AGONISTS OF ROR GAMMAt

The present invention is directed to compounds of the formula wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.

FIELD OF THE INVENTION

The invention provides novel compounds, pharmaceutical compositions comprising the compounds, and methods of using them, for example, for the treatment or prophylaxis of certain cancers and to their use in therapy.

BACKGROUND OF THE INVENTION

RORgamma t (RORgt, RORyt) is a key lineage-defining transcription factor involved in the differentiation of naive T cells to Th17 and Tc17 cells. IL-17 is a signature cytokine of RORgt transactivation (Ivanov et al;Cell2006, 126, 1121).

High IL-17 levels have been associated with various autoimmune diseases. Consequently, several groups have identified RORgt inverse agonists to decrease IL-17 production aimed at suppressing immunity to treat various autoimmune diseases, most notably psoriasis (Bronner et al.Expert Opin. Ther.Pat. 2017, 27, 1, 101)

More recently RORgt agonism has been reported to increase the production of antitumor cytokines and chemokines (such as IL-17A and GM-CSF), as well as augment the expression of co-stimulatory receptors (such as CD137 and CD226) and decrease the levels of co-inhibitory receptors (such as PD1 and TIGIT) (Hu et al.Oncoimmunology, 2016, 5, 12, e1254854). High levels of Th17 cells or IL-17 has been associated with patient survival in certain cancers (Kryczek et al.Blood2009, 114, 1141; Sfanos et al.Clin. Can. Res.2008, 14, 3254). Therefore RORgt agonism has the potential to boost immune response to tumors and thus confer durable antitumor response. A recent review (Qiu et alJ. Med. Chem.2018, 61, 5794) summarizes the progress by various research groups towards the identification of RORgt agonists.

The present invention, therefore, provides novel cyclic dinucleotides which may be useful for the treatment of cancer.

SUMMARY OF THE INVENTION

There is provided a compound of formula (I)

wherein all substituents are defined herein.

In another aspect, there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect, there is provided a method of treating cancer which comprises administering to a subject in need thereof a therapeutically effective amount of an agonist of RORγ.

DETAILED DESCRIPTION OF THE INVENTION

The following are aspects and embodiments of the present invention, as well as additional aspects and embodiments that can be within the scope of those shown. The aspects of the invention are not limited to those described below.

In a first aspect, there is disclosed a compound of formula I

In a second aspect, there is disclosed a compound of the formula

In a third aspect, there is disclosed a compound of the formula

In a fourth aspect, there is disclosed a compound of the formula

In a fifth aspect, there is disclosed a compound of the formula

In a sixth aspect, there is disclosed a compound of the formula

In a seventh aspect, there is disclosed a compound of the formula

In another aspect, there is provided a compound selected from any subset list of compounds within the scope of any of the above aspects.

OTHER EMBODIMENTS OF THE INVENTION

In another embodiment, the invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the invention provides a process for making a compound of the invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the invention provides a method for the treatment and/or prophylaxis of various types of cancer, comprising administering to a patient in need of such treatment and/or prophylaxis a therapeutically effective amount of one or more compounds of the invention, alone, or, optionally, in combination with another compound of the invention and/or at least one other type of therapeutic agent.

In another embodiment, the invention provides a method for the treatment and/or prophylaxis of various types of cancer, including small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin’s lymphoma, bladder cancer, esophageal carcinoma, gastric carcinoma, ovarian carcinoma, cervical carcinoma, pancreatic carcinoma, prostate carcinoma, breast cancers, urinary carcinoma,, brain tumors such as glioblastoma, non-Hodgkin’s lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, multiple myeloma, gastrointestinal stromal tumors, mesothelioma, and other solid tumors or other hematological cancers

In another embodiment, the invention provides a method for the treatment and/or prophylaxis of various types of cancer, including without limitation, small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin’s lymphoma or bladder cancer.

In another embodiment, the invention provides a compound of the present invention for use in therapy.

In another embodiment, the invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

THERAPEUTIC APPLICATIONS

The compounds of the invention induce the expression of pro-inflammatory cytokines such as IL17 in vitro in human cells, animal cells and human blood.

The compounds of the invention are agonists of RORgt.

The term “agonist” refers to any substance that activates a biologic receptor in vitro or in vivo to provoke a physiological response.

“RORgt” is an abbreviation of “Retinoic acid receptor related Orphan Receptor Gamma t”. RORgt is a transcription factor that in humans is encoded by the gene RORC. Since RORgt and RORg have identical ligand binding domains, in the context of small molecule modulators, RORgt and RORg can be used interchangeably. RORgt and RORg are two isoforms produced from the same RORC gene. Activation of RORgt by agonists leads to induction of pro-inflammatory cytokines, including IL-17.

Another object of the present invention is the compounds of Formula (I), for use in a therapeutic treatment in humans or animals. In particular, the compounds of the present invention may be used for therapeutic or diagnostic applications in human or animal health.

The term “therapeutic agent” refers to one or more substances that are administered to a human or animal in order to achieve some kind of therapeutic effect in that human or animal, including to prevent, cure, or mitigate the effects of, infection or disease, and/or to otherwise improve the health of that human or animal.

The term “monotherapy” refers to the use of a single substance and/or strategy to treat a human or animal in any clinical or medical context, as opposed to the use of multiple substances and/or strategies to treat a human or animal in the same clinical or medical context, regardless of whether the multiple substances and/or strategies are used sequentially in any order or concurrently.

The term “chemotherapeutic agent” herein refers to one or more chemical substances that are administered to a human or animal in order to kill tumors, or slow or stop the growth of tumors, and/or slow or stop the division of cancerous cells and/or prevent or slow metastasis. Chemotherapeutic agents are often administered to treat cancer, but are also indicated for other diseases.

The term “chemotherapy” refers to medical treatment of a human or animal with one or more chemotherapeutic agents (see definition above).

The term “chemoimmunotherapy” refers to the combined use, whether sequentially in any order or concurrently, of chemotherapy substances and/or strategies, and immunotherapy substances and/or strategies. Chemoimmunotherapy is often employed to treat cancer, but can also be employed to treat other diseases.

The term “immune system” refers to the ensemble, or to any one or more components, of the molecules, substances (e.g. bodily fluids), anatomic structures (e.g. cells, tissue and organs) and physiologic processes involved in preventing infection in the body, in protecting the body during infection or during disease, and/or in helping the body to recuperate after infection or disease. A complete definition of “immune system” is beyond the scope of this patent; however, this term should be understood by any ordinary practitioner in the field.

The term “immune agent” refers to any endogenous or exogenous substance that can interact with any one or more components of the immune system. The term “immune agent” includes antibodies, antigens, vaccines and their constituent components, nucleic acids, synthetic drugs, natural or synthetic organic compounds, cytokines, natural or modified cells, synthetic analogs thereof, and/or fragments thereof.

The term “antagonist” refers to any substance that inhibits, counteracts, downregulates, and/or desensitizes a biologic receptor in vitro or in vivo to provoke a physiological response.

The term “immunotherapy” refers to any medical treatment in which one or more components of a human’s or animal’s immune system is deliberately modulated in order to directly or indirectly achieve some therapeutic benefit, including systemic and/or local effects, and preventative and/or curative effects. Immunotherapy can involve administering one or more immune agents (see definition above), either alone or in any combination, to a human or animal subject by any route (e.g. orally, intravenously, dermally, by injection, by inhalation, etc.), whether systemically, locally or both.

“Immunotherapy” can involve provoking, increasing, decreasing, halting, preventing, blocking or otherwise modulating the production of cytokines, and/or activating or deactivating cytokines or immune cells, and/or modulating the levels of immune cells, and/or delivering one or more therapeutic or diagnostic substances to a particular location in the body or to a particular type of cell or tissue, and/or destroying particular cells or tissue. Immunotherapy can be used to achieve local effects, systemic effects or a combination of both.

The term “immunosuppressed” describes the state of any human or animal subject whose immune system is functionally diminished, deactivated or otherwise compromised, or in whom one or more immune components is functionally diminished, deactivated or otherwise compromised.

“Immunosuppression” can be the cause, consequence or byproduct of disease, infection, exhaustion, malnutrition, medical treatment or some other physiologic or clinical state.

The terms “immunomodulating substance”, “immunomodulatory substance”, “immunomodulatory agent” and “immunomodulator”, used here synonymously, refer to any substance that, upon administration to a human or animal, directly influences the functioning of the immune system of that human or animal. Examples of common immunomodulators include, but are not limited to, antigens, antibodies and small-molecule drugs.

The term “vaccine” refers to a biological preparation administered to a human or animal in order to elicit or enhance a specific immune system response and/or protection against one or more antigens in that human or animal.

The term “vaccination” refers to treatment of a human or animal with a vaccine or to the act of administering a vaccine to a human or animal.

The term “adjuvant” refers to a secondary therapeutic substance that is administered together (either sequentially in any order, or concurrently) with a primary therapeutic substance to achieve some kind of complimentary, synergic or otherwise beneficial effect that could not be achieved through use of the primary therapeutic substance alone. An adjuvant can be used together with a vaccine, chemotherapy, or some other therapeutic substance. Adjuvants can enhance the efficacy of the primary therapeutic substance, reduce the toxicity or side effects of the primary therapeutic substance, or provide some kind of protection to the subject that receives the primary therapeutic substance, such as, but not limited to, improved functioning of the immune system.

In one embodiment, the compounds of Formula (I) can increase the amount of IL-17 in a subject. This includes but is not limited to IL-17 produced by TH17 cells.

In one embodiment, the compounds of Formula (I) can be administered as immunotherapy to a human or an animal to induce in vivo production of one or more cytokines that are therapeutically beneficial to that human or animal. This type of immunotherapy could be used alone or in combination with other treatment strategies, whether sequentially in any order, or concurrently. It could be used to prevent, cure, and/or mitigate the effects of infection or disease in that human or animal, and/or to modulate the immune system of that human or animal to achieve some other therapeutic benefit.

In one particular embodiment, the compounds of the present invention can be used for cytokine induction immunotherapy of immunosuppressed individuals.

In this example, a compound of Formula (I) would be administered to an immunosuppressed human or animal subject to induce in vivo production of one or more cytokines that directly or indirectly enhance the immune system of that human or animal. Subjects that might benefit from such treatment include those suffering from autoimmune disorders, immune system deficiencies or defects, microbial or viral infections, infectious diseases, or cancer.

The present invention thus discloses a method for inducing cytokine in immunosuppressed individuals, said method comprising administering to a patient in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the compounds of the present invention can be used for cytokine induction immunotherapy in combination with chemotherapy. In this example, a compound of Formula (I) would be administered together with one or more chemotherapeutic agents, sequentially in any order or concomitantly, to a cancer patient to stop the growth of, shrink and/or destroy tumors in that patient. The chemoimmunotherapy resulting from the combination of cytokine induction, provided by the compound(s) of the present invention, and cytotoxicity, provided by the chemotherapeutic agent(s), might be less toxic to the patient, cause fewer side effects in the patient and/or exhibit greater anti-tumor efficacy than would the chemotherapeutic agent(s) when used as monotherapy.

The present invention thus discloses a method for treating cancer, said method comprising administering to a patient in need thereof: a chemotherapeutic agent; and a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Another object of the present invention is the compound of Formula (I) for use in the treatment of a bacterial infection, a viral infection or a cancer.

As used herein, “cancer” refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth or death. The term “cancer” includes solid tumors and blood-born tumors, whether malignant or benign.

In a preferred embodiment, the cancer is from the following group: small cell lung cancer, non-small cell lung cancer, colorectal cancer, melanoma, renal cell carcinoma, head and neck cancer, Hodgkin’s lymphoma or bladder cancer.

The present invention thus discloses a method for treating a bacterial infection, a viral infection or a cancer, said method comprising administering to a patient in need thereof a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Another object of the present invention is the compound of Formula (I) for use in the treatment of a pathology that may be alleviated by the induction of an immune response via the RORg or RORgt pathway.

While it is possible that for use in therapy, a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as the compound itself, it is more commonly presented as a pharmaceutical composition.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient pep unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered more than once a day. Preferred unit dosage compositions are those containing a daily dose or sub-dose (for administration more than once a day), as herein above recited, or an appropriate fraction thereof, of an active ingredient.

Compounds of the invention are useful for the treatment of certain types of cancer by themselves or in combination or co-administration with other therapeutic agents or radiation therapy. Thus, in one embodiment, the compounds of the invention are co-administered with radiation therapy or a second therapeutic agent with cytostatic or antineoplastic activity. Suitable cytostatic chemotherapy compounds include, but are not limited to (i) antimetabolites; (ii) DNA-fragmenting agents, (iii) DNA-crosslinking agents, (iv) intercalating agents (v) protein synthesis inhibitors, (vi) topoisomerase I poisons, such as camptothecin or topotecan; (vii) topoisomerase II poisons, (viii) microtubule-directed agents, (ix) kinase inhibitors (x) miscellaneous investigational agents (xi) hormones and (xii) hormone antagonists. It is contemplated that compounds of the invention may be useful in combination with any known agents falling into the above 12 classes as well as any future agents that are currently in development. In particular, it is contemplated that compounds of the invention may be useful in combination with current Standards of Care as well as any that evolve over the foreseeable future. Specific dosages and dosing regimens would be based on physicians’ evolving knowledge and the general skill in the art.

Further provided herein are methods of treatment wherein compounds of the invention are administered with one or more immuno-oncology agents. The immuno-oncology agents used herein, also known as cancer immunotherapies, are effective to enhance, stimulate, and/or up-regulate immune responses in a subject. In one aspect, the administration of a compound of the invention with an immuno-oncology agent has a synergistic effect in inhibiting tumor growth.

In one aspect, the compound(s) of the invention are sequentially administered prior to administration of the immuno-oncology agent. In another aspect, compound(s) of the invention are administered concurrently with the immunology-oncology agent. In yet another aspect, compound(s) of the invention are sequentially administered after administration of the immuno-oncology agent.

In another aspect, compounds of the invention may be co-formulated with an immuno-oncology agent.

Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.

In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co-inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses (often referred to as immune checkpoint regulators).

In one aspect, T cell responses can be stimulated by a combination of a compound of the invention and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

Other agents that can be combined with compounds of the invention for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, compounds of the invention can be combined with antagonists of KIR, such as lirilumab.

Yet other agents for combination therapies include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In another aspect, compounds of the invention can be used with one or more of agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell anergy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.

In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. The PD-1 antibody can be selected from Opdivo (nivolumab), Keytruda (pembrolizumab), PDR001 (Novartis; see WO2015/112900), MEDI-0680 (AMP-514) (AstraZeneca; see WO2012/145493), REGN-2810 (Sanofi/Regeneron; see WO2015/112800), JS001 (Taizhou Junshi), BGB-A317 (Beigene; see WO2015/35606), INCSHR1210 (SHR-1210) (Incyte/Jiangsu Hengrui Medicine; see WO2015/085847), TSR-042 (ANB001) (Tesara/AnaptysBio; see WO2014/179664), GLS-010 (Wuxi/Harbin Gloria Pharmaceuticals), AM-0001 (Armo/Ligand), or STI-1110 (Sorrento; see WO2014/194302). The immuno-oncology agent may also include pidilizumab (CT-011), though its specificity for PD-1 binding has been questioned. Another approach to target the PD-1 receptor is the recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, called AMP-224 In one aspect,

In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. The PD-L1 antibody can be selected from Tecentriq (atezolizumab), durvalumab, avelumab, STI-1014 (Sorrento; see WO2013/181634), or CX-072 (CytomX; see WO2016/149201)..

In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12/32433).

In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06/029879).

In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

The combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms 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, intratumoral 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. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further 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.

Another object of the present invention is the compounds of Formula (I) for use in adoptive cellular therapy to treat cancer, immune disorders and infections.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

PHARMACEUTICAL COMPOSITIONS AND DOSING

The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective amount of one or more of the compounds of Formula I, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally, one or more additional therapeutic agents described above. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intratumoral, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; or intratumorally.

The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.

While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

DEFINITIONS

Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

For purposes of clarity and in accordance with standard convention in the art, the symbol

is used in formulas and tables to show the bond that is the point of attachment of the moiety or substituent to the core/nucleus of the structure.

Additionally, for purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -CONH2is attached through the carbon atom.

Additionally, for purposes of clarity, when there is no substituent shown at the end of a solid line, this indicates that there is a methyl (CH3) group connected to the bond.

The term “counter ion” is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), ammonium (RnNHm+ where n=0-4 and m=0-4) and the like.

As used herein, the term “amine protecting group” means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Wuts, P. G. M. and Greene, T.W. Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C1-10alkyl” (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10alkyl groups. Additionally, for example, “C1-C6alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group, for example, aryl or heteroaryl groups which are optionally substituted for example with alkyl, halo or haloalkyl. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. C3-7cycloalkyl is intended to include C3, C4, C5, C6, and C7cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl. When the term “carbocycle” is used, it is intended to include “aryl”. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, or “heterocyclyl” may be used interchangeably and refer to substituted and unsubstituted 3-to 7-membered monocyclic groups, 7- to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups, in which at least one of the rings has at least one heteroatom (O, S or N), said heteroatom containing ring preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of such a group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or fully unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. As used herein the terms “ heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, and “heterocyclyl” include “heteroaryl” groups, as defined below.

In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:a) Bundgaard, H., ed.,Design of Prodrugs, Elsevier (1985), and Widder, K. et al., eds.,Methods in Enzymology, 112:309-396, Academic Press (1985);b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);c) Bundgaard, H.,Adv. Drug Deliv. Rev., 8:1-38 (1992);d) Bundgaard, H. et al.,J. Pharm. Sci., 77:285 (1988);e) Kakeya, N. et al.,Chem. Pharm. Bull., 32:692 (1984); andf) Rautio, J (Editor).Prodrugs and Targeted Delivery (Methods and Principles in Medicinal Chemistry), Vol 47, Wiley-VCH, 2011

Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield formula I compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C1-6alkyl, C1-6alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C1-6alkanoyloxy-C1-6alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C1-6alkoxycarbonyloxy-C1-6alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

Preparation of prodrugs is well known in the art and described in, for example, King, F.D., ed.,Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (2ndedition, reproduced, 2006); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed.,The Practice of Medicinal Chemistry, 3rdedition, Academic Press, San Diego, CA (2008).

The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably refers to humans.

As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent, i.e., a compound of the invention, that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. The term also includes within its scope amounts effective to enhance normal physiological function

As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4alkyl, and the like.

METHODS OF PREPARATION

The compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Fourth Edition, Wiley and Sons, 2007).

Compounds of Formula (I) may be prepared by reference to the methods illustrated in the following Scheme. As shown therein, the end product is a compound having the same structural formula as Formula (I). It will be understood that any compound of Formula (I) may be produced by the schemes by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.

METHODS OF PREPARATION

Compounds of general formula i can be prepared according to the method outlined in Scheme i. Conversion of aryl iodide iA to the corresponding boronic acid iB followed by copper mediated coupling can afford ether iC. Alternatively, palladium mediated coupling of aryl iodide iA with an alcohol can directly yield ether iC. Deprotection of compound iC followed by acylation can afford compounds of general formula i. It should be noted and obvious to those skilled in the art that intermediates such as iD can be reductively aminated with various aldehydes or reacted with various electrophiles such as sulfonyl chlorides, isocyanates or isothiocyanates to yield the corresponding N-substituted compounds.

In another variation, the aryl iodide iA can undergo palladium mediated coupling with olefins to afford intermediate iiA (Scheme ii). Removal of the Boc group in olefin iiA followed by hydrogenation can yield amine iiC. Acyation of amine iiC can afford compounds of general formula ii.

In another variation, the boronic acid iB can undergo metal mediated coupling with substituted phenols to yield aryl ethers of general formula iii (Scheme iii) which can be derivatized similar to intermediate iiB as outlined in Scheme ii.

In yet another variation, aryl iodide iA can undergo palladium mediated coupling to various alkyl halides followed by removal of Boc group to provide amine ivA that can be acylated to obtain compounds of general formula iv (Scheme iv).

In another variation, aryl iodide iA can undergo lithium-iodine exchange followed by a quench with DMF to obtain aldehyde vA (Scheme v). Reduction of the formyl group of vA to the corresponding alcohol followed by alkylation can provide ether vB, that can be acylated to yield compounds of general formula v.

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in the preparation of compounds of Formula (I), can be prepared using procedures shown in the following Examples and related procedures. The methods and conditions used in these examples, and the actual compounds prepared in these Examples, are not meant to be limiting, but are meant to demonstrate how the compounds of Formula (I) can be prepared. Starting materials and reagents used in these examples, when not prepared by a procedure described herein, are generally either commercially available, or are reported in the chemical literature, or may be prepared by using procedures described in the chemical literature.

Analytical LCMS Methods

Preparation of intermediate 1B: ((3aR,9bR)-3-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-7-yl)boronic acid

Preparation of intermediate 1D: (3aR,9bR)-7-((2-chloro-6-fluorobenzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

Intermediate 1C (35 mg, 0.059 mmol) was dissolved in 0.5 mL of 4 N HCl in dioxane and stirred at room temperature for 60 min. The mixture was concentrated in vacuo to give a quantitative yield of 1D (31 mg, 0.059 mmol) as a HCl salt. LCMS m/z 489.8 (M+H); rt 2.95 min; Method D.

Preparation of Example 1: (1r,4r)-4-[(3aR,9bR)-7-[(2-chloro-6-fluorophenyl)methoxy]-9b-(4-fluorobenzenesulfonyl)-1H,2H,3H,3aH,4H,5H,9bH-benzo[e]indole-3-carbonyl]cyclohexane-1-carboxylic acid

Preparation of intermediate 2B: (3aR,9bR)-7-((E)-2,6-dichlorostyryl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

Intermediate 2A was treated with 2 mL of 4 N HCl in dioxane for 1 h. The resulting mixture was concentrated in vacuo to give a quantitative yield of 2B (189 mg, 0.35 mmol) as an HCl salt. LCMS m/z 501.8 (M+H); rt 3.39 min; Method D.

Preparation of intermediate 2C: (3aR,9bR)-7-(2,6-dichlorophenethyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

Preparation of Example 2: (1r,4r)-4-[(3aR,9bR)-7-[2-(2,6-dichlorophenyl)ethyl]-9b-(4-fluorobenzenesulfonyl)-1H,2H,3H,3aH,4H,5H,9bH-benzo[e]indole-3-carbonyl]cyclohexane-1-carboxylic acid

Preparation of intermediate 3A: ((3aR,9bR)-3-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-7-yl)boronic acid

To a mixture of (3ar,9br)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1h-benzo[e]indole-3(2h)-carboxylate 1A (4.00 g, 7.18 mmol), tetrahydroxydiboron (2.57 g, 28.7 mmol), 2ndgeneration XPhos precatalyst (0.28 g, 0.036 mmol), potassium acetate (3.52 g, 36 mmol) and 2-(dicyclohexylphosphino)-2’,4’,6′-triisopropylbiphenyl (0.34 g, 0.72 mmol) was added degassed ethanol (72 mL). The resulting mixture was degassed for 4 minutes and then heated for 18 h at 55° C. An aliquot of the reaction mixture was analyzed by LCMS to verify complete conversion. The reaction mixture was cooled to room temperature and concentrated. The crude product was adsorbed onto Celite and purified by silica gel chromatography eluting with methanol in DCM to obtain ((3aR,9bR)-3-(tert-butoxycarbonyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-7-yl)boronic acid 3A (2.72 g, 5.72 mmol, 80% yield). LCMS m/z 951.5 (2 M+H); rt 0.91 min; Method C.

Preparation of Example 3: (1r,4r)-4-((3aR,9bR)-7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fhiorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Preparation of intermediate 4A: (3aR,9bR)-7-(2-fluoro-6-(trifluoromethyl)phenoxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

Preparation of Example 4: (1R,4r)-4-((3aR,9bR)-7-(2-fluoro-6-(trifluoromethyl)phenoxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexane-1-carboxylic acid

Preparation of intermediate 5A: (3aR,9bR)-7-(2-chloro-6-fluorobenzyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

Preparation of Example 5: (1R,4r)-4-((3aR,9bR)-7-(2-chloro-6-fluorobenzyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylic acid

To a -78° C. solution of (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-iodo-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3(2H)-carboxylate (2 g, 3.59 mmol) in THF (100 mL) was added BuLi (2.5 M hexanes) (3.0 mL, 7.5 mmol) and stirred at -78° C. for 1 h. To the resulting mixture was added DMF (1.111 mL, 14.35 mmol). The reaction was warmed to room tempetature and quenched with saturated aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-100% EtOAc in hexanes to afford (3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-formyl-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3(2H)-carboxylate 6A (807 mg, 1.76 mmol, 49 % yield). LCMS m/z 460.3 (M+H); rt 1.06 min; Method C.

Preparation of intermediate 6C: (3aR,9bR)-7-((2,6-dichlorophenoxy)methyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole

To a stirring solution of triphenylphosphine (62.5 mg, 0.238 mmol) and DIAD (0.051 mL, 0.260 mmol) in toluene (4 mL), was added a solution of .(3aR,9bR)-tert-butyl 9b-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3(2H)-carboxylate 6B (50 mg, 0.108 mmol) in toluene (4 mL). After 80 h the reaction mixture was concentrated in vacuo and purified by silica gel chromatography using 0-100% EtOAc in hexanes. The resulting product was then dissolved in DCM (10 mL) and 4 N HCl in dioxane (1 mL, 4.00 mmol) was added. After 16 h, the reaction mixture was concentrated under reduced pressure and used as is. Obtained (3aR,9bR)-7-((2,6-dichlorophenoxy)methyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole 6C (51 mg, 0.1 mmol, 92 % yield). LCMS m/z 506.2 (M+H); rt 0.94 min; Method C.

Preparation of Example 6: (1R,4r)-4-((3aR,9bR)-7-((2,6-dichlorophenoxy)methyl)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexanecarboxylic acid

Preparation of Example 7: ((3aR,9bR)-7-((2-chloro-6-fluorobenzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[e]indol-3(2H,3aH,9bH)-yl)(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanone

Preparation of intermediate 8A: Synthesized employing a procedure similar to that described for Example 6.

Preparation of Example 8: (1R,4r)-4-((3aR,9bR)-7-((2-chloro-6-fluorobenzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-1-methylcyclohexanecarboxylic acid

Preparation of intermediate 9A: Synthesized employing a procedure similar to that described for Example 6.

Preparation of Example 9: (1R,4r)-4-((3aR,9bR)-7-((2-chloro-6-fluorobenzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-4-methylcyclohexanecarboxylic acid

Preparation of Intermediate 10A

Preparation of Example 10: Synthesized employing a procedure similar to that described for Example 8.

Preparation of Example 11

Preparation of intermediate 12A: Synthesized employing a procedure analogous to that described for 5A.

Preparation of Example 12: (1R,4r)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(2-methylbenzyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-4-methylcyclohexane-1-carboxylic acid

Preparation of intermediate 13A: ((3aR,9bR)-7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl)methanone

To a solution of (3aR,9bR)-tert-butyl 7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-3a,4,5,9b-tetrahydro-1H-benzo[e]indole-3(2H)-carboxylate 3B (100 mg, 0.160 mmol) in DCM (5 mL) was added TFA (0.124 mL, 1.604 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in acetonitrile (10 mL). To the resulting solution was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexanecarboxylic acid (97 mg, 0.382 mmol), BOP (169 mg, 0.382 mmol) and TEA (0.133 mL, 0.955 mmol). The reaction mixture was stirred at room temperature for 1 h. LCMS indicated the reaction was complete. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes to obtain ((3aR,9bR)-7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indol-3-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl)methanone 13A (35 mg, 0.046 mmol, 24 % yield). LCMS m/z 760.2 (M+H); rt 1.19 min; Method C.

Preparation of Example 13: (4-((3aR,9bR)-7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)cyclohexyl)boronic acid

To a solution of ((3aR,9bR)-7-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)-9b-((4-fluorophenyl)sulfonyl)-4,5-dihydro-1H-benzo[e]indol-3(2H,3aH,9bH)-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl)methanone 13A (45 mg, 0.059 mmol) in THF (1 mL) and water (0.5 mL), was added sodium periodate (76 mg, 0.355 mmol). The reaction mixture was stirred at room temperature for 10 min. To the resulting mixture was added a solution of 1 N HCl (0.118 mL, 0.118 mmol). The reaction solution was stirred at room temperature for 1 h. The resulting suspension was filtered. The filtrate was purified by reverse phase preparative HPLC to obtain two isomers Example 13 and Example 14.

General procedure A for formation boronic acid: An aryl iodide (1eq), tetrahydrahydroxydiboron (4 eq), potassium acetate (5 eq), 2ndgeneration X-Phos precatalyst (0.1 eq) and 2-(dicyclohexylphosphino)-2’,4’,6′-triisopropylbiphenyl (0.2 eq) were dissolved in degassed ethanol and the mixture was degassed for additional 4 min. The resulting mixture was stirred at 55° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using 0-100% EtOAc in hexanes, followed by 0-10% MeOH in DCM to give the corresponding boronic acid. General procedure B for formation of aryl ether: A mixture of an aryl boronic acid (1 eq), N,N-dimethylpyridin-4-amine (1 eq), diacetoxy copper (1 eq) and an alcohol (2 eq) was suspended in DCM (3 mL). To the resulting mixture was added 4 Å molecular sieves.The reaction was stirred under air untill complete consumption of starting material. The reaction was filtered and purified by silica gel chromatography with 0-30% EtOAc in hexanes to give desired aryl ether.

General procedure C for removal of Boc group: The Boc group was removed with 3-5 eq of 4 N HCl in dioxane. Then the solvent was removed in vaccuo to give an HCl salt. General procedure D for amide formation: To a mixture of free amine (or an HCl salt) (1eq) and a carboxylic acid (1.5 eq) in DMF was added DIEA (3 eq) and HATU (1.5 eq). The reaction was stirred for 1 h at room temperature. The resulting mixture was purified via a preparative HPLC to give the desired amide.

The following examples were synthesized according to the procedures described above.

Biological Assay

The inhibition potency of each final compound was determined using engineered Jurkat cells overexpressing constitutively active RORgT proteins fused with Gal4 Luc reporter (Jurkat pEx/Gal/hRORγ CLBD/HYG pG51uc/blast). 25 µL of cryopreserved Jurkat cells over expressing ligand binding domain (LBD) of RORgT (aa267-516, NM_005060) and Gal4 Luc, or full length of human RORgT and Gal4 Luc, were plated in 384-well solid white cell culture plates (PerkinElmer 6007899), with a density of 10,000 cells/well in RPMI 1640 cell culture media (Gibco 11875-085). The media contained 0.1% BSA, 10 mM HEPES (Gibco 15360-080), 100 mM Sodium Pyruvate (Gibco 11360-040), 50 mg/mL Hygromycin B (Invitrogen 10687-010), and 10 mg/mL Blasticidin (Invitrogen R210-01).

100 nL of compound at varying concentrations in 3-fold serial dilution, with final concentrations ranging from 40 µM to 0.67 nM, were added to the cells using Labcyte Echo 550. The compound and the cells were incubated for 18 hours at 37° C. in a cell culture incubator. Cells were then lysed with 15 uL of Steady-Glo Luciferase Assay reagent (Promega EZ550), followed by centrifuging the assay plates at 1500 RPM for 1 minute. Subsequently, the plates were read on the Envision (PerkinElmer). The inhibition of constitutive activity of RORgT achieved by graded concentrations of compound was calculated as a percentage of the luminescence signal window reduction over a control compound.