g. daily, every other day, every 7 days), where one or more of the administrations of the HIF-2α inhibitor is accompanied by or followed by one or more administrations (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or more) of an immunotherapeutic agent with any desired temporal spacing. In some embodiments, a HIF-2α inhibitor is administered one or more times (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or more) every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more weeks (e.g. administration on 1, 2, 3, 4, 5, 6, and/or 7 days of a week, which may or may not be consecutive days), where one or more of the administrations of the HIF-2α inhibitor is accompanied by or followed by one or more administrations (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or more) of an immunotherapeutic agent with any desired temporal spacing. In some embodiments, a given dosing schedule comprising one or more administrations of a HIF-2α inhibitor and one or more administrations of an immunotherapeutic agent may be repeated on a daily, weekly, biweekly, monthly, bimonthly, annually, semi-annually, or any other period as may be determined by a medical professional. A repeated dosing schedule may be repeated for a fixed period of time determined at the start of the schedule; may be terminated, extended, or otherwise adjusted based on a measure of therapeutic effect, such as a level of reduction in the presence of detectable disease tissue (e.g. a reduction of at least 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%); or may be terminated, extended, or otherwise adjusted for any other reason as determined by a medical professional. 
     A combination treatment may further comprise the administration of one or more additional therapeutic agents, including one or more additional agents described herein as candidate HIF-2α inhibitors, and one or more additional agents described herein as candidate immunotherapeutic agents. Such one or more additional agents can be administered simultaneously or separately with respect to the HIF-2α inhibitor, the immunotherapeutic agent, or both. Administration in combination utilizing one or more additional agents includes, for example, simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, multiple therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, multiple therapeutic agents can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, an inhibitor of the present invention can be administered after any of the agents described above, or vice versa. In the separate administration protocol, an inhibitor of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart, or a few weeks apart. The term “combination treatments” also embraces the administration of the therapeutic agents as described herein in further combination with other biologically active compounds or ingredients and non-drug therapies (e.g., surgery or radiation treatment). 
     Administration of the compounds of the present invention can proceed by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. An effective amount of an inhibitor of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Sequential or simultaneous administration of a HIF-2a inhibitor, an immunotherapeutic agent, and/or any additional therapeutic agent can be effected by any appropriate route as noted above and including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. 
     Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell or tissue being treated, and the subject being treated. Single or multiple administrations (e.g. about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more doses) can be carried out with the dose level and pattern being selected by the treating physician. 
     A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. A pharmaceutical composition of the present disclosure typically contains an active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt and/or coordination complex thereof), and one or more pharmaceutically acceptable excipients, carriers, including but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. A composition of the present disclosure may be formulated in any suitable pharmaceutical formulation. In some embodiments, the pharmaceutical acceptable carriers, excipients are selected from the group consisting of water, alcohol, glycerol, chitosan, alginate, chondroitin, Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO). 
     Pharmaceutical formulations may be provided in any suitable form, which may depend on the route of administration. In some embodiments, the pharmaceutical composition disclosed herein can be formulated in dosage form for administration to a subject. In some embodiments, the pharmaceutical composition is formulated for oral, intravenous, intraarterial, aerosol, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, intranasal, intrapulmonary, transmucosal, inhalation, and/or intraperitoneal administration. In some embodiments, the dosage form is formulated for oral intervention administration. For example, the pharmaceutical composition can be formulated in the form of a pill, a tablet, a capsule, an inhaler, a liquid suspension, a liquid emulsion, a gel, or a powder. In some embodiments, the pharmaceutical composition can be formulated as a unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form. 
     The amount of each compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage may be in the range of about 0.001 to about 100 mg per kg body weight per day, in single or divided doses. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day. 
     In some embodiments, the disclosure provides a pharmaceutical composition comprising an amount of a HIF-2α inhibitor formulated for administration to a subject in need thereof. In some embodiments, the pharmaceutical composition comprises between about 0.0001-500 g, 0.001-250 g, 0.1-50 g, or 1-10 g of a HIF-2α inhibitor. In some embodiments, the pharmaceutical composition comprises about or more than about 0.0001 g, 0.001 g, 0.01 g, 0.1, 0.5 g, 1 g, 2 g, 3 g, 4 g, 5 g, 6 g, 7 g, 8 g, 9 g, 10 g, 15 g, 20 g, 25 g, 50 g, 2.0 g, 100 g, 200 g, 250 g, 300 g, 350 g, 400 g, 450 g, 500 g or more of a HIF-2α inhibitor. In some embodiments, the pharmaceutical composition comprises between 0.001-2 g of a HIF-2α inhibitor in a single dose. In some embodiments, the pharmaceutical composition comprises an amount between about 50-150 g of a HIF-2α inhibitor. 
     In some embodiments, a therapeutically effective amount of HIF-2α inhibitor, typically a daily amount administered over the course of a period of treatment, can sufficiently provide any one or more of the therapeutic effects described herein. As an example, the therapeutic effect amount can be found in the range of about 0.001-1000 mg/kg body weight, 0.001-50 mg/kg body weight, 0.01-100 mg/kg body weight, 0.01-30 mg/kg body weight, 0.1-200 mg/kg body weight, 3-200 mg/kg body weight, 5-500 mg/kg body weight, 10-100 mg/kg body weight, 10-1000 mg/kg body weight, 50-200 mg/kg body weight, 100-1000 mg/kg body weight, 200-500 mg/kg body weight, 250-350 mg/kg body weight, or 300-600 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the therapeutic amount can be about or more than about 0.001 mg/kg body weight, 0.01 mg/kg body weight, 0.1 mg/kg body weight, 0.5 mg/kg body weight, 1 mg/kg body weight, 2 mg/kg body weight, 3 mg/kg body weight, 4 mg/kg body weight, 5 mg/kg body weight, 6 mg/kg body weight, 7 mg/kg body weight, 8 mg/kg body weight, 9 mg/kg body weight, 10 mg/kg body weight, 15 mg/kg body weight, 20 mg/kg body weight, 25 mg/kg body weight, 50 mg/kg body weight, 100 mg/kg body weight, 200 mg/kg body weight, 250 mg/kg body weight, 300 mg/kg body weight, 350 mg/kg body weight, 400 mg/kg body weight, 450 mg/kg body weight, 500 mg/kg body weight, 600 mg/kg body weight, 800 mg/kg body weight, 1000 mg/kg body weight, or more of a HIF-2a inhibitor. In some embodiments, the effective amount is at least about 0.01 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the effective amount is an amount between about 0.01-30 mg/kg body weight of a HIF-2α inhibitor. In some embodiments, the therapeutic amount can be an amount between about 50-150 mg/kg body weight of a HIF-2α inhibitor. 
     In some embodiments, dosage regimens are adjusted to provide the optimum desired response. For administration of an immunotherapeutic agent, the dosage ranges from about 0.0001 to about 100 mg/kg, usually from about 0.001 to about 20 mg/kg, and more usually from about 0.01 to about 10 mg/kg, of the subject&#39;s body weight. Preferably, the dosage of immunotherapeutic agent is within the range of 0.1-10 mg/kg body weight. For example, dosages can be about 0.1, 0.3, 1, 3, 5 or 10 mg/kg body weight, and more preferably about 0.3, 1, 3 or 10 mg/kg body weight. 
     In some embodiments, a HIF-2α inhibitor, an immunotherapeutic agent and/or any additional therapeutic compound of the invention is provided in one or more unit doses. For example, the composition can be administered in 1, 2, 3, 4, 5, 6, 7, 14, 30, 60, or more doses. Such amount can be administered each day, for example in individual doses administered once, twice, or three or more times a day. However, dosages stated herein on a per day basis should not be construed to require administration of the daily dose each and every day. For example, if one of the agents is provided in a suitably slow-release form, two or more daily dosage amounts can be administered at a lower frequency, e.g., as a depot every second day to once a month or even longer. Most typically and conveniently for the subject, a HIF-2α inhibitor, an immunotherapeutic agent and/or any additional therapeutic compound can be administered once a day, for example in the morning, in the evening or during the day. 
     The unit doses can be administered simultaneously or sequentially. The composition can be administered for an extended treatment period. Illustratively, the treatment period can be at least about one month, for example at least about 3 months, at least about 6 months or at least about 1 year. In some cases, administration can continue for substantially the remainder of the life of the subject. 
     When a combination treatment of the invention is administered as a composition that comprises one or more compounds, and one compound has a shorter half-life than another compound, the unit dose forms may be adjusted accordingly. 
     In some embodiments, combination treatments of the invention are tested to estimate pharmacokinetic properties and expected side effect profile. Various assays are known in the art for this purpose. For example, oral availability can be estimated during early stages of drug development by performing a Caco-2 permeability assay. Further, oral pharmacokinetics in humans can be approximated by extrapolating from the results of assays in mice, rats or monkey. In some embodiments, compounds of the invention show good oral availability across multiple species of organisms. 
     In some embodiments, a HIF-2α inhibitor and an immunotherapeutic agent can be administered as part of a therapeutic regimen that comprises administering one or more other agents (e.g. 1, 2, 3, 4, 5, or more other agents), either simultaneously or sequentially with the HIF-2α inhibitor and the immunotherapeutic agent. When administered sequentially, the HIF-2a inhibitor and/or the immunotherapeutic agent may be administered before or after the one or more other agents. When administered simultaneously, the HIF-2α inhibitor, the immunotherapeutic agent and the one or more other agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a HIF-2α inhibitor, an immunotherapeutic agent and one or more other agents). 
     In some embodiments, the concentration of one or more of the compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v. 
     In some embodiments, the concentration of one or more of the compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v. 
     In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, or approximately 1% to approximately 10% w/w, w/v or v/v. 
     In some embodiments, the concentration of one or more of the compounds of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, or approximately 0.1% to approximately 0.9% w/w, w/v or v/v. 
     In some embodiments, the amount of one or more of the compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. 
     In some embodiments, the amount of one or more of the compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g. 
     In some embodiments, the amount of one or more of the compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. 
     The combination treatments according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. 
     Pharmaceutical Composition for Oral Administration 
     In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing at least one compound of the present disclosure and a pharmaceutical excipient suitable for oral administration. The composition may be in the form of a solid, liquid, gel, semi-liquid, or semi-solid. In some embodiments, the composition further comprises a second agent. 
     In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) a HIF-2α inhibitor; (ii) a second compound which is an immunotherapeutic agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, each compound or agent is present in a therapeutically effective amount. In other embodiments, one or more compounds or agents is present in a sub-therapeutic amount, and the compounds or agents act synergistically to provide a therapeutically effective pharmaceutical composition. 
     In some embodiments, the invention provides for a pharmaceutical composition comprising a combination of a HIF-2α inhibitor and an immunotherapeutic agent. In some embodiments, the HIF-2α inhibitor and the immunotherapeutic agent are packaged as a single oral dosage form. In other embodiments, the HIF-2α inhibitor and the immunotherapeutic agent can be packaged as separate dosage forms, such as separate tablets. 
     Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as hard or soft capsules, cachets, troches, lozenges, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion, or dispersible powders or granules, or syrups or elixirs. Such dosage forms can be prepared by any of the methods of pharmacy, which typically include the step of bringing the active ingredient(s) into association with the carrier. In general, the composition are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient(s) in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. 
     This disclosure further encompasses anhydrous pharmaceutical composition and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs. 
     An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the composition for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. 
     Binders suitable for use in pharmaceutical composition and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof. 
     Examples of suitable fillers for use in the pharmaceutical composition and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. 
     Disintegrants may be used in the composition of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may alter the rate and extent of release of the active ingredient(s) from the dosage form. A sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof. 
     Lubricants which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition. 
     When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof. 
     The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. 
     Surfactant which can be used to form pharmaceutical composition and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. 
     A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. 
     Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. 
     Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof. 
     Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof. 
     Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide. 
     Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. 
     Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides. 
     In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for composition for non-oral use, e.g., composition for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion. 
     Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. 
     Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. 
     The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. If present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight. 
     The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. 
     In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. 
     Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. 
     Pharmaceutical Composition for Topical (e.g., Transdermal) Delivery. 
     In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing at least one compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery. For example a pharmaceutical composition for topical delivery is provided comprising at least one HIF-2α inhibitor and/or an immunotherapeutic agent. The HIF-2α inhibitor and the immunotherapeutic agent may be formulated separately, and may further include a third therapeutic agent. 
     Composition of the present disclosure can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area. 
     The pharmaceutical composition also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. 
     Formulations for topical administration may include ointments, lotions, creams, gels (e.g., poloxamer gel), drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The disclosed compositions can be administered, for example, in a microfiber, polymer (e.g., collagen), nanosphere, aerosol, lotion, cream, fabric, plastic, tissue engineered scaffold, matrix material, tablet, implanted container, powder, oil, resin, wound dressing, bead, microbead, slow release bead, capsule, injectables, intravenous drips, pump device, silicone implants, or any bio-engineered materials. 
     Another exemplary formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present disclosure in controlled amounts, either with or without another agent. 
     The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. 
     Pharmaceutical Composition for Injection. 
     In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound of the present disclosure and a pharmaceutical excipient suitable for injection. For example a pharmaceutical composition for injection is provided comprising a HIF-2α inhibitor and/or an immunotherapeutic agent. The HIF-2α inhibitor and the immunotherapeutic agent may be formulated separately, and may further include a third therapeutic agent. Components and amounts of agents in the composition are as described herein. 
     The forms in which the novel composition of the present disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. 
     Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. 
     Sterile injectable solutions are prepared by incorporating the compound of the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. 
     Pharmaceutical Composition for Inhalation. 
     Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described vide supra. Preferably, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. For example a pharmaceutical composition for delivery by inhalation is provided comprising at least one HIF-2α inhibitor and/or an immunotherapeutic agent. Compositions comprising a HIF-2α inhibitor and an immunotherapeutic agent may be formulated separately and may further include a third therapeutic agent. 
     Other Pharmaceutical Composition. 
     Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds.,  Principles of Drug Action , Third Edition, Churchill Livingston, N.Y., 1990; Katzung, ed.,  Basic and Clinical Pharmacology , Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds.,  The Pharmacological Basis of Therapeutics , Tenth Edition, McGraw Hill, 2001 ; Remingtons Pharmaceutical Sciences,  20th Ed., Lippincott Williams &amp; Wilkins., 2000; Martindale,  The Extra Pharmacopoeia , Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety. 
     The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., “Methods in Cell Biology”, Volume XIV, ISBN: 978-0-12-564114-2, Academic Press, New York, N.W., p. 33 (1976) and Medina, Zhu, and Kairemo, “Targeted liposomal drug delivery in cancer”,  Current Pharm. Des.  10: 2981-2989, 2004. For additional information regarding drug formulation and administration, see “Remington: The Science and Practice of Pharmacy,” Lippincott Williams &amp; Wilkins, Philadelphia, ISBN-10: 0781746736, 21st Edition (2005). 
     The invention also provides kits. The kits include one or more HIF-2α inhibitor, one or more immunothereaputic agent, and/or other compounds of the present invention as described herein, in suitable packaging with written material that can include instructions for use, discussion of clinical studies, listing of side effects, and the like. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer. 
     In some embodiments, the subject is a human in need of treatment for cancer, or a precancerous condition or lesion, wherein the cancer is preferably renal cell carcinoma. Subjects that can be treated with combination treatments of the present invention, or pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivatives of the therapeutic agents, according to the methods of this invention include, for example, subjects that have been diagnosed as having prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to the bone; kidney cancer; psoriasis; restenosis; atherosclerosis; BPH; breast cancer such as a ductal carcinoma in duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervix epithelial including squamous cell carcinoma and adenocarcinomas; pancreatic cancer such as epitheliod carcinoma in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct; bladder cancer such as a transitional cell carcinoma in urinary bladder, urothelial carcinomas (transitional cell carcinomas), tumors in the urothelial cells that line the bladder, squamous cell carcinomas, adenocarcinomas, and small cell cancers; leukemia such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disorders, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; skin cancer such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; eye retinoblastoma; cutaneous or intraocular (eye) melanoma; primary liver cancer (cancer that begins in the liver); thyroid cancer such as papillary, follicular, medullary and anaplastic; AIDS-related lymphoma such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi&#39;s Sarcoma; viral-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer; central nervous system cancers (CNS) such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancers such as acoustic neuromas and malignant peripheral nerve sheath tumor (MPNST) including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Müllerian tumor; oral cavity and oropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such as lymphomas, gastric stromal tumors, and carcinoid tumors; testicular cancer such as germ cell tumors (GCTs), which include seminomas and nonseminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors; thymus cancer such as to thymomas, thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; colon cancer; and lung cancer such as non-small cell lung cancer (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, and large cell undifferentiated carcinomas, and small cell lung cancer; 
     This invention further relates to a method for using the compounds or pharmaceutical composition in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, or implants, e.g., with corticosteroids, hormones, or used as radiosensitizers. 
     One such approach may be, for example, radiation therapy in inhibiting abnormal cell growth or treating the proliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein. 
     Radiation therapy can be administered through one of several methods, or a combination of methods, including without limitation external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. The term “brachytherapy,” as used herein, refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. The term is intended without limitation to include exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres. 
     Without being limited by any theory, the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a HIF-2α inhibitor followed by administering an amount of an immunotherapeutic agent of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, which in combined amounts are effective in sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. 
     Further therapeutic agents that can be combined with a subject compound may be found in Goodman and Gilman&#39;s “The Pharmacological Basis of Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or the Physician&#39;s Desk Reference, both of which are incorporated herein by reference in their entirety. 
     In some embodiments, the compositions and methods further comprise administering, separately or simultaneously one or more additional agents (e.g. 1, 2, 3, 4, 5, or more). Additional agents can include those useful in wound healing. Non-limiting examples of additional agents include antibiotics (e.g. Aminoglycosides, Cephalosporins, Chloramphenicol, Clindamycin, Erythromycins, Fluoroquinolones, Macrolides, Azolides, Metronidazole, Penicillin&#39;s, Tetracycline&#39;s, Trimethoprim-sulfamethoxazole, Vancomycin), steroids (e.g. Andranes (e.g. Testosterone), Cholestanes (e.g. Cholesterol), Cholic acids (e.g. Cholic acid), Corticosteroids (e.g. Dexamethasone), Estraenes (e.g. Estradiol), Pregnanes (e.g. Progesterone), narcotic and non-narcotic analgesics (e.g. Morphine, Codeine, Heroin, Hydromorphone, Levorphanol, Meperidine, Methadone, Oxydone, Propoxyphene, Fentanyl, Methadone, Naloxone, Buprenorphine, Butorphanol, Nalbuphine, Pentazocine), chemotherapy (e.g. anti-cancer drugs such as but not limited to Altretamine, Asparaginase, Bleomycin, Busulfan, Carboplatin, Carmustine, Chlorambucil, Cisplatin, Cladribine, Cyclophosphamide, Cytarabine, Dacarbazine, Diethylstilbesterol, Ethinyl estradiol, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Goserelin, Hydroxyurea, Idarubicin, Ifosfamide, Leuprolide, Levamisole, Lomustine, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Paclitaxel, pentastatin, Pipobroman, Plicamycin, Prednisone, Procarbazine, Streptozocin, Tamoxifen, Teniposide, Vinblastine, Vincristine), anti-inflammatory agents (e.g. Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Decanoate; Deflazacort; Delatestryl; Depo-Testosterone; Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Mesterolone; Methandrostenolone; Methenolone; Methenolone Acetate; Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Nandrolone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxandrolane; Oxaprozin; Oxyphenbutazone; Oxymetholone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Stanozolol; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Testosterone; Testosterone Blends; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium), or anti-histaminic agents (e.g. Ethanolamines (like diphenhydrmine carbinoxamine), Ethylenediamine (like tripelennamine pyrilamine), Alkylamine (like chlorpheniramine, dexchlorpheniramine, brompheniramine, triprolidine), other anti-histamines like astemizole, loratadine, fexofenadine, Bropheniramine, Clemastine, Acetaminophen, Pseudoephedrine, Triprolidine). 
     EXAMPLES 
     The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. The present examples, along with the methods described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. Changes therein and other uses which are encompassed within the spirit of the invention as defined by the scope of the claims will occur to those skilled in the art. 
     Example 1: Synthesis of 3-[(1S)-7-(difluoromethylsulfonyl)-2,2-difluoro-1-hydroxy-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 15) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile: A mixture of 3-fluoro-5-hydroxy-benzonitrile (1.33 g, 9.7 mmol), 7′-(difluoromethylsulfonyl)-4′-fluoro-spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.24 mmol), and cesium bicarbonate (1.26 g, 6.5 mmol) in 1-methyl-2-pyrrolidone (1.8 mL) was heated under N 2  at 110° C. (microwave) for 1 hour and 5 minutes. The reaction was repeated ten times. The reaction mixtures were combined, diluted with EtOAc, and washed twice with 1 N NaOH. The combined aqueous layer was extracted with EtOAc. The EtOAc extracts were combined and washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to about 100 mL to give a suspension. The suspension was filtered to give 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile as an off-white solid (6.25 g). The filtrate was diluted with EtOAc, washed with brine (3×), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with EtOAc/hexane (0% to 40%) to give additional 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile (3.3 g, 69% combined yield) as a white solid. LCMS ESI (+) m/z 426 (M+H). 
     Step B: Preparation of 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile: A mixture of 3-((7-((difluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile (10.9 g, 25.6 mmol) and PPTS (667 mg, 2.66 mmol) in acetone (100 mL)/water (15 mL) was heated at 82° C. for 5 hours and then 75° C. overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, diluted with EtOAc, washed with saturated aqueous NaHCO 3 , dried over MgSO 4 , filtered, and concentrated. The residue was filtered and washed with water. The solid obtained was briefly dried under vacuum at 50° C. and then triturated with EtOAc/hexane to give 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (8 g). Flash column chromatography of the mother liquor on silica gel with EtOAc/hexane (0% to 80%) provided additional 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.3 g, combined 9.3 g, quant. yield). LCMS ESI (+) m/z 382 (M+H). 
     Step C: Preparation of (E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile: A mixture of 3-((7-((difluoromethyl)sulfonyl)-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.42 g, 3.72 mmol), butylamine (6.0 mL) and 5 drops of trifluoroacetic acid (˜0.1 mL) in benzene (40 mL) was refluxed overnight with removal of water using a Dean-Stark trap. The reaction mixture was concentrated under reduced pressure, diluted with methyl tert-butyl ether, washed with saturated aqueous NaHCO 3  and brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was used in the next step without further purification. 
     Step D: Preparation of 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile: A mixture of (E,Z)-3-((1-(butylimino)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (1.29 g, 3 mmol, crude from step C), Selectfluor® (2.62 g, 7.4 mmol) and sodium sulfate (4 g, 28.2 mmol) under N 2  was heated at 82° C. for 4 hours. After cooling to room temperature, concentrated HCl (37%, 3 mL) was added. The mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. The residue was diluted with methyl t-butyl ether, washed with half saturated aqueous NaHCO 3  and then brine, dried over Na 2 SO 4 , filtered, and triturated with EtOAc/hexane to give 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile as an off-white solid (0.5 g). The mother liquor was purified by flash column chromatography with EtOAc/hexane (5% to 40%) to give additional 3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-oxo-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (0.13 g, 51% combined yield). LCMS ESI (+) m/z 418 (M+H) and 435 (M+NH 4 ). 
     Step E: Preparation of (S)-3-((7-((difluoromethyl)sulfonyl)-2,2-difluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 15): An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.6 mg) in dichloromethane (0.2 mL) was added by syringe under nitrogen to an ice cold solution of 3-[7-(difluoromethylsulfonyl)-2,2-difluoro-1-oxo-indan-4-yl]oxy-5-fluoro-benzonitrile (28 mg, 0.07 mmol), triethylamine (18.7 μL, 0.13 mmol) and formic acid (7.6 μL, 0.2 mmol) in dichloromethane (0.5 mL) and then placed in a refrigerator at 4° C. overnight. The reaction mixture was directly purified on preparative TLC with EtOAc/hexane (40%) to give Compound 15 (23.4 mg, 0.06 mmol, 83% yield). The ee was determined to be greater than 95% by  19 F NMR analysis of the corresponding Mosher ester. LCMS ESI (+) m/z 420 (M+H);  1 H NMR (400 MHz, CDCl 3 ): δ 7.94 (d, 1H), 7.33-6.98 (m, 4H), 6.44 (t, 1H), 5.51 (d, 1H), 3.61-3.45 (m, 2H). 
     Example 2: Synthesis of_(S)-3-((2,2-Difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 163) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane]: Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4′-fluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (100 mg, 0.37 mmol) and 3-bromo-5-fluoro-phenol (105 mg, 0.55 mmol) in 1-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150° C. for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (118 mg, 0.26 mmol, 72% yield). 
     Step B: Preparation of 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile: Dichloro[1;1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (784 mg, 0.97 mmol) was quickly added to a degassed mixture of 4′-(3-bromo-5-fluoro-phenoxy)-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (4.3 g, 9.7 mmol), zinc cyanide (1.14 g, 9.7 mmol) and zinc powder (761 mg, 11.6 mmol) in DMF (60 mL) under nitrogen. The reaction mixture was then warmed to 110° C. for 2 hours. After cooling, the mixture was filtered through a pad of celite. The filtrate was diluted with water (100 mL), extracted with MTBE (5×100 mL), washed with brine (100 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified on silica gel (100 g SNAP, 14 CV, 15-100% EtOAc/hexanes) then purified again on silica gel (25 g Ultra SNAP, 14 CV, 0-20% dichloromethane/EtOAc) affording 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile (3.77 g, 9.7 mmol, 100% yield). 
     Step C: Preparation of 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile: Pyridinium para-toluenesulfonate (354 mg, 1.4 mmol) was added all at once to a solution of 3-fluoro-5-(7′-methylsulfonylspiro[1,3-dioxolane-2,1′-indane]-4′-yl)oxy-benzonitrile (550 mg, 1.4 mmol) in acetone (6 mL)/water (2 mL) at room temperature and then warmed to reflux until completion. The mixture was concentrated in vacuo then purified on silica gel (10 g SNAP, 14 CV, 20-100% EtOAc/hexane) affording 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg, 1.3 mmol, 92% yield). 
     Step D: Preparation of 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile: Butan-1-amine (5.15 mL, 52 mmol) was added to 3-fluoro-5-(7-methylsulfonyl-1-oxo-indan-4-yl)oxy-benzonitrile (450 mg, 1.3 mmol) and trifluoroacetic acid (19.96 μL, 0.26 mmol) in benzene (10 mL) at room temperature then warmed to reflux with the azeotropic removal of water by a Dean-Stark apparatus. Progress of the reaction was monitored by  1 H-NMR. When complete, the reaction was cooled to room temperature then concentrated in vacuo. The residue was diluted with water (10 mL), extracted with MTBE (3×10 mL), washed with brine and dried over Na 2 SO 4 , filtered and concentrated. Crude 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile was used immediately without purification in the next step. 
     Step E: Preparation of 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile: Selectfluor® (1.15 g, 3.25 mmol) was added to crude 3-[(E,Z)-1-butylimino-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (520 mg, 1.3 mmol) and sodium sulfate (369 mg, 2.6 mmol) in acetonitrile (10 mL) then warmed to reflux for 6 hours. The reaction was cooled to room temperature, concentrated HCl (1.0 mL, 12 mmol) was added and stirred for 15 minutes. The mixture was diluted with water (10 mL), extracted with EtOAc (3×10 mL), washed with brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo. The residue was purified on silica gel (25 g SNAP, 14 CV, 20-100% EtOAc/hexane) afforded 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (437 mg, 1.2 mmol, 88% yield). 
     Step F: Preparation of (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile (Compound 163): An ice cold solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (40.7 mg, 0.06 mmol) in CH 2 Cl 2  (30 mL) was added by syringe under nitrogen to an ice cold solution of 3-(2,2-difluoro-7-methylsulfonyl-1-oxo-indan-4-yl)oxy-5-fluoro-benzonitrile (2.44 g, 6.4 mmol), triethylamine (1.78 mL, 12.8 mmol) and formic acid (724 μL, 19.2 mmol) in CH 2 Cl 2  (30 mL). The reaction was placed in a refrigerator at 4° C. for 16 hours. The mixture was concentrated to 10 mL then purified directly on silica gel (25 g SNAP ULTRA, 14 CV, 10-50% EtOAc/hexane) affording Compound 163 (2.15 g, 5.6 mmol, 87% yield). Enantiomeric excess (98%) was determined by chiral HPLC. Retention time for (S)-enantiomer: 1.93 minutes; retention time for (R)-enantiomer: 2.32 minutes. LCMS ESI (−) 428 (M+HCO 2   − ).  1 HNMR (400 MHz, CDCl 3 ): δ 7.93 (d, 1H), 7.27-7.24 (m, 1H), 7.15-7.14 (m, 1H), 7.07-7.03 (m, 1H), 7.00 (d, 1H), 5.63-5.58 (m, 1H), 3.56-3.35 (m, 3H), 3.24 (s, 3H). 
     Example 3: Synthesis of N-(3-Chlorophenyl-4,6-t2)-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine (Compound 183) 
     
       
         
         
             
             
         
       
     
     Step A: Synthesis of 3-chlorobenzen-4,6-t 2 -amine: 3-Chloro-4,6-diiodoaniline (100 mg) was dissolved in methanol (3 mL) and added with triethylamine (0.1 mL) and submitted for overnight tritiation using 50 Ci of tritium gas, at room temperature. Labile tritium was removed by dissolving the crude reaction mixture in methanol (3 mL) and bringing to dryness under vacuum. Labile removal was done in duplicate. The crude tritiated material was purified by preparative TLC (Silica gel, 1000μ) using hexane:ethyl acetate:AcOH (85:14:1). The product band was eluted with ethyl acetate to give 3-chlorobenzen-4,6-t 2 -amine (yield=600 mCi, radiochemical purity was &gt;98%). 
     Step B: Synthesis of Compound 183: A stirred mixture of 5-chloro-4-nitro-2,1,3-benzoxadiazole (20 mg, 0.1 mmol), 3-chlorobenzen-4,6-t 2 -amine (600 mCi) and Cs 2 CO 3  (65 mg, 0.20 mmol) in DMF (1 mL) was heated at 60° C. for 1 h. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by preparative HPLC on an ACE-5 C18 Semi-prep column, 250×10 mm, 100 Å. Elution was carried out isocratically using 0.1% TFA in water/Acetonitrile (35:65) to give Compound 183 (478 mCi, 80%). 
     Example 4: Synthesis of Isomer 1 of N—((S)-7-(3-Cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (Compound 240) 
     
       
         
         
             
             
         
       
     
     Step A: N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide: Sodium hydrogen carbonate (79.3 mg, 0.94 mmol) was added to a solution of 3-fluoro-5-hydroxy-benzonitrile (86.27 mg, 0.63 mmol) and N-((7-fluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (80 mg, 0.31 mmol) in DMF (3 mL). The vial was sealed and heated at 100° C. over a weekend. The reaction mixture was partitioned between EtOAc and dilute aqueous NaOH. The EtOAc was washed with water, two portions of brine, dried over MgSO 4 , filtered, and evaporated. The residue was chromatographed on a Biotage 25M reverse phase column with a 20% to 90% ACN:water gradient to afford N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (80 mg, 0.21 mmol, 69% yield). m/z (ES-API-pos) [M+H]=372. 
     Step B: N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide: Dess-Martin periodinane (192 mg, 0.45 mmol) was added to a solution of N-((7-(3-cyano-5-fluorophenoxy)-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (200 mg, 0.54 mmol) in dichloromethane (50 mL). After 10 minutes, the reaction mixture was evaporated and the residue was partitioned between EtOAc and aqueous sodium thiosulfate and saturated aqueous NaHCO 3 . The EtOAc layer was washed with water, brine, dried over MgSO 4 , filtered, and evaporated to afford N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (174 mg, 0.47 mmol, 88% yield) as a colorless film. m/z (ES-API-pos) [M+H]=370. 
     Step C: (E/Z)—N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide: Pivalic acid (9.4 mg, 0.09 mmol) was added to a mixture of N-((7-(3-cyano-5-fluorophenoxy)-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (170 mg, 0.46 mmol) and 3-methoxypropylamine (0.12 mL, 1.2 mmol) in cyclohexane (7 mL) and toluene (7 mL). The mixture was heated at reflux with a Hickman still attached. After 1 hour, the reaction mixture was evaporated and the residue was used as is in the next step. 
     Step D: N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide: 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (406 mg, 1.15 mmol) was added to a mixture of (E/Z)—N-((7-(3-cyano-5-fluorophenoxy)-3-((3-methoxypropyl)imino)-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (202 mg, 0.46 mmol) and sodium sulfate (162 mg, 1.15 mmol) in acetonitrile (5 mL). The mixture was heated at 70° C. After 3.5 hours, the reaction mixture was evaporated and the residue was partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgSO 4 , filtered, and evaporated. The residue was taken up in EtOAc, absorbed on silica gel, and chromatographed on a Biotage 25 g SNAP column with a 50% to 100% EtOAc:hexane gradient to afford N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (48 mg, 0.118 mmol, 26% yield. m/z (ES-API-pos) [M+H]=406. 
     Step E: N—(((S)-7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (Compound 240): RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.5 mg, 0.020 mmol) was added to a nitrogen-sparged, ice-cold solution of N-((7-(3-cyano-5-fluorophenoxy)-2,2-difluoro-3-oxo-2,3-dihydro-1H-inden-4-yl)(methyl)(oxo)-λ 6 -sulfanylidene)cyanamide (49 mg, 0.120 mmol), triethylamine (0.022 mL, 0.16 mmol), and formic acid (0.01 mL, 0.24 mmol) in dichloromethane (5 mL). The flask was placed in a 4° C. refrigerator over a weekend. The reaction mixture was evaporated and the residue was chromatographed on a Biotage 10 g SNAP Ultra column with a 20% to 80% EtOAc:hexane gradient to afford a solid, which was triturated twice with chloroform to afford Compound 240 (8.6 mg, 0.021 mmol, 18% yield) as a single diastereomer in 93% d.e. by chiral chromatography.  1 H NMR (400 MHz, CD 3 OD): δ 8.01 (d, 1H), 7.54-7.49 (m, 1H), 7.46-7.44 (m, 1H), 7.40-7.36 (m, 1H), 7.20-7.14 (m, 1H), 5.56 (d, 1H), 3.78-3.61 (m, 1H), 3.62 (s, 3H), 3.55-3.47 (m, 1H). m/z (ES-API-pos) [M+H]=408. 
     Example 5: Synthesis of 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile (Compound 289) 
     
       
         
         
             
             
         
       
     
     Step A: [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate: To a stirred solution of 3-fluoro-5-[(1S,2R)-2-fluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (2.00 g, 5.47 mmol) in DCM (27 mL) was added 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) and triethylamine (1.53 mL, 10.9 mmol). Acetic anhydride (1.00 mL, 10.9 mmol) was added dropwise at 0° C. under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO 3  and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate (1.95 g, 87%). LCMS ESI (+) m/z 408 (M+H). 
     Step B: [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate and [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate: To a stirred solution of [(1S,2R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate (1.95 g, 4.79 mmol) in 1,2-dichloroethane (24 mL) was added N-bromosuccinimide (0.94 g, 5.27 mmol) and 2,2′-azobisisobutyronitrile (8 mg, 0.05 mmol). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO 3  and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (20-30% EtOAc/hexane) to give [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate (1.52 g, 65%). LCMS ESI (+) m/z 486, 488 (M+H). Further elution with 30-50% EtOAc/hexane gave the more polar product [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate (0.583 g, 25%). LCMS ESI (+) m/z 486, 488 (M+H). 
     Step C: [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate: To a combined mixture of [(1S,2S,3S)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate and [(1S,2S,3R)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-1-yl] acetate prepared in Step B (2.05 g, 4.22 mmol) were added 1,2-dimethoxyethane (28 mL) and water (0.050 mL) followed by silver perchlorate hydrate (1.42 g, 6.32 mmol). The reaction mixture was heated at 70° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-50%) to give [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate (0.416 g, 23%) as the less polar product. LCMS ESI (+) m/z 441 (M+NH 4   + ). Further elution with 60% EtOAc/hexane gave [(1S,2R,3R)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate (0.58 g, 32%). LCMS ESI (+) m/z 441 (M+NH 4   + ). 
     Step D: [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl] acetate: To a stirred solution of [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate (416 mg, 0.98 mmol) in DCM (10 mL) was added (diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.0 mmol) at −78° C. under nitrogen. The reaction mixture was allowed to warm to 0° C. and stirred for 15 minutes. The reaction was quenched by saturated aqueous NaHCO 3 . The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl] acetate (310 mg, 74%). LCMS ESI (+) m/z 426 (M+H). 
     Step E: 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]ox-5-fluoro-benzonitrile (Compound 289): To a stirred solution of [(1S,2S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-1-yl] acetate (0.23 mmol) in tetrahydrofuran (1.5 mL) was added 0.5 N LiOH solution (0.68 mL, 0.34 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (30-70% EtOAc/hexane) to give Compound 289. LCMS ESI (+) m/z 384 (M+H);  1 H NMR (400 MHz, CDCl 3 ): δ 8.13 (d, 1H), 7.31-7.25 (m, 1H), 7.23-7.19 (m, 1H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09-5.91 (m, 1H), 5.87-5.80 (m, 1H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H). 
     Example 6: Synthesis of 3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (Compound 292) 
     
       
         
         
             
             
         
       
     
     Step A: [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate and [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate: To a stirred solution of [(1S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-7-methylsulfonyl-indan-1-yl] acetate (1.0 g, 2.35 mmol) in DCE (24 mL) were added N-bromosuccinimide (0.46 g, 2.59 mmol) and 2,2′-azobisisobutyronitrile (4 mg, 0.02 mmol). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO 3  and brine, dried and concentrated. The crude product was dissolved in 1,2-dimethoxyethane (11 mL) and water (0.11 mL). Silver perchlorate hydrate (0.35 g, 1.55 mmol) was added. The reaction mixture was heated at 70° C. overnight. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-60% EtOAc/hexane) to give [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate (39 mg, 9% yield) as the less polar product. LCMS ESI (+) m/z 459 (M+NH 4   + ). Further elution gave [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate (80 mg, 18%). LCMS ESI (+) m/z 459 (M+NH 4   + ). 
     Step B: [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl] acetate: Prepared as described in Example 5 Step D substituting [(1S,2R,3S)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl] acetate with [(1S,3S)-4-(3-cyano-5-fluoro-phenoxy)-2,2-difluoro-3-hydroxy-7-methylsulfonyl-indan-1-yl]acetate. LCMS ESI (+) m/z 444 (M+H). 
     Step C: 3-fluoro-5-[(1S,3R)-2,2,3-trifluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (Compound 292): Prepared as described in Example 5 Step E substituting [(1R)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan-1-yl]acetate with [(1S,3R)-4-(3-cyano-5-fluoro-phenoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-yl] acetate. LCMS ESI (+) m/z 419 (M+NH 4   + );  1 H NMR (400 MHz, CDCl 3 ): δ 8.14-8.11 (m, 1H), 7.33-7.29 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.12 (m, 1H), 7.05 (d, 1H), 5.91-5.75 (m, 1H), 5.71-5.65 (m, 1H), 3.39 (d, 1H), 3.25 (s, 3H). 
     Example 7: Synthesis of (R)-3-((4-(Difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (Compound 349) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene: A solution of 2-bromo-3,6-difluorobenzaldehyde (40.0 g, 181 mmol) dissolved in dichloromethane (800 mL) was cooled to 0° C., then treated with (diethylamino)sulfur trifluoride (70.0 g, 454 mmol). After the addition, the reaction mixture was warmed to ambient temperature and stirred at this temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added slowly until the pH was 8-9. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene (44.0 g, quant.) as solid which was used immediately in the next step without purification.  1 H NMR (400 MHz, CDCl 3 ): δ 7.28-7.22 (m, 1H), 7.17-7.10 (m, 1H), 7.04 (t, 1H). 
     Step B: Preparation of 2-(difluoromethyl)-3,6-difluorobenzonitrile: A suspension of 2-bromo-3-(difluoromethyl)-1,4-difluorobenzene (44.0 g, 181 mmol) and copper (I) cyanide (21.1 g, 235 mmol) in 1-methyl-2-pyrrolidinone (400 mL) was heated to 180° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate to give 2-(difluoromethyl)-3,6-difluorobenzonitrile as a solid (23 g, 67%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.48-7.35 (m, 2H), 6.98 (t, 1H). 
     Step C: Preparation of 2-(difluoromethyl)-3-fluoro-6-(methylthio)benzonitrile: A solution of 2-(difluoromethyl)-3,6-difluorobenzonitrile (31.3 g, 65.5 mmol) in acetonitrile (500 mL) was cooled to −30° C., then treated with sodium methanethiolate (12.8 g, 174 mmol). After addition of the solid, the reaction mixture was stirred for 7 hours while maintaining the temperature between −30° C. and −40° C. A mixture of water (200 mL) and methyl t-butyl ether (500 mL) were added and the reaction mixture was warmed to ambient temperature. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile as yellow solid (36.3 g, 150 mmol, 91%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.47-7.44 (m, 1H), 7.36-7.32 (m, 1H), 6.99 (t, 1H), 2.58 (s, 3H). 
     Step D: Preparation of 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile: A slurry of 2-(difluoromethyl)-3-fluoro-6-methylsulfanyl-benzonitrile (36.3 g, 167 mmol) in acetonitrile (350 mL) and water (175 mL) was treated with Oxone® (257 g, 418 mmol), then the mixture was heated at 56° C. for 4 hours. After cooling to ambient temperature, the remaining solids were removed by filtration and washed with dichloromethane (300 mL). The filtrate was concentrated in vacuo to remove volatile solvents. The resulting aqueous solution was extracted with dichloromethane (400 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was suspended in 4:1 hexane/methyl t-butyl ether (200 mL) and stirred for 10 minutes at ambient temperature. The undissolved solid was collected by filtration and air-dried to give 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile (29.9 g, 71%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.41-8.37 (m, 1H), 7.66-7.61 (m, 1H), 7.11 (t, 1H), 3.34 (s, 3H). 
     Step E: Preparation of 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile: A suspension of 2-(difluoromethyl)-3-fluoro-6-(methylsulfonyl)benzonitrile (9.52 g, 38.2 mmol), 3-fluoro-5-hydroxy-benzonitrile (5.23 g, 38.2 mmol), and cesium carbonate (7.77 g, 40.1 mmol) in N, N-dimethylformamide (76 mL) was heated to 45° C. for 3 hours. Additional cesium carbonate (0.46 g, 1.4 mmol) was added and the reaction mixture was heated at 45° C. for three hours, then stirred at ambient temperature for 54 hours. The reaction mixture was vigorously stirred while water (800 mL) was added. The resulting suspension was stirred for 30 minutes, then the solids were collected by filtration, washed with water (1.2 L), and dried under high vacuum to give 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile as a white solid (13.3 g, 96%). LCMS ESI (+) m/z 384 (M+NH 4 ).  1 H NMR (400 MHz, DMSO-d 6 ): δ 8.22 (d, 1H), 7.86-7.82 (m, 1H), 7.72-7.62 (m, 3H), 7.49 (t, 1H), 3.44 (s, 3H). 
     Step F: Preparation of 3-((4-(difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile: A solution of 3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)-6-(methylsulfonyl)benzonitrile (13.3 g, 36 mmol) was dissolved in tetrahydrofuran (380 mL) and treated with sodium hydride (60% in mineral oil, 2.26 g, 56 mmol) in two equal portions at five minute intervals. The resulting suspension was stirred at ambient temperature for 60 minutes. The reaction mixture was quenched by addition of a mixture of 4:1 methanol/10% aqueous HCl (200 mL) and the resulting suspension was stirred for 1 hour. The mixture was concentrated to remove volatile solvents, then the remaining slurry was diluted with additional water (800 mL) and stirred for an additional 30 minutes. The solids were recovered by filtration and washed with additional water and the resulting beige solid was dried under high vacuum in the presence of solid NaOH. 3-((4-(Difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile was obtained as a beige solid (13.3 g, quant.) and was used without further purification. LCMS ESI (−) m/z 366 (M−H).  1 H NMR (400 MHz, DMSO-d 6 ): δ 8.35 (d, 1H), 7.79 (d, 1H), 7.76 (t, 1H), 7.76-7.72 (m, 1H), 7.56-7.50 (m, 2H), 4.72 (s, 2H). 
     Step G: Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile: A solution of 3-((4-(difluoromethyl)-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (1.40 g, 3.82 mmol) dissolved in acetonitrile (38 mL) was treated at ambient temperature with sodium carbonate (890 mg, 8.4 mmol) followed by Selectfluor® (2.98 g, 8.4 mmol). The reaction mixture was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated in vacuo to remove volatile solvents, then the residue was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL portions). The combined organic layers were washed with saturated NaCl, dried over MgSO 4 , filtered and concentrated in vacuo to give 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile as a solid (1.48 g, quant.).  1 H NMR (400 MHz, DMSO-d 6 , sample exists as hydrate): δ 8.81 (s, 2H), 8.29 (d, 1H), 7.80-7.76 (m, 1H), 7.74 (t, 1H), 7.57-7.50 (m, 3H). 
     Step H: Preparation of 3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile: A solution of 3-((4-(difluoromethyl)-2,2-difluoro-1,1-dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile (1.48 g, 3.67 mmol) in methanol (37 mL) was cooled to 0° C., then treated with sodium borohydride (139 mg, 3.7 mmol) and stirred for 1 hour. The reaction was quenched by addition of water (0.5 mL) and saturated NH 4 Cl (0.25 mL). The reaction mixture was concentrated in vacuo to remove volatile solvents, then diluted with 0.5 M NaOH (10 mL). The aqueous was extracted three times with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried over MgSO 4 , filtered and concentrated in vacuo. The crude product was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexane to give 3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile as a white solid (1.24 g, 83%). 
     Step I: Preparation of (R)-3-((4-(difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile: 3-((4-(Difluoromethyl)-2,2-difluoro-3-hydroxy-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)oxy)-5-fluorobenzonitrile was resolved using preparative SFC chromatography under the following conditions: ChiralPak AS(-H) (2×15 cm) column, 20% ethanol with carbon dioxide at 100 bar, 60 mL/min flow rate, injection volume was 0.5 mL of a 20 mg/mL solution in ethanol, peak detection at 220 nm. Compound 349 was recovered as the first peak (1.50 minutes) to elute from the column. LCMS ESI (−) m/z 404 (M−H).  1 H NMR (400 MHz, CDCl 3 ): δ 7.98 (d, 1H), 7.33-7.30 (m, 1H), 7.23 (t, 1H), 7.22-7.18 (m, 2H), 7.10-7.06 (m, 1H), 5.69-5.65 (m, 1H), 3.23 (d, 1H). 
     Example 8: Synthesis of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0° C. was treated with tert-butyl hydroperoxide (˜70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58 mL, 18.86 mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO 3 . Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 30-90% CH 2 Cl 2 /hexane to afford 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off-white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280/282. 
     Step B: Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine: Trimethylsilyl trifluoromethanesulfonate (75.9 μL, 0.42 mmol) was added to a solution of 4-bromo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (389 mg, 1.39 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.37 mL, 5.56 mmol) in dichloromethane (13.6 mL) cooled in an ice bath. The mixture was allowed to slowly warm to ambient temperature. After 5 h, an additional 1.3 mL of trimethyl(2-trimethylsilyloxyethoxy)silane and 76 μL of trimethylsilyl trifluoromethanesulfonate were added. After another 16 h, the reaction mixture was treated with triethylamine (770 μL, 5.56 mmol), stirred for 10 min, and then concentrated. The residue was treated with 20 mL EtOAc and 20 mL of water and the layers separated. The aqueous portion was extracted further with 2×20 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered, and evaporated. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a shite solid (262 mg, 58%) and 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine as a white solid (170 mg, 31%). Data for 4-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 324/326. Data for 4-bromo-1-(trifluoromethyl)-7-(2-((trimethylsilyl)oxy)ethoxy)-5H-cyclopenta[c]pyridine:  1 H NMR (400 MHz, CDCl 3 ): δ 8.56 (s, 1H), 5.59 (t, 1H), 4.10 (t, 2H), 3.96 (t, 2H), 3.36 (d, 2H), 0.15 (s, 9H). 
     Step C: Preparation of 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: A solution of 2-[[4-bromo-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-7-yl]oxy]ethoxy-trimethyl-silane (146.6 mg, 0.37 mmol) and sodium sulfate (262.7 mg, 1.85 mmol) in acetonitrile (3.7 mL) was stirred for 10 min and then treated with Selectfluor® (145.2 mg, 0.41 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a white solid (96.2 mg, 76%). LCMS ESI (+) (M+H) m/z 342/344. 
     Step D: Preparation of 6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol and 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol: A solution of 4′-bromo-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine](96.2 mg, 0.2800 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.4 mg, 0.007 mmol) in 1,4-dioxane (5.0 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (47.3 mg, 0.84 mmol), water (101 μL. 5.62 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-t-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (6.0 mg, 0.007 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (64.3 μL, 1.13 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification (87 mg). During the reaction, some of the hydrodefluorinated product formed as an impurity. Data for 6-fluoro-1-(trifluoromethyl)-56-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol: LCMS ESI (+) (M+H) m/z 280. Data for 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-72′-[1.3]dioxolan]-4-ol: LCMS ESI (+) (M+H) m/z 262. 
     Step E: Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-56-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: A solution of impure 6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (44.0 mg, 0.16 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g, 306.2 mg, 0.63 mmol), and 3,3-difluoro-cyclobutanol (68.1 mg, 0.63 mmol) in tetrahydrofuran (3.2 mL) was treated with diisopropyl azodicarboxylate (120 μL, 0.61 mmol) and stirred at 60° C. for 2 h. The reaction mixture was filtered and the filter cake rinsed with 20 mL EtOAc. The filtrate was concentrated and purified by chromatography on silica using 10-30% EtOAc/hexane to afford a clear solid (39.0 mg, 67%) that was a 2:1 mixture of the fluorinated and hydrodefluorinated products. LCMS ESI (+) (M+H) m/z 370. Data for 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 370. Data for 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: LCMS ESI (+) (M+H) m/z 352. 
     Step F: Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one and 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: A solution of impure 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (39.0 mg, 0.106 mmol) in dichloromethane (2.0 mL) at 0 C was treated with perchloric acid (70% in water, 200 μL) and stirred at 0 C for 3 h. The reaction mixture was quenched by the addition of 5 mL of saturated aqueous NaHCO 3 . The resulting mixture was extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification as a 2:1 mixture of fluorinated and hydrodefluorinated ketones. LCMS ESI (+) (M+H) m/z 326. Data for 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: LCMS ESI (+) (M+H) m/z 326. Data for 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: LCMS ESI (+) (M+H) m/z 308. 
     Step G: Preparation of (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466): A solution of impure 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (33.8 mg, 0.10 mmol) in dichloromethane (4.0 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (11.8 μL, 0.31 mmol) and triethylamine (28.8 μL, 0.21 mmol) were sequentially added. Once sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.3 mg, 0.002 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and placed into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 4-18% EtOAc/CH 2 Cl 2  to afford (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465) as a clear solid (5.4 mg, 16%) and (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466) as a clear solid (7.4 mg, 23%). Data for (6R,7S)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 465): Retention time HPLC (14 min)=3.59 min; LCMS ESI (+) (M+H) m/z 328;  1 H NMR (400 MHz, CDCl 3 ): δ 8.04 (s, 1H), 5.46-5.26 (m, 2H), 4.89-4.79 (m, 1H), 3.36-3.08 (m, 4H), 2.91-2.74 (m, 2H), 2.60 (dd, 1H). Data for (R)-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 466): Retention time HPLC (14 min)=3.95 min; LCMS ESI (+) (M+H) m/z 310;  1 H NMR (400 MHz, CDCl 3 ): δ 7.98 (s, 1H), 5.59-5.54 (m, 1H), 4.88-4.79 (m, 1H), 3.24-3.07 (m, 3H), 2.89 (dd, 1H), 2.89-2.74 (m, 2H), 2.44-2.34 (m, 1H), 2.28-2.21 (m, 1H), 2.12-2.09 (m, 1H). 
     Example 9: Synthesis of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-ol: A solution of 4′-bromo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (226.4 mg, 0.70 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (8.5 mg, 0.017 mmol) in 1,4-dioxane (7.0 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (117.6 mg, 2.10 mmol), water (252 μL, 13.97 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (14.9 mg, 0.017 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (160 μL, 2.79 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The brown solid was used without further purification. LCMS ESI (−) (M−H) m/z 260. 
     Step B: Preparation of 3-fluoro-5-((1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A suspension of potassium tert-butoxide (28.4 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) at 0 C was treated with 1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (60.0 mg, 0.23 mmol) and stirred at 0 C for 15 min. The resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (144.8 mg, 0.28 mmol) and heated to 40 C. The reaction mixture was filtered through a plastic filter cup using EtOAc to rinse. Volatiles were removed by concentration under reduced pressure. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford a solid (42 mg, 48%). LCMS ESI (+) (M+H) m/z 381. 
     Step C: Preparation of 3-fluoro-5-((7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile: A solution of 3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (42.0 mg, 0.11 mmol) in dichloromethane (2.0 mL) at 0 C was treated with perchloric acid (70% in water, 240 μL) and stirred at 0 C for 30 min. The reaction mixture was carefully quenched by the addition of 15 mL of saturated NaHCO 3  and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The solid residue was used immediately in the next step without further purification. LCMS ESI (+) (M+H) m/z 337. 
     Step D: Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile: A solution of triethylamine (122 μL, 0.88 mmol) and 3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (37.0 mg, 0.11 mmol) in dichloromethane (2.2 mL) at 0° C. was treated with tert-butyldimethylsilyl triflate (152 ul, 0.66 mmol). The ice bath was removed and the reaction mixture left to stir for 2 h. The reaction mixture was poured into 30 mL of saturated NaHCO 3  and extracted with 3×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 451. 
     Step E: Preparation of 3-fluoro-5-((6-fluoro-7-oxo-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile: A solution of 3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile (49.56 mg, 0.110 mmol) in acetonitrile (2.2 mL) at 25° C. was treated with Selectfluor® (42.9 mg, 0.12 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford a thin film (37.8 mg, 97%). LCMS ESI (+) (M+H) m/z 355. 
     Step F: Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467): A solution of 3-fluoro-5-[[6-fluoro-7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (15.3 mg, 0.043 mmol) in dichloromethane (1.5 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (4.9 μL, 0.13 mmol) and triethylamine (12.0 μL, 0.086 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.5 mg, 0.00086 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and placed into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 10-30% EtOAc/hexane to afford 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 467) as a clear solid (11.8 mg, 77%). Retention time HPLC (14 min)=4.19 min; LCMS ESI (+) (M+H) m/z 357;  1 H NMR (400 MHz, CDCl 3 ): δ 8.33 (s, 1H), 7.22 (ddd, 1H), 7.10-7.08 (m, 1H), 6.99 (dt, 1H), 5.54-5.46 (m, 1H), 5.46-5.28 (m, 1H), 3.26 (ddd, 1H), 3.11 (ddd, 1H), 2.67 (dd, 1H). 
     Example 10: Synthesis of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 5-bromo-2-(methylthio)nicotinic acid: A solution of 5-bromo-2-fluoro-pyridine-3-carboxylic acid (3.50 g, 15.91 mmol) in DMF (62 mL) at 0° C. was treated with potassium carbonate (2.42 g, 17.5 mmol) and vigorously stirred at 0° C. for 7 minutes. During this time, nitrogen was sparged through the solution. Then sodium thiomethoxide (1.23 g, 16.7 mmol) was added in one portion to the reaction vessel under continuous nitrogen stream. The reaction vessel was sealed and the ice bath removed. The solution turned from a tan color to faint yellow. The reaction mixture was left to stir overnight. The reaction mixture was poured onto 10% citirc acid solution inducing precipitation of a white solid. The solid was filtered and rinsed exhausitvely with water. Finally, the white solid was dried overnight under high vacuum in the presence of solid NaOH and used without further purification (3.63 g, 92%). LCMS ESI (+) (M+H) m/z 248/250. 
     Step B: Preparation of 5-bromo-4-formal-2-(methylthio)nicotinic acid: A solution of 2,2,6,6-tetramethyl-piperidine (3.26 mL, 19.35 mmol) in tetrahydrofuran (40.3 mL) at −50 C was treated with n-butyllithium (˜2.5M in hexanes, 7.09 mL, 17.73 mmol) and stirred for 5 min. Then 5-bromo-2-methylsulfanyl-pyridine-3-carboxylic acid (2.00 g, 8.06 mmol) was added via cannula over 30 min as a solution in 60 mL of THF. The resulting mixture stirred for 30 min at −50 C. The reaction mixture was quenched by the addition of N,N-dimethylformamide (0.94 mL, 12.09 mmol). 15 minutes following addition of the DMF, the reaction mixture was quenched by the addition of 40 mL of 10% citiric acid solution (aqueous) and the reaction warmed to room temperature. After stirring for 30 min, excess THF removed by concentration under reduced pressure. The leftover mixture was poured into 120 mL of 3% citric acid (aqueous) and extracted with 3×50 mL EtOAc. The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. 2.41 g of an orange solid was isolated and used without further purification. The material was contaminated with about 22% citric acid based on proton integration of the unpurified NMR spectra. LCMS ESI (+) (M+H) m/z 276/278. 
     Step C: Preparation of methyl (E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate: A solution of 7-bromo-1-hydroxy-4-methylsulfanyl-1H-furo[3,4-c]pyridin-3-one (2.21 g, 8.00 mmol), lithium chloride (anhydrous, 339.1 mg, 8.00 mmol) and ethyl 2-diethoxyphosphorylacetate (1.60 mL, 8.00 mmol) in acetonitrile (80 mL) at 25 C was treated with 1;8-Diazabicyclo[5.4.0]undec-7-ene (2.87 mL, 19.20 mmol) and stirred at 25 C for 2 h. Initially, the solution is heterogenous with the pyridine being insoluble. Upon addition of the DBU the solution becomes homogeneous and darkens in color. After 1 h, the reaction appears to be mostly complete. In addition a precipitate has formed. Volatiles were removed by concentration under reduced pressure. The product residue was solubilized with 25 mL of DMF and treated with dimethyl sulfate (1.89 mL, 20.00 mmol). After 2 h, the reaction mixture was poured into 300 mL of water and extracted with 4×40 mL Et 2 O. The combined organics were rinsed with 20 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford methyl (E)-5-bromo-4-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-(methylthio)nicotinate as a white solid (1.90 g, 66%). LCMS ESI (+) (M+H) m/z 360/362. 
     Step D: Preparation of methyl 5-bromo-4-(3-ethoxy-3-oxopropyl)-2-(methylthio)nicotinate: A solution of methyl 5-bromo-4-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2-methylsulfanyl-pyridine-3-carboxylate (1.87 g, 5.19 mmol) and cobalt(ii) chloride hexahydrate (123.5 mg, 0.52 mmol) in methanol (20.8 mL) at 0° C. was sparged with nitrogen for 3 min and treated with sodium borohydride (98.2 mg, 2.60 mmol) under continuous nitrogen stream. The vessel was sealed and the contents stirred at 0° C. for 10 min. LCMS at this time indicated partial consumption of the olefin. An additional portion of sodium borohydride (98.2 mg, 2.60 mmol) was added to drive the reaction to completion. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH 4 Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-15% EtOAc/hexane to afford the desired product as a solid (1.08 g, 57%). LCMS ESI (+) (M+H) m/z 362/364. 
     Step E: Preparation of ethyl 4-bromo-1-(methylthio)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: A solution of methyl 5-bromo-4-(3-ethoxy-3-oxo-propyl)-2-methylsulfanyl-pyridine-3-carboxylate (1.08 g, 2.98 mmol) in tetrahydrofuran (29.8 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (˜1.0 M in THF, 7.16 mL, 7.16 mmol) by dropwise addition over 30 minutes. Once the addition was complete, LCMS indicated a small amount of starting material remained so an additional 1 mL of lithium bis(trimethylsilyl)amide was added and the reaction allowed to stir for a further 15 minutes. The reaction mixture was quenched by the addition of 30 mL of saturated aqueous NH 4 Cl. THF was removed by concentration under reduced pressure. The reaction mixture diluted with 60 mL of EtOAc and an additional 30 mL of water. A thick precipitate formed that can be eliminated by the addition of 10% citric acid solution. The reaction mixture was extracted with 3×30 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The intermediate product was transferred into a microwave tube using 9.1 mL of DMSO. The resulting mixture was diluted with 900 μL of water. The vessel was sealed and heated to 150 C by microwave irradiation for 40 min. The reaction mixture was diluted with 120 mL of water to induce precipitation of the product and vigorously stirred for 30 min. The precipitate was collected, dried overnight under high vacuum in the presence of solid NaOH, and used without further purification. Beige solid (705 mg, 92%). LCMS ESI (+) (M+H) m/z 258/260. 
     Step F: Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one: A solution of 4-bromo-1-methylsulfanyl-5,6-dihydrocyclopenta[c]pyridin-7-one (364.5 mg, 1.41 mmol) in methanol (11.3 mL) at 0° C. was treated with a solution of Oxone® (1.91 g, 3.11 mmol) in water (11.3 mL). The reaction was left to stir for 24 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 40 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The off white solid was used without further purification. LCMS ESI (+) (M+H) m/z 290/292. 
     Step G: Preparation of 4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: Trimethylsilyl trifluoromethanesulfonate (331 μL, 1.83 mmol) was added to a solution of 4-bromo-1-methylsulfonyl-5,6-dihydrocyclopenta[c]pyridin-7-one (354 mg, 1.22 mmol) and trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) in dichloromethane (14 mL) cooled in an ice bath. The ice bath was removed. After 3 h, an additional portion of trimethyl(2-trimethylsilyloxyethoxy)silane (1.20 mL, 4.88 mmol) was added. The reaction was left to stir overnight. After stirring, for the rest of the day, the reaction was quenched by the addition of triethylamine (1.02 mL, 7.32 mmol). The reaction mixture stirred for 10 min. Volatiles were removed and the residue suspended into 30 mL of saturated aqueous NaHCO 3  and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 15-50% EtOAc/hexane to afford 4-bromo-1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a white solid (74.5 mg, 18%). LCMS ESI (+) (M+H) m/z 334/336. The bulk of the product was isolated as the enol ether (295 mg, 59%). 
     Step H: Preparation of 1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1.3]dioxolan]-4-ol: A solution of 4′-bromo-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (74.5 mg, 0.22 mmol) and 2-(di-t-butylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (5.4 mg, 0.011 mmol) in 1,4-dioxane (1.5 mL) was sparged with nitrogen for 3 mins. The reaction mixture was then treated sequentially with potassium hydroxide (37.5 mg, 0.67 mmol), water (80.3 μL, 4.46 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (9.5 mg, 0.011 mmol) under continuous nitrogen stream. The vessel was sealed and heated to 80 C for 1 h and 30 min. The reaction mixture was quenched by the addition of acetic acid (51.0 μL, 0.89 mmol). The reaction mixture was poured into 75 mL of water and extracted with 4×20 mL EtOAc. The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification (77.9 mg). LCMS ESI (+) (M+H) m/z 272. 
     Step I: Preparation of 3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A suspension of potassium carbonate (30.6 mg, 0.22 mmol) in acetonitrile (1.5 mL) at 25 C was treated with 1′-methylsulfonylspiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (40.0 mg, 0.15 mmol) and stirred at 25 C for 10 min. The resulting mixture was treated with (3-cyano-5-fluoro-phenyl)-(4-methoxyphenyl)iodonium; 4-methylbenzenesulfonate (116.2 mg, 0.22 mmol) and heated to 50 C for 3 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 20-50% EtOAc/hexane to afford (3-fluoro-5-((1-(methylsulfonyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a solid (25.1 mg, 44%). LCMS ESI (+) (M+H) m/z 391. 
     Step J: Preparation of 3-fluoro-5-((1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile: A solution of 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-methylsulfonyl-spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (25.1 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0 C was treated with perchloric acid (70% in water, 330 μL) and stirred at 0 C for 2 h and then at room temperature for 30 min. The reaction mixture was carefully quenched with 5 mL of saturated NaHCO 3 /10 mL of water and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 347. 
     Step K: Preparation of 3-((7-((tert-butyldimethylsilyl)oxy)-1-(methylsulfonyl)-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile: A solution of triethylamine (71.4 μL, 0.51 mmol) and 3-fluoro-5-[[7-oxo-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-4-yl]oxy]benzonitrile (22.2 mg, 0.064 mmol) in dichloromethane (3.0 mL) at 0° C. was treated with tert-butyldimethylsilyl trifluoromethanesulfonate (58.2 μL, 0.38 mmol). The ice bath was removed and the reaction mixture stirred for 2 h. The reaction mixture was poured into 30 mL of saturated NaHCO 3  and extracted with 3×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 461. 
     Step L: Preparation of 3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile: A solution of 3-[[7-[tert-butyl(dimethyl)silyl]oxy-1-(trifluoromethyl)-5H-cyclopenta[c]pyridin-4-yl]oxy]-5-fluoro-benzonitrile (29.5 mg, 0.064 mmol) in acetonitrile (2.6 mL) at 25° C. was treated with Selectfluor® (24.9 mg, 0.070 mmol) and stirred at 25° C. for 1 h. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford 3-fluoro-5-((6-fluoro-1-(methylsulfonyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile as a thin film (11.1 mg, 48%). LCMS ESI (+) (M+H) m/z 365. 
     Step M: Preparation of 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468): A solution of 6-fluoro-4-[(5-fluoro-3-pyridyl)oxy]-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (11.1 mg, 0.031 mmol) in dichloromethane (2.0 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (3.4 μL, 0.091 mmol) and triethylamine (8.4 μL, 0.061 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.4 mg, 0.0006 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 20-60% EtOAc/hexane to afford 3-fluoro-5-(((6R,7S)-6-fluoro-7-hydroxy-1-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)benzonitrile (Compound 468) as a white solid (7.0 mg, 63%). Retention time HPLC (14 min)=3.16 min; LCMS ESI (+) (M+H) m/z 367;  1 H NMR (400 MHz, CDCl 3 ): δ 8.27 (s, 1H), 7.25 (ddd, 1H), 7.14 (m, 1H), 7.03 (dt, 1H), 5.69 (dt, 1H), 5.53-5.36 (m, 1H), 4.24 (d, 1H), 3.34 (s, 3H), 3.31-3.24 (m, 1H), 3.09 (ddd, 1H). 
     Example 11: Synthesis of 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469) and 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470) 
     
       
         
         
             
             
         
       
     
     Step A: 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine: A mixture of 4-bromo-2,5,6,7-tetrahydrocyclopenta[c]pyridin-1-one (420 mg, 1.96 mmol) and POCl 3  (2.20 mL, 23.6 mmol) was heated at reflux for 40 hours. After cooling, excess POCl 3  was removed under reduced pressure. The residue was taken up in EtOAc, washed with saturated aqueous NaHCO 3  and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (2-10% EtOAc/hexanes) to give 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (207 mg, 45%). LCMS ESI (+) m/z 232/234/236 (M+H) + . 
     Step B: 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469): A mixture of 4-bromo-1-chloro-6,7-dihydro-5H-cyclopenta[c]pyridine (62 mg, 0.27 mmol), 3,5-difluorophenol (38 mg, 0.29 mmol), cesium carbonate (130 mg, 0.400 mmol) and NMP (1.8 mL) was heated at 90° C. overnight under nitrogen. The reaction mixture was heated to 140° C. and stirred overnight again. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by Biotage C18 reverse phase flash chromatography (20-95% acetonitrile/water) to give 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 469, 21 mg, 24%) as a pale yellow solid. LCMS ESI (+) m/z 326/328 (M+H) + . 
     Step C: S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate: To a vial containing a solution of 4-bromo-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (20 mg, 0.060 mmol) in 1,4-dioxane (0.3 mL) were added acetylsulfanylpotassium (8.8 mg, 0.080 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (4.3 mg, 0.010 mmol). The mixture was sparged with nitrogen. Then tris(dibenzylideneacetone)dipalladium(0) (3.4 mg, 0.004 mmol) was added, and the vial was sealed and heated at 110° C. for 4 hours. After cooling, the reaction mixture was filtered through Celite. The filtrate was concentrated. The residue was purified by Biotage C18 reverse phase flash chromatography (10-80% acetonitrile/water) to give S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl] ethanethioate (10 mg, 51%). LCMS ESI (+) m/z 322 (M+H) + . 
     Step D: 1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol: To a stirred solution of S-[1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl]ethanethioate (10 mg, 0.030 mmol) in MeOH (0.3 mL) was added 1 N LiOH solution (0.050 mL, 0.050 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then concentrated. To the residue was added water. The pH was added to 2-3 using 0.1 N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The crude was used in the next step without further purification. LCMS ESI (+) m/z 280 (M+H) + . 
     Step E: 4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine: To a stirred solution of crude 1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-thiol (9 mg, 0.03 mmol) in acetonitrile (0.3 mL) was added potassium hydroxide (36 mg, 0.64 mmol) in water (0.3 mL). The reaction mixture was purged with nitrogen and then cooled to −78° C. Bromodifluoromethyl diethylphosphonate (17 mg, 0.060 mmol) was added. The resulting mixture was allowed to warm to ambient temperature and stirred for 3 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were washed with water and brine, dried over Na 2 SO4, filtered, and concentrated to dryness. The crude was used in the next step without further purification. LCMS ESI (+) m/z 330 (M+H) + . 
     Step F: 4-(difluoromethylsulfonyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (Compound 470): Sodium periodate (18 mg, 0.080 mmol) was added all at once to crude 4-(difluoromethylsulfanyl)-1-(3,5-difluorophenoxy)-6,7-dihydro-5H-cyclopenta[c]pyridine (11 mg, 0.030 mmol) and ruthenium(III) chloride (0.2 mg, 0.001 mmol) in acetonitrile (0.2 mL)/CCl 4  (0.2 mL)/water (0.4 mL). The reaction mixture was stirred at ambient temperature for 3 hours. Solids were removed by filtration and rinsed with CH 2 Cl 2 . The organic layer was separated. The aqueous layer was extracted with CH 2 Cl 2 . The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (4-12% EtOAc/hexanes) affording Compound 470 (3 mg, 25% overall yield for three steps) as a white solid. LCMS ESI (+) m/z 362 (M+H) + .  1 H NMR (400 MHz, CDCl 3 ): δ 7.49 (s, 1H), 6.80-6.71 (m, 3H), 6.19 (t, 1H), 3.36 (t, 2H), 3.06 (t, 2H), 2.31-2.23 (m, 2H). 
     Example 12: Synthesis of racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of racemic (6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol: A solution of 4-bromo-6-fluoro-1-(trifluoromethyl)-5,6-dihydrocyclopenta[c]pyridin-7-one (6.7 mg, 0.022 mmol) in methanol (0.8 mL) at 0° C. was treated with sodium borohydride (0.9 mg, 0.022 mmol) and stirred at 0° C. for 10 min. The reaction mixture was quenched by the addition of 0.2 mL of saturated NH 4 Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) (M+H) m/z 300/302. 
     Step B: Preparation of racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471): A suspension of racemic (6R,7S)-4-bromo-6-fluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (6.7 mg, 0.022 mmol), 3-cyano-5-fluorophenylboronic acid (5.5 mg, 0.033 mmol), cesium fluoride (10.5 mg, 0.069 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.8 mg, 0.0011 mmol) in a mixture 1,4-dioxane (0.8 mL) and water (80 μL) was sparged with nitrogen for 3 mins. The vessel was sealed and heated to 80° C. for 1 h. LCMS indicates product formation. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford racemic 3-fluoro-5-((6R,7S)-6-fluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)benzonitrile (Compound 471) as an orange solid (1.8 mg, 24%). Retention time HPLC (14 min)=3.80 min; LCMS ESI (+) (M+H) m/z 341;  1 H NMR (400 MHz, CDCl 3 ): δ 8.65 (s, 1H), 7.53-7.48 (m, 2H), 7.40 (ddd, 1H), 5.56-5.48 (m, 1H), 5.35 (ddt, 1H), 3.41 (ddd, 1H), 3.21 (ddd, 1H), 2.65 (dd, 1H). 
     Example 13: Synthesis of (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione: A solution of 3,6 difluorophthalic anhydride (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0° C. and treated with 10% hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75° C. for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3×50 mL CH 2 Cl 2 . The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. 
     Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione: A solution of the unpurified 4,7-difluoro-1H-indene-1,3(2H)-dione (4.2 g, 23.1 mmol) in acetonitrile (100 mL) cooled in a 25° C. water bath was treated with sodium carbonate (5.38 g, 50.7 mmol). Selectfluor® (17.97 g, 50.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was poured into 100 mL of 0.1% HCl and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 40 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel 1:1 hexane/ethyl acetate to give 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.5 g, 70%) as a solid.  1 H NMR (400 MHz, CDCl 3 ): δ 7.70 (t, 2H). 
     Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one: To a solution of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.48 g, 16.0 mmol) in dichloromethane (150 mL) at 0° C. was added formic acid (600 μL, 16.0 mmol) and triethylamine (1.55 mL, 11.2 mmol). The resulting mixture was sparged with nitrogen for 5 minutes and then RuCl(p-cymene)[(S,S)-Ts-DPEN] (203.6 mg, 0.32 mmol) was added. The reaction vessel was sealed and put into a 4 OC refrigerator to stand for 18 hours. The reaction mixture was poured into 40 mL 1 N HCl. The CH 2 Cl 2  layer was separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried with Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 25% EtOAc/hexane to give (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2.9 g, 83%) as an oil.  1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (ddd, 1H), 7.29-7.23 (m, 1H), 5.44 (dd, 1H), 2.79 (dd, 1H). 
     Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one: A solution of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (966 mg, 4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogen for 5 minutes and treated with sodium thiomethoxide (353.7 mg, 5.05 mmol). The ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between 40 mL of EtOAc and 40 mL of water. The aqueous layer was further extracted with 2×40 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered, and evaporated. The residue was chromatographed on silica using 10-60% EtOAc/hexane to afford (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (870 mg, 80%) as a yellow solid. LCMS ESI (+) m/z 249 (M+H). 
     Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (400 mg, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.18 g, 3.55 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The aqueous filtrate was extracted 3×30 mL of EtOAc and then the combined organics were washed with saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to a yellow solid that was used without further purification (467 mg). LCMS ESI (+) m/z 281.1 (M+H). 
     Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (450 mg, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C. and treated dropwise with diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and the mixture was stirred at 0° C. for 2 hours, then the whole homogeneous reaction mixture was placed into the refrigerator overnight. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 hours at 0° C. The cold reaction was treated with saturated NaHCO 3  (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO 2  (Biotage SNAP Ultra) and eluted with a gradient of ethyl acetate/hexanes. The desired material was concentrated to a pale yellow solid (258 mg). LCMS ESI (+) m/z 283 (M+H). 
     Step G: Preparation of (R)-2,2,3-trifluoro-4-((S)-3-hydroxypiperidin-1-yl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: A solution of (3R)-2,2,3,4-tetrafluoro-7-methylsulfonyl-indan-1-one (28.7 mg, 0.10 mmol) and (3S)-3-piperidinol, hydrochloride (14.0 mg, 0.10 mmol) in DMF (700 μL) was treated with cesium bicarbonate (59.2 mg, 0.31 mmol) and stirred at 35° C. for 3 h. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL Et 2 O. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) m/z 364 (M+H). 
     Step H: Preparation of (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484): A solution of (3R)-2,2,3-trifluoro-4-[(3S)-3-hydroxy-1-piperidyl]-7-methylsulfonyl-indan-1-one (36.3 mg, 0.10 mmol) in dichloromethane (4 mL) was cooled to 0° C. and sparged with nitrogen for 5 min. During this time formic acid (12.1 μL, 0.32 mmol) and triethylamine (27.9 μL, 0.20 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (1.3 mg, 2 mol %) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 45-75% EtOAc/hexane to afford (S)-1-((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)piperidin-3-ol (Compound 484) as a white solid (23.9 mg, 65%). Retention time HPLC (14 min)=2.63 min; LCMS ESI (+) m/z 366 (M+H);  1 H NMR (400 MHz, CDCl 3 ): δ 7.97 (dd, 1H), 7.07 (d, 1H), 5.74 (dd, 1H), 5.55 (dd, 1H), 4.01-3.93 (m, 1H), 3.46-3.34 (m, 3H), 3.33 (d, 1H), 3.20-3.13 (m, 1H), 3.18 (s, 3H), 2.01-1.91 (m, 2H), 1.89 (d, 1H), 1.82-1.62 (m, 2H). 
     Example 14: Synthesis of (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480) and (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 481) and (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482) and (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of (S)-3-(2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)cyclohex-2-en-1-one: A suspension of (1S)-4-bromo-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-ol (102.0 mg, 0.27 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (89.2 mg, 0.40 mmol), cesium fluoride (126.0 mg, 0.83 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9.5 mg, 0.013 mmol) in 1,4-dioxane (4.5 mL) was sparged with nitrogen for 3 mins. The vessel was sealed and heated to 80° C. for 1 h. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 20-50% EtOAc/hexane. LCMS ESI (−) (M−H) m/z 395. 
     Step B: Preparation of (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480) and (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 481) and (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482) and (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483): A solution of 3-[(1S)-2,2-difluoro-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]cyclohex-2-en-1-one (60.0 mg, 0.15 mmol) in methanol (3.0 mL) at 0° C. was treated with sodium borohydide (11.5 mg, 0.30 mmol) and stirred at 0° C. for 1 h. The reaction mixture was quenched by the addition of 0.5 mL of saturated NH 4 Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Initial purification was achieved by chromatography on silica using 10-40% EtOAc/CH 2 Cl 2  to isolate 2 components. A second purification was necessary on the first eluting component by chromatography on silica using 20-45% EtOAc/hexanes. Finally, each product was purified individually, as described in the characterization section. Data for (S)-2,2-difluoro-4-((1R,3R)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 480): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a white solid (1.5 mg, 2%). Retention time HPLC (14 min)=4.69 min; LCMS ESI (−) (M+HCO 2   − ) m/z 445;  1 H NMR (400 MHz, CDCl 3 ): δ 7.92 (d, 1H), 7.52 (d, 1H), 5.40 (dd, 1H), 4.33-4.28 (m, 1H), 3.59 (ddd, 1H), 3.49 (t, 1H), 3.22-3.13 (m, 2H), 1.97-1.82 (m, 4H), 1.75-1.58 (m, 3H), 1.46 (dd, 1H), 1.42-1.37 (m, 1H). Data for (1S)-2,2-difluoro-4-(3-hydroxycyclohex-1-en-1-yl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-H-inden-1-ol (Compound 481): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a clear solid (3.5 mg, 6%). Retention time HPLC (14 min)=4.70 min; LCMS ESI (+) (M-OH) m/z 381;  1 H NMR (400 MHz, CDCl 3 ): δ 7.93 (d, 1H), 7.50 (d, 1H), 5.91-5.88 (m, 1H), 5.39 (dd, 1H), 4.49-4.43 (m, 1H), 3.64 (ddd, 1H), 3.39 (t, 1H), 3.18 (dd, 1H), 2.49-2.39 (m, 1H), 2.22-2.11 (m, 1H), 2.09-1.92 (m, 2H), 1.81-1.59 (m, 3H). Data for (S)-2,2-difluoro-4-((1R,3S)-3-hydroxycyclohexyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 482): Final purification was achieved by chromatography on silica using 30-70% EtOAc/hexanes to afford the desired product as a clear solid (6.7 mg, 11%). Retention time HPLC (14 min)=4.27 min; LCMS ESI (−) (M+HCO 2 −) m/z 445;  1 H NMR (400 MHz, CDCl 3 ): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.56 (ddd, 1H), 3.42 (t, 1H), 3.20 (dd, 1H), 2.67 (tt, 1H), 2.17-2.08 (m, 2H), 2.01-1.94 (m, 1H), 1.82-1.75 (m, 1H), 1.60-1.42 (m, 3H), 1.40-1.27 (m, 2H). Data for (S)-2,2-difluoro-4-((1S,3R)-3-hydroxycyclohexyl)-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 483): Final purification was achieved by chromatography on silica using 20-60% EtOAc/hexanes to afford the desired product as a white solid (8.6 mg, 14%). Retention time HPLC (14 min)=4.77 min; LCMS ESI (−) (M+HCO 2   − ) m/z 445;  1 H NMR (400 MHz, CDCl 3 ): δ 7.94 (d, 1H), 7.55 (d, 1H), 5.41 (dd, 1H), 3.82-3.72 (m, 1H), 3.58 (ddd, 1H), 3.40 (t, 1H), 3.18 (d, 1H), 2.67 (tt, 1H), 2.16-2.06 (m, 2H), 2.02-1.95 (m, 1H), 1.86-1.78 (m, 1H), 1.58-1.28 (m, 5H). 
     Example 15: (S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)-5-fluorobenzonitrile (Compound 489) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4-bromophenyl 3-chloropropanoate: A solution of 4-bromophenol (45.0 g, 260 mmol) in dichloromethane (1.0 L) was cooled to 0° C., treated with triethylamine (44.7 g, 442 mmol). A solution of 3-chloropropionyl chloride (36.3 g, 286 mmol) dissolved in dichloromethane (100 mL) was added dropwise to the reaction vessel. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. Saturated NaCl was added to the reaction mixture, (300 mL). After stirring for 1 hour, the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organics were washed with saturated NaCl, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was used without further purification. 
     Step B: Preparation of 4-bromo-7-hydroxy-2,3-dihydro-1H-inden-1-one: A flask containing crude (4-bromophenyl) 3-chloropropanoate (68.0 g, 258 mmol) was cooled to 0° C., then treated in several portions with aluminum trichloride (275 g, 2060 mmol). The reaction mixture was then heated at 155° C. under N 2  for 3 hours. Stirring became difficult as the reaction proceeded. HCl (g) which was generated from the reaction was trapped by a beaker containing 1 N NaOH. After cooling to ambient temperature, the reaction mixture was further cooled in an ice bath. Water was added very carefully (dropwise initially and then added in small volumes) to the reaction to quench excess AlCl 3 . The mixture was then extracted with twice with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated. The crude product was used without additional purification. 
     Step C: Preparation of O-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate: A mixture of 4-bromo-7-hydroxy-2,3-dihydro-1H-inden-1-one (900 mg, 4.0 mmol) dissolved in DMF (15 mL) was treated with DABCO 33LV (1.3 mL, 12 mmol) and N,N-dimethylcarbamothioyl chloride (1.5 g, 12 mmoil) was stirred overnight at ambient temperature. The reaction was treated with water and ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate then the combined organic layers were washed with water and saturated NaCl. After drying, the organic layer was concentrated in vacuo and purified by chromatography on SiO2 eluting with a gradient of ethyl acetate/hexanes, (670 mg, 54%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.78-7.76 (d, 1H), 6.97-6.95 (d, 1H), 3.44 (s, 3H), 3.41 (s, 3H), 3.08 (m, 2H), 2.76-2.69 (m, 2H). 
     Step D: Preparation of S-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate: A mixture of O-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate (670 mg, 2.1 mmol) and diphenyl ether (15 mL) was heated at 220° C. under N 2  for 30 minutes. After cooling to ambient temperature, the mixture was diluted with hexanes and the mixture was applied to a pad of SiO 2  and eluted with hexanes. After removal of the diphenyl ether, the desired product was eluted with ethyl acetate. After concentration in vacuo, the crude product was used without further purification. 
     Step E: Preparation of 4-bromo-7-mercapto-2,3-dihydro-1H-inden-1-one: A solution of S-(7-bromo-3-oxo-2,3-dihydro-1H-inden-4-yl) dimethylcarbamothioate (670 mg, 2.1 mmol) dissolved in ethanol (25 mL) was treated with 3N sodium hydroxide)10.7 mL, 32.1 mmol). The mixture was heated to reflux for 1 hour then cooled to 0° C. Aqueous HCl (3M) was added dropwise to neutralize the reaction. Ethanol was removed by concentration in vacuo followed by addition of aqueous HCl (1M) to adjust to pH 3-4. The aqueous was extracted twice with ethyl acetate and the combined organic layers were washed with saturated NaCl, dried and concentrated in vacuo. The crude product was used without further purification. 
     Step F: Preparation of 4-bromo-7-((trifluoromethyl)thio)-2,3-dihydro-1H-inden-1-one: Methyl viologen dichloride hydrate (0.11 g, 0.41 mmol), 4-bromo-7-mercapto-2,3-dihydro-1H-inden-1-one (2.0 g, 8.2 mmol) and triethylamine (1.25 g, 12.3 mmol) were dissolved in DMF (50 mL) and cooled to −50° C. The flask was placed under gentle vacuum then trifluoromethyl iodide (3.2 g, 16 mmol) gas was introduced using a balloon. This reaction was warmed to ambient temperature and stirred at overnight. The reaction mixture was diluted with ethyl acetate and water, filtered through a celite pad, and the layers were partitioned. The organic layer was washed with water, brine, dried over Na 2 SO 4 , filtered, and evaporated. The crude oil was then purified by flash column chromatography on SiO 2  eluting with petroleum ether/ethyl acetate, (0.96 g, 51.7%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.72 (d, 1H), 7.41 (d, 1H), 3.10-3.07 (m, 2H), 2.79-2.77 (m, 2H). 
     Step G: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: Ruthenium(III) chloride (19 mg, 0.09 mmol) was added to a mixture of 4-bromo-7-((trifluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (0.96 g, 3.1 mmol) and sodium periodate (1.98 g, 9.26 mmol) in a mixture of carbon tetrachloride (20 mL), acetonitrile (20 mL), and water (40 mL). The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on SiO 2  eluting with petroleum ether/ethyl acetate, (1.7 g, 79%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.05-8.02 (m, 2H), 3.21-3.18 (m, 2H), 2.89-2.86 (m, 2H). 
     Step H: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]: Trimethylsilyl trifluoromethanesulfonate (177 mg, 0.80 mmol) was added dropwise to a pre-cooled (−78° C.) solution of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one and trimethyl(2-trimethylsilyloxyethoxy)silane (410 mg, 2.0 mmol) dissolved in dichloromethane (50 mL). The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction was quenched by addition of triethylamine then concentrated in vacuo. The residue was redissolved in ethyl acetate and washed twice with water, and saturated NaCl. The organic layer was separated, dried over Na 2 SO 4  and concentrated in vacuo. The crude product was purified by chromatography on SiO 2  eluting with ethyl acetate/isohexane, (600 mg, 77%). 
     Step I: Preparation of 4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: 4-Bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane] (3.5 g, 9.1 mmol) was dissolved in THF (72 mL) and treated with 10% aqueous HCl (27 mL, 27 mmol). The mixture was stirred for several minutes then warmed to 60° C. for 2 hours. The mixture was cooled, diluted with diethyl ether and separated. The aqueous was washed with diethyl ether and the combined organics were washed with water, saturated NaHCO 3 , saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to a yellowish solid, (3.09 g, quant.).  1 H NMR (400 MHz, CDCl 3 ): δ 8.05-8.02 (m, 2H), 3.21-3.18 (m, 2H), 2.89-2.86 (m, 2H). 
     Step J: Preparation of (E,Z)-3-((4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)amino)propan-1-ol: 4-Bromo-7-(trifluoromethylsulfonyl)indan-1-one (3.09 g, 9.02 mmol] was slurried in toluene (35 mL) and cyclohexane (35 mL) then treated with 3-methoxypropylamine (2.15 mL, 27.1 mmol) and pivalic acid (46 mg, 0.45 mmol). The mixture was refluxed through a Dean-Stark trap (sidearm pre-filled with cyclohexane) for 8 hours. The reaction mixture was cooled and concentrated in vacuo. The crude material was taken directly into the fluorination. 
     Step K: Preparation of 4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: Crude (E.Z)-3-((4-bromo-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ylidene)amino)propan-1-ol (3.75 g, 9.1 mmol) was dissolved in dry acetonitrile (23 mL) and added dropwise to a warm (60° C.), suspension of Selectfluor (9.6 g, 27.2 mmol) and sodium sulfate (12.9 g, 90.5 mmol) slurried in acetonitrile (10 mL). After the addition, the mixture was heated to 60° C. for 10 minutes then cooled to ambient temperature and treated with 10% HCl (15 mL) and stirred for 20 minutes. The mixture was adjusted to pH 8 with solid NaHCO 3  then diluted with ethyl acetate and separated. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO 3 , saturated NaCl, dried over Na 2 SO 4  filtered, and concentrated in vacuo to dark oil. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired product was concentrated to a light yellow solid, (2.27 g, 66%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.22-8.14 (m, 2H), 3.60-3.55 (t, 2H). 
     Step L: Preparation of (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol: 4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one_(1.65 g, 4.35 mmol) was dissolved in isopropanol (21 mL) and treated with triethylamine (1.2 mL, 8.7 mmol), formic acid (0.49 mL, 13.1 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (27.7 mg, 0.040 mmol). The reaction mixture was stirred at ambient temperature for 4 hours. The solvent was removed in vacuo then the crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The product was isolated as a more pure fraction (1.83 g) and a slightly less pure fraction. Both of these fractions were successfully utilized in the coupling reaction.  1 H NMR (400 MHz, CDCl 3 ): δ 7.88-7.80 (m, 2H), 5.50-5.45 (m, 1H), 3.66-3.58 (m, 1H), 3.20 (m, 1H). 
     Step M: Preparation of (S)-3-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)-5-fluorobenzonitrile: (S)-4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (98 mg, 0.26 mmol) was dissolved in 1,4-dioxane (0.80 mL) and treated with benzonitrile, 3-amino-5-fluoro-(42 mg, 0.31 mmol), palladium (II) acetate (2.9 mg, 0.010 mmol), and Xantphos (14.9 mg, 0.030 mmol). The mixture was heated to 120° C. for 1.5 hours in the microwave reactor. The reaction mixture was cooled, diluted with ethyl acetate and water then separated. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO 3 , saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo. The crude dark oil was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered in a slightly impure form. This material was re-chromatographed on reversed-phase SiO 2  eluting with a gradient of MeCN/water. A single fraction was collected and to light tan solid, (35 mg, 31%). LCMS ESI (−) m/z (M−H) 435;  1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (d, 1H), 7.31-7.29 (m, 2H), 7.21-7.19 (m, 2H), 6.18 (m, 1H), 5.42-5.38 (m, 1H), 3.52-3.41 (m, 1H), 3.32-3.24 (m, 1H). 
     Example 16: Synthesis of (S)-5-((2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)amino)nicotinonitrile (Compound 488) 
     
       
         
         
             
             
         
       
     
     (S)-4-Bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (23 mg, 0.060 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with 3-pyridinecarbonitrile, 5-amino-(8.6 mg, 0.070 mmol), cesium carbonate (27.5 mg, 0.080 mmol), palladium (II) acetate (0.68 mg, 0.003 mmol), and Xantphos (3.5 mg, 0.010 mmol). After cooling, the mixture was diluted with water and ethyl acetate then separated. This mixture didn&#39;t separate well and there was insoluble yellow solid present, which was removed by filtration. The aqueous was washed with ethyl acetate and the combined organics were washed with saturated NaHCO 3 , saturated NaCl, dried over Na2SO4, and concentrated in vacuo to a dark residue. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The product was recovered as light tan solid, (12 mg, 47%). LCMS ESI (+) m/z (M+H) 420;  1 H NMR (400 MHz, CDCl 3  plus CD 3 OD): δ 8.66 (s, 1H), 8.60 (s, 1H), 7.79-7.75 (m, 2H), 7.22-7.20 (m, 1H), 5.30 (d, 1H), 3.92-3.90 (m, 1H), 3.46-3.32 (m, 1H), 3.31-3.21 (m, 1H). 
     Example 17: Synthesis of (S)-2,2-difluoro-4-morpholino-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 490) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of (S)-((4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane: (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (0.30 g, 0.78 mmol) was dissolved in methylene chloride (3.3 mL) and treated with 2,6-lutidine (0.40 mL, 3.1 mmol), cooled to 0° C., followed by treatment with t-butyldimethylsilyl triflate (0.45 mL, 1.9 mmol). The mixture was warmed to ambient temperature and stirred for two hours. The reaction mixture was re-cooled to 0° C. and cold 10% KHSO 4  was added along with additional methylene chloride then the layers were separated. The organic layer was washed with 10% KHSO 4 , water, then with one-half saturated NaHCO 3 . The organic layer was dried over Na 2 SO 4  and concentrated in vacuo to a light yellow oil. The crude product was chromatographed on SiO 2  eluting with a gradient of methylene chloride/hexanes. The product was concentrated to colorless oil, (466 mg, 92%). 
     Step B: Preparation of (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)morpholine: (S)-((4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane (0.030 g, 0.060 mmol) was dissolved in DMF (0.25 mL) and treated with sodium acetate (14 mg, 0.17 mmol) followed by morpholine (0.020 mL, 0.17 mmol). The mixture was heated at 120° C. for 1 hour in the microwave reactor. After cooling, the mixture was diluted with ethyl acetate then washed 7 times with water, saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo. The residue was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The product was recovered as a colorless film, (17 mg, 58%). LCMS ESI (+) m/z (M+H) 502. 
     Step C: Preparation of (S)-2,2-difluoro-4-morpholino-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol: (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)morpholine (0.02 g, 0.04 mmol) was dissolved in THF (0.25 mL) and treated with glacial acetic acid (2 μL, 0.04 mmol) followed by a solution of 1 M tetrabutylammonium fluoride in THF (0.04 mL, 0.04 mmol). The mixture was heated to 60° C. for 45 minutes. The darkened reaction mixture was cooled and added into saturated aqueous NaHCO 3 . The mixture was vortexed vigorously then diluted with ethyl acetate and separated. The organic layer was washed with saturated NaHCO 3 , saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. Compound 490 was recovered as light orange oil, (10.8 mg, 78%). LCMS ESI (+) m/z (M+H) 388;  1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (d, 1H), 7.01 (d, 1H), 5.35-5.31 (m, 1H), 3.93-3.81 (m, 4H), 3.56-3.45 (m, 1H), 3.35-3.23 (m, 3H), 3.16-3.09 (m, 3H). 
     Example 18: Synthesis of (1S,3R)-4-((3-chloro-5-fluorophenyl)thio)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 491) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione (0.52 g, 2.8 mmol) was slurried acetic anhydride (2.5 mL, 27 mmol) and treated with tert-butyl 3-oxobutanoate (0.52 mL, 3.1 mmol) and triethylamine (1.4 mL, 10 mmol). The mixture was stirred at ambient temperature for 60 hours. The reaction was cooled to 0° C. and treated with 10% aqueous hydrochloric acid (8.6 mL, 25 mmol) by dropwise addition. After the addition, the mixture was warmed to ambient temperature then heated to 75° C. for 10 minutes. After cooling, the mixture was diluted with water (20 mL) and extracted three times with methylene chloride (20 mL portions). The combined organics were dried over Na 2 SO 4  and concentrated in vacuo to crude orange solid. This material was carried forward without purification. 
     Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione: 4,7-difluoro-1H-indene-1,3(2H)-dione (0.51 g, 2.8 mmol) was dissolved in acetonitrile (27 mL), placed in an ambient temperature water bath then treated with solid sodium carbonate (950 mg, 9.0 mmol) followed by Selectfluor® (2.18 g, 6.2 mmol). The mixture was stirred at ambient temperature for 1 hour. The mixture was filtered to removed undissolved solids, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The residue was redissolved in water (ca. 20 mL) and extracted four times with ethyl acetate (20 mL each). The combined organics were washed with saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to orange solid. The crude solid was chromatographed on SiO 2  eluting with an aggressive gradient of ethyl acetate/hexanes. The desired material concentrated to orange solid, (493 mg, 81%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.70-7.65 (2H). 
     Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one: 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (5.81 g, 26.6 mmol) was suspended in methylene chloride (260 mL), cooled to 0° C., and treated with formic acid (1.01 mL, 26.6 mmol), triethylamine (2.60 mL, 18.6 mmol), then the reaction mixture was sparged with argon for 5 minutes. RuCl(p-cymene)[(S,S)-Ts-DPEN] (339 mg, 0.530 mmol) was added and the reaction was transferred to the refrigerator and allowed to stand at 4° C. for 20 hours. The cold reaction mixture was poured into cold 1N aqueous HCl (70 mL) and separated. The aqueous was washed twice with ethyl acetate then the combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to a brown semi-solid. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The product was recovered as yellow solid, (3.48 g, 59%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.86-7.80 (m, 1H), 7.60-7.54 (m, 1H), 5.79-5.74 (m, 1H), 3.23-3.18 (m, 1H). 
     Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (0.40 g, 1.8 mmol) was dissolved in dry acetonitrile (18 mL), cooled to 0° C., and sparged with argon for 5 minutes. The solution was treated in a single portion with sodium thiomethoxide (144 mg, 2.06 mmol) and after 5 minutes, the ice bath was removed and the reaction was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was redissolved in water and ethyl acetate. After separation, the aqueous was washed twice with ethyl acetate and the combined organics were washed with saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo. The orange residue was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered as bright yellow solid, (314 mg, 70%). LCMS ESI (+) m/z (M+H) 249. 
     Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (0.40 g, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.2 g, 3.6 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo to remove volatile solvents. The aqueous filtrate was extracted three times with ethyl acetate then the combined organics were washed with saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to yellow solid, (467 mg, quant.). LCMS ESI (+) m/z (M+H) 281. 
     Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (0.45 g, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C., and treated dropwise with diethylaminosulfur trifluoride (DAST) (0.32 mL, 2.4 mmol) and stirred at 0° C. for 14 hours. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 hours at 0° C. The cold reaction was treated with saturated NaHCO 3  (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired material was recovered as pale yellow solid, (258 mg, 53%). LCMS ESI (+) m/z (M+H) 283. 
     Step G: Preparation of (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol: (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (0.098 g, 0.35 mmol) was suspended in methylene chloride (3.3 mL), cooled to 0° C., and treated with triethylamine (97 μL, 0.69 mmol), formic acid (39 μL, 1.0 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (2.2 mg, 0.003 mmol). The solution was allowed to stand at 4° C. in the refrigerator for 60 hours. The reaction mixture was concentrated in a stream of nitrogen gas then chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired fractions were concentrated to colorless film, (53 mg, 53%). LCMS ESI (+) m/z (M+H) 285. 
     Step H: Preparation of (1S,3R)-4-((3-chloro-5-fluorophenyl)thio)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol: (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (0.005 g, 0.02 mmol) was treated with cesium bicarbonate (17 mg, 0.090 mmol) and suspended in DMF (0.1 mL) then stirred at ambient temperature for 1 hour. 3-Chloro-5-fluorothiophenol (14 mg, 0.090 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction was concentrated in a stream of nitrogen gas to remove DMF. The residue was chromatographed on SiO 2  eluting with a stepped gradient of ethyl acetate/hexanes. Compound 491 was concentrated to light pink oil, (7 mg, 93%). LCMS ESI (+) m/z (M+Na) 449;  1 H NMR (400 MHz, CDCl 3 ): δ 7.99-7.95 (m, 1H), 7.33-7.32 (m, 1H), 7.24-7.19 (m, 2H), 7.16-7.13 (m, 1H), 5.75 (dd, 1H), 5.68-5.65 (m, 1H), 3.37-3.36 (m, 1H), 3.23 (s, 3H). 
     Example 19: Synthesis of 3-(((1S,3R)-2,2,3-trifluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)thio)benzonitrile (Compound 492) 
     
       
         
         
             
             
         
       
     
     (1S,3R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (0.0073 g, 0.030 mmol) was treated with cesium bicarbonate (25 mg, 0.13 mmol) and suspended in DMF (0.1 mL) then 3-mercapto-benzonitrile (17 mg, 0.13 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The reaction was concentrated in a stream of nitrogen gas to remove DMF. The residue was chromatographed on SiO 2  eluting with a stepped gradient of ethyl acetate/hexanes. The product was concentrated to light oil, (7 mg, 91%). LCMS ESI (+) m/z (M+Na) 422;  1 H NMR (400 MHz, CDCl 3 ): δ 7.97-7.87 (m, 1H), 7.81 (m, 1H), 7.77-7.74 (m, 2H), 7.61-7.57 (m, 1H), 7.16-7.14 (m, 1H), 5.77 (dd, 1H), 5.69-5.65 (m, 1H), 3.40-3.39 (m, 1H), 3.23 (s, 3H). 
     Example 20: Synthesis of (S)-4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 485) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]: A solution of 4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.07 mmol) and 4-methoxybenzyl alcohol (760 μL, 6.13 mmol) in acetonitrile (9.3 mL) at 25° C. was treated with potassium hydroxide (516 mg, 9.2 mmol) and stirred at 25° C. for 1.5 h. The reaction mixture was poured into 150 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 20 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-25% EtOAc/hexane to afford 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane] as a solid (1.08 g, 79%). LCMS ESI (+) [M+H] +  m/z 445. 
     Step B: Preparation of 4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: In a glass pressure vessel, a solution of 4′-[(4-methoxyphenyl)methoxy]-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.08 g, 2.43 mmol) in a mixture acetone (20 mL) and water (20 mL) was treated with pyridinium p-toluenesulfonate (122 mg, 0.49 mmol), sealed and stirred at 80° C. overnight. Volatiles were removed by concentration under reduced pressure. The residue was poured into 40 mL of saturated aqueous NaHCO 3  and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 30 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purificaction. LCMS ESI (+) [M+H] +  m/z 401. 
     Step C: Preparation of 2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: 2,2-Dimethylpropanoic acid (50 mg, 0.46 mmol) was added to a flask containing a suspension of 4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-one (922 mg, 2.3 mmol) and 3-methoxypropan-1-amine (0.35 mL, 3.45 mmol) in a mixture of toluene (14 mL) and cyclohexane (14 mL). This was refluxed with a Dean-Stark trap attached at 104° C. After 2.5 h, the reaction mixture was cooled and volatiles removed by concentration under reduced pressure. The residue was dissolved in acetonitrile (24 mL) and treated sequentially with sodium sulfate (850 mg, 6.0 mmol) and and 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (2.13 g, 6.0 mmol). The resulting suspension stirred at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was treated with concentrated hydrochloric acid (600 μL, 7.2 mmol) and water (10 mL). The resulting mixture stirred for 20 min. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×30 mL EtOAc. The combined organics were rinsed with 20 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-40% EtOAc/hexane to afford 2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one as a solid (520 mg, 50%). LCMS ESI (+) [M+H] +  m/z 437. 
     Step D: Preparation of (S)-2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol: A solution of 2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-one (520 mg, 1.19 mmol) in dichloromethane (11.9 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time, formic acid (130 μL, 3.58 mmol) and triethylamine (330 μL, 2.38 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN](22.8 mg, 0.036 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Once complete, the reaction mixture was poured into 30 mL of saturated aqueous NaHCO 3  and extracted with 3×30 mL CH 2 Cl 2 . The combined organics were rinsed with 20 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford (S)-2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol as a solid (370 mg, 71%). LCMS ESI (+) [M+NH 4 ] +  m/z 456. 
     Step E: Preparation of (S)-tert-butyl((2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane: A solution of (1S)-2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-ol (370 mg, 0.84 mmol) and 2,6-lutidine (780 μL, 7.76 mmol) in dichloromethane (8.4 mL) at −78° C. was treated with tert-butyldimethylsilyl trifluoromethanesulfonate (980 μL, 4.22 mmol) and allowed to warm to room temperature over 2 h. The reaction mixture was poured into 30 mL of saturated aqueous NaHCO 3  and extracted with 3×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford (S)-tert-butyl((2,2-difluoro-4-((4-methoxybenzyl)oxy)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane (460 mg, quant). LCMS ESI (−) [M−H] −  m/z 551. 
     Step F: Preparation of (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol: A solution of tert-butyl-[(1S)-2,2-difluoro-4-[(4-methoxyphenyl)methoxy]-7-(trifluoromethylsulfonyl)indan-1-yl]oxy-dimethyl-silane (460 mg, 0.83 mmol) in dichloromethane (3.0 mL) at 25° C. was treated with trifluoroacetic acid (3.0 mL) and stirred at 25° C. After 1 h, volatiles were removed by concentration under reduced pressure. To the resulting residue was added 6 mL of toluene and the organic volatiles were once again removed by concentration under reduced pressure. This process was repeated twice. Purification was achieved by chromatography on reverse phase by injection of a DMF solution of the product residue. 40-100% CH 3 CN/Water was used as eluent. (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol was isolated a thick orange oil (236 mg, 89%). LCMS ESI (−) [M−H] −  m/z 431. 
     Step G: Preparation of (S)-2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate: A solution of (S)-1-((tert-butyldimethylsilyl)oxy)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-ol (215 mg, 0.50 mmol) and 2,6-bis(1,1-dimethylethyl)-4-methyl-pyridine (408 mg, 1.99 mmol) in dichloromethane (10 mL) was cooled to −78° C. and treated with trifluoromethanesulfonic anhydride (0.17 mL, 0.99 mmol). The mixture was stirred at −78° C. for 1 h. The reaction mixture was poured into 20 mL of saturated NaHCO 3  and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on SiO 2  eluting with a gradient of ethyl acetate/hexanes. 
     Step H: Preparation of tributyl(3-chlorophenyl)stannane: A solution of 3-chlorophenylmagnesium bromide (0.5 M in THF) (1.40 mL, 0.70 mmol) was cooled to −78° C. and treated dropwise with a solution of tributyl(chloro)stannane (230 mg, 0.70 mmol) dissolved in THF (0.5 mL). The solution was stirred for 5 minutes then allowed to warm to ambient temperature slowly without the bath and stirred at ambient temperature for 45 hours. The reaction was quenched by addition of saturated NH 4 Cl and water. Diethyl ether was added and the mixture was separated. The aqueous was washed twice with diethyl ether and the combined organics were washed saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo. The crude material was chromatographed on SiO 2  eluting with cyclohexane. The desired product was concentrated to colorless liquid, (234 mg, 84%).  1 H NMR (400 MHz, CDCl 3 ): δ 7.58-7.30 (m, 4H), 1.60-1.45 (m, 6H), 1.40-1.28 (m, 6H), 1.17-1.00 (m, 6H), 0.92-0.85 (m, 9H). 
     Step I: Preparation of (S)-tert-butyl((4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane: (S)-2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (17 mg, 0.030 mmol) was dissolved in toluene (0.4 mL) then tributyl-(3-chlorophenyl)stannane (23 mg, 0.060 mmol), tetrakis(triphenylphosphine)palladium (1.7 mg, 0.001 mmol), and lithium chloride (4 mg, 0.09 mmol) were added. The reaction mixture was sparged with argon then heated to reflux for 16 hours. After cooling, the mixture was concentrated in a stream of nitrogen gas. The crude material was chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The less polar UV-active spot was recovered as colorless oil, (9.8 mg, 63%). 
     Step J: Preparation of (S)-4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol: (S)-tert-butyl((4-(3-chlorophenyl)-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-yl)oxy)dimethylsilane (9.8 mg, 0.020 mmol) was dissolved in THF (0.2 mL) containing glacial acetic acid (3.2 μL, 0.060 mmol) and the mixture was treated with a 1M solution of tetrabutylammonium fluoride in THF (28 μL, 0.030 mmol). The mixture was heated to 60° C. for 2 hours, then the reaction was cooled, treated with one-half saturated NaHCO 3 , diluted with ethyl acetate and separated. The aqueous was washed twice with ethyl acetate and the combined organics were washed with saturated NaHCO 3 , saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to dark oil. The crude material was chromatographed on SiO 2  eluting with a stepped gradient of ethyl acetate/hexanes. The desired product was concentrated to light yellow solid, (2.5 mg, 32%). LCMS ESI (−) m/z (M−H) 411/413; 1H NMR (400 MHz, CDCl 3 ): δ 8.06-8.04 (d, 1H), 7.66-7.64 (d, 1H), 7.48-7.41 (m, 3H), 7.29-7.26 (m, 1H), 5.47-5.43 (m, 1H), 3.78-3.65 (m, 1H), 3.33 (t, 1H), 3.19-3.17 (m, 1H). 
     Example 21: Synthesis of (S)-2,2-difluoro-4-phenyl-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 487) 
     
       
         
         
             
             
         
       
     
     (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (20 mg, 0.050 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with phenylboronic acid (9.6 mg, 0.080 mmol), Pd(dppf)Cl 2 -DCM adduct (3 mg, 0.004 mmol), and potassium fluoride (6.1 mg, 0.10 mmol). The mixture was heated to 100° C. for 10 hours. After cooling, the reaction mixture was concentrated in a stream of nitrogen gas then chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired material was concentrated to white solid, (17 mg, 86%). LCMS ESI (−) m/z (M−H) 377;  1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (d, 1H), 7.67 (d, 1H), 7.54-7.47 (m, 3H), 7.42-7.39 (m, 2H), 5.47-5.43 (m, 1H), 3.80-3.67 (m, 1H), 3.40-3.31 (t, 1H), 3.22-3.21 (m, 1H). 
     Example 22: Synthesis of (S)-3-(2,2-difluoro-1-hydroxy-7((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)-5-fluorobenzonitrile (Compound 486) 
     
       
         
         
             
             
         
       
     
     (S)-4-bromo-2,2-difluoro-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (20 mg, 0.050 mmol) was dissolved in 1,4-dioxane (0.20 mL) and treated with 3-cyano-5-fluorophenylboronic acid (10 mg, 0.060 mmol), Pd(dppf)Cl 2 -DCM adduct (3 mg, 0.004 mmol), and potassium fluoride (6.1 mg, 0.10 mmol). The mixture was heated to 100° C. for 10 hours. After cooling, the mixture was concentrated in a stream of nitrogen gas, then directly chromatographed on SiO 2  eluting with a gradient of ethyl acetate/hexanes. The desired product was recovered as colorless film, (12 mg, 54%). LCMS ESI (−) m/z (M−H) 420;  1 H NMR (400 MHz, CDCl 3 ): δ 8.09 (d, 1H), 7.65 (d, 1H), 7.61-7.60 (m, 2H), 7.40-7.37 (m, 1H), 5.49-5.46 (m, 1H), 3.78-3.65 (m, 1H), 3.33-3.25 (t, 1H), 3.20 (m, 1H). 
     Example 23: Synthesis of (R)-4-((3-chloro-5-fluorophenyl)thio)-7-((difluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 493) 
     
       
         
         
             
             
         
       
     
     Sodium bicarbonate (18.9 mg, 0.23 mmol) was added all at once to (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (20.0 mg, 0.08 mmol) and 3-chloro-5-fluoro-benzenethiol (24.4 mg, 0.15 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) at room temperature then the reaction vial was sealed with a threaded cap. The reaction mixture was then warmed to 90° C. and continued to stir at this temperature until complete as judged by LC-MS (4 h). Cooled to room temperature then purified directly on reverse phase silica gel (25 +  M, 14 CV, 20-100% MeCN/water) affording (1R)-4-(3-chloro-5-fluoro-phenyl)sulfanyl-7-(difluoromethylsulfonyl)indan-1-ol (25.5 mg, 0.062 mmol, 83% yield). LC-MS ESI (−) m/z 453/455 (M+HCO 2   − ).  1 H-NMR (400 MHz, CDCl 3 ): δ 7.84 (d, 1H), 7.19-7.17 (m, 1H), 7.08 (s, 1H), 7.00-6.97 (m, 2H), 5.71-5.68 (m, 1H), 3.64 (d, 1H), 3.21 (s, 3H), 3.12-3.04 (m, 1H), 2.84-2.76 (m, 1H), 2.52-2.43 (m, 1H), 2.27-2.19 (m, 1H). 
     Example 24: Synthesis of (1R)-7-(difluoromethylsulfonyl)-4-(tetrahydropyran-4-ylamino)indan-1-ol (Compound 494) 
     
       
         
         
             
             
         
       
     
     4-Piperidone (8.4 mg, 0.08 mmol) was added all at once to (1R)-7-(difluoromethylsulfonyl)-4-fluoro-indan-1-ol (22.0 mg, 0.08 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) at room temperature. The reaction mixture was then stirred at 50° C. for 24 h. Additional 4-piperidone (8.4 mg, 0.08 mmol) was added at room temperature and then warmed to 90° C. for an additional 4 h. Cooled to room temperature and added additional 4-piperidone (8.4 mg, 0.08 mmol). Warmed to 90° C. for an additional 4 h. Cooled to room temperature then purified directly on reverse phase silica gel (12 +  M, 14 CV, 20-100% MeCN/water) affording (1R)-7-(difluoromethylsulfonyl)-4-(tetrahydropyran-4-ylamino)indan-1-ol (15.8 mg, 0.046 mmol, 55% yield). LC-MS ESI (−) m/z 346 (M−H).  1 H-NMR (400 MHz, CDCl 3 ): δ 7.69 (d, 1H), 6.64 (d, 1H), 6.26 (t, 1H), 5.57-5.56 (m, 1H), 4.14 (d, 1H), 4.06-4.01 (m, 2H), 3.72-3.62 (m, 1H), 3.58-3.51 (m, 2H), 3.32 (d, 1H), 2.95-2.84 (m, 1H), 2.61-2.55 (m, 1H), 2.47-2.38 (m, 1H), 2.28-2.20 (m, 1H), 2.09-2.03 (m, 2H), 1.62-1.52 (m, 2H). 
     Example 25: Synthesis of 4-(2-hydroxyethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 495) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate: Tetrahydrofuran (12.0 mL) was added all at once to sodium hydride (735.6 mg, 18.39 mmol) at 0° C. under nitrogen followed by the slow addition of diethyl malonate (1.86 mL, 12.26 mmol). Stirred for 15 min then a solution of 4′-fluoro-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (1.0 g, 3.07 mmol) in tetrahydrofuran (3.0 mL) was added by syringe over 2 minutes. The reaction mixture was then removed from the cooling bath and stirred at room temperature overnight. Additional sodium hydride (200 mg) was added as well as diethyl malonate (0.5 mL) and stirred an additional 6 h. Cooled to 0° C., quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purified on silica gel (25 g SNAP Ultra, 10-100% ethyl acetate/hexanes) affording diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (940.0 mg, 2.01 mmol, 66% yield). 
     Step B: Preparation of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid: HCl (4.84 mL, 29.03 mmol) was added to diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (300.0 mg, 0.64 mmol) then warmed to 100° C. for 6 h. Cooled to room temperature, extracted with MTBE, washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo affording 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (200.0 mg, 0.62 mmol, 96% yield). Used without further purification. 
     Step C: Preparation of 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol: Borane dimethylsulfide complex (434.4 μL, 0.87 mmol) was added slowly to 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (70.0 mg, 0.22 mmol) in tetrahydrofuran (1.5 mL) at room temperature and stirred for 2 h. Cooled to 0° C. and quenched with 1 N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 60-100% ethyl acetate/hexanes) affording 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol (36.0 mg, 0.12 mmol, 53% yield). Hexanes was added to the clear oil and then cooled to −78° C. with scratching until a white gum was observed, warmed to room temperature and continued scratching until a white powder formed. Hexanes was then removed under a stream of nitrogen to afford Compound 495. LC-MS (−) ESI m/z 309 (M−H).  1 H-NMR (400 MHz, CDCl 3 ): δ 7.83 (d, 1H), 7.47 (d, 1H), 5.61 (d, 1H), 3.95-3.92 (m, 1H), 3.27-3.18 (m, 1H), 3.10 (s, 1H), 2.99-2.96 (m, 3H), 2.41-2.26 (m, 2H). 
     Example 26: Synthesis of (S)-2,2-difluoro-4-(2-hydroxyethyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 496) 
     
       
         
         
             
             
         
       
     
     Step A: Borane dimethylsulfide complex (439.0 μL, 0.88 mmol) was added dropwise to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (268.0 mg, 0.73 mmol) in tetrahydrofuran (7.0 mL) at 0° C. under nitrogen then slowly warmed to room temperature. Stirred until complete as judged by LC-MS. Quenched carefully with saturated sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 40-100% ethyl acetate/hexanes) affording 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]ethanol (95.0 mg, 0.27 mmol, 37% yield). 
     Step B: HCl (1.0 mL, 1.0 mmol) was added all at once to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]ethanol (95.0 mg, 0.27 mmol) in acetone (4.0 mL) at room temperature then stirred until complete as judged by LC-MS. Diluted with water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Used without further purification. 
     Step C: Tert-Butyldimethylsilyl chloride (46.9 mg, 0.31 mmol) was added all at once to a solution of 4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (80.0 mg, 0.26 mmol) and imidazole (53.0 mg, 0.78 mmol) in dichloromethane (2.0 mL) at room temperature then stirred overnight. Diluted with water, extracted with MTBE, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP, 12 CV, 5-60% ethyl acetate/hexanes) affording 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7-(trifluoromethylsulfonyl)indan-1-one (89.0 mg, 0.21 mmol, 81% yield). 
     Step D: Pivalic acid (2.2 mg, 0.02 mmol) was added to a mixture of 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7-(trifluoromethylsulfonyl)indan-1-one (89.0 mg, 0.21 mmol) and 3-methoxypropylamine (37.6 mg, 0.42 mmol) in cyclohexane (1.5 mL): toluene (1.5 mL) at room temperature then warmed to reflux with the azeotropic removal of water by Dean-Stark trap. Monitored by  1 H-NMR. Cooled to room temperature then concentrated in vacuo. Used without further purification. 
     Step E: Crude 4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-(3-methoxypropyl)-7-(trifluoromethylsulfonyl)indan-1-imine (103.0 mg, 0.21 mmol) in acetonitrile (1.5 mL) was added to 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (184.8 mg, 0.52 mmol) and sodium Sulfate (59.3 mg, 0.42 mmol) in acetonitrile (1.5 mL) at 60° C. and stirred for 1 h. Cooled to room temperature then 1 N HCl (3.0 mL) was added and stirred overnight. Extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on reverse phase silica gel (12 +  M, 14 CV, 20-100% acetonitrile/water) affording 2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (40.0 mg, 0.12 mmol, 56% yield). 
     Step F: Chloro{[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) (1.5 mg, 0.002 mmol) was added all at once to an ice cold solution of 2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-one (40.0 mg, 0.12 mmol), triethylamine (32.4 μL, 0.23 mmol) and formic acid (13.2 μL, 0.35 mmol) in dichloromethane (1.0 mL) then sealed with a threaded teflon cap and placed in a 4° C. fridge over the weekend. Purified directly on silica gel (10 g SNAP Ultra, 14 CV, 25-100% ethyl acetate/hexanes) affording (1S)-2,2-difluoro-4-(2-hydroxyethyl)-7-(trifluoromethylsulfonyl)indan-1-ol (Compound 496) (28.0 mg, 0.081 mmol, 70% yield) as a clear oil. Swirled with hexanes to yield a white solid. LC-MS ESI (−) m/z 345 (M−H). 
     Example 27: Synthesis of 3-(2,2-difluoro-1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)propane-1,2-diol (Compound 521) 
     
       
         
         
             
             
         
       
     
     Step A: Tetrakis(triphenylphosphine)palladium(0) (59.69 mg, 0.0500 mmol) was added all at once to a degassed solution of 4′-bromo-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (200.0 mg, 0.52 mmol) and allyltributyltin (0.19 mL, 0.62 mmol) in DMF (5.0 mL) under nitrogen then warmed to 90° C. until complete as judged by LC-MS. Cooled to room temperature, saturated KF (5.0 mL) was added and stirred for 30 min, extracted with MTBE, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 5-50% ethyl acetate/hexanes) affording 4′-allyl-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (145.0 mg, 0.42 mmol, 81% yield). 
     Step B: HCl (2.0 mL, 2.0 mmol) was added all at once to a solution of 4′-allyl-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (145.0 mg, 0.42 mmol) in acetone (5.0 mL) then stirred overnight at room temperature. Diluted with water, extracted with MTBE, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Used without further purification. 
     Step C: Pivalic acid (2.6 mg, 0.02 mmol) was added all at once to 4-allyl-7-(trifluoromethylsulfonyl)indan-1-one (76.0 mg, 0.25 mmol) and 3-methoxypropylamine (76.4 μL, 0.75 mmol) in cyclohexane (1.5 mL): toluene (1.5 mL) at room temperature then warmed to reflux with azeotropic removal of water via a Dean-Stark trap until complete as judged by  1 H-NMR. Cooled to room temperature then concentrated in vacuo. Used without further purification. 
     Step D: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (219.4 mg, 0.62 mmol) was added all at once to crude 4-allyl-N-(3-methoxypropyl)-7-(trifluoromethylsulfonyl)indan-1-imine (93.0 mg, 0.25 mmol) and sodium sulfate (70.4 mg, 0.50 mmol) in acetonitrile (3.0 mL) at 60° C. then stirred for 1 h. Cooled to room temperature, 1 N HCl was added (3.0 mL) and stirred for 15 min, extracted with MTBE, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Used without further purification. 
     Step E: Sodium borohydride (25.0 mg, 0.66 mmol) was added all at once to a solution of 4-allyl-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-one (75.0 mg, 0.22 mmol) and 2,2-difluoro-4-[(E)-prop-1-enyl]-7-(trifluoromethylsulfonyl)indan-1-one (75.0 mg, 0.22 mmol) in methanol (2.0 mL) at room temperature and stirred for 30 min. Quenched with 1 N HCl (2.0 mL), diluted with water, extracted with MTBE, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Used without further purification. 
     Step F: Osmium tetroxide, 4 wt. % solution (27.9 μL, 0.004 4 mmol) was added all at once to a solution of 4-allyl-2,2-difluoro-7-(trifluoromethylsulfonyl)indan-1-ol (75.0 mg, 0.22 mmol), 4-methylmorpholine N-oxide (51.3 mg, 0.44 mmol) in acetone (2.0 mL) then stirred over the weekend in a sealed vial. Diluted with water, extracted with ethyl acetate, washed with brine dried over Na 2 SO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 50-100% ethyl acetate/hexanes) affording Compound 521 (17.4 mg, 0.046 mmol, 21% yield). LC-MS ESI (−) m/z 375 (M−H) 
     Example 28: Synthesis of 4-(3-hydroxypropyl)-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 522) 
     
       
         
         
             
             
         
       
     
     Step A: 3-Ethoxy-3-oxopropylzinc bromide (0.77 mL, 0.39 mmol) was added to a solution of 4′-bromo-7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane] (50.0 mg, 0.13 mmol), palladium(II) acetate (2.9 mg, 0.01 mmol) and SPhos (10.6 mg, 0.03 mmol) in tetrahydrofuran (0.5 mL) at room temperature under nitrogen in a sealed microwave vial then warmed to 60° C. until complete as judged by LC-MS. Cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 5-50% ethyl acetate/hexanes) affording ethyl 3-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanoate (25.0 mg, 0.061 mmol, 47% yield). 
     Step B: 1 N HCl (1.0 mL, 1.0 mmol) was added all at once to a solution of ethyl 3-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanoate (25.0 mg, 0.06 mmol) in acetone (2.0 mL) then stirred at room temperature until complete as judged by LC-MS (30 min). Diluted with brine, extracted with ethyl acetate, dried over Na 2 SO 4 , filtered and concentrated in vacuo. Used without further purification. 
     Step C: Lithium borohydride solution (0.2 mL, 0.40 mmol) was added to a solution of crude ethyl 3-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]propanoate (22.0 mg, 0.06 mmol) in tetrahydrofuran (0.50 mL) at room temperature under nitrogen then stirred until complete as judged by LC-MS. Warmed to 75° C. after 5 h at room temperature and held for 3 h. Cooled to room temperature, poured into 1 N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and concentrated in vacuo. Purified on silica gel (10 g SNAP Ultra, 14 CV, 50%-100% EtOAc/hexanes) affording Compound 522 (4.4 mg, 0.014 mmol, 22% yield). LC-MS ESI (−) m/z 323 (M−H). 
     Example 29: Synthesis of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (Compound 523) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 2-17′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-ylacetic acid: Sodium hydroxide (0.55 mL, 1.66 mmol) added by syringe to diethyl 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]propanedioate (515.0 mg, 1.10 mmol) in ethanol 95% (2.2 mL) at room temperature and stirred for 30 min. Warmed to 60° C. for 3 h. Added additional sodium hydroxide (0.55 mL, 1.66 mmol) and stirred until complete as judged by LC-MS. Acidified to pH 2 with 1 N HCl, diluted with brine, extracted with ethyl acetate, dried over Na 2 SO 4 , filtered and concentrated in vacuo affording 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (368 mg, 1.00 mmol, 91% yield). Used without further purification. 
     Step B: Preparation of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-ylacetamide: N,N-Diisopropylethylamine (142.7 μL, 0.82 mmol) added all at once to 2-[7′-(trifluoromethylsulfonyl)spiro[1,3-dioxolane-2,1′-indane]-4′-yl]acetic acid (100.0 mg, 0.27 mmol), ammonium chloride (73.0 mg, 1.4 mmol) and HATU (156.1 mg, 0.41 mmol) in DMF (2.0 mL) at room temperature then stirred until complete as judged by LC-MS. Purified directly on reverse phase silica gel (12+M, 14 CV, 20-100% acetonitrile/water) affording 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (12.0 mg, 0.037 mmol, 14% yield). LC-MS ESI (+) m/z 322 (M+H). 
     Step C: Preparation of 2-[1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide: Sodium borohydride (4.2 mg, 0.11 mmol) was added all at once to 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetamide (12.0 mg, 0.04 mmol) in methanol (1.0 mL) at room temperature and stirred for 20 min. Quenched with 1 N HCl, extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo. A portion was purified by preparative TLC (ethyl acetate) affording Compound 523 (1.6 mg, 0.005 mmol, 13% yield). LC-MS ESI (−) m/z 322 (M−H). 
     Example 30: Synthesis of (R)-2-(1-hydroxy-7-((trifluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-4-yl)acetic acid (Compound 524) 
     
       
         
         
             
             
         
       
     
     Chloro {[(1R,2R)-(−)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido}(p-cymene)ruthenium(II) (2.0 mg, 0.003 mmol) was added all at once to an ice cold solution of 2-[1-oxo-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (102.0 mg, 0.32 mmol), triethylamine (88.2 μL, 0.63 mmol) and formic acid (35.8 μL, 0.95 mmol) in dichloromethane (3.0 mL), sealed with a teflon lined cap and placed in a 4° C. fridge overnight. Warmed to room temperature then stirred for an additional 3 days. Concentrated in vacuo then purified on reverse phase silica gel (25+M, 14 CV, 20-100% acetonitrile/water), diluted with ethyl acetate, washed with 1 N HCl to remove triethylamine, washed with brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo affording 2-[(1R)-1-hydroxy-7-(trifluoromethylsulfonyl)indan-4-yl]acetic acid (45.0 mg, 0.14 mmol, 44% yield). LC-MS ESI (−) m/z 323 (M−H). 
     Example 31: Synthesis of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 574) and (1S,3S)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 575) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione: A solution of 3,6 difluorophthalic anhydride (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 h. The reaction mixture was cooled to 0° C. and treated with 10% hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75° C. for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3×50 mL CH 2 Cl 2 . The combined organics were dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. 
     Step B: Preparation of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione: A solution of the unpurified 4,7-difluoro-1H-indene-1,3(2H)-dione (4.2 g, 23.1 mmol) in acetonitrile (100 mL) cooled in a 25° C. water bath was treated with sodium carbonate (5.38 g, 50.7 mmol). Selectfluor® (17.97 g, 50.7 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were removed under reduced pressure and the residue was poured into 100 mL of 0.1% HCl and extracted with 3×50 mL EtOAc. The combined organics were rinsed with 40 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel 1:1 hexane/ethyl acetate to give 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.5 g, 70%) as a solid.  1 H NMR (400 MHz, CDCl 3 ): δ 7.70 (t, 2H). 
     Step C: Preparation of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one: To a solution of 2,2,4,7-tetrafluoro-1H-indene-1,3(2H)-dione (3.48 g, 16.0 mmol) in dichloromethane (150 mL) at 0° C. was added formic acid (600 μL, 16.0 mmol) and triethylamine (1.55 mL, 11.2 mmol). The resulting mixture was sparged with nitrogen for 5 minutes and then RuCl(p-cymene)[(S,S)-Ts-DPEN] (203.6 mg, 0.32 mmol) was added. The reaction vessel was sealed and put into a 4 OC refrigerator to stand for 18 hours. The reaction mixture was poured into 40 mL 1 N HCl. The CH 2 Cl 2  layer was separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The combined organics were dried with Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using 25% EtOAc/hexane to give (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2.9 g, 83%) as an oil.  1 H NMR (400 MHz, CDCl 3 ): δ 7.51 (ddd, 1H), 7.29-7.23 (m, 1H), 5.44 (dd, 1H), 2.79 (dd, 1H). 
     Step D: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one: A solution of (S)-2,2,4,7-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (966 mg, 4.39 mmol) in acetonitrile (40 mL) at 0° C. was sparged with nitrogen for 5 minutes and treated with sodium thiomethoxice (353.7 mg, 5.05 mmol). The ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was evaporated and the residue partitioned between 40 mL of EtOAc and 40 mL of water. The aqueous layer was further extracted with 2×40 mL of EtOAc. The combined organic extracts were washed with brine, dried over MgSO 4 , filtered, and evaporated. The residue was chromatographed on silica using 10-60% EtOAc/hexane to afford (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (870 mg, 80%) as a yellow solid. LCMS ESI (+)[M+H] +  m/z 249. 
     Step E: Preparation of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (400 mg, 1.6 mmol) was dissolved in MeOH (10 mL) and the reaction was treated dropwise with a solution of Oxone® (2.18 g, 3.55 mmol) dissolved in water (10 mL). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was filtered, the solids were washed with ethyl acetate and the filtrate was concentrated in vacuo. The aqueous filtrate was extracted 3×30 mL of EtOAc and then the combined organics were washed with saturated NaCl, dried over Na 2 SO 4  and concentrated in vacuo to a yellow solid that was used without further purification (467 mg). LCMS ESI (+) [M+H] +  m/z 281. 
     Step F: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: (S)-2,2,4-trifluoro-3-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one (450 mg, 1.6 mmol) was dissolved in dichloromethane (16 mL), cooled to 0° C. and treated dropwise with diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and the mixture was stirred at 0° C. for 2 hours, then the whole homogeneous reaction mixture was placed into the refrigerator overnight. The reaction was treated with additional diethylaminosulfur trifluoride (0.32 mL, 2.4 mmol) and stirring continued for 6 h at 0° C. The cold reaction was treated with saturated NaHCO 3  (10 mL) and stirred vigorously for 20 minutes. The mixture was diluted with additional methylene chloride and the layers were separated. The aqueous was re-extracted with methylene chloride and the combined organic layers were dried over Na 2 SO 4  and concentrated in vacuo to a yellow solid. The crude material was chromatographed on SiO 2  (Biotage SNAP Ultra) and eluted with a gradient of ethyl acetate/hexane. The desired material was concentrated to a pale yellow solid (258 mg). LCMS ESI (+) [M+H] +  m/z 283. 
     Step G: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]: A solution of (3R)-2,2,3,4-tetrafluoro-7-methylsulfonyl-indan-1-one (2.03 g, 7.2 mmol) and 2-bromoethanol (1.53 mL, 21.6 mmol) in DMF (16 mL) at 25° C. was treated with potassium carbonate (2.98 g, 21.6 mmol) and stirred at 25° C. for 30 min. The reaction mixture was poured into 200 mL of water and extracted with 3×50 mL Et2O. The combined organics were rinsed with 30 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. The off-white solid was used without further purification. LCMS ESI (+) [M+H] +  m/z 327. 
     Step H: Preparation of (R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydrospiro[indene-1,2′-[1,3]dioxolane]: A solution of (3′R)-2′,2′,3′,4′-tetrafluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (1.95 g, 5.98 mmol) and 3,3-difluoro-cyclobutanol (770 μL, 7.95 mmol) in acetonitrile (30 mL) at 25° C. was treated with potassium hydroxide (402.4 mg, 7.17 mmol) and stirred at 25° C. for 1 h. Excess acetonitrile was removed by concentration under reduced pressure. The reaction mixture was poured into 40 mL of water and extracted with 3×40 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 15-45% EtOAc/hexane to afford a white solid (2.2 g, 89%). LCMS ESI (+) [M+H] +  m/z 415. 
     Step I: Preparation of (R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-one: A solution of (3′R)-4′-(3,3-difluorocyclobutoxy)-2′,2′,3′-trifluoro-7′-methylsulfonyl-spiro[1,3-dioxolane-2,1′-indane] (2.2 g, 5.31 mmol) in dichloromethane (30 mL) at 25° C. was treated with perchloric acid (70% in water, 10 mL) and left to stir for 2 days. The reaction mixture was carefully quenched by the addition of 100 mL of saturated aqueous NaHCO 3  and extracted with 3×50 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 25-65% EtOAc/hexane to afford a solid (1.41 g, 72%). LCMS ESI (+) [M+H] m/z 371. 
     Step J: Preparation of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 574) and (1S,3S)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-(methylsulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 575): A solution of (3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-methylsulfonyl-indan-1-one (1.41 g, 3.81 mmol) in dichloromethane (40 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time formic acid (430 μL, 11.42 mmol) and triethylamine (1.06 mL, 7.62 mmol) were sequentially added. Once the sparging was complete, RuCl(p-cymene)[(R,R)-Ts-DPEN] (48.5 mg, 0.076 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. The residue was purified by chromatography on silica using 25-55% EtOAc/hexane. Additional purifications by chromatography on silica using 20-50% EtOAc/hexane were necessary to isolate material of sufficient purity. A flash crystallization was preformed from CHCl 3 . The sample was dissolved in a minimum of refluxing CHCl 3  and then cooled to 0° C. The collected solid was rinsed with CHCl 3  and dried under high vacuum overnight to afford Compound 574 as a white solid (550 mg, 39%). From the repeated purifications, Compound 575 was isolated as a white solid. Data for Compound 574: LCMS ESI (+) [M+H] +  m/z 373;  1 H NMR (400 MHz, (CD 3 ) 2 CO): δ 8.11 (dd, 1H), 7.33 (d, 1H), 5.87 (dd, 1H), 5.65-5.59 (m, 1H), 5.17-5.08 (m, 1H), 3.40-3.26 (m, 2H), 3.27 (s, 3H), 2.98-2.81 (m, 2H), 2.80 (t, 1H). Data for Compound 575: LCMS ESI (+) [M+H] +  m/z 373;  1 H NMR (400 MHz, CDCl 3 ): δ 8.06 (dd, 1H), 6.87 (d, 1H), 5.92 (dd, 1H), 5.78 (td, 1H), 4.86-4.76 (m, 1H), 3.98 (d, 1H), 3.25-3.14 (m, 2H), 3.22 (s, 3H), 2.95-2.78 (m, 2H). 
     Example 32: Synthesis of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 576) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of (R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one: A solution of (S)-2,2,4-trifluoro-3-hydroxy-7-(methylthio)-2,3-dihydro-1H-inden-1-one (402 mg, 1.62 mmol) in dichloromethane (16.2 mL) at 0° C. was treated with diethylaminosulfur trifluoride (390 μL, 2.92 mmol). The ice bath was removed from the resulting reaction mixture and the reaction mixture was stirred for 2 hours at room temperature. Volatiles were removed by concentration under reduced pressure. The residue was suspended in 30 mL of EtOAc, cooled to 0° C., and quenched by the addition of 20 mL of saturated aqueous NaHCO 3 . The reaction mixture was vigorously stirred for 30 minutes and then extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used without further purification. LCMS ESI (+) [M+H] +  m/z 251. 
     Step B: Preparation of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one: A solution of (R)-2,2,3,4-tetrafluoro-7-(methylthio)-2,3-dihydro-1H-inden-1-one (393 mg, 1.57 mmol) in acetonitrile (15.7 mL) at 0° C. was treated with Selectfluor® (584.3 mg, 1.65 mmol) and stirred at 0° C. for 2 hours. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×20 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (153 mg, 36%) as a yellow oil. LCMS ESI (+) [M-F] +  m/z 249. 
     Step C: Preparation of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one: A solution of (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)thio)-2,3-dihydro-1H-inden-1-one (91.8 mg, 0.34 mmol) in a mixture of methanol (3.4 mL) and water (3.4 mL) was treated with Oxone® (252.5 mg, 0.41 mmol). The resulting suspension was heated to 60° C. overnight. Additional Oxone® (252.5 mg, 0.41 mmol) was added and the reaction mixture heated for an additional 6 hours. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 100 mL of water and extracted with 3×25 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford (R)-2,2,3,4-tetrafluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-one as a white solid (73 mg, 71%). LCMS ESI (+) [M+H] +  m/z 301. 
     Step D: Preparation of (1S,3R)-4-(3,3-difluorocyclobutoxy)-2,2,3-trifluoro-7-((fluoromethyl)sulfonyl)-2,3-dihydro-1H-inden-1-ol (Compound 576): Prepared similarly as described in Example 31, Steps G-J. Purification was achieved by chromatography on silica using 15-30% EtOAc/hexane to afford Compound 576 (29.8 mg, 49%) as a white solid. Retention time HPLC (14 min)=4.63 min; LCMS ESI (+) [M+H] +  m/z 391;  1 H NMR (400 MHz, CDCl 3 ): δ 8.13 (dd, 1H), 6.93 (d, 1H), 5.76 (dd, 1H), 5.59-5.53 (m, 1H), 5.47 (dd, 1H), 5.18 (dd, 1H), 4.90-4.80 (m, 1H), 3.29-3.16 (m, 2H), 3.16 (d, 1H), 2.97-2.81 (m, 2H). 
     Example 33: Synthesis of 3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile (Compound 813) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 3-((5-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile: A suspension of 3-fluoro-5-[1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (1520 mg, 4 mmol), 2,2′-azobisisobutyronitrile (66 mg, 0.4 mmol), magnesium oxide (483 mg, 12 mmol) and N-bromosuccinimide (925 mg, 5.2 mmol) in 1,2-dichloroethane (40 mL) was sparged with nitrogen for 3 minutes. The vessel was sealed and heated to 80° C. for 3 h. Additional 2,2′-azobisisobutyronitrile (66 mg, 0.4 mmol) and N-bromosuccinimide (925 mg, 5.2 mmol) was added to help drive the reaction to completion. Heating was continued for an additional 1.5 h. The reaction mixture was left at room temperature overnight. MgO was removed by filtration through the celite and rinsing of the filter cake with CH 2 Cl 2 . The filtrate was treated with 30 mL of saturated aqueous NaHCO 3 , stirred for 10 minutes, and extracted with 3×30 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-25% EtOAc/hexane to afford 3-((5-bromo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile as a yellow foam (931 mg, 51%). LCMS ESI (+) (M+H) m/z 459/461. 
     Step B: Preparation of 3-fluoro-5-((5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A solution of 3-[5′-bromo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-5-fluoro-benzonitrile (931 mg, 2 mmol) in a mixture of 1,2-dimethoxyethane (15 mL) and water (5 mL) at 25° C. was treated with silver(I) carbonate (1.12 g, 4.1 mmol) and stirred at 85° C. for 8 h. An additional portion of silver(I) carbonate (1.12 g, 4.05 mmol) was added and the reaction mixture left to heat at 85° C. overnight. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was washed with water and brine, dried and concentrated. Purification was achieved by chromatography on silica using 20-55% EtOAc/hexane to afford 3-fluoro-5-((5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a yellow solid (295 mg, 37%). LCMS ESI (+) (M+H) m/z 397. 
     Step C: Preparation of 3-fluoro-5-((5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A solution of 3-fluoro-5-[5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (296 mg, 0.75 mmol) in dichloromethane (15 mL) at 25° C. was treated with Dess-Martin periodinane (396 mg, 0.93 mmol). After 1 h, an additional 20 mg of Dess-Martin periodinane was added. After stirring for another 30 minutes, the reaction was quenched by the addition of 6 mL of saturated Na 2 S 2 O 3  solution and 6 mL of saturated NaHCO 3  solution. The resulting biphase was stirred for 10 minutes. The reaction mixture was poured into 10 mL of water and extracted with 3×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product, 3-fluoro-5-((5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile (264 mg), was used without further purification. LCMS ESI (+) (M+H) m/z 395. 
     Step D: Preparation of 3-fluoro-5-((6-fluoro-5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A solution of 3-fluoro-5-[5′-oxo-1′-(trifluoromethyl)spiro[1,3]-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (294 mg, 0.75 mmol) and triethylamine (520 μL, 3.7 mmol) in dichloromethane (15 mL) at 0° C. was treated with tert-butyldimethylsilyl trifluoromethane (690 μL, 2.98 mmol) and stirred at 0° C. for 30 minutes. The reaction mixture was left to stir for 5 h during which it was slowly warmed to room temperature. The reaction mixture was poured into 15 mL of saturated NaHCO 3 , stirred for 10 minutes, and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The crude residue was dissolved in 4 mL of acetonitrile and treated with Selectfluor® (264 mg, 0.75 mmol). The reaction mixture was stirred for 3 h at room temperature. Volatiles were removed by concentration under reduced pressure. The mixture was poured into 30 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-30% EtOAc/hexane to afford 3-fluoro-5-((6-fluoro-5-oxo-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a white solid (206 mg, 67%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.51 (s, 1H), 7.32-7.28 (m, 1H), 7.21-7.18 (m, 1H), 7.13-7.08 (m, 1H), 5.20 (d, 1H), 4.51-4.31 (m, 4H). 
     Step E: Preparation of 3-fluoro-5-(((5R,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A solution of 3-fluoro-5-[6′-fluoro-5′-oxo-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (206 mg, 0.5 mmol) in dichloromethane (10 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time, formic acid (57 μL, 1.50 mmol) and triethylamine (104 μL, 0.75 mmol) were sequentially added. Once sparging was complete, RuCl(p-cymene)[(S,S)-Ts-DPEN] (6.4 mg, 0.01 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. Purification was achieved by chromatography on silica using 20-45% EtOAc/hexane to afford 3-fluoro-5-(((5R,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a clear solid (200 mg, 97%). LCMS ESI (+) (M+H) m/z 415. 
     Step F: Preparation of (5S,6R)-4-(3-cyano-5-fluorophenoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl 4-nitrobenzoate: A solution of 3-fluoro-5-[(5′R,6′R)-6′-fluoro-5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (200 mg, 0.48 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g, 938 mg, 1.93 mmol), and 4-nitrobenzoic acid (323 mg, 1.93 mmol) in tetrahydrofuran (9.7 mL) at 25° C. was treated with diisopropyl azodicarboxylate (371 μL, 1.88 mmol) and stirred for 2 h. The reaction mixture was filtered and the filter cake rinsed with EtOAc. The filtrate was concentrated and purified by chromatography on silica using 10-35% EtOAc/hexane to afford (5S,6R)-4-(3-cyano-5-fluorophenoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl 4-nitrobenzoate as a white solid (221 mg, 81%). LCMS ESI (+) (M+H) m/z 564. 
     Step G: Preparation of 3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile: A solution of [(5&#39;S,6′R)-4′-(3-cyano-5-fluoro-phenoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-yl]4-nitrobenzoate (238 mg, 0.42 mmol) in tetrahydrofuran (8 mL) at 25° C. was treated with a solution of freshly prepared lithium hydroxide hydrate (19.5 mg, 0.46 mmol) in water (2.4 mL) and stirred at 25° C. for 30 minutes. An additional portion of lithium hydroxide hydrate (10 mg, 0.24 mmol) in water (1.2 mL) was added and the reaction mixture stirred for 30 minutes. 2.0 mL of saturated NH 4 Cl was added to the reaction mixture and volatiles were removed under reduced pressure. The reaction mixture was poured into 10 mL of saturated NaHCO 3  and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-10% EtOAc/dichloromethane to afford 3-fluoro-5-(((5S,6R)-6-fluoro-5-hydroxy-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)benzonitrile as a white solid (137 mg, 78%). LCMS ESI (+) (M+H) m/z 415. 
     Step H: Preparation of 3-(((5R,6S)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile: A solution of 3-fluoro-5-[(5&#39;S,6′R)-6′-fluoro-5′-hydroxy-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-benzonitrile (137 mg, 0.33 mmol) in dichloromethane (6.6 mL) at 25° C. was treated with diethylaminosulfur trifluoride (87.4 L, 0.66 mmol). The reaction mixture was allowed to stir for 30 minutes. The reaction mixture was quenched by the careful addition of 2 mL of aqueous saturated NaHCO 3 . The resulting mixture vigorously stirred for 30 minutes. The reaction mixture was poured into 20 mL of water and extracted with 3×10 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford 3-(((5R,6S)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-4-yl)oxy)-5-fluorobenzonitrile as a white solid (92.7 mg, 67%). LCMS ESI (+) (M+H) m/z 417. 
     Step I: Preparation of 3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile (Compound 813): A solution of 3-[(5′R,6&#39;S)-5′,6′-difluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-yl]oxy-5-fluoro-benzonitrile (93 mg, 0.22 mmol) in dichloromethane (5 mL) at 0 C was treated with 70% aqueous perchloric acid (1.0 mL) and stirred at 44 C for 3 h. The reaction mixture was cooled to 0° C., carefully quenched with a mixture of 10 mL of saturated NaHCO 3 /10 mL of water and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The intermediate ketone product was used immediately without further purification by dissolving in 4 mL of MeOH, cooling to 0° C., and treating with sodium borohydride (8.4 mg, 0.22 mmol). The reaction stirred for 15 min and was then quenched by the addition of 1 mL of saturated NH 4 Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-45% EtOAc/hexane to afford 3-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)-5-fluorobenzonitrile as a white solid (60 mg, 72%). Retention time HPLC (14 min)=4.18 minutes; LCMS ESI (+) (M+H) m/z 375;  1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 7.28 (ddd, 1H), 7.20-7.18 (m, 1H), 7.09 (dt, 1H), 5.92 (dt, 1H), 5.53-5.46 (m, 1H), 5.19 (ddt, 1H), 2.66 (ddd, 1H). 
     Example 34: Synthesis of 5-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrile (Compound 825) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 5-(((5R,6S,7S)-5,6-difluoro-7-hydro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrile (Compound 825): A solution of tetrahydrofuran (2.0 mL) and Water (4.0 mL) was sparged with nitrogen for 3 minutes. Sparging was ceased and to the solution were sequentially added under continuous nitrogen stream (5R,6S,7S)-4-[(5-bromo-3-pyridyl)oxy]-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (50 mg, 0.12 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (19 mg, 0.024 mmol) and zinc cyanide (20 mg, 0.17 mmol). The vessel was sealed and heated to 40° C. for 3 h. An additional portion of [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (19 mg, 0.024 mmol) and zinc cyanide (20 mg, 0.17 mmol) were added and the reaction mixture was heated to 65° C. for 18 h. The reaction mixture was poured into 10 mL of saturated NaHCO 3  and extracted with 3×10 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 20-60% EtOAc/hexane to afford 5-(((5R,6S,7S)-5,6-difluoro-7-hydroxy-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)oxy)nicotinonitrile as a white solid (34.3 mg, 80%). Retention time HPLC (14 min)=2.55 minutes; LCMS ESI (+) (M+H) m/z 358;  1 H NMR (400 MHz, CDCl 3 ): δ 8.79 (dd, 1H), 8.71 (d, 1H), 8.41 (s, 1H), 7.67 (dd, 1H), 5.94 (dt, 1H), 5.53-5.46 (m, 1H), 5.21 (ddt, 1H), 2.73 (ddd, 1H). 
     Example 35: Synthesis of (5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 828) 
     
       
         
         
             
             
         
       
     
     Step A: Preparation of 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: A solution of 1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol (1.9 g, 7.27 mmol), (3,3-difluorocyclobutyl) 4-methylbenzenesulfonate (2.86 g, 10.9 mmol), potassium iodide (1.81 g, 10.9 mmol) and potassium carbonate (2.0 g, 14.6 mmol) in acetonitrile (20 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (100 mL), washed with water (100 mL) and brine (20 mL). The organic phase was collected, dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated. Purification was achieved by chromatography on silica using 10-20% EtOAc/petroleum ether to afford 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] as a white solid (1.00 g, 2.85 mmol, 39%). LCMS ESI (+) (M+H) m/z 352. (The Mitsunobu reaction can also be used to derivatize the 1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-4′-ol.) 
     Step B: Preparation of 5-bromo-4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: A solution of 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (1.00 g, 2.85 mmol), 2,2′-azobisisobutyronitrile (94 mg, 0.57 mmol), NaHCO 3  (420 mg, 5.0 mmol) and 1-bromopyrrolidine-2,5-dione (1.27 g, 7.12 mmol) in 1,2-dichloroethane (20 mL) was sparged with nitrogen for 3 minutes. The vessel was sealed and heated to 80° C. for 1 h. The reaction mixture was poured into 30 mL of saturated aqueous Na 2 SO 3  and extracted with 3×30 mL CH 2 Cl 2 . The combined organics were rinsed with 20 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-25% EtOAc/hexane to afford 5′-bromo-4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] as an off-white solid (650 mg, 1.5 mmol, 53%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.11 (s, 1H), 5.36-5.31 (m, 1H), 4.98-4.88 (m, 1H), 4.36-4.21 (m, 2H), 4.16-4.07 (m, 2H), 3.26-3.13 (m, 2H), 2.96-2.71 (m, 4H). 
     Step C: Preparation of 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol: A solution of 5′-bromo-4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (650 mg, 1.5 mmol) in a mixture of 1,2-dimethoxyethane (15 mL) and water (5 mL) was treated with silver carbonate (417 mg, 1.5 mmol) and stirred at 85° C. overnight. The mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated to remove the dimethoxyethane. The residue was re-suspended in 60 mL of 1:1 EtOAc/H 2 O and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol as a solid (280 mg, 50%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.11 (s, 1H), 5.39-5.32 (m, 1H), 4.97-4.87 (m, 1H), 4.33-4.20 (m, 2H), 4.17-4.04 (m, 2H), 3.27-3.13 (m, 2H), 2.96-2.75 (m, 2H), 2.63 (dd, 1H), 2.53 (d, 1H), 2.28 (dd, 1H). 
     Step D: Preparation of 4-(3,3-difluorocyclobutoxy)-1-(trifluoromethyl)spiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5(6H)-one: A solution of 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol (280 mg, 0.76 mmol) in dichloromethane (10 mL) at 25° C. was treated with Dess-Martin periodinane (500 mg, 1.18 mmol). After 2 h, the reaction was quenched by the addition of 10 mL of saturated Na 2 S 2 O 3  solution and 10 mL of saturated NaHCO 3  solution. The resulting biphase stirred for 10 minutes. The reaction mixture was poured into 20 mL of water and extracted with 3×20 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness to afford 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one as a solid (270 mg, 97%) that was used without further purification. LCMS ESI (+) (M+H) m/z 366. 
     Step E: Preparation of 4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)spiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5(6H)-one: A solution of 4′-(3,3-difluorocyclobutoxy)-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one (270 mg, 0.74 mmol) and triethylamine (410 μL, 3 mmol) in dichloromethane (10 mL) at 0° C. was treated with tert-butyl-dimethyl-(trifluoromethylsulfonyl)silane (480 μL, 2.2 mmol) and stirred at 0° C. for 30 minutes. The reaction mixture was left to stir overnight at room temperature. The reaction mixture was poured into 10 mL of saturated NaHCO 3 , stirred for 10 minutes, and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The unpurified residue was dissolved in acetonitrile (10 mL) and treated with Selectfluor® (322 mg, 0.92 mmol). The reaction stirred for 6 h at room temperature. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 30 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-20% EtOAc/hexane to afford 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one as a white solid (180 mg, 56%).  1 H NMR (400 MHz, CDCl 3 ): δ 8.35 (s, 1H), 5.13 (d, 1H), 5.01-4.91 (m, 1H), 4.47-4.38 (m, 1H), 4.38-4.26 (m, 3H), 3.30-3.14 (m, 2H), 3.04-2.86 (m, 2H). 
     Step F: Preparation of (5R,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol: A solution of 4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-6H-cyclopenta[c]pyridine]-5′-one (180 mg, 0.47 mmol) in dichloromethane (10 mL) was cooled to 0° C. and sparged with nitrogen for 5 minutes. During this time formic acid (53.1 μL, 1.4 mmol) and triethylamine (98.2 μL, 0.70 mmol) were sequentially added. Once sparging was complete, RuCl(p-cymene)[(S,S)-Ts-DPEN] (15 mg, 0.023 mmol) was added under a continuous stream of nitrogen. The reaction vessel was sealed and put into the refrigerator to react overnight. Volatiles were removed by concentration under reduced pressure. Purification was achieved by chromatography on silica using 10-30% EtOAc/hexane to afford (5′R,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol as a clear solid (152 mg, 84%). LCMS ESI (+) (M+H) m/z 386. 
     Step G: Preparation of (5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl 4-nitrobenzoate: A solution of (5′R,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol (124 mg, 0.32 mmol), polymer supported triphenylphosphine (˜2.06 mmol/g, 627 mg, 1.29 mmol), and 4-nitrobenzoic acid (216 mg, 1.29 mmol) in tetrahydrofuran (3.3 mL) was treated with diisopropyl azodicarboxylate (248 μL, 1.26 mmol) and stirred at 25° C. for 2 h. The reaction mixture was filtered and the filter cake rinsed with 30 mL EtOAc. The filtrate was concentrated and purified by chromatography on silica using 10-25% EtOAc/hexane to afford (5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-yl 4-nitrobenzoate as a white solid (160 mg, 93%). LCMS ESI (+) (M+H) m/z 535. 
     Step H: Preparation of (5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol: A solution of [(5&#39;S,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-yl]4-nitrobenzoate (194 mg, 0.36 mmol) in tetrahydrofuran (7 mL) at 25° C. was treated with a solution of freshly prepared hydroxylithium hydrate (16.8 mg, 0.4 mmol) in water (2.1 mL) and stirred at 25° C. for 30 minutes. An additional portion of hydroxylithium hydrate (8.4 mg, 0.20 mmol) in water (1.0 mL) was added and the reaction mixture stirred for another 30 minutes. Saturated NH 4 Cl (0.5 mL) was added and volatiles were removed under reduced pressure. The reaction mixture was poured into 10 mL of saturated NaHCO 3  and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-35% EtOAc/hexane to afford (5S,6R)-4-(3,3-difluorocyclobutoxy)-6-fluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolan]-5-ol as a white solid (74 mg, 53%). LCMS ESI (+) (M+H) m/z 386. 
     Step I: Preparation of (5R,6S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane]: A solution of (5&#39;S,6′R)-4′-(3,3-difluorocyclobutoxy)-6′-fluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine]-5′-ol (74 mg, 0.19 mmol) in dichloromethane (3.8 mL) at 25° C. was treated with diethylaminosulfur trifluoride (51 μL, 0.38 mmol). The reaction mixture was allowed to stir for 30 minutes. The reaction mixture was quenched by the careful addition of 1 mL of aqueous saturated NaHCO 3 . The resulting mixture stirred for 30 minutes, poured into 20 mL of water and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 5-25% EtOAc/hexane to afford (5R,6S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-5,6-dihydrospiro[cyclopenta[c]pyridine-7,2′-[1,3]dioxolane] as a white solid (72 mg, 97%). LCMS ESI (+) (M+H) m/z 388. 
     Step J: Preparation of (5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (Compound 828): A solution of (5′R,6&#39;S)-4′-(3,3-difluorocyclobutoxy)-5′,6′-difluoro-1′-(trifluoromethyl)spiro[1,3-dioxolane-2,7′-5,6-dihydrocyclopenta[c]pyridine] (72 mg, 0.19 mmol) in dichloromethane (4.0 mL) at 0° C. was treated with 70% aqueous perchloric acid (800 μL). The reaction mixture was heated to 44° C. for 5 h. The reaction mixture was cooled to 0° C., carefully quenched with a mixture of 10 mL of saturated NaHCO 3 /10 mL of water and extracted with 3×15 mL CH 2 Cl 2 . The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. The product was used immediately without further purification by dissolving in 2 mL of MeOH, cooling to 0° C., and treating with sodium borohydride (7.0 mg, 0.19 mmol). The reaction stirred for 15 min and was then quenched by the addition of 1 mL of saturated NH 4 Cl. Volatiles were removed by concentration under reduced pressure. The reaction mixture was poured into 20 mL of water and extracted with 3×15 mL EtOAc. The combined organics were rinsed with 10 mL of brine, dried with MgSO 4 , filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 10-40% EtOAc/hexane to afford (5R,6S,7S)-4-(3,3-difluorocyclobutoxy)-5,6-difluoro-1-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol as a white solid (53 mg, 83%). Retention time HPLC (14 min)=3.37 minutes; LCMS ESI (+) (M+H) m/z 346;  1 H NMR (400 MHz, CDCl 3 ): δ 8.24 (s, 1H), 5.95 (ddd, 1H), 5.47-5.41 (m, 1H), 5.07 (ddt, 1H), 4.97-4.88 (m, 1H), 3.30-3.15 (m, 2H), 2.99-2.79 (m, 2H), 2.54-2.49 (m, 1H). 
     Example 36: HIF-2α Scintillation Proximity Assay (SPA) 
     The total assay volume was about 100 μL in the following configuration: 2 μL compound in 100% DMSO, 88 μL buffer with protein and probe and 10 μL of SPA beads. The compound was diluted in a master plate consisting of a 10-point dose response with a 3-fold compound dilution from 100 μM to 5 nM. Assays were run on a 96-well plate in which one column, designated as the high signal control, contained DMSO with no compound and another column, designated as the low signal control, contained no protein. Prior to plating out of compound, a buffer solution, consisting of 25 mM TRIS pH 7.5 (Sigma), 150 mM NaCl (Sigma), 15% Glycerol (Sigma), 0.15% BSA (Sigma), 0.001% Tween-20 (Sigma), 150 nM N-(3-Chlorophenyl-4,6-t 2 )-4-nitrobenzo[c][1,2,5]oxadiazol-5-amine (Compound 183) and 100 nM HIF-2α HIS TAG-PASB Domain, was made and allowed to equilibrate for 30 minutes. Compounds that were to be tested were then plated in to a 96-well white clear bottom Isoplate-96 SPA plate (Perkin Elmer). To the compounds was added 88 μL of the buffer solution, then the plate covered with a plastic cover and aluminum foil, placed onto a shaker and equilibrated for 1 hour. After equilibration, 10 μL of a 2 mg/mL solution of YSi Cu His tagged SPA beads (Perkin Elmer) were then added to each well of the plate, covered and equilibrated for another 2 hours. The plates were then removed from the shaker, placed into a 1450 LSC and luminescence counter MicroBeta Trilux (Perkin Elmer) to measure the extent of probe displacement. The percent inhibition was determined and IC 50  values were calculated using the Dotmatics system based on the following equation: % inhibition=[(high control−sample)/(high control−low control)]×100. 
     Example 37: VEGF ELISA Assay 
     About 7500 786-O cells in 180 μL of growth medium were seeded into each well of a 96-well, white, clear bottom plate (07-200-566, Fisher Scientific) on day one in the layout presented in  FIG. 4 . 
     Four hours later, serial dilutions of 10× compound stocks were made in growth medium from 500×DMSO stocks, and 20 μL of those 10× stocks were added to each well to make final concentrations as follows (μM): 20, 6.67, 2.22, 0.74, 0.25, 0.082, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was plated in duplicate. About 20 hours later, medium was removed by suction and each well was supplied with 180 μL of growth medium. About 20 □l freshly-made 10× compound stocks were added to each well. About 24 hours later, cell culture medium was removed and the VEGF concentration determined using an ELISA kit purchased from R&amp;D systems, following the manufacturer&#39;s suggested method. The EC 50  was calculated by GraphPad Prism using the dose-response-inhibition (four parameter) equation. The cell-seeded plate was then subjected to CellTiter-Glo luminescence cell viability assay (Promega) by adding 50 μL of Celltiter Glo reagent into each well and shaking the plate for 8 minutes at 550 rpm (Thermomixer R, Eppendorf) then the luminescence signal immediately read in a plate reader (3 second delay, 0.5 second/well integration time, Synergy 2 multi Detection Microplate reader). 
     Example 38: Luciferase Assay 
     786-O-Hif-Luc single clone cells were obtained by infecting 786-0 cells (ATCC® CRL-1932™) with commercial lentivirus that delivers a luciferase gene driven by multiple HIF responsive elements (Cignal Lenti HIF Reporter (luc): CLS-007L, Qiagen) at Multiplicity of Infection (MOI) of 25 for 24 hours. The cells were replenished with fresh medium (Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM, D5796, Sigma) supplemented with 10% FBS (F6178, Sigma), 100 units penicillin and 100 μg streptomycin/mL (P4333, Sigma)) for another 24 hours. A pool of infected cells were then selected against 2 μg/mL of puromycin (P8833, Sigma) for 10 days followed by limited dilution to select single clones. The clones were tested for their response to HIF2 inhibitors and the ones that showed the biggest dynamic range (786-0-Hif-Luc) were expanded and used for the luciferase assay. For the luciferase assay, about 7500 786-0-Hif-Luc cells in 90 μL growth medium were seeded into each well of a 96-well white opaque plate (08-771-26, Fisher scientific) a day before treatment with the layout presented in  FIG. 5 . 
     On treatment day, serial dilutions of 10× compound stocks were made in growth medium from 500×DMSO stocks, and 10 μL of the 10× stocks were added to each well to make final concentrations as follows (μM): 20, 6.67, 2.22, 0.74, 0.25, 0.08, 0.027, 0.009, 0.003, 0.001, and 0. Each concentration was tested in triplicate. After about 24 hours, luciferase activity was determined using ONE-Glo Luciferase Assay Reagent (E6110, Promega) following the manufacturer&#39;s recommended procedure. EC 50  were calculated using Dotmatics software. 
     Table 2 shows biological activities of selected compounds in Luciferase, VEGF ELISA and Scintillation Proximity assays. Compound numbers correspond to the numbers and structures provided in Table 1 and Examples 1-35. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                 Less than 
                 50 nM to 
                 250 nM to 
                 Greater than 
               
               
                   
                 50 nM (++++) 
                 249 nM (+++) 
                 1000 nM (++) 
                 1000 nM (+) 
               
               
                   
               
             
            
               
                 Scintillation 
                 1, 2, 6, 7a, 8, 9, 
                 17, 18, 21, 33, 38, 
                 3, 5, 16, 22, 24, 
                 4, 7b, 12, 13, 14, 
               
               
                 Proximity Assay 
                 11, 15, 25, 26, 29, 
                 39, 41, 50, 54, 74, 
                 27, 31, 40, 42, 43, 
                 19, 20, 23, 28, 35, 
               
               
                 IC 50  (nM) 
                 30, 32, 34, 52, 55, 
                 75, 90, 93, 94, 99, 
                 46, 48, 53, 70, 71, 
                 36, 37, 44, 45, 47, 
               
               
                   
                 56, 57, 58, 59, 60, 
                 100, 102, 107, 
                 72, 76, 78, 81, 91, 
                 49, 51, 66, 68, 69, 
               
               
                   
                 61, 62, 63, 64, 65, 
                 116, 117, 118, 
                 103, 104, 106, 
                 73, 77, 79, 82, 83, 
               
               
                   
                 67, 80, 92, 98, 
                 119, 128, 136, 
                 115, 120, 131, 
                 84, 85, 86, 87, 88, 
               
               
                   
                 101, 111, 112, 
                 141, 145, 146, 
                 132, 133, 134, 
                 89, 95, 96, 97, 
               
               
                   
                 123, 124, 140, 
                 147, 148, 153, 
                 135, 137, 152, 
                 105, 108, 109, 
               
               
                   
                 143, 144, 155, 
                 156, 162, 165, 
                 157, 172, 178, 
                 110, 113, 114, 
               
               
                   
                 158, 159, 160, 
                 187, 192, 195, 
                 182, 184, 190, 
                 121, 122, 125, 
               
               
                   
                 161, 163, 166, 
                 203, 204, 214, 
                 193, 197, 202, 
                 126, 127, 129, 
               
               
                   
                 167, 168, 179, 
                 224, 237, 241, 
                 207, 209, 212, 
                 130, 138, 139, 
               
               
                   
                 185, 186, 188, 
                 242, 252, 254, 
                 213, 218, 220, 
                 142, 149, 150, 
               
               
                   
                 191, 194, 196, 
                 260, 265, 267, 
                 243, 244, 249, 
                 151, 154, 164, 
               
               
                   
                 198, 200, 201, 
                 270, 274, 275, 
                 258, 261, 264, 
                 169, 170, 171, 
               
               
                   
                 206, 215, 221, 
                 276, 277, 285, 
                 269, 271, 281, 
                 173, 174, 175, 
               
               
                   
                 223, 225, 227, 
                 295, 302, 308, 
                 287, 293, 307, 
                 176, 177, 180, 
               
               
                   
                 228, 229, 230, 
                 312, 324, 325, 
                 339, 346, 369, 
                 181, 189, 199, 
               
               
                   
                 231, 232, 233, 
                 333, 334, 336, 
                 374, 411, 422, 
                 205, 208, 210, 
               
               
                   
                 234, 235, 236, 
                 353, 358, 361, 
                 423, 432, 433, 
                 211, 216, 217, 
               
               
                   
                 240, 245, 247, 
                 370, 378, 381, 
                 434, 471, 476, 
                 219, 222, 226, 
               
               
                   
                 251, 256, 263, 
                 383, 387, 388, 
                 481, 482, 487, 
                 238, 239, 246, 
               
               
                   
                 266, 273, 286, 
                 399, 405, 409, 
                 496, 505, 506, 
                 248, 250, 253, 
               
               
                   
                 289, 290, 292, 
                 412, 414, 421, 
                 511, 513, 522, 
                 255, 257, 259, 
               
               
                   
                 303, 304, 305, 
                 424, 426, 427, 
                 523, 531, 542, 
                 262, 268, 272, 
               
               
                   
                 306, 309, 310, 
                 437, 442, 444, 
                 575, 580, 591, 
                 278, 279, 280, 
               
               
                   
                 314, 315, 316, 
                 462, 468, 477, 
                 595, 601, 603, 
                 282, 283, 284, 
               
               
                   
                 317, 319, 321, 
                 480, 488, 517, 
                 612, 622, 637, 
                 288, 291, 294, 
               
               
                   
                 327, 328, 329, 
                 545, 547, 551, 
                 644, 648, 678, 
                 296, 297, 298, 
               
               
                   
                 331, 338, 340, 
                 554, 563, 569, 
                 703, 707, 711, 
                 299, 300, 301, 
               
               
                   
                 341, 342, 344, 
                 584, 586, 598, 
                 735, 748, 749, 
                 311, 313, 318, 
               
               
                   
                 347, 348, 349, 
                 604, 609, 614, 
                 750, 754, 762, 
                 320, 322, 323, 
               
               
                   
                 355, 356, 357, 
                 616, 620, 660, 
                 765, 770, 775, 
                 326, 330, 332, 
               
               
                   
                 359, 360, 364, 
                 663, 669, 672, 
                 781, 812, 816, 
                 335, 337, 343, 
               
               
                   
                 365, 368, 371, 
                 676, 681, 682, 
                 827 
                 345, 350, 351, 
               
               
                   
                 372, 375, 376, 
                 686, 696, 697, 
                   
                 352, 354, 362, 
               
               
                   
                 379, 386, 389, 
                 700, 701, 706, 
                   
                 363, 366, 367, 
               
               
                   
                 392, 397, 398, 
                 714, 717, 718, 
                   
                 373, 377, 380, 
               
               
                   
                 401, 403, 430, 
                 730, 734, 737, 
                   
                 382, 384, 385, 
               
               
                   
                 431, 435, 436, 
                 747, 751, 755, 
                   
                 390, 391, 393, 
               
               
                   
                 440, 443, 446, 
                 759, 768, 769, 
                   
                 394, 395, 396, 
               
               
                   
                 451, 458, 465, 
                 771, 782, 784, 
                   
                 400, 402, 404, 
               
               
                   
                 466, 467, 472, 
                 788, 795, 808, 
                   
                 406, 407, 408, 
               
               
                   
                 473, 478, 483, 
                 815, 818 
                   
                 410, 413, 415, 
               
               
                   
                 485, 486, 489, 
                   
                   
                 416, 417, 418, 
               
               
                   
                 491, 507, 509, 
                   
                   
                 419, 420, 425, 
               
               
                   
                 532, 549, 550, 
                   
                   
                 428, 429, 438, 
               
               
                   
                 557, 571, 572, 
                   
                   
                 439, 441, 445, 
               
               
                   
                 573, 574, 576, 
                   
                   
                 447, 448, 449, 
               
               
                   
                 577, 578, 579, 
                   
                   
                 450, 452, 453, 
               
               
                   
                 581, 582, 585, 
                   
                   
                 454, 455, 456, 
               
               
                   
                 587, 593, 594, 
                   
                   
                 457, 459, 460, 
               
               
                   
                 602, 605, 607, 
                   
                   
                 461, 463, 464, 
               
               
                   
                 608, 610, 617, 
                   
                   
                 469, 470, 474, 
               
               
                   
                 623, 626, 654, 
                   
                   
                 475, 484, 490, 
               
               
                   
                 655, 656, 657, 
                   
                   
                 492, 493, 494, 
               
               
                   
                 658, 659, 661, 
                   
                   
                 495, 497, 498, 
               
               
                   
                 675, 677, 699, 
                   
                   
                 499, 500, 501, 
               
               
                   
                 704, 709, 710, 
                   
                   
                 502, 503, 504, 
               
               
                   
                 712, 713, 715, 
                   
                   
                 508, 510, 512, 
               
               
                   
                 716, 727, 728, 
                   
                   
                 514, 515, 516, 
               
               
                   
                 731, 736, 739, 
                   
                   
                 518, 519, 520, 
               
               
                   
                 740, 741, 742, 
                   
                   
                 521, 524, 525, 
               
               
                   
                 743, 744, 746, 
                   
                   
                 526, 527, 528, 
               
               
                   
                 753, 756, 760, 
                   
                   
                 529, 530, 533, 
               
               
                   
                 761, 766, 774, 
                   
                   
                 534, 535, 536, 
               
               
                   
                 778, 783, 786, 
                   
                   
                 537, 538, 539, 
               
               
                   
                 787, 789, 790, 
                   
                   
                 540, 541, 543, 
               
               
                   
                 794, 796, 811, 
                   
                   
                 544, 546, 548, 
               
               
                   
                 813, 814, 825, 
                   
                   
                 552, 553, 555, 
               
               
                   
                 828, 831 
                   
                   
                 556, 558, 559, 
               
               
                   
                   
                   
                   
                 560, 561, 562, 
               
               
                   
                   
                   
                   
                 564, 565, 566, 
               
               
                   
                   
                   
                   
                 567, 568, 570, 
               
               
                   
                   
                   
                   
                 583, 588, 589, 
               
               
                   
                   
                   
                   
                 590, 592, 596, 
               
               
                   
                   
                   
                   
                 597, 599, 600, 
               
               
                   
                   
                   
                   
                 606, 611, 613, 
               
               
                   
                   
                   
                   
                 615, 618, 619, 
               
               
                   
                   
                   
                   
                 621, 624, 625, 
               
               
                   
                   
                   
                   
                 627, 628, 629, 
               
               
                   
                   
                   
                   
                 630, 631, 632, 
               
               
                   
                   
                   
                   
                 633, 634, 635, 
               
               
                   
                   
                   
                   
                 636, 638, 639, 
               
               
                   
                   
                   
                   
                 640, 641, 642, 
               
               
                   
                   
                   
                   
                 643, 645, 646, 
               
               
                   
                   
                   
                   
                 647, 649, 650, 
               
               
                   
                   
                   
                   
                 651, 652, 653, 
               
               
                   
                   
                   
                   
                 662, 664, 665, 
               
               
                   
                   
                   
                   
                 666, 667, 668, 
               
               
                   
                   
                   
                   
                 670, 671, 673, 
               
               
                   
                   
                   
                   
                 674, 679, 680, 
               
               
                   
                   
                   
                   
                 683, 684, 685, 
               
               
                   
                   
                   
                   
                 687, 688, 689, 
               
               
                   
                   
                   
                   
                 690, 691, 692, 
               
               
                   
                   
                   
                   
                 693, 694, 695, 
               
               
                   
                   
                   
                   
                 698, 702, 705, 
               
               
                   
                   
                   
                   
                 708, 719, 720, 
               
               
                   
                   
                   
                   
                 721, 722, 723, 
               
               
                   
                   
                   
                   
                 724, 725, 726, 
               
               
                   
                   
                   
                   
                 729, 732, 733, 
               
               
                   
                   
                   
                   
                 738, 745, 752, 
               
               
                   
                   
                   
                   
                 757, 758, 763, 
               
               
                   
                   
                   
                   
                 764, 767, 772, 
               
               
                   
                   
                   
                   
                 773, 776, 777, 
               
               
                   
                   
                   
                   
                 779, 780, 785, 
               
               
                   
                   
                   
                   
                 791, 792, 793, 
               
               
                   
                   
                   
                   
                 797, 807, 809, 
               
               
                   
                   
                   
                   
                 810, 817, 819, 
               
               
                   
                   
                   
                   
                 820, 821, 822, 
               
               
                   
                   
                   
                   
                 823, 824, 826, 
               
               
                   
                   
                   
                   
                 829, 830, 833 
               
               
                 Mean 
                 8, 9, 11, 15, 25, 
                 2, 17, 67, 155, 
                 1, 34, 41, 74, 78, 
                 98, 133, 179, 274 
               
               
                 VEGF 
                 55, 60, 63, 64, 
                 166, 188, 191, 
                 80, 99, 102, 124, 
                   
               
               
                 ELISA 
                 158, 159, 161, 
                 225, 231, 234, 
                 132, 165, 203, 
                   
               
               
                 EC 50  (nM) 
                 163, 167, 185, 
                 240, 245, 252, 
                 267, 353, 387, 
                   
               
               
                   
                 186, 196, 228, 
                 254, 256, 303, 
                 424, 473, 495, 
                   
               
               
                   
                 230, 233, 235, 
                 304, 310, 325, 
                 577, 734 
                   
               
               
                   
                 236, 251, 273, 
                 342, 347, 349, 
                   
                   
               
               
                   
                 289, 292, 305, 
                 355, 357, 360, 
                   
                   
               
               
                   
                 306, 309, 316, 
                 365, 372, 398, 
                   
                   
               
               
                   
                 317, 364, 368, 
                 399, 421, 431, 
                   
                   
               
               
                   
                 375, 389, 403, 
                 467, 507, 574, 
                   
                   
               
               
                   
                 446, 451, 458, 
                 576, 578, 605, 
                   
                   
               
               
                   
                 465, 478, 489, 
                 610, 620, 659, 
                   
                   
               
               
                   
                 571, 572, 579, 
                 706, 710, 713, 
                   
                   
               
               
                   
                 617, 654, 655, 
                 736, 740, 743, 
                   
                   
               
               
                   
                 656, 657, 658, 
                 760, 761, 783, 
                   
                   
               
               
                   
                 709, 712, 742, 
                 784, 825 
                   
                   
               
               
                   
                 744, 813, 828 
                   
                   
                   
               
               
                 Mean 
                 8, 9, 11, 15, 25, 
                 1, 2, 6, 17, 26, 27, 
                 3, 5, 7a, 34, 38, 
                 16, 18, 20, 21, 22, 
               
               
                 Luciferase 
                 55, 63, 64, 65, 
                 56, 57, 58, 59, 60, 
                 39, 41, 42, 43, 52, 
                 31, 32, 33, 35, 40, 
               
               
                 EC 50  (nM) 
                 158, 159, 160, 
                 61, 62, 67, 155, 
                 54, 74, 80, 81, 90, 
                 46, 50, 53, 75, 85, 
               
               
                   
                 161, 163, 166, 
                 162, 165, 187, 
                 92, 93, 94, 99, 
                 91, 98, 100, 103, 
               
               
                   
                 167, 185, 186, 
                 188, 191, 200, 
                 101, 107, 112, 
                 104, 110, 111, 
               
               
                   
                 196, 215, 221, 
                 206, 223, 224, 
                 115, 124, 144, 
                 114, 116, 117, 
               
               
                   
                 225, 227, 228, 
                 237, 241, 245, 
                 145, 146, 156, 
                 118, 119, 120, 
               
               
                   
                 229, 230, 231, 
                 251, 252, 254, 
                 168, 192, 194, 
                 128, 131, 132, 
               
               
                   
                 232, 233, 234, 
                 260, 267, 270, 
                 198, 203, 207, 
                 134, 135, 136, 
               
               
                   
                 235, 236, 240, 
                 274, 276, 277, 
                 213, 242, 243, 
                 140, 143, 147, 
               
               
                   
                 247, 256, 266, 
                 285, 286, 290, 
                 263, 265, 271, 
                 148, 151, 152, 
               
               
                   
                 273, 289, 292, 
                 302, 310, 314, 
                 275, 287, 293, 
                 157, 172, 181, 
               
               
                   
                 303, 304, 305, 
                 315, 334, 336, 
                 294, 295, 308, 
                 182, 190, 195, 
               
               
                   
                 306, 309, 316, 
                 342, 348, 355, 
                 312, 324, 325, 
                 201, 202, 209, 
               
               
                   
                 317, 338, 347, 
                 357, 360, 365, 
                 339, 353, 359, 
                 212, 214, 218, 
               
               
                   
                 349, 364, 368, 
                 369, 372, 381, 
                 361, 370, 377, 
                 220, 222, 226, 
               
               
                   
                 371, 375, 380, 
                 383, 387, 388, 
                 378, 390, 411, 
                 244, 249, 250, 
               
               
                   
                 386, 389, 399, 
                 392, 398, 401, 
                 414, 416, 422, 
                 253, 255, 258, 
               
               
                   
                 403, 430, 431, 
                 405, 409, 421, 
                 426, 432, 434, 
                 259, 261, 264, 
               
               
                   
                 435, 446, 451, 
                 423, 424, 436, 
                 437, 440, 443, 
                 268, 269, 272, 
               
               
                   
                 458, 465, 467, 
                 473, 477, 480, 
                 444, 462, 466, 
                 279, 291, 296, 
               
               
                   
                 478, 489, 571, 
                 486, 488, 507, 
                 468, 471, 472, 
                 300, 301, 307, 
               
               
                   
                 572, 576, 579, 
                 523, 547, 549, 
                 482, 483, 505, 
                 313, 352, 356, 
               
               
                   
                 582, 584, 602, 
                 573, 574, 578, 
                 517, 531, 532, 
                 358, 363, 374, 
               
               
                   
                 605, 617, 654, 
                 593, 594, 598, 
                 550, 557, 563, 
                 376, 379, 385, 
               
               
                   
                 655, 656, 657, 
                 604, 610, 620, 
                 569, 577, 585, 
                 394, 397, 400, 
               
               
                   
                 658, 661, 675, 
                 623, 626, 659, 
                 591, 595, 608, 
                 412, 427, 428, 
               
               
                   
                 704, 709, 710, 
                 676, 677, 681, 
                 616, 622, 644, 
                 433, 439, 441, 
               
               
                   
                 712, 716, 727, 
                 686, 696, 697, 
                 660, 663, 669, 
                 455, 456, 464, 
               
               
                   
                 728, 742, 743, 
                 699, 706, 713, 
                 678, 682, 707, 
                 470, 474, 476, 
               
               
                   
                 744, 746, 783, 
                 715, 717, 730, 
                 711, 714, 718, 
                 481, 485, 487, 
               
               
                   
                 786, 787, 789, 
                 731, 734, 736, 
                 747, 748, 750, 
                 491, 492, 495, 
               
               
                   
                 790, 794, 813, 
                 740, 760, 761, 
                 753, 756, 759, 
                 496, 506, 509, 
               
               
                   
                 828, 831 
                 781, 782, 784, 
                 762, 766, 768, 
                 511, 513, 516, 
               
               
                   
                   
                 795, 814, 818, 
                 769, 771, 774, 
                 534, 538, 542, 
               
               
                   
                   
                 825 
                 775, 788, 796 
                 545, 551, 554, 
               
               
                   
                   
                   
                   
                 558, 565, 570, 
               
               
                   
                   
                   
                   
                 575, 580, 581, 
               
               
                   
                   
                   
                   
                 586, 601, 603, 
               
               
                   
                   
                   
                   
                 607, 609, 612, 
               
               
                   
                   
                   
                   
                 614, 618, 619, 
               
               
                   
                   
                   
                   
                 637, 639, 665, 
               
               
                   
                   
                   
                   
                 670, 672, 683, 
               
               
                   
                   
                   
                   
                 692, 700, 701, 
               
               
                   
                   
                   
                   
                 703, 721, 722, 
               
               
                   
                   
                   
                   
                 723, 724, 725, 
               
               
                   
                   
                   
                   
                 726, 735, 737, 
               
               
                   
                   
                   
                   
                 739, 741, 749, 
               
               
                   
                   
                   
                   
                 751, 752, 754, 
               
               
                   
                   
                   
                   
                 755, 764, 765, 
               
               
                   
                   
                   
                   
                 767, 770, 778, 
               
               
                   
                   
                   
                   
                 779, 780, 808, 
               
               
                   
                   
                   
                   
                 811, 812, 833 
               
               
                   
               
            
           
         
       
     
     Example 39: Antitumor Activity of Compound 163 in Combination with α-PD-1 in Mouse Melanoma B16-F10 Syngeneic Tumor Model 
     B16-F10 mouse melanoma cells (1×10 5  cells) in 50 μL of PBS and Matrigel (1:1 in volume) were inoculated subcutaneously in the right flank of each C57BL/6 mouse at 6-7 weeks of age for tumor development. When the xenografts reached about 100 mm 3  in size, the tumor bearing mice were stratified into four groups (n=8) and treatment was started with vehicle (BID), and Compound 163 (30 mg/kg, BID) in combination with α-PD-1 (10 mg/kg, BIW) or IgG control (10 mg/kg, BIW) as indicated in  FIG. 1 , for two weeks. Tumor sizes were measured in two dimensions using a caliper and the volume was expressed in mm 3  using the formula V=0.5×a×b 2 , where a and b were the long and short diameters of the tumor, respectively. All data were displayed as Mean and the standard error of the mean (SEM).  FIG. 1  illustrates the observed synergistic effect of the described combination treatment. Table 3 gives the mean tumor size of each treatment group after 14 days of treatment. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Treatment 
                 Vehicle + 
                 Vehicle + 
                 Compound  
                 Compound 163 + 
               
               
                 groups 
                 IgG 
                 α-PD-1 
                 163 + IgG 
                 α-PD-1 
               
               
                   
               
             
            
               
                 Tumor size  
                 3055.05 ±  
                 1958.2 ±  
                 2133.89 ±  
                 1018.86 ±  
               
               
                 (mm 3 ) 
                 416.62 
                 362.48 
                 306.44 
                 109.23 
               
               
                 Mean ± SEM 
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     Example 40: Assay for Testing Inhibition of HIF-2α Dimerization 
     This example describes an example assay for testing inhibition of HIF-2α dimerization using co-immunoprecipitation. 
     Cell Culture and Compound Treatment: 
     786-0 cells were cultured in Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM, D5796, Sigma) supplemented with 10% FBS (F6178, Sigma), 100 units penicillin, and 100 μg/mL streptomycin (P4333, Sigma). About 5×10 5  cells were plated into 6-well cell culture plates (Corning Cat #3506) in 2 mL of media and were placed in a 37° C. cell culture incubator with atmospheric levels of oxygen and 5% CO 2 . As the cultures reached confluence, 2 μl of Compound 163 or 226 diluted in DMSO at 1000× of final concentration was added. 
     Co-Immunoprecipitation Analysis of HIF and ARNT: 
     Cells in a 6-well plate were washed with 1 ml of DPBS and lysed in 1 ml of cell lysis buffer (Tris-HCl 20 mM, pH 7.5, Triton X100 1%, NaCl 150 mM, Glycerol 5%, EDTA 1 mM, DTT 1 mM and 1 tablet per 10 mls of Roche Proteinase Inhibitor Tablet Complete). The cell lysate was transferred to a 1.5 mL Eppendorf tube, and was incubated on ice for 15 to 20 min. The debris was spun down in an Eppendorf microfuge tube at 15,000 RPM for 15 min at 4° C., and the supernatant was transferred into a new tube. 1 μg of mouse mAb against human ARNT (Santa Cruz, sc-55526) or 1 μg of antibody against HIF-2α (Abcam Ab199) and 50 μl of Protein AG beads (Santa Cruse, 50% slurry in lysis buffer) were added. The tubes were rotated at 4° C. for 2 to 16 hours. The beads were spun down and washed three times with 1 ml cold lysis buffer and resuspended in 30 μl of SDS sample buffer (10% Glycerol, 60 mM Tri-HCl pH6.8, 2% Sodium Dodecyl Sulfate, 0.01% Bromophenol Blue and 1.25% β-mercaptoethanol). The tubes were boiled for 3 min. The beads were spun down, and supernatant was loaded on a denaturing acrylamide gel (Bio-Rad precasted gel) for electrophoresis. The proteins in the gels were then transferred to 0.2 μM PVDF membrane (Bio-Rad) using Bio-Rad Trans-Blot Turbo transfer system. 
     For Western Blotting, the membranes were incubated in TBST (10 mM Tris-HCl pH 7.4, 150 mM Sodium Chloride and 0.1% Tween 20) containing 5% dry milk for 1 hour. The membranes were incubated with antibody to HIF-2α (Abcam Ab199) at 1:500 dilutions in the blocking buffer overnight. The membrane was washed three times in TBST then incubated in TBST with 5% dry milk with HPR-conjugated goat anti rabbit (Bio-Rad 172-1019) at 1:5000 dilution for ARNT detection. The Western blot signals were developed using Thermo Super-Western Pico Lumino/Enhancer Solution following the protocol provided by the manufacturer. 
     Disruption of HIF-2α and ARNT Dimerization: 
     Total protein was extracted from 786-O cells treated with the indicated concentration of Compound 163 and Compound 226. HIF-2α protein complex was immunoprecipitated with antibody to HIF-2α. The immunoprecipitants were blotted with antibody against ARNT. ARNT protein coprecipitated with HIF-2α was reduced in a lysate of cells treated with Compound 163 in a dose-dependent manner ( FIG. 2 ). Compound 226 reduced ARNT protein in complex with HIF-2α only at the highest concentration (10 μM). 
     Example 41: Antitumor Activity of Compound 163 in Combination with α-CTLA-4 in Mouse Colon CT26 Syngeneic Tumor Model 
     CT26.WT mouse carcinoma cells (5×10 5  cells) in 50 μL of PBS and Matrigel (1:1 in volume) were inoculated subcutaneously in the right flank of each BALB/c mouse at 6-7 weeks of age for tumor development. When the xenografts reached about 90 mm 3  in size, the tumor bearing mice were stratified into four groups (n=8) and treatment was started with vehicle (BID), and Compound 163 (30 mg/kg, BID) in combination with α-CTLA-4 (10 mg/kg, BIW) or IgG control (10 mg/kg, BIW) as indicated in  FIG. 3 , for 20 days. Tumor sizes were measured in two dimensions using a caliper and the volume was expressed in mm 3  using the formula V=0.5×a×b 2 , where a and b were the long and short diameters of the tumor, respectively. All data were displayed as Mean and the standard error of the mean (SEM).  FIG. 3  illustrates the observed synergistic effect of the described combination treatment. Table 4 gives the mean tumor size of each treatment group after 20 days of treatment. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                 Treatment 
                 Vehicle + 
                 Vehicle + 
                 Compound  
                 Compound 163 + 
               
               
                 groups 
                 IgG 
                 α-CTLA-4 
                 163 + IgG 
                 α-CTLA-4 
               
               
                   
               
             
            
               
                 Tumor size 
                 1801 ± 190 
                 830 ± 356 
                 1612 ± 305 
                 403 ± 108 
               
               
                 (mm 3 ) 
                   
                   
                   
                   
               
               
                 Mean ± SEM 
               
               
                   
               
            
           
         
       
     
     While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the appended claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.