# Patent

## Title
Chemokine receptor binding compounds

## Abstract

The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR5. These compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Application Ser. No. 60/528,975, filed Dec. 11, 2003. The contents of this document are incorporated herein by reference.


TECHNICAL FIELD
This invention generally relates to novel compounds, pharmaceutical compositions and their use. More specifically, these novel compounds may be modulators of chemokine receptor activity, preferably modulators of chemokine receptor CCR5, and may further demonstrate protective effects against infection in target cells by a human immunodeficiency virus (HIV). In another aspect, the compounds in the present invention may be useful in the treatment and prevention of various inflammatory and autoimmune diseases.
BACKGROUND OF THE INVENTION
Approximately 40 human chemokines have been described that function at least in part, by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs, 7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute a family of proteins, approximately 8-10 kDa in size, that are released by a wide variety of cells, to attract macrophages, T cells, eosinophils, basophils, and neutrophils to sites of inflammation and also play a role in the maturation of cells of the immune system. Chemokines appear to share a common structural motif that consists of 4 conserved cysteines involved in maintaining tertiary structure. There are two major subfamilies of chemokines: the “CC” or β-chemokines and the “CXC” or α-chemokines, depending on whether the first two cysteines are separated by a single amino acid, i.e., CXC or are adjacent, i.e., CC.
These chemokines bind specifically to cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane proteins which are referred to as “chemokine receptors”, and mediate biological activity through these receptors. The chemokine receptor is classified based upon the chemokine that constitutes the receptor's natural ligand. Chemokine receptors of the β-chemokines are designated “CCR”; while those of the β-chemokines are designated “CXCR.” These chemokine receptors include but are not limited to CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CXCR3 and CXCR4 (see for a complete review, Murphy et al. Pharmacol. Rev. 52(1), 145-176 (2000)).
Chemokines are considered to be principal mediators in the initiation and maintenance of inflammation (see Chemokines in Disease published by Humana Press (1999), Edited by C. Herbert; Murdoch et al. Blood 95, 3032-3043 (2000)). More specifically, chemokines have been found to play an important role in the regulation of endothelial cell function, including proliferation, migration and differentiation during angiogenesis and re-endothelialization after injury (Gupta et al., J. Biolog. Chem., 7:4282-4287, 1998). Both chemokine receptors CXCR4 and CCR5 have been implicated in the etiology of infection by human immunodeficiency virus (HIV).
In most instances, HIV initially binds via its gp120 envelope protein to the CD4 receptor of the target cell. A conformational change appears to take place in the gp120 which results in its subsequent binding to a chemokine receptor, such as CCR5 (Wyatt et al., Science, 280:1884-1888 (1998)). HIV-1 isolates arising subsequently in the infection bind to the CXCR4 chemokine receptor. The observed binding of another related retrovirus, feline immunodeficiency virus, to a chemokine receptor without needing to bind first to the CD4 receptor, suggests that chemokine receptors may be the primordial obligate receptors for immunodeficiency retroviruses.
Following the initial binding by HIV to CD4, virus-cell fusion results, which is mediated by members of the chemokine receptor family, with different members serving as fusion cofactors for macrophage-tropic (M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carroll et al., Science, 276: 273-276 1997; Feng et al. Science 272, 872-877 (1996); Bleul et al. Nature 382, 829-833 (1996); Oberlin et al. Nature 382, 833-835 (1996); Cocchi et al. Science 270, 1811-1815 (1995); Dragic et al. Nature 381, 667-673 (1996); Deng et al. Nature 381, 661-666 (1996); Alkhatib et al. Science 272, 1955-1958, (1996)). During the course of infection within a patient, it appears that a majority of HIV particles shift from the M-tropic to the more aggressive pathogenic T-tropic viral phenotype (Miedema et al., Immune. Rev., 140:35 (1994); Blaak et al. Proc. Natl. Acad. Sci. 97, 1269-1274 (2000); Simmonds et al. J. Virol. 70, 8355-8360 (1996); Tersmette et al. J. Virol. 62, 2026-2032, (1988); Connor, R. I., Ho, D. D. J. Virol. 68, 4400-4408 (1994); Schuitemaker et al. J. Virol. 66, 1354-1360 (1992)). The M-tropic viral phenotype correlates with the virus' ability to enter the cell following binding of the CCR5 receptor, while the T-tropic viral phenotype correlates with viral entry into the cell following binding and membrane fusion with the CXCR4 receptor. Clinically, observations suggest that patients who possess genetic mutations in the CCR5 or CXCR4 appear resistant or less susceptible to HIV infection (Liu et al. Cell 86, 367-377 (1996); Samson et al. Nature 382, 722-725 (1996); Michael et al. Nature Med. 3, 338-340 (1997); Michael et al. J. Virol. 72, 6040-6047 (1998); Obrien et al. Lancet 349, 1219 (1997); Zhang et al. AIDS Res. Hum. Retroviruses 13, 1357-1366 (1997); Rana et al. J. Virol. 71, 3219-3227 (1997); Theodorou et al. Lancet 349, 1219-1220 (1997)). Despite the number of chemokine receptors which have been reported to mediate HIV entry into cells, CCR5 and CXCR4 appear to be the only physiologically relevant coreceptors used by a wide variety of primary clinical HIV-1 strains (Zhang et al. J. Virol. 72, 9307-9312 (1998); Zhang et al. J. Virol. 73, 3443-3448 (1999); Simmonds et al. J. Virol. 72, 8453-8457 (1988)). Fusion and entry of T-tropic viruses that use CXCR4 are inhibited by the natural CXC-chemokine stromal cell-derived factor-1 (SDF-1). On the other hand, fusion and entry of M-tropic viruses that use CCR5 are inhibited by the natural CC-chemokines namely, Regulated on Activation Normal T-cell Expressed and Secreted (RANTES or CCL5) and Macrophage Inflammatory proteins (MIP-1 alpha and MIP-1 beta or CCL3 and CCL4, respectively). SDF-1 is known as CXCL12 or Pre B-cell stimulating factor (PBSF).
However, the binding of chemokine receptors to their natural ligands appears to serve a more evolutionary and central role than only as mediators of HIV infection. The binding of the natural ligand, PBSF/SDF-1 to the CXCR4 chemokine receptor provides an important signaling mechanism. CXCR4 or SDF-1 knock-out mice exhibit cerebellar, cardiac and gastrointestinal tract abnormalities and die in utero (Zou et al., Nature, 393:591-594 (1998); Tachibana et al., Nature, 393:591-594 (1998); Nagasawa et al. Nature 382, 635-638 (1996)). CXCR4-deficient mice also display hematopoietic defects (Nagasawa et al. Nature 382, 635-638 (1996)). Furthermore, the migration of CXCR4 expressing leukocytes and hematopoietic progenitors to SDF-1 appears to be important for maintaining B-cell lineage and localization of CD34+ progenitor cells in bone marrow (Bleul et al. J. Exp. Med. 187, 753-762 (1998); Viardot et al. Ann. Hematol. 77, 195-197 (1998); Auiti et al. J. Exp. Med. 185, 111-120 (1997); Peled et al. Science 283, 845-848 (1999); Qing et al. Immunity 10, 463-471 (1999); Lataillade et al. Blood 95, 756-768 (1999); Ishii et al. J. Immunol. 163, 3612-3620 (1999); Maekawa et al. Internal Medicine 39, 90-100 (2000); Fedyk et al. J. Leukocyte Biol. 66, 667-673 (1999); Peled et al. Blood 95, 3289-3296 (2000)).
The signal provided by SDF-1 on binding to CXCR4 may also play an important role in tumor cell proliferation and regulation of angiogenesis associated with tumor growth (See “Chemokines and Cancer” published by Humana Press (1999); Edited by B. J. Rollins; Arenburg et al. J. Leukocyte Biol. 62, 554-562 (1997); Moore et al. J. Invest. Med. 46, 113-120 (1998); Moore et al. Trends cardiovasc. Med. 8, 51-58 (1998); Seghal et al. J. Surg. Oncol. 69, 99-104 (1998)). Known angiogenic growth factors VEG-F and bFGF, up-regulated levels of CXCR4 in endothelial cells, and SDF-1 can induce neovascularization in vivo (Salcedo et al. Am. J. Pathol. 154, 1125-1135 (1999)). Furthermore, leukemia cells that express CXCR4 migrate and adhere to lymph nodes and bone marrow stromal cells that express SDF-1 (Burger et al. Blood 94, 3658-3667 (1999); Arai et al. Eur. J. Haematol. 64, 323-332 (2000); Bradstock et al. Leukemia 14, 882-888 (2000)).
The binding of SDF-1 to CXCR4 has also been implicated in the pathogenesis of atherosclerosis (Abi-Younes et al. Circ. Res. 86, 131-138 (2000)), renal allograft rejection (Eitner et al. Transplantation 66, 1551-1557 (1998)), asthma and allergic airway inflammation (Yssel et al. Clinical and Experimental Allergy 28, 104-109 (1998); J. Immunol. 164, 5935-5943 (2000); Gonzalo et al. J. Immunol. 165, 499-508 (2000)), Alzheimer's disease (Xia et al. J. Neurovirology 5, 32-41 (1999)) and arthritis (Nanki et al. J. Immunol. 164, 5010-5014 (2000)).
Platelets have also been shown to secrete the chemokine RANTES upon activation, and that the presence of RANTES on the endothelium promotes the arrest of monocytes on the inflamed endothelium, an important step in atherogenesis as the conversion of macrophages into foam cells in the subendothelium is a central process in atheroma formation (Tan, et al., Expert Opin. Investig. Drugs, 12(11):1765-1776 (2003)). Hence, the inhibition or prevention of the binding of RANTES, directly or indirectly, to the CCR5 receptor could potentially attenuate the development of atherosclerosis. For example, Met_RANTES has also been shown to inhibit the binding of monocytes to the activated endothelium (Tan, et al., supra).
In attempting to better understand the relationship between chemokines and their receptors, recent experiments to block the fusion, entry and replication of HIV via the CXCR4 chemokine receptor were carried out through the use of monoclonal antibodies or small molecules that appear to suggest a useful therapeutic strategy (Schols et al., J. Exp. Med. 186:1383-1388 (1997); Schols et al., Antiviral Research 35:147-156 (1997); Bridger et al. J. Med. Chem. 42, 3971-3981 (1999); Bridger et al. “Bicyclam Derivatives as HIV Inhibitors” in Advances in Antiviral Drug Design Volume 3, p 161-229; Published by JAI press (1999); Edited by E. De Clercq). Small molecules, such as bicyclams, appear to specifically bind to CXCR4 and not CCR5 (Donzella et al., Nature Medicine, 4:72-77 (1998)). These experiments demonstrated interference with HIV entry and membrane fusion into the target cell in vitro. More recently, bicyclams were also shown to inhibit fusion and replication of Feline Immunodeficiency Virus (FIV) that uses CXCR4 for entry (Egberink et al. J. Virol. 73, 6346-6352 (1999)). CCR5 blocking agents include monoclonal antibodies, some which selectively block HIV coreceptor activity but not chemokine binding, and chemokine derivatives, such as truncated versions of RANTES, Met-RANTES, and AOP-RANTES and the viral chemokine KSHV vMIP-II, all which block both chemokine and HIV interaction with CCR5 but are not selective (reviewed by Murphy et al. Pharmacol. Rev. 52(1), 145-176 (2000)).
Additional experiments have shown that the bicyclam dose-dependently inhibits binding of 125I-labeled SDF-1 to CXCR4 and the signal transduction (indicated by an increase in intracellular calcium) in response to SDF-1. Thus, the bicyclam also functioned as an antagonist to the signal transduction resulting from the binding of stromal derived factor or SDF-1α, the natural chemokine to CXCR4. Bicyclams also inhibited HIV gp120 (envelope)-induced apoptosis in non-HIV infected cells (Blanco et al. Antimicrobial Agents and Chemother. 44, 51-56 (2000)).
Passive immunization with anti-MIP-1 alpha has been shown to delay the onset and reduce the severity of collagen-induced-arthritis (CIA) in mice, where the CIA model is an established murine model representing human rheumatoid arthritis (Szekanecz, Z., et al., AP, Seminars in Immunology, 15 (2003), p. 15-21). Other studies have also shown that agents that block the CCR5 receptor may provide a rational approach to the treatment of multiple sclerosis. Administration of anti-MIP-1 alpha antiserum has been shown to prevent CNS infiltration by PBMC in mice with experimental allergic encephalomyelitis, a rodent model of multiple sclerosis (Balashov, K. E., et al., Proc. Natl. Acad. Sci. USA, Vol. 96 (1999), p. 6873-6878). Other studies involving chronic rejection of transplanted hearts or cardiac allograft vasculopathy (CAV) and acute renal allograft rejection have shown that blocking chemokine receptors such as CCR5 may provide unique therapeutic approaches in the treatment or prevention of such diseases (Yun J J, et al., Circulation, 2004, Vol. 109(7), p. 932-7, Panzer U., et al., Transplantation, 2004, Vol. 78(9), p. 1341-50). For example, antagonism of the chemokine receptors CCR1 and CCR5 with Met-RANTES attenuated CAV development by reducing mononuclear cell recruitment to the transplanted heart. Met-CCL5, an antagonist of CCR1 and CCR5, had been tested and shown to inhibit the growth of breast tumors (Robinson S C. et al, Cancer Res., 2003, Vol. 63(23), p. 8360-5).
Chemokines, as indicated above, play an important role and are implicated in a wide variety of human disease such as in autoimmune disease, allograft rejection, infection, allergies, neoplasia, and vascular abnormalities. In addition to its contributory role in HIV infection, the chemokine receptor CCR5 has been associated with diseases such as the inflammatory demyelinating diseases of the central nervous system, including multiple sclerosis and experimental autoimmune encephalomyelitis, rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, and cardiovascular disease (reviewed in Gerard et al. Natl. Immunol. 2(2), 108-115 (2001) and Luster, A., N. Eng. J. Med., 338 (7), 436-445 (1998)). The CCR5 receptor is expressed on T-lymphocytes, and macrophages and reports of CCR5 on neurons, astrocytes, capillary endothelial cells, epithelium, vascular smooth muscle, and fibroblast have been published. The natural ligands that bind to the CCR5 receptor, in addition to RANTES and MIP-1 alpha/beta, are monocyte chemoattractant protein 2 (MCP-2 or CCL8).
U.S. Pat. Nos. 5,583,131; 5,698,546; 5,817,807; 5,021,409; and 6,001,826 which are incorporated herein in their entirety by reference, disclose cyclic compounds that are active against HIV-1 and HIV-2 in in vitro tests. It was subsequently discovered and further disclosed in PCT WO 02/34745 that these compounds exhibit anti-HIV activity by binding to the chemokine receptor CXCR4 and/or CCR5 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 receptor for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor 1α (SDF-1). Furthermore, these compounds demonstrate protective effects against HIV infection of target cells by binding in vitro to the CCR5 receptor.
Additionally, U.S. Pat. No. 6,365,583 discloses that these cyclic polyamine antiviral agents described in the above-mentioned patents/patent applications have the effect of enhancing production of white blood cells as well as exhibiting antiviral properties. Thus, these agents are useful for controlling the side-effects of chemotherapy, enhancing the success of bone marrow transplantation, enhancing wound healing and burn treatment, as well as combating bacterial infections in leukemia.
More recently, PCT WO 00/56729, PCT WO 02/22600, PCT WO 02/22599, and PCT WO 02/34745 describe a series of heterocyclic compounds that exhibit anti-HIV activity by binding to the chemokine receptors CXCR4 and CCR5 expressed on the surface of certain cells of the immune system. This competitive binding thereby protects these target cells from infection by HIV which utilize the CXCR4 or CCR5 receptors for entry. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CXCR4, the chemokine stromal cell-derived factor 1α (SDF-1) and/or the natural ligand for CCR5, the chemokine RANTES.
The chemokine receptor, CXCR4 has been found to be associated with the vascularization of the gastrointestinal tract (Tachibana et al., Nature, 393:591-594 (1998)) as well as in hematopoiesis and cerebellar development (Zou et al., Nature, 393:591-594 (1998)). Interference with any of these important functions served by the binding of pre-B-cell growth-stimulating factor/stromal derived factor (PBSF/SDF-1) to the CXCR4 chemokine receptor results in lethal deficiencies in vascular development, hematopoiesis and cardiogenesis. Similarly, fetal cerebellar development appears to rely upon the effective functioning of CXCR4 in neuronal cell migration and patterning in the central nervous system. This G-protein-coupled chemokine receptor appears to play an important role in ensuring the necessary patterns of migration of granule cells in the cerebellar anlage.
Herein, we disclose compounds that have unique chemical attributes and that exhibit protective effects against HIV infection of target cells by binding to chemokine receptor CCR5. In addition, these compounds antagonize the binding, signaling and chemotactic effects of the natural ligand for CCR5, the chemokine RANTES.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are hereby incorporated in their entirety by reference herein.
DISCLOSURE OF THE INVENTION
The present invention provides novel compounds that may modulate chemokine receptors and interfere with the binding of the natural ligand thereto. The compounds of the present invention may be useful as agents demonstrating protective effects on target cells from HIV infection. In another aspect, the present invention provides novel compounds that may be useful for the treatment and prevention of inflammatory and autoimmune diseases. Embodiments of the present invention are compounds that may act as antagonists or agonists of chemokine receptors, which may be useful as agents capable of reconstituting the immune system by increasing the level of CD4+ cells; as antagonist agents of apoptosis in immune cells, such as CD8+ cells, and neuronal cells; as antagonist agents of migration of human bone marrow B lineage cells to stromal-derived factor 1, as well as other biological activities related to the ability of these compounds to inhibit the binding of chemokines to their receptors.
More particularly, the present invention relates to novel piperidine derivatives that may bind to chemokine receptors, preferably CCR5 receptors. In one example, the invention is directed to a compound or a pharmaceutically acceptable salt thereof, having the formula




    
    
        or a pharmaceutically acceptable salt thereof,
        where X is carbon or nitrogen;
        Y is oxygen if X is carbon, or a bond if X is nitrogen;
        n is 0-1;
        R1 is an optionally substituted aryl or heteroaryl;
        R2 is an optionally substituted aryl or heteroaryl, or N═(C1-6 alkyl);
        R3 is an optionally substituted aryl, heteroaryl, or a phenyl fused with a 5- or 6-membered heterocyclic ring; and
        R4 is hydrogen or alkyl.
    
    


In the above formula 1, X may be carbon and Y is oxygen. Alternatively, X may be nitrogen and Y is a bond.
In the above formula 1, R1 may be phenyl, pyrimidinyl, pyridinyl, pyridine N-oxide, thiophenyl, isoxazolyl, or pyrazolyl, each of which is optionally substituted by one or more halogen, alkyl, amine or heteroaryl.
In the above formula 1, R2 may be phenyl, pyridinyl, thiazolyl, furanyl, or thiophenyl, each of which is optionally linked to one or more C1-6 alkyl, alkoxy, trifluoromethyl, carboxylalkyl, cyano, or halogen.
In the above formula 1, R3 may be phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl or phthalanyl, each of which is optionally linked to one or more C1-6 alkyl, trifluoromethyl, oxotrifluoromethyl, carboxylalkyl, cyano, halogen, sulfanyl, SO2R9, where R9 is alkyl, amine or amino alkyl, C(O)R10, where R10 is alkyl, amine, morpholine, NMe2, N(OMe)Me, NPh, piperidine, NHMe, piperazine, NHCH2C(O)OMe or PhC(O)OH, OR11, where R11 is H, alkyl, (CH2)2OMe, CH2C(O)NH2, CH2C(O)NHNH2, CH2C(O)OCMe3, CH2C(O)OMe, CH2C(O)OH, PhC(O)OH, PhC(O)NH2, SO2Me, C(O)Me, C(O)OMe, C(O)NEt2, C(O)NMe2 or




NHR12, where R12 is H, C(O)Me, C(O)CF3, SO2Me, C(O)NH2, C(O)NMe2 or





NO2, CH2PhC(O)OH, SOMe, CH2NHC(O)Me, morpholine, CH═CHC(O)OMe, CH═CHC(O)OH,





In one aspect, R3 is a phenyl fused with a 5- or 6-membered heterocyclic ring. For example, R3 may be indolyl, benzodioxolyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzofuranyl, or dihydrobenzodioxinyl.
In the above formula 1, R4 may be hydrogen or alkyl. In particular examples, R4 is hydrogen.
In another example, the invention is directed to a compound or a pharmaceutically acceptable salt thereof, having the formula




    
    
        or a pharmaceutically acceptable salt thereof,
        where A and B are independently CH2, O, or C═NH;
        Ring D is an optionally substituted 6-membered aromatic ring; and
        R1 and R3 are independently an optionally substituted aryl or heteroaryl.
    
    


In the above formula 2, ring D may be pyridine or phenyl.
In the above formula 2, R1 may be phenyl, pyrimidinyl, pyridine N-oxide or pyridinyl, each optionally substituted by one or more halogen or alkyl.
In the above formula, R3 may be phenyl, which may be linked to a substituent selected from the group consisting of alkoxy, trifluoromethyl, oxotrifluoromethyl, cyano, halogen, sulfanyl, SO2R9 where R9 is alkyl or amino alkyl, sulfinyl, carbonyl and




The present invention also provides pharmaceutical compositions comprising compounds having Formula 1 or 2, and a pharmaceutically acceptable carrier. Furthermore, the present invention provides methods for treating a CCR5 mediated disease in a cell, tissue or organ, comprising contacting a compound having Formula 1 or 2 with the system, thereby treating a CCR5-mediated disease. The present invention also provides methods for treating a CCR5 mediated disease in a human or animal subject, comprising administering a compound having Formula 1 or 2 with the subject, thereby treating a CCR5-mediated disease.
Examples of CCR5-mediated diseases that may be treated using the compounds of the present invention include but are not limited to HIV, an inflammatory demyelinating disease of the central nervous system, an autoimmune disease, multiple sclerosis, experimental autoimmune encephalomyelitis, psoriatic or rheumatoid arthritis, intestinal inflammation, allograft rejection, asthma, cardiovascular disease, atherosclerosis, allergic disease, allergic rhinitis, dermatitis, conjunctivitis, hypersensitivity lung disease, hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis, dermatomyositis, systemic anaphylaxis, myastenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, graft rejection, allograft rejection, graft-versus-host disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, spondyloarthropathy, scleroderma; psoriasis, inflammatory dermatosis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis, eosinphilic myotis, eosiniphilic fasciitis, tumor or cancer.
The compounds of Formula 1 or 2 may form hydrates or solvates, and may be in any stereoisomeric forms and mixtures of stereoisomeric forms thereof. Racemate compounds may be separated into individual isomers using known separation and purification methods. Individual optical isomers and a mixture thereof, are included in the scope of the present invention.
MODES OF CARRYING OUT THE INVENTION
In one aspect, the invention provides compounds having Formula 1 or 2 described above, which may be chemokine modulators of chemokine receptors.
In more detail, the compounds may bind chemokine receptors and interfere with the binding of the natural ligand thereto, and may demonstrate protective effects on target cells from HIV infection. The compounds may be useful as antagonists or agonists of chemokine receptors, and are thus capable of reconstituting the immune system by increasing the level of CD4+ cells; as antagonist agents of apoptosis in immune cells, such as CD8+ cells, and neuronal cells; as antagonist agents of migration of human bone marrow B lineage cells to stromal-derived factor 1, as well as other biological activities related to the ability of these compounds to inhibit the binding of chemokines to their receptors.
Chemokine antagonists that interfere in the binding of a chemokine to its receptor are useful to reconstitute the immune system by increasing the level of CD4+ cells (Biard-Piechaczyk, et al., Immunol. Lett., 70: 1-3 (1999)); as antagonist agents of apoptosis in immune cells, such as CD8+ cells (Herbin, et al., Nature 395: 189-193, (1998)), and as antagonist agents of apoptosis in neuronal cells (Ohagen et al., J. of Virol., 73: 897-906, (1999); and Hesselgesser, et al., Curr. Biol. 8: 595-598, (1998)). Chemokine receptor antagonist agents also inhibit the migration of human bone marrow B lineage cells to stromal-derived factor 1 (See e.g., E. Fedyk, et al., J. of Leukocyte Biol., 66:667-783, (1999)).
The invention includes pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula 1 or 2 along with at least one excipient, and methods of treating diseases of the human body or the bodies of other mammals with such compositions. The term “therapeutically effective amount” means the amount of a compound of Formula 1 or 2 that will elicit the biological or medical response of a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician. The invention provides a method for blocking or interfering with the binding by a chemokine receptor with its natural ligand, comprising contacting of the chemokine receptor with an effective amount of the compound according to Formula 1 or 2. The present invention also provides methods of protecting target cells possessing chemokine receptors, which binding to a pathogenic agent results in disease or pathology, comprising administering to a mammalian subject a pharmaceutical composition comprising a therapeutically effective amount of the compound according to Formula 1 or 2. The invention includes the use of a compound of Formula 1 or 2 in the manufacture of a medicament for the treatment of a disease in which blocking or interfering with binding of a chemokine receptor with its natural ligand is advantageous. The compound is formulated into a composition in an amount corresponding to a therapeutically effective amount of a compound of Formula 1 or 2.
The Invention Compounds
The invention compounds are described generally by Formula 1 or 2. In one embodiment, the compounds of the present invention are of formula 1




    
    
        or a pharmaceutically acceptable salt thereof,
        wherein X is carbon or nitrogen;
        Y is O, S, SO or SO2 if X is carbon, or a bond if X is nitrogen;
        n is 0-3;
        R1 is a cyclic or acyclic alkyl or 5- or 6-membered non-aromatic heterocyclic ring, each of which is optionally substituted by one or more of cyclic alkyl, acyclic alkyl, alkene, alkyne, halogen, CN, OH, NH2, NHR5, or OR5; or
        phenyl, pyridine, pyridine N-oxide or heteroaryl, each of which is optionally substituted by one or more of cyclic or acyclic alkyl, alkene, alkyne, OH, OMe, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, halogen, CN, CF3, OCF3, NHC(O)(C1-6 alkyl), C(O)(C1-6 alkyl), C(O)O(C1-6 alkyl), OC(O)(C1-6 alkyl), C(O)OH, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, S(C1-6 alkyl), SOnR6, NHS(O)n(C1-6 alkyl) where n is 1 or 2; or phenyl, pyridine or pyridine N-oxide, each of which is optionally substituted by one or more of cyclic or acyclic alkyl, alkene, alkyne, halogen, CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, or C(O)O(C1-6 alkyl); or
        an N-linked phenyl, pyridine, pyridine N-oxide or heteroaryl ring, each of which is optionally substituted by one or more of cyclic or acyclic alkyl, alkene, alkyne, halogen, CN, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, or C(O)O(C1-6 alkyl);
        R2 is phenyl, pyridine or heteroaryl, each of which is optionally substituted by one or more of cyclic or acyclic alkyl, alkene, alkyne, halogen, CN, NO2, OH, NH2, CF3, CH2OH, C(O)O(C1-6 alkyl), OR7, or 5- or 6-membered non aromatic heterocyclic ring; or
        a C1-6 alkyl, alkene or alkyne, OC(O)(C1-6 alkyl), NHC(O)(C1-6 alkyl), NHR8, or a 5- or 6-membered non aromatic heterocyclic ring;
        R3 is phenyl, pyridine, or heteroaryl, each of which is optionally substituted by one or more of cyclic or acyclic alkyl, alkene, alkyne, halogen, CN, CHO, CF3, OCF3, NO2, OH, NHC(O)(C1-6 acyclic or C3-6 cyclic alkyl), NHC(O)CF3, NHSO2(C1-6 alkyl), NHC(O)NH2, NHC(O)(C1-6 alkyl), C(O)NH2, C(O)NHC6H5, C(O)C6H4C(O)OH, C(O)N(OC1-6 alkyl)(C1-6 alkyl), C(O)NHCH2C(O)O(C1-6 alkyl), C(O)(C1-6 alkyl), C(O)O(C1-6 alkyl), C(O)(non-aromatic heterocylic ring), OC(O)(C1-6 alkyl), O(C1-6 alkyl), O(C1-6 alkyl)O(C1-6 alkyl), O(C1-6 alkyl)C(O)OH, OC6H4C(O)OH, OC6H4C(O)NH2, O(C1-16 alkyl)C(O)O(C1-6 alkyl), O(C1-6 alkyl)C(O)NH2, O(C1-6 alkyl)C(O)NHNH2, OSO2(C1-6 alkyl), OC(O)O(C1-6 alkyl), OC(O)N(C1-6 alkyl)2, OC(O)(heteroaryl), COOH, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, S(C1-6 alkyl), CH═NOH, CH═NO(C1-6 alkyl), CH═N(C1-6 alkyl), (C1-6 alkyl)C═NOH, (C1-6 alkyl)C═NO(C1-6 alkyl), (C1-6 alkyl)C═N(C1-6 alkyl), (C1-6 alkyl)C6H4C(O)OH, (C1-6 alkyl)NHC(O)(C1-6 alkyl), CH═CHC(O)O(C1-6 alkyl), CH═CHC(O)OH, SOnR6 where n is 1 or 2; or phenyl, pyridine N-oxide, pyridine or heteroaryl each of which is optionally substituted by one or more of alkyl, alkene, alkyne, halogen, CN, CF3, OH, NH2, OR7, (C1-6 alkyl)R5, (C1-6 alkene)R5, (C1-6 alkyne)R5, or a 5- or 6-membered non aromatic heterocyclic ring;
        R4 is hydrogen or C1-6 alkyl;
        R5 is a C1-6 alkyl, phenyl, pyridine, pyridine N-oxide or heteroaryl, each of which is optionally substituted by one or more of C1-6 alkyl, OH, OMe, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, halogen, CN, CF3, OCF3, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, C(O)O(C1-6 alkyl), COOH, SOnNH(C1-6 alkyl), or SOn(C1-6 alkyl) where n is 1 or 2;
        R6 is C1-6 alkyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, or benzyl;
        R7 is a cyclic or acyclic alkyl, alkene, alkyne, phenyl, pyridine or heteroaryl, each of which is optionally substituted by one or more of C1-6 alkyl, halogen, CN, NH2, C(O)OH, C(O)O(C1-6 alkyl), OH, SOnNH2 where n is 1 or 2, SOn(C1-6 alkyl) where n is 1 or 2, SO2NH(C1-6 alkyl), C(O)NH2, C(O)NH(C1-6 alkyl), or C(O)N(C1-6 alkyl)2; and
        R8 is a C1-6 alkyl, alkene or alkyne, OH, or OMe.
    
    


In another embodiment, the compounds of the present invention are of formula 2




    
    
        or a pharmaceutically acceptable salt thereof,
        wherein R1 and R3 are as defined in formula 1;
        A and B are independently selected from C1-4 alkyl, O, C═NH, C═O, OC(O), (O)CO, S, SO, SO2, NR8, NR8C(O), OC═NR8, NOR8, C═NR8, or NR O where R8 is as defined above; and
        Ring D is phenyl, pyridine, pyridine N-oxide or heteroaryl, each of which is optionally substituted by one or more of C1-6 alkyl, C1-6 alkene, C1-6 alkyne, OH, OMe, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, halogen, CN, CF3, OCF3, NHC(O)(C1-6 alkyl), C(O)(C1-6 alkyl), C(O)O(C1-6 alkyl), OC(O)(C1-6 alkyl), C(O)OH, C(O)NH(C1-6 alkyl), C(O)N(C1-6 alkyl)2, S(C1-4 alkyl), NHS(O)2(C1-6 alkyl), or SOnR6 where n is 1 or 2 and R6 is as defined above.
    
    


Examples of heteroaryl substituents in the above Formula 1-2 include but are not limited to pyridine, quinoline, isoquinoline, imidazole, benzimidazole, benzotriazole, furan, morpholine, benzofuran, dihydrobenzofuran, thiazole, benzothiazole, benzodioxole, benzodioxane, oxazole, isoxazole, benzoxazole, pyrrole, indole, indoline, isoindoline, indazole, pyrrolidine, pyrrolidone, tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole, benzopyran, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, cinnoline, tetrahydrocinnoline, quinazoline, tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, phthalan or phthalazine.
The present invention also relates to pharmaceutical compositions comprising compounds of Formula 1 or 2, and a pharmaceutically acceptable carrier. Furthermore, the present invention relates to methods for treating a CCR5 mediated disease in a system, comprising contacting a compound of Formula 1 or 2 with a system (e.g., cell, tissue or organ), or in a subject.
Examples of piperidine compounds of the present invention include but are not limited to:

    N-(3-{4-[(4-Bromophenyl)-phenoxymethyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxynicotinamide (1);
    N-(3-{4-[(4-Bromophenyl)-phenoxymethyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (2);
    N-(3-{4-[(4-Bromo-phenyl)-o-tolyloxy-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (3);
    2,4-Dimethyl-1-oxy-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-nicotinamide (4);
    2,6-Dimethyl-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (5);
    3,5-Dichloro-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (6);
    3,5-Dichloro-N-(3-{4-[(3-trifluoromethyl-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (7);
    3,5-Dichloro-N-(3-{4-[(2-trifluoromethyl-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (8);
    3,5-Dichloro-N-(3-{4-[(3-chloro-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (9);
    3,5-Dichloro-N-(3-{4-[(2-fluoro-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (10);
    3,5-Dichloro-N-(3-{4-[(3-fluoro-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (11);
    2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[m-tolyloxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)benzamide (12);
    2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[o-tolyloxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-benzamide (13);
    3,5-Dichloro-N-(3-{4-[(3-cyano-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (14);
    3,5-Dichloro-N-(3-{4-[ethylideneaminooxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (15);
    2,6-Dimethyl-N-(3(R)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (16);
    2,6-Dimethyl-N-(3(S)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (17);
    N-(3-{4-[(6-Chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (18);
    N-(3-{4-[(6-Chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (19);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-amide (20);
    N-(3-{4-[(4-Bromo-phenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (21);
    3,5-Dichloro-N-(3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (22);
    3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (23);
    3,5-Dichloro-N-(3-{4-[(6-ethyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (24);
    3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (25);
    3,5-Dichloro-N-(3-{4-[(4-trifluoromethyl-phenyl)-(6-trifluoromethyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (26);
    3,5-Dichloro-N-(3-{4-[(6-cyano-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (27);
    3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (28);
    3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-methanesulfonyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (29);
    3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-methanesulfonyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (30);
    3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (31);
    3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (32);
    3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (33);
    3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-methylsulfamoyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (34);
    N-(3-{4-[(R)-4-Bromophenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}butyl)-3,5-dichloro-isonicotinamide (35);
    N-(3-{4-[(4-Bromo-phenyl)-(3-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (36);
    3,5-Dichloro-N-(3-{4-[(4-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (37);
    3,5-Dichloro-N-(3-{4-[(3-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (38);
    3,5-Dichloro-N-(3-{4-[(3-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (39);
    3,5-Dichloro-N-(3-{4-[(4-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (40);
    6-[(1-{3-[(3,5-Dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-trifluoromethyl-phenyl)-methoxy]-pyridine-2-carboxylic acid methyl ester (41);
    3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (42);
    3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-cyano-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (43);
    3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (44);
    3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (45);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (46);
    4-[(1-{3-[(3,5-Dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(6-methyl-pyridin-2-yloxy)-methyl]-benzoic acid methyl ester (47);
    N-(3-{4-[(4-Bromo-phenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (48);
    2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-benzamide (49);
    2,6-Dimethyl-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (50);
    2,6-Dimethyl-N-(3(R)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (51);
    2,6-Dimethyl-N-(3(S)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide (52);
    3,5-Dichloro-N-(3-{4-methyl-4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (53);
    3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-thiazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (54);
    3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-thiazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (55);
    3,5-Dichloro-N-(3-{4-[(6-chloropyridin-2-yloxy)-oxazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (56);
    3,5-Dichloro-N-(3-{4-[(6-fluoropyridin-2-yloxy)-oxazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (57);
    3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-pyridin-3-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (58);
    3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-pyridin-4-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (59);
    N-(3-{4-[(4-Bromo-phenyl)-(thiazol-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (60);
    3,5-Dichloro-N-(3-{4-[(thiazol-2-yloxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide (61);
    N-(3-{4-[(4-Bromo-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (62);
    N-(3-{4-[Benzyl-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (63);
    3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (64);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (65);
    3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (66);
    N-(3-{4-[Benzyl-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (67);
    3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (68);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (69);
    N-(3-{4-[Benzyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (70);
    3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (71);
    3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (72);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (73);
    3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (74);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (75);
    3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (76);
    3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (77);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (78);
    N-(3-{4-Benzyl-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (79);
    Methanesulfonic acid 4-[benzyl-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (80);
    N-(3-{4-[Benzyl-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (81);
    3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (82);
    N-(3-{4-[Benzyl-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (83);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-fluoro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (84);
    4-((3-Chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid methyl ester (85);
    N-[3-(4-{(3-Chloro-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (86);
    N-(3-{4-[(3-Chloro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (87);
    N-[3-(4-{(3-Chloro-benzyl)-[4-(methoxy-methyl-carbamoyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (88);
    N-(3-{4-[(3-Chloro-benzyl)-(4-phenylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (89);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (90);
    N-(3-{4-[Benzyl-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (91);
    N-(3-{4-[Benzyl-(4-carbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (92);
    N-(3-{4-[(4-Cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (93);
    N-(3-{4-[(4-Cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (94);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (95);
    4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (96);
    4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-benzoic acid (97);
    4-{4-[Benzyl-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (98);
    4-{4-[Benzyl-(1-{1-methyl-3-[(4-methyl-pyridine-3-carbonyl)-amino]-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (99);
    4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzyl]-benzoic acid (100);
    4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoyl]-benzoic acid (101);
    4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzyl}-benzoic acid (102);
    N-(3-{4-[(4-Bromo-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (103);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (104);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (105);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (106);
    4-[(3-Cyano-benzyl)-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (107);
    3,5-Dichloro-N-(3-{4-[(4-chloro-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (108);
    N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (109);
    N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (110);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (111);
    N-(3-{4-[(4-Acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (112);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (113);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (114);
    N-(3-{4-[(3-Cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (115);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (116);
    N-(3-{4-[(3-Cyano-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (117);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methanesulfonylamino-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (118);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (119);
    N-(3-{4-[(3-Cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (120);
    N-(3-{4-[(3-Cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (121);
    N-(3-{4-[(3-Cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (122);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (123);
    N-(3-{4-[(3-Cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (124);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (125);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (126);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (127);
    3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (128);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (129);
    N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (130);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (131);
    N-(3-{4-[(3-Cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (132);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (133);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (134);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (135);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (136);
    Acetic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester (137);
    Acetic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (138);
    Carbonic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester methyl ester (139);
    Carbonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester methyl ester (140);
    Diethyl-carbamic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester (141);
    N-(3-{4-[(4-Amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (142);
    [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid tert-butyl ester (143);
    {4-[(Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (144);
    Dimethyl-carbamic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester (145);
    Dimethyl-carbamic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (146);
    [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid methyl ester (147);
    {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (148);
    [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid (149);
    {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid (150);
    N-(3-{4-[(3-Cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (151);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (152);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (153);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (154);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(3,3-dimethyl-ureido)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (155);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (156);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (157);
    N-(3-{4-[(3-Cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (158);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (159);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide (160);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (161);
    4-{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (162);
    4-{4-[{1-[3-(2-Chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid (163);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (164);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2-chloro-6-methyl-benzamide (165);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (166);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (167);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl}-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (168);
    Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (169);
    Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (170);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (171);
    N-(3-{4-[[4-(Acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (172);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (173);
    N-(3-{4-[(4-Acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (174);
    {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoylamino}-acetic acid methyl ester (175);
    N-[3-(4-{(3-Cyano-benzyl)-[4-(1-methoxyimino-ethyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide (176);
    N-(3-{4-[(3-Cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (177);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (178);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (179);
    N-(3-{4-[Benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (180);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (181);
    N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (182);
    N-(3-{4-[(3-Cyano-benzyl)-(1,3-dihydro-isobenzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (183);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (184);
    N-(3-{4-[Benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (185);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (186);
    N-(3-{4-[(3-Cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (187);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (188);
    2-Chloro-N-(3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo [1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide (189);
    N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (190);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-amide (191);
    N-(3-{4-[(3-Cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (192);
    N-(3-{4-[(2-Acetyl-2,3-dihydro-1H-isoindol-5-yl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (193);
    N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (194);
    3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (195);
    N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (196);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (197);
    3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-chloro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (198);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (199);
    N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (200);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (201);
    N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (202);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (203);
    N-[3-(4-{(5-Chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide (204);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (205);
    N-(3-{4-[(4-Acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (206);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (207);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2-chloro-6-methyl-benzamide (208);
    4,6-Dimethyl-pyrimidine-5-carboyxlic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (209);
    2-Chloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide (210);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (211);
    N-(3-{4-[(4-Acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (212);
    3-[(5-Chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (213);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(3-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (214);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (215);
    N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (216);
    N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-1-oxy-isonicotin-amide (217);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (218);
    3,5-Dichloro-N-(3-{4-[(5-cyano-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (219);
    N-(3-{4-[(4-Bromo-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (220);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (221);
    N-(3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (222);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (223);
    N-[3-(4-{(5-Cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide (224);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (225);
    N-(3-{4-[(4-Acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (226);
    (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid methyl ester (227);
    4-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (228);
    4-[4-((5-Cyano-2-fluoro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-benzoic acid (229);
    N—((R)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (230);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (231);
    N—((R)-3-{4-[(4-Acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (232);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(5-cyano-2-fluoro-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (233);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (234);
    {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (235);
    {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid (236);
    {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (237);
    {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid (238);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (239);
    (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid (240);
    (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid (241);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (242);
    N-(3-{4-[Benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (243);
    N-(3-{4-[(5-Cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (244);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (245);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (246);
    3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (247);
    3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-2,3-dihydrobenzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (248);
    3,5-Dichloro-N-(3-{4-[2-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (249);
    3,5-Dichloro-N-(3-{4-[2-(4-methylsulfamoyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (250);
    3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (251);
    3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (252);
    3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (253);
    3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-methylsulfamoyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (254);
    3,5-Dichloro-N-(3-{4-[6-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (255);
    N-(3-{4-[2-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (256);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-amide (257);
    3,5-Dichloro-N-(3-{4-[1-imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (258);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[1-imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-amide (259);
    N-(3-{4-[1-Imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (260);
    N-(3-{4-[2-(4-Bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (261);
    N-(3-{4-[2-(4-Bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (262);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (263);
    3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (264);
    2,4-Dimethyl-1-oxy-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo [1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide (265);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (266);
    2,6-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-benzamide (267);
    2,4-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide (268);
    2-Chloro-6-methyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-benzamide (269);
    3,5-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (270);
    3,5-Dichloro-N-(3-{4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin 1-yl}-butyl)-isonicotinamide (271);
    3,5-Dichloro-N-(3-{4-[2-(4-methanesulfinyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (272);
    3,5-Dichloro-N-(3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (273);
    N-(3-{4-[2-(4-Methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (274);
    3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (275);
    2,4-Dimethyl-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide (276);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (277);
    N-(3-{4-[2-(4-Cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (278);
    N-(3-{4-[2-(4-Cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (279);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (280);
    N-(3-{4-[2-(4-Chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (281);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-acetyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (282);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{2-[4-(1-methoxyimino-ethyl)-phenyl]-benzo[1,3]dioxol-2-yl}-piperidin-1-yl)-butyl]-amide (283);
    N-(3-{4-[2-(4-Methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (284);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide (285);
    3,5-Dichloro-N-(3-{4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (286);
    3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (287);
    3,5-Dichloro-N-(3-{4-[5-fluoro-2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide (288);
    N-(3-{4-[5-Fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (289);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (290);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (291);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-chloro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (292);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (293);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(1-methoxyimino-ethyl)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (294);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethyl-phenyl)-amino-piperidin-1-yl}-butyl)-amide (295);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-hydroxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (296);
    {4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid (297);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (298);
    4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-benzoic acid methyl ester (299);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (300);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (301);
    4-{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-benzoic acid (302);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(4-carbamoyl-phenoxy)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (303);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-fluoro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (304);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-ethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (305);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (306);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methylsulfanyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (307);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methanesulfonyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (308);
    3,5-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (309);
    2,6-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide (310);
    2-Chloro-6-methyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide (311);
    3,5-Dimethyl-isoxazole-4-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (312);
    1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (313);
    2,4-Dimethyl-1-oxy-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (314);
    2,6-Dimethyl-4-pyridin-4-yl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide (315);
    2,4-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (316);
    2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (317);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (318);
    2-Chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide (319);
    1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (320);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (321);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (322);
    3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-isonicotinamide (323);
    3,5-Dimethyl-isoxazole-4-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (324);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (325);
    2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (326);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (327);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (328);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (329);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (330);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-ethoxy-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (331);
    2,6-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-benzamide (332);
    2-Chloro-6-methyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-benzamide (333);
    2,4-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide (334);
    2,4-Dimethyl-1-oxy-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide (335);
    3,5-Dichloro-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (336);
    3,5-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (337);
    2,4-Dimethyl-thiophene-3-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (338);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (339);
    2,4-Dimethyl-1-oxy-N-{3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide (340);
    2,6-Dimethyl-N-{3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-benzamide (341);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (342);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-thiophen-3-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (343);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methoxy-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (344);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(benzo[1,3]dioxol-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (345);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (346);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (347);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(3-methyl-thiophen-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (348);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-thiophen-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (349);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[furan-2-ylmethyl-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (350);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (351);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (352);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-amide (353);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (354);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (355);
    4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (356);
    N-(3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (357);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (358);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (359);
    2-Amino-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide (360);
    2-Chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide (361);
    3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}1-butyl)-isonicotinamide (362);
    N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide (363);
    2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (364);
    N—((R)-3-{1-[(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide (365);
    N-(3-{4-[(4-Carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (366);
    N—((R)-3 {4-[(4-Carbamoylmethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (367);
    Methanesulfonic acid 4-[(1-{(R)-3-[(2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-methyl-pyridin-3-ylmethyl)-amino]-phenyl ester (368);
    2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (369);
    N-(3-{4-[(4-Methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (370); and
    2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-1-oxy-nicotinamide (371).


The present invention also relates to pharmaceutical compositions comprising a piperidine derivative including but not limited to compounds 1-371, and a pharmaceutically acceptable carrier. Furthermore, the present invention relates to methods for treating a CCR5 mediated disease in a system, comprising contacting a piperidine derivative, including but not limited to compounds 1-371, with the system. In one embodiment, the system is a cell or tissue. The present invention also relates to methods for treating a CCR5 mediated disease in a subject, comprising administering a piperidine derivative, including but not limited to compounds 1-371, to the subject. The subject may be human or an animal.
Moreover, the compounds may be supplied as “pro-drugs” or protected forms, which release the compound after administration to a subject. The terms “administration” and or administering” as used herein should be understood to mean providing a compound of the invention to the subject in need of treatment. For example, the compound may carry a protective group which is split off by hydrolysis in body fluids, e.g., in the bloodstream, thus releasing the active compound or is oxidized or reduced in body fluids to release the compound. A discussion of pro-drugs may be found in “Smith and Williams' Introduction to the Principles of Drug Design,” H. J. Smith, Wright, Second Edition, London (1988).
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts that are non-toxic. The term “pharmaceutically acceptable salt” as used herein means an active ingredient comprising compounds of Formula 1 or 2 used in the form of a salt thereof, particularly where the salt form confers on the active ingredient improved pharmacokinetic properties as compared to the free form of the active ingredient or other previously disclosed salt form. The term “pharmaceutically acceptable salt” encompasses all acceptable salts including but not limited to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartarate, mesylate, borate, methylbromide, bromide, methylnitrite, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutame, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydradamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like.
Pharmaceutically acceptable salts of the compounds of the present invention can be used as a dosage for modifying solubility or hydrolysis characteristics, or can be used in sustained release or pro-drug formulations. Also, pharmaceutically acceptable salts of the compounds of this invention may include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
All of the compounds of the invention contain at least one chiral center. The invention includes mixtures of stereoisomers, individual stereoisomers, and enantiomeric mixtures, and mixtures of multiple stereoisomers. In short, the compound may be supplied in any desired degree of chiral purity.
Utility and Administration
In one aspect, the invention is directed to compounds of Formula 1 or 2 that may modulate chemokine receptor activity. Chemokine receptors include but are not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, and CXCR4.
In one embodiment, the invention provides compounds of Formula 1 or 2 that may demonstrate protective effects on target cells from HIV infection by binding specifically to the chemokine receptor, thus affecting the binding of a natural ligand to the CCR5 and/or CXCR4 of a target cell.
In another embodiment, the compounds of the present invention may be useful as agents which affect chemokine receptors, such as CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, CXCR4 where such chemokine receptors have been correlated as being important mediators of many inflammatory as well as immunoregulatory diseases.
Other diseases that are also implicated with chemokines as mediators include angiogenesis, and tumorigenesis such as brain, and breast tumors. Thus, a compound that modulates the activity of such chemokine receptors is useful for the treatment or prevention of such diseases.
As used herein, the terms “modulators and/or modulation” encompass antagonist/antagonism, agonist/agonism, partial antagonist/partial antagonism, and or partial agonist/partial agonism, i.e., inhibitors, and activators. The compounds of Formula 1 or 2 described herein may possess biological activity such that they are able to modulate CCR5 chemokine receptor activity and consequent or associated pathogenic processes subsequently mediated by the CCR5 receptor and its natural ligands. In one embodiment, compounds of Formula 1 or 2 demonstrate a protective effect against HIV infection by inhibiting the binding of HIV to a chemokine receptor of a target cell such as CCR5 and/or CXCR4. Such modulation is obtained by a method which comprises contacting a target cell with an effective amount of the compound to inhibit the binding of the virus to the chemokine receptor. As used herein, the terms “modulation and/or modulation” encompass modulating activity in all types and subtypes of CCR5 receptors of a target cell, in any tissues of a particular patient where they are found, and in any cell components comprising those tissues that the target cell may be located.
Compounds that inhibit chemokine receptor activity and function may be used for the treatment of diseases that are associated with inflammation, including but not limited to, inflammatory or allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, atherosclerosis, interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune throiditis, graft rejection, including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myotis, eosiniphilic fasciitis; and cancers.
In addition, compounds that activate or promote chemokine receptor function are used for the treatment of diseases associated with immunosuppression, such as in individuals undergoing chemotherapy, radiation therapy, enhanced wound healing and burn treatment, therapy for autoimmune disease or other drug therapy (e.g., corticosteroid therapy) or combination of conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, which causes immunosuppression; or immunosuppression due to congenital deficiency in receptor function or other causes. Compounds that activate or promote chemokine receptor function are also used for the treatment of infectious diseases, such as parasitic diseases, including but not limited to helminth infections, such as nematodes (round worms); Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis; trematodes; visceral worms, visceral larva migtrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostoma caninum); the malaria-causing protozoan Plasmodium vivax, Human cytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus, also known as human herpesvirus 8, and poxvirus Moluscum contagiosum. 
Compounds of the present invention may be used in combination with any other active agents or pharmaceutical compositions where such combined therapy is useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and immunoregulatory diseases.
Furthermore, the compounds may be used in combination with one or more agents useful in the prevention or treatment of HIV. Examples of such agents include:

    
    
        (1) nucleotide reverse transcriptase inhibitor such as tenofovir disoproxil fumarate; lamivudine/zidovudine; abacavir/lamivudine/zidovudine; emtricitabine; amdoxovir; alovudine; DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta)-L-F d4C; didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil, fozivudine todoxil, etc.;
        (2) non-nucleotide reverse transcriptase inhibitor (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, TMC-125; DPC-083; capravarine; calanolide A; SJ-3366 series, etc.;
        (3) protease inhibitors such as saquinavir, lopinavir/ritonavir, atazanavir, fosamprenavir, tipranavir, TMC-114, DPC-684, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.;
        (4) entry inhibitors such as T-20; T-1249; PRO-542; PRO-140; TNX-355; BMS-806 series; and 5-Helix;
        (5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D (or SCH350634); TAK779; UK 427,857 and TAK 449; or CXCR4-receptor inhibitors such as T22, T134, T140, 18 amino acid analogs of polyphemusin II, ALX40-4C, ALK40-4C, AMD3100 and AMD070;
        (6) Integrase inhibitors such as L-870,810; GW-810781 (S-1360); and
        (7) Budding inhibitors such as PA-344; and PA-457.
    
    


Combinations of compounds of the present invention with HIV agents are not limited to the above examples, but include the combination with any agent useful for the treatment of HIV. Combinations the compounds of the invention and other HIV agents may be administered separately or in conjunction. The administration of one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds according to the present invention may be administered by oral, intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, transdermal or transmucosal administration or by implant. They may also be administered by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
The compounds of the invention may be used to treat animals, including mice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However, compounds of the invention can also be used in other species, such as avian species (e.g., chickens). The compounds of the invention may also be effective for use in humans. The term “subject” or alternatively referred to herein as “patient” is intended to be referred to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. However, the compounds, methods and pharmaceutical compositions of the present invention may be used in the treatment of animals.
The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of compound of Formula 1 or 2. The compounds may be administered alone or as a mixture with a pharmaceutically acceptable carrier (e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.). The compounds may be administered orally or non-orally. Examples of non-oral formulations include injections. drops, suppositories, pessaryies.
In the treatment or prevention of conditions which require chemokine receptor modulation, an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day, and can be administered in singe or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.
In another aspect of the present invention, a compound of Formula 1 or 2 may be used in screening assays for compounds which modulate the activity of chemokine receptors, preferably CCR5 receptors. The ability of a test compound to inhibit gp120 and CD4/CCR5-dependent cell-cell fusion may be measured using a cell fusion assay known in the art.
The compounds of Formula 1 or 2 as disclosed herein may be useful for isolating receptor mutants, which can then be made into screening tools for the discovery of even more potent compounds, following procedures described herein and procedures known in the art. The compounds of Formula 1 or 2 may also be useful in establishing or characterizing the binding sites of other ligands, including compounds other than those of Formula 1 or 2 to chemokine receptors, e.g., by competitive inhibition. The compounds of the present invention may also be useful for the evaluation of putative specific modulators of various chemokine receptors. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus, the compounds of this invention are commercial products to be sold for these purposes.
The invention is further described by means of examples, but not in any limitative sense.


Experimental
General Procedures
General procedure A: Reductive Amination with NaBH(OAc)3 
To a stirred solution of the amine (1 equivalent) in CH2Cl2 (concentration  ̃0.2M) at room temperature were added the carbonyl compound (1-2 equivalents), glacial AcOH (0-2 equivalents) and sodium triacetoxyborohydride (NaBH(OAc)3) ( ̃1.5-3 equivalents) and the resultant solution was stirred at room temperature. In a standard workup, the reaction mixture was poured into either saturated aqueous NaHCO3 or 1N NaOH. The phases were separated and the aqueous extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel or by recrystallization.
General procedure B: Reductive Amination with NaCNBH3 
To a stirred solution of the amine (1 equivalent) in MeOH (concentration  ̃0.1M) at room temperature were added the carbonyl compound (1-3 equivalents), glacial AcOH (0-1 equivalents) and sodium cyanoborohydride (NaCNBH3) ( ̃1.5-3 equivalents) and the resultant solution was heated to reflux. In a standard workup, the reaction mixture was concentrated under reduced pressure and diluted with saturated aqueous NaHCO3. The aqueous was extracted with CH2Cl2 and the combined organic extracts were dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel or by recrystallization.
General Procedure C: Boc deprotection with TFA
The Boc-protected amine was dissolved in CH2Cl2 ( ̃4 mL/mmol) and trifluoroacetic acid (TFA) ( ̃2 mL/mmol) was added. The mixture was stirred at room temperature for 0.5-5 hours. In a standard work-up, the mixture was neutralized with saturated aqueous NaHCO3 or 1N NaOH and the aqueous extracted with CH2Cl2. The combined extracts were dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was used in the next reaction as is or was purified by flash column chromatography on silica gel.
General Procedure D: Phthalimide Deprotection
To a solution of the phthalimide-protected amine in EtOH (0.05-0.2M) was added hydrazine hydrate ( ̃10 equivalents). The resulting mixture was stirred at room temperature overnight or heated at 40-50° C. for 2-16 hours. In a standard work-up, the mixture was concentrated under reduced pressure, diluted with CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel.
General Procedure E: EDCI coupling
To a stirred solution of a primary or secondary amine (1 equivalent), a carboxylic acid (1.1-2.0 equivalents), 1-hydroxy-benzotriazole hydrate (HOBT) (1.1-2.0 equivalents) and diisopropylethylamine (DIPEA) or N-methylmorpholine (NMM) (1.5-3 equivalents) in CH2Cl2 or DMF (concentration  ̃0.05-1.5M) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) (1.1-2.0 equivalents). The solution was stirred at room temperature for 1-3 days and concentrated in vacuo. In a standard work-up, the mixture was diluted with CH2Cl2 or EtOAc and washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography or by radial chromatography on silica gel.
General Procedure F: Coupling with the Acid Chloride
To a stirred suspension of a carboxylic acid (2 equivalents) in CH2Cl2 (concentration  ̃0.1-0.2M) were added DMF (1-5 drops) followed by oxalyl chloride (6 equivalents) and the resultant mixture was stirred at room temperature for 1-2 hours. The mixture was concentrated under reduced pressure and the acid chloride was dried in vacuo for 10-45 minutes. To the acid chloride was added a solution of the amine (1 equivalent) and Et3N (1.5-2 equivalents) in THF (concentration  ̃0.1-0.2M) and the mixture was stirred at room temperature for 1-18 hours. In a standard work-up, the mixture was diluted with CH2Cl2 or EtOAc and washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography or by radial chromatography on silica gel.
General Procedure G: Reaction of Alcohols with MsCl
To a stirred solution of the alcohol (1 equivalent) and Et3N (1.5-2 equivalents) in CH2Cl2 (or THF) (concentration  ̃0.1M) at room temperature (or 0° C.) was added methanesulfonyl chloride (MsCl) ( ̃1.5 equivalents) and the reaction was stirred at room temperature for 0.5-2 hours. In a standard work-up, the reaction mixture was poured into either saturated aqueous NaHCO3 or saturated aqueous NH4Cl. The phases were separated and the aqueous extracted with CH2Cl2. The combined organic layers were dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was either purified by flash column chromatography or used without further purification in the next step.
General Procedure H: N-Alkylation with Mesylates, Alkyl or Benzyl Halides
To a solution of the amine (1 equivalent), the mesylate or alkyl or benzyl halide (1-2 equivalents) in CH3CN or DMF (concentration  ̃0.1-0.3M) were added DIPEA or K2CO3 (1.5-2 equivalents) and KI (0-0.2 equivalents) and the mixture was stirred at 50-90° C. for 2-72 hours. In a standard work-up, the reaction was cooled to room temperature, concentrated under reduced pressure, diluted with CH2Cl2 and washed with either saturated aqueous NaHCO3 or brine. The aqueous was extracted with CH2Cl2 and the combined organic extracts were dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel.
General Procedure I: Michael Addition with Crotononitrile
A solution of the amine (1 equivalent) and crotononitrile (2-4 equivalents) in MeOH (concentration  ̃0.1-0.3M) was heated at 50-60° C. overnight. The mixture was concentrated under reduced pressure and used in the next reaction as is or was purified by flash column chromatography on silica gel.
General Procedure J: Hydrogenation of Nitrile with Raney Nickel
The nitrile (1 equivalent) was dissolved in NH3 saturated MeOH (concentration  ̃0.05-0.2M), treated with Raney nickel (excess), and placed under 45 psi H2 on a Parr shaker for 1-8 hours. In a standard work-up the mixture was diluted with MeOH and filtered through Celite®. The cake was washed with MeOH and the combined filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel.
General Procedure K: Ester Hydrolysis
To a solution of the ester (1 equivalent) in MeOH (or 1:1 THF/I2O) was added 10N NaOH (excess) (or LiOH) and the mixture was heated at 40-60° C. for 3-24 hours. The mixture was acidified with 4-6N HCl to pH ̃5-6 and extracted with CH2Cl2, CHCl3 or MeOH/CH2Cl2. The combined organic extracts were dried (MgSO4 or Na2SO4), filtered and concentrated under reduced pressure. The crude acid was used as is or was purified by flash column chromatography on silica gel.
Intermediates
The preparation of various intermediates used in preparing the present compounds is described below. The intermediates 4-formyl-piperidine-1-carboxylic acid tert-butyl ester, 2-(3-oxo-butyl)-isoindole-1,3-dione; and 3-(bromomethyl)thiophene were prepared according to procedures desribed in literature. (Shu, Min; et al., Bioorg Med. Chem. Lett., 14, 4, 2004, 947-952; Pave, Gregoire; et al., Syn. Lett., 7, 2003, 987-990; and Moustrou, Corinne; et al., Helv. Chim. Acta., 78, 1995, 1887-1893, respectively).
4-(4-Bromo-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 1-[4-(4-bromo-benzoyl)-piperidin-1-yl]-2,2,2-trifluoroethanone (11.6 g, 31.9 mmol) (Palani A.; et al., J. Med. Chem., 2001, 44, 3339-3342) in MeOH (60 mL) and H2O (15 mL) at room temperature was added K2CO3 (10.0 g, 72.5 mmol) and the mixture was stirred for 16 hours to give (4-bromophenyl)-piperidin-4-yl-methanone as a pale yellow solid (7.81 g, 96%) following work-up and purification.
To a solution of the above amine (28.9 g, 108 mmol) in CH2Cl2 (200 mL) and Et3N (22.5 mL, 162 mmol) at room temperature was added a solution of Boc2O (25.8 g, 119 mmol) in CH2Cl2 dropwise and the mixture was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was crystallized (EtOAc/Hexanes) to give 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (29.5 g). The mother liquor was purified by column chromatography to give further product (9.4 g) as a white solid (combined yield: 38.9 g, 98%). 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.61-1.75 (m, 2H), 1.82 (d, 2H, J=10.5 Hz), 2.89 (t, 2H, J=12.0 Hz), 3.34 (tt, 1H, J=10.8, 3.9 Hz), 4.16 (br s, 2H), 7.62 (d, 2H, J=8.7 Hz), 7.81 (d, 2H, J=8.7 Hz).
4-[(4-Bromo-phenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester.
To a solution of 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.47 g, 4.00 mmol) in absolute EtOH (25 mL) was added NaBH4 (227 mg, 6.00 mmol). The mixture was stirred at room temperature for 2 hours. Standard work-up and purification gave 4-[(4-bromo-phenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.480 g, 100%). 1H NMR (CDCl3) δ 1.07-1.27 (m, 2H), 1.62-1.72 (m, 1H), 1.88 (d, 1H, J=13.2 Hz), 2.35 (d, 1H, J=3.3 Hz), 2.50-2.65 (m, 2H), 4.04-4.13 (m, 2H), 4.33 (dd, 1H, J=7.2, 3.3 Hz), 7.16 (d, 2H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz).
4-[Hydroxy-(4-trifluoromethylphenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester. To a −78° C. solution of 1-bromo-4-trifluoromethylbenzene (32.9 g, 146 mmol) in anhydrous THF (500 mL) was added n-BuLi (2.5M in Hexanes, 63.4 mL, 158 mmol) dropwise. The mixture was stirred at −78° C. for 1 hour. TMEDA (22.1 mL, 146 mmol) was added followed by 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (26.0 g, 122 mmol) and the mixture was stirred at −78° C. for 1.5 hours. Saturated aqueous NH4Cl (5000 mL) was added and the mixture was warmed to room temperature. The phases were separated and the aqueous phase was extracted with EtOAc (2×300 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude material was crystallized (CH2Cl2/Hexanes) to give 4-[hydroxy-(4-trifluoromethylphenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (29.0 g). The mother liquor was purified by column chromatography to give further product (3.8 g) as a white solid (combined yield: 32.8 g, 75%). 1H NMR (CDCl3) δ 1.15-1.32 (m, 3H), 1.44 (s, 9H), 1.68-1.81 (m, 1H), 1.89 (d, 1H, J=13.8 Hz), 1.98 (br s, 1H), 2.54-2.68 (m, 2H), 4.12 (br s, 2H), 7.43 (d, 2H, J=8.7 Hz), 7.62 (d, 2H, J=8.7 Hz).
4-(4-Trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-[hydroxy-(4-trifluoromethylphenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.07 g, 2.98 mmol) in CH2Cl2 (15 mL) were added PCC (1.93 g, 8.94 mmol) and SiO2 (3.86 g) and the mixture was stirred at room temperature for 75 minutes. The mixture was filtered through a silica gel plug (1:4, EtOAc/Hexanes) to afford 4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 75%) as a white solid. 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.68-1.75 (m, 2H), 1.85 (d, 2H, J=12.0 Hz), 2.91 (t, 2H, J=11.4 Hz), 3.36-3.43 (m, 1H), 4.13-4.19 (m, 2H), 7.75 (d, 2H, J=8.1 Hz), 8.03 (d, 2H, J=8.1 Hz).
4-Fluoro-3-hydroxymethyl-benzonitrile. To a stirred solution of 5-bromo-2-fluorobenzaldehyde (9.2 g, 45 mmol) in DMF (5 mL) was added CuCN (4.8 g, 54 mmol) and the mixture was heated at 100° C. for 2 hours and at 130° C. overnight. The mixture was cooled to room temperature, added to a solution of FeCl2 (11 g) in conc. HCl (100 mL) and H2O (500 mL) and stirred at room temperature for 30 minutes. The aqueous was extracted with CH2Cl2 (4×200 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified to afford 5-cyano-2-fluorobenzaldehyde as a yellow solid (5.0 g, 75%).
To a stirred solution of the above aldehyde (5.0 g, 33.5 mmol) in MeOH (330 mL) cooled to 0° C. was added NaBH4 (1.51 g, 40 mmol) and the mixture was stirred at 0° C. for 1 hour. Standard work-up and purification afforded 4-fluoro-3-hydroxymethyl-benzonitrile (4.9 g, 98%) as an off-white solid. 1H NMR (CDCl3) δ 1.95 (br s, 1H), 4.81 (s, 2H), 7.13-7.19 (m, 1H), 7.60-7.62 (m, 1H), 7.83-7.85 (m, 1H).
(R)-3-(4-Oxo-piperidin-1-yl)-butyronitrile. As described in literature (Stanfield; et al., JOC., 1981, 46, 4799-800), a solution of Boc-D-Ala-OH (50.0 g, 0.264 mol) in THF (250 mL) was added dropwise to a 0° C. solution of BH3-THF (1.0M in THF, 380 mL, 380 mmol). The mixture was stirred for 2 hours at 0° C. and quenched with a 10% solution of AcOH in MeOH (200 mL). The mixture was concentrated under reduced pressure, diluted with EtOAc (500 mL) and washed with 1N HCl (150 mL). The aqueous was extracted with EtOAc (100 mL) and the combined organic extracts were washed consecutively with H2O (150 mL) and 1N NH4HCO3 (150 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give ((S)-2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester as a colourless oil (43.6 g) that was used in the next step without further purification.
Using standard procedure G the above alcohol gave methanesulfonic acid (S)-2-tert-butoxycarbonylamino-propyl ester as an orange crystalline solid (48.34 g, 76% over 2 steps).
To the above mesylate (48.34 g, 0.190 mol) in DMSO (100 mL) was added NaCN (27.93 g, 0.570 mol) followed by DMSO (75 mL) and the mixture was heated at 45° C. for 18 hours. The mixture was cooled to room temperature, quenched with H2O (200 mL) and extracted with Et2O (3×200 mL). The combined organic layers were washed with brine (3×120 mL) and the combined aqueous layers were extracted with Et2O (200 mL). The organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting orange oil was dissolved in iPr2O (45 mL) and warmed to 60° C. Heptane (130 mL) was added and the mixture was cooled to room temperature and concentrated under reduced pressure. The precipitate was collected by filtration and the filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel (49:1, MeOH/CH2Cl2) to give ((S)-2-cyano-1-methyl-ethyl)-carbamic acid tert-butyl ester as a pale orange solid (combined yield: 22 g, 63%).
To a solution of the above carbamate (21.43 g, 0.116 mol) in CH3CN (58 mL) and EtOAc (29 mL) was added methanesulfonic acid (9.0 mL, 0.23 mol) (Allen, et al. U.S. 2003/0065207A1). The mixture was diluted with CH3CN (20 mL) to facilitate stirring and the mixture was heated to 70° C. for 1 hour. The mixture was cooled to room temperature and placed in an ice bath for 20 minutes with stirring. The resulting solid with isolated via filtration and then dissolved in NH4OH (50 mL). The aqueous phase was extracted with CH2Cl2 (4×120 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford (S)-3-amino-butyronitrile as a pale yellow liquid (6.87 g, 90%).
To a solution of 1-ethyl-4-piperidone (21.0 g, 0.165 mol) in acetone (175 mL) cooled to 10° C. was added a solution of MeI (12.3 mL, 0.198 mmol) in acetone (15 mL) dropwise. The mixture was stirred at room temperature overnight and the precipitate was isolated by filtration, washed with acetone and dried in vacuo to give 1-ethyl-1-methyl-4-oxo-piperidinium iodide as a pale yellow solid (42.03 g, 95%).
To a solution of the above amine (6.85 g, 81.5 mmol) in EtOH (150 mL) heated to 100° C. was added a solution of the above piperidone salt (32.9 g, 122 mmol) in H2O (150 mL) dropwise. The resulting solution was stirred at reflux for 1 hour and then slowly cooled to room temperature. The mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (4×150 mL). The combined organic extracts were washed with H2O (150 mL) and the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to give (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile as an orange liquid (11.74 g, 87%). 1H NMR (CDCl3) δ 1.22 (d, 3H, J=6.0 Hz), 2.38-2.59 (m, 6H), 2.82-2.83 (m, 4H), 3.20-3.27 (m, 1H).
EXAMPLE 1




COMPOUND 1: N-(3-{4-[(4-Bromophenyl)-phenoxymethyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxynicotinamide
To a solution of 4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (370 mg, 1.00 mmol), phenol (141 mg, 1.50 mmol) and Ph3P (393 mg, 1.50 mmol) in THF (6 mL) at room temperature was added DIAD (0.295 mL, 1.50 mmol) dropwise. The mixture was stirred at room temperature for 2.5 hours. Aqueous work-up and purification gave 4-[(4-bromophenyl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (213 mg, 48%).
Using general procedure C with the above compound (213 mg, 0.48 mmol), then general procedure B with the resulting amine, 2-(3-oxo-butyl)-isoindole-1,3-dione (156 mg, 0.72 mmol) and CH(OMe)3 (0.15 mL) and then using general procedure D gave 3-{4-[(4-bromophenyl)-phenoxymethyl]-piperidin-1-yl}-butylamine as a colorless oil (79 mg, 40% over 3 steps).
Using general procedure E, the above primary amine (24.0 mg, 0.058 mmol) and 2,4-dimethyl-1-oxynicotinic acid (11.0 mg, 0.063 mmol) gave COMPOUND 1 as a white foam (26.8 mg, 82%). 1H NMR (CDCl3) δ 0.84-1.10 (m, 1H), 1.00 (d, 3H, J=6.3 Hz), 1.26 (br d, 1H, J=9.9 Hz), 1.53-1.66 (m, 2H), 1.84 (br s, 1H), 2.05 (br d, 2H, J=11.4 Hz), 2.28 and 2.29 (s, 3H), 2.40 (s, 3H), 2.27-2.49 (m, 2H), 2.67-2.85 (m, 3H), 3.35 (m, 1H), 3.75 (m, 1H), 4.36 (t, 1H, J=7.5 Hz), 6.75 (d, 2H, J=7.5 Hz), 6.76-6.90 (m, 2H), 7.19 (t, 4H, J=8.1 Hz), 7.43 (d, 2H, J=8.1 Hz), 7.95 and 7.99 (d, 1H, J=6.6 Hz), 9.10 and 9.17 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 13.4, 18.4, 28.7, 29.0, 29.4, 29.7, 30.8, 31.1, 39.5, 42.9, 44.3, 51.8, 59.9, 60.0, 83.6, 83.9, 115.96, 116.00, 121.05, 121.09, 121.6, 124.9, 128.6, 129.4, 131.7, 133.6, 136.9, 138.1, 139.0, 145.5, 145.6, 157.9, 158.1, 165.3, 165.5. ES-MS m/z 568 (M+H). Anal. Calcd. for C30H36BrN3O3.0.6CH2Cl2.0.2C6H14: C, 60.17; H, 6.25; N, 6.62; Br, 12.59. Found. C, 60.35; H, 6.27; N, 6.94; Br, 12.53.
EXAMPLE 2




COMPOUND 2: N-(3-{4-[(4-Bromophenyl)-phenoxymethyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
To a solution of (−)-DIP-chlorideTM (6.42 g, 20.0 mmol) in THF (10 mL) at 0° C. was added 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.68 g, 10.0 mmol). The mixture was stirred at room temperature for 29 hours. Aqueous work-up and purification gave (S)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (ee 78% determined by both chiral HPLC and Mosher ester) as a crystalline solid (2.22 g, 54%). This material was recrystallized (CH2Cl2/hexane) three times to provide (S)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.29 g, 35%) with ee of 96%.
To a solution of the above alcohol (370 mg, 1.00 mmol), phenol (141 mg, 1.50 mmol) and Ph3P (393 mg, 1.50 mmol) in THF (6 mL) at room temperature was added DIAD (0.295 mL, 1.50 mmol) dropwise. The mixture was stirred at room temperature for 3 hours. Aqueous work-up and purification gave (R)-4-[(4-bromophenyl)-phenoxymethyl]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (257 mg, 58%).
Using general procedure C with the above carbamate, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (157 mg, 0.724 mmol) and then using general procedure D gave 3-{4-[(-(R)-4-bromophenyl)phenoxymethyl]-piperidin-1-yl}-butylamine as a colorless oil (96 mg, 48% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (64.5 mg, 0.336 mmol) and the above amine (70.0 mg, 0.168 mmol) gave COMPOUND 2 as a white foam (90 mg, 91%). 1H NMR (CDCl3) δ 0.45-85 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 1.19 (br d, 1H, J=12.6 Hz), 1.45-1.65 (m, 2H), 1.71-1.82 (m, 1H), 1.92-2.02 (m, 2H), 2.33-2.41 (m, 1H), 2.64-2.89 (m, 3H), 3.27-3.35 (m, 1H), 3.82-3.93 (m, 1H), 4.18 (t, 1H, J=6.8 Hz), 6.70 (d, 2H, J=8.1 Hz), 6.88 and 6.89 (t, 1H, J=7.2 Hz), 7.02 and 7.03 (d, 2H, J=8.4 Hz), 7.16-7.22 (m, 2H), 7.42 (d, 2H, J=8.4 Hz), 8.50 and 8.54 (s, 2H), 9.31 and 9.43 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.7, 29.0, 29.1, 29.8, 30.1, 30.3, 30.5, 40.7, 40.8, 43.2, 44.1, 44.2, 52.4, 52.5, 61.0, 84.0, 84.1, 116.35, 116.43, 121.5, 121.6, 122.0, 128.78, 128.80, 129.6, 129.8, 132.0, 139.4, 143.9, 148.0, 158.3, 158.4, 161.77, 161,83. ES-MS m/z 592 (M+H). Anal. Calcd. for C28H30BrCl2N3O2: C, 56.87; H, 5.11; N, 7.11; Br, 13.51; Cl, 11.99. Found. C, 56.81; H, 5.10; N, 7.07; Br, 13.17; Cl, 12.24.
EXAMPLE 3




COMPOUND 3: N-(3-{4-[(4-Bromo-phenyl)-o-tolyloxy-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (740 mg, 2.00 mmol), m-cresol (0.31 mL, 3.00 mmol), Ph3P (786 mg, 3.00 mmol) and THF (13 mL) cooled to 0° C. was added DIAD (0.59 mL, 3.00 mmol) dropwise. The reaction mixture was stirred at room temperature overnight to give a colourless syrup after aqueous work-up and purification.
Using general procedure C with the above substrate, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (203 mg, 1.00 mmol) and then using general procedure D afforded 3-{4-[(4-bromo-phenyl)-o-tolyloxy-methyl]-piperidin-1-yl}-butylamine as a colourless syrup (81 mg, 10% over 4 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (45 mg, 0.24 mmol) and the above amine (51 mg, 0.12 mmol) afforded COMPOUND 3 as a white solid (34 mg, 48%). 1H NMR (CDCl3) δ 0.34-0.99 (m, 2H), 0.96, 0.97 (d, 3H, J=6.6 Hz), 1.12-1.20 (m, 1H), 1.46-1.56 (m, 1H), 1.58-2.05 (m, 3H), 2.07-2.16 (m, 1H), 2.22 (s, 3H), 2.28-2.50 (m, 1H), 2.61-2.93 (m, 3H), 3.27-3.40 (m, 1H), 3.81-3.96 (m, 1H), 4.14, 4.17 (d, 1H, J=8.4 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.78 (dd, 1H, J=7.5, 7.5 Hz), 6.98-7.04 (m, 3H), 7.09 (d, 1H, J=7.2 Hz), 7.42 (d, 2H, J=8.1 Hz), 8.52, 8.56 (s, 2H), 9.18, 9.39 (d, 1H, J=5.4 Hz). 13C NMR (CDCl3) δ 13.60, 13.72, 16.95, 28.92, 29.70, 29.89, 30.16, 30.69, 40.64, 40.80, 43.24, 44.16, 52.34, 52.54, 60.93, 61.09, 83.42, 83.62, 112.84, 112.97, 120.89, 122.00, 127.05, 127.34, 128.79, 129.69, 131.09, 132.04, 139.44, 143.88, 148.01, 155.91, 155.99, 161.69, 161.86. ES-MS m/z 604 (M+H). Anal. Calcd. for C29H32N3O2BrCl2: C, 57.54; H, 5.33; N, 6.94; Cl, 11.71; Br, 13.20. Found. C, 57.51; H, 5.31; N, 6.94; Cl, 11.99; Br, 12.99.
Scheme 1 describes the preparation of Examples 4-14, using various general procedures previously described, and reagents listed below.
















Example
R2—OH
R1COOH







 4a
phenol
2,4-dimethyl-1-oxy-nicotinic acid


 5a
phenol
2,6-dimethyl-4-pyridin-4-yl-




benzoic acid


 6a
phenol
3,5-dichloroisonicotinic acid


 7a
3-(trifluoromethyl)phenol
3,5-dichloroisonicotinic acid


 8a
2-(trifluoromethyl)phenol
3,5-dichloroisonicotinic acid


 9b
3-chlorophenol
3,5-dichloroisonicotinic acid


10b
2-fluorophenol
3,5-dichloroisonicotinic acid


11b
3-fluorophenol
3,5-dichloroisonicotinic acid


12c
m-cresol
2,6-dimethyl-4-pyridin-4-yl-




benzoic acid


13c
o-cresol
2,6-dimethyl-4-pyridin-4-yl-




benzoic acid


14c
3-cyanophenol
3,5-dichloroisonicotinic acid





aiii) general procedure I, iv) general procedure J


biii) general procedure I, iv) BH3—Me2S, THF, reflux


ciii) 2-(3-oxo-butyl-isoindole-1,3-dione, general procedure B, iv) general procedure D






EXAMPLE 4




COMPOUND 4: 2,4-Dimethyl-1-oxy-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.50-0.92 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.16-1.24 (m, 1H), 1.46-1.83 (m, 3H), 1.89-2.08 (m, 2H), 2.28, 2.29 (s, 3H), 2.31-2.48 (m, 1H), 2.51 (s, 3H), 2.59-2.87 (m, 3H), 3.24-3.38 (m, 1H), 3.77-3.91 (m, 1H), 4.32, 4.37 (d, 1H, J=7.8 Hz), 6.74-6.93 (m, 4H), 7.18-7.23 (m, 2H), 7.44 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 7.97, 8.02 (d, 1H, J=6.6 Hz), 9.09, 9.18 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 13.44, 15.26, 18.38, 28.70, 29.37, 29.47, 30.91, 31.17, 39.68, 43.00, 44.24, 51.74, 59.73, 59.88, 76.63, 77.05, 77.47, 86.67, 83.95, 115.88, 115.94, 121.14, 121.18, 124.05 (q, J=272 Hz), 124.83, 125.47, 127.23, 129.42, 129.88 (q, J=32 Hz), 133.64, 133.72, 137.01, 138.04, 144.25, 145.50, 145.60, 157.94, 158.05, 165.23, 165.36. ES-MS m/z 556 (M+H). Anal. Calcd. for C31H36N3O3F3.0.2H2O.0.2CH2Cl2: C, 65.03; H, 6.44; N, 7.29; F, 9.89. Found. C, 65.10; H, 6.46; N, 7.29; F, 9.88.
EXAMPLE 5




COMPOUND 5: 2,6-Dimethyl-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
White solid. 1H NMR (CDCl3) δ 0.47-1.09 (m, 3H), 0.95, 0.96 (d, 3H, J=6.0 Hz), 1.48-1.64 (m, 2H), 1.68-2.11 (m, 3H), 2.23-2.46 (m, 1H), 2.43, 2.44 (s, 6H), 2.57-2.91 (m, 3H), 3.26-3.38 (m, 1H), 3.85-3.96 (m, 1H), 4.09-4.13 (d, 1H, J=8.1 Hz), 6.45-6.50 (m, 2H), 6.78-6.85 (m, 1H), 6.93-7.01 (m, 2H), 7.09-7.14 (m, 2H), 7.36 (d, 2H, J=10.5 Hz), 7.42-7.48 (m, 4H), 8.61-8.64 (m, 2H), 8.80 (br s, 1H). 13C NMR (CDCl3) δ 13.25, 13.33, 19.42, 28.20, 28.68, 29.17, 29.86, 30.68, 30.80, 39.85, 43.04, 43.84, 43.94, 52.08, 52.17, 60.52, 60.64, 83.61, 83.79, 115.70, 115.91, 121.12, 121.28, 124.16 (q, J=306 Hz), 125.32, 125.82, 126.86, 129.29, 129.92 (q, J=32 Hz), 135.34, 135.40, 137.75, 139.63, 144.17, 147.36, 150.39, 150.43, 157.58, 157.72, 169.19, 169.34. ES-MS m/z 616 (M+H). Anal. Calcd. for C37H40N3O2F3.0.5H2O: C, 71.13; H, 6.61; N, 6.73; F, 9.12. Found. C, 71.05; H, 6.55; N, 6.66; F, 9.48.
EXAMPLE 6




COMPOUND 6: 3,5-Dichloro-N-(3-{4-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.49-0.93 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.15-1.22 (m, 1H), 1.45-1.72 (m, 2H), 1.73-2.04 (m, 3H), 2.30-2.46 (m, 1H), 2.64-2.92 (m, 3H), 3.28-3.38 (m, 1H), 3.86-3.96 (m, 1H), 4.26-4.31 (m, 1H), 6.71 (d, 2H, J=7.8 Hz), 6.87-6.93 (m, 1H), 7.17-7.28 (m, 4H), 7.57 (d, 2H, J=8.1 Hz), 8.52, 8.55 (s, 2H), 9.29, 9.38 (d, 1H, J=5.7 Hz). 13C NMR (CDCl3) δ 13.27, 28.55, 28.70, 29.50, 29.97, 30.14, 40.32, 40.39, 42.86, 43.70, 43.79, 52.02, 52.12, 60.68, 83.53, 83.75, 115.90, 115.98, 121.26, 121.32, 124.00 (q, J=272 Hz), 125.47, 125.51, 126.98, 129.29, 129.47, 129.97 (q, J=32 Hz), 143.51, 144.11, 147.63, 157.79, 157.92, 161.42. ES-MS m/z 580 (M+H). Anal. Calcd. for C29H30N3Cl2O2F3.0.1CH2Cl2: C, 59.34; H, 5.17; N, 7.13; Cl, 13.24; F, 9.68. Found. C, 59.17; H, 5.18; N, 7.07; Cl, 13.38; F, 9.84.
EXAMPLE 7




COMPOUND 7: 3,5-Dichloro-N-(3-{4-[(3-trifluoromethyl-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.52-1.01 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.15-1.26 (m, 1H), 1.46-1.57 (m, 1H), 1.60-1.83 (m, 2H), 1.87-2.04 (m, 2H), 2.31-2.46 (m, 1H), 2.64-2.94 (m, 3H), 3.27-3.40 (m, 1H), 3.82-3.95 (m, 1H), 4.32 and 4.33 (d, 1H, J=7.5 Hz), 6.81 (d, 1H, J=8.1 Hz), 7.03 (s, 1H), 7.12-7.18 (m, 1H), 7.24-7.32 (m, 3H), 7.59 (d, 2H, J=8.4 Hz), 8.52 and 8.54 (s, 2H), 9.20 and 9.27 (br d, 1H, J=5.0 Hz). 13C NMR (CDCl3) δ 13.10 and 13.16, 28.25 and 28.47, 29.23, 30.04 and 30.11, 40.00 and 40.05, 42.62 and 42.66, 43.61 and 43.73, 51.73 and 51.78, 60.23 and 60.31, 83.76 and 83.88, 113.23 and 113.25 (q, J=3.9 Hz), 117.75 and 117.80 (q, J=3.8 Hz), 118.34 and 118.38, 123.68 (q, J=272 Hz), 123.80 (q, J=271 Hz), 125.55 (q, J=3.8 Hz), 126.80 and 126.86, 129.17 and 129.20, 129.96, 130.12 and 130.14 (q, J=32.5 Hz), 131.73 and 131.74 (q, J=32.4 Hz), 143.10 (q, J=1.3 Hz), 143.35 and 143.37, 147.45, 157.72 and 157.82, 161.31. ESI-MS m/z 648 (MH)+, 650 (MH+2)+. Anal. Calcd. for C30H29Cl2F6N3O2.0.2C4H10O.0.1CH2Cl2: C, 55.25; H, 4.68; N, 6.25; Cl, 11.61; F, 16.97. Found. C, 55.22; H, 4.49; N, 6.54; Cl, 11.57; F, 16.66.
EXAMPLE 8




COMPOUND 8: 3,5-Dichloro-N-(3-{4-[(2-trifluoromethyl-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.41-0.93 (m, 2H), 0.96 and 0.97 (d, 3H, J=6.3 Hz), 1.09-1.19 (m, 1H), 1.47-2.19 (m, 5H), 2.29-2.51 (m, 1H), 2.61-2.95 (m, 3H), 3.27-3.41 (m, 1H), 3.81-3.95 (m, 1H), 4.27 and 4.32 (d, 1H, J=8.3 Hz), 6.60 (d, 1H, J=8.7 Hz), 6.93 (dd, 1H, J=7.7, 7.7 Hz), 7.27-7.35 (m, 3H), 7.54 (d, 1H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 8.53 and 8.57 (s, 2H), 9.15 and 9.36 (br s, 1H). 13C NMR (CDCl3) δ 13.14 and 13.28, 28.32 and 29.01, 29.05 and 29.68, 29.89 and 30.34, 40.08 and 40.20, 42.61 and 42.70, 43.62 and 43.66, 51.78 and 51.99, 60.38 and 60.46, 83.19 and 83.36, 113.21 and 113.26, 118.81 (q, J=30.4 Hz), 120.05 and 120.07, 123.70 (q, J=272 Hz), 123.84 (q, J=272 Hz), 125.62 and 125.64 (q, J=3.8 Hz), 127.02 and 127.05, 127.22 (q, J=5.4 Hz), 129.36 and 129.40, 130.32 (q, J=32.4 Hz), 133.10, 142.91 (q, J=1.3 Hz), 143.50 and 143.52, 147.53 and 147.55, 154.97 (q, J=1.9 Hz), 161.26 and 161.38. ESI-MS m/z 648 (MH)+, 650 (MH+2)+. Anal. Calcd. for C30H29Cl2F6N3O2: C, 55.57; H, 4.51; N, 6.48; Cl, 10.93; F, 17.58. Found. C, 55.42; H, 4.44; N, 6.35; Cl, 10.66; F, 17.24.
EXAMPLE 9




COMPOUND 9: 3,5-Dichloro-N-(3-{4-[(3-chloro-phenoxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.51-0.92 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.15-1.24 (m, 1H), 1.47-2.04 (m, 5H), 2.30-2.46 (m, 1H), 2.64-2.92 (m, 3H), 3.28-3.39 (m, 1H), 3.84-3.96 (m, 1H), 4.26 and 4.29 (d, 1H, J=6.9 Hz), 6.55 (dd, 1H, J=8.4, 2.7 Hz), 6.75 (s, 1H), 6.89 (ddd, 1H, J=8.0, 2.2, 2.2 Hz), 7.11 (ddd, 1H, J=8.1, 8.1, 2.0 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.1 Hz), 8.55 and 8.57 (s, 2H), 9.20 and 9.30 (br d, 1H, J=4.2 Hz). 13C NMR (CDCl3) δ 13.19 and 13.22, 28.30 and 28.59, 29.23 and 29.36, 30.03 and 30.18, 40.17 and 40.23, 42.70 and 42.75, 43.64 and 43.75, 51.88 and 51.96, 60.47 and 60.52, 83.78 and 83.96, 113.73 and 113.81, 116.65 and 116.68, 121.48 and 121.53, 123.87 (q, J=272 Hz), 125.56 (q, J=3.6 Hz), 126.84 and 126.88, 129.23 and 129.26, 130.14 and 130.16 (q, J=32.6 Hz), 130.22, 134.79, 143.33 (q, J=1.2 Hz), 143.40 and 143.43, 147.58, 158.43 and 158.53, 161.35 and 161.36. ESI-MS m/z 614 (MH)+, 616 (MH+2)+, 618 (MH+4)+. Anal. Calcd. for C29H29Cl3F3N3O2: C, 56.64; H, 4.75; N, 6.83; Cl, 17.30; F, 9.27. Found. C, 56.41; H, 4.67; N, 6.71; Cl, 17.19; F, 9.09.
EXAMPLE 10




COMPOUND 10: 3,5-Dichloro-N-(3-{4-[(2-fluoro-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.43-1.18 (m, 2H), 0.957 and 0.963 (d, 3H, J=6.6 Hz), 1.45-1.56 (m, 1H), 1.63-2.18 (m, 5H), 2.29-2.49 (m, 1H), 2.61-2.97 (m, 3H), 3.27-3.39 (m, 1H), 3.85-3.95 (m, 1H), 4.21 and 4.25 (d, 1H, J=8.3 Hz), 6.60-6.66 (m, 1H), 6.82-6.94 (m, 2H), 7.00-7.08 (m, 1H), 7.27 and 7.29 (d, 2H, J=7.9 Hz), 7.57 (d, 2H, J=7.9 Hz), 8.51 and 8.53 (s, 2H), 9.38 and 9.53 (br s, 1H). 13C NMR (CDCl3) δ 13.19, 28.48 and 28.72, 29.23 and 29.51, 29.74 and 30.05, 40.15 and 40.27, 42.56, 43.55 and 43.65, 51.75 and 51.87, 60.49 and 60.53, 85.54 and 85.81, 116.35 (d, J=18.4 Hz), 117.74 and 117.76 (d, J=9.8 Hz), 122.06 and 122.12 (d, J=6.9 Hz), 123.86 (q, J=272 Hz), 124.14 (d, J=4.0 Hz), 125.40 (q, J=3.6 Hz), 127.08, 129.16 and 129.19, 130.12 (q, J=32.8 Hz), 143.40 (q, J=1.5 Hz), 145.47 (d, J=7.5 Hz), 145.56 and 145.66, 147.48, 153.2 (d, J=245 Hz), 161.27 and 161.36. ESI-MS m/z 598 (MH)+, 600 (MH+2)+. Anal. Calcd. for C29H29Cl2F4N3O2.0.2H2O: C, 57.85; H, 4.92; N, 6.98; Cl, 11.78; F, 12.62. Found. C, 57.82; H, 4.72; N, 6.92; Cl, 12.01; F, 12.25.
EXAMPLE 11




COMPOUND 11: 3,5-Dichloro-N-(3-{4-[(3-fluoro-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.51-1.04 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.14-1.26 (m, 1H), 1.46-2.05 (m, 5H), 2.30-2.46 (m, 1H), 2.64-2.95 (m, 3H), 3.28-3.40 (m, 1H), 3.84-3.94 (m, 1H), 4.27 and 4.29 (d, 1H, J=6.8 Hz), 6.41-6.51 (m, 2H), 6.56-6.66 (m, 1H), 7.09-7.18 (m, 1H), 7.26 (d, 2H, J=8.0 Hz), 7.58 (d, 2H, J=8.0 Hz), 8.53 and 8.56 (s, 2H), 9.18 and 9.28 (br s, 1H). 13C NMR (CDCl3) δ 13.17 and 13.20, 28.36 and 28.52, 29.26 and 29.28, 30.01 and 30.17, 40.07 and 40.14, 42.68 and 42.72, 43.66 and 43.76, 51.80 and 51.88, 60.37 and 60.40, 83.77 and 83.94, 103.66 and 103.69 (d, J=24.8 Hz), 108.06 and 108.11 (d, J=21.3 Hz), 111.29 and 111.36 (d, J=2.9 Hz), 123.86 (q, J=272 Hz), 125.52 (q, J=3.7 Hz), 126.83 and 126.87, 129.19 and 129.22, 130.08 (q, J=32.4 Hz), 130.18 (d, J=10.0 Hz), 143.41 (q, J=1.7 Hz), 147.53, 158.97 and 159.11 (d, J=7.8 Hz), 161.33 and 161.35, 163.34 (d, J=245 Hz). ESI-MS m/z 598 (MH)+, 600 (MH+2)+. Anal. Calcd. for C29H29Cl2F4N3O2.0.2C3H7NO.0.1CH2Cl2: C, 57.39; H, 4.96; N, 7.21; Cl, 12.55; F, 12.23. Found. C, 57.62; H, 4.97; N, 6.92; Cl, 12.39; F, 11.89.
EXAMPLE 12




COMPOUND 12: 2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[m-tolyloxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)benzamide
White foam. 1H NMR (CDCl3) δ 0.52-1.10 (m, 2H), 0.95 and 0.96 (d, 3H, J=6.3 Hz), 1.50-1.60 (m, 2H), 1.70-2.10 (m, 4H), 2.17 and 2.20 (s, 3H), 2.21-2.39 (m, 1H), 2.43 (s, 6H), 2.65-2.93 (m, 3H), 3.30 (m, 1H), 3.90 (m, 1H), 4.14 and 4.16 (d, 1H, J=7.2 Hz), 6.18 (t, 1H, J=9 Hz), 6.48 (s, 1H), 6.65 (t, 1H, J=7.5 Hz), 6.79 and 6.83 (t, 1H, J=7.1 Hz), 7.11 and 7.12 (d, 2H, J=7.8 Hz), 7.29-7.47 (m, 6H), 8.60 (td, 2H, J=4.2, 1.8 Hz), 8.68 (m, 1H). 13C NMR (CDCl3) δ 13.6, 13.7, 19.8, 21.8, 28.6, 29.0, 29.6, 30.2, 31.1, 31.3, 40.2, 43.5, 44.3, 44.4, 52.4, 52.5, 60.8, 60.9, 83.9, 84.0, 112.4, 112.7, 117.5, 117.7, 121.7, 122.4, 122.5, 124.2 (q, J=230 Hz), 125.7, 126.2, 127.2, 129.4, 130.1 (q, J=34.7 Hz), 135.68, 135.74, 138.1, 138.2, 139.8, 139.9, 144.7, 147.8, 150.72, 150.76, 158.0, 158.2, 169.6, 169.8. ES-MS m/z 630 (M+H). Anal. Calcd. for C38H42F3N3O2.0.3CH2Cl2: C, 70.21; H, 6.55; N, 6.41; F, 8.70. Found. C, 70.07; H, 6.47; N, 6.39; F, 8.35.
EXAMPLE 13




COMPOUND 13: 2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[o-tolyloxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-benzamide
White foam. 1H NMR (CDCl3) δ 0.50-0.85 (m, 1H), 0.95 (t, 3H, J=6.5 Hz), 1.50-1.64 (m, 2H), 1.70-2.20 (m, 3H), 2.21 (s, 3H), 2.22-2.47 (m, 2H), 2.41 (s, 3H), 2.43 (s, 3H), 2.65-2.90 (m, 3H), 3.30 (m, 1H), 3.90 (m, 1H), 4.13 (t, 1H, J=7.5 Hz), 6.01 and 6.05 (d, 1H, J=8.1 Hz), 6.50-6.74 (m, 2H), 7.04 (t, 1H, J=5.4 Hz), 7.11 (d, 2H, J=7.8 Hz), 7.37 (d, 2H, J=9.6 Hz), 7.43-7.50 (m, 4H), 8.63 (d, 2H, J=6.3 Hz), 8.75 and 8.80 (d, 1H, J=6.3 Hz). 13C NMR (CDCl3) δ 13.6, 13.8, 19.8, 28.6, 29.5, 29.7, 30.7, 30.9, 31.3, 40.2, 40.3, 43.5, 44.2, 44.4, 52.4, 52.6, 60.8, 61.0, 83.4, 83.6, 112.4, 112.7, 120.85, 120.91, 125.7, 126.2, 126.9 127.2, 130.3 (q, J=31.8 Hz), 131.1, 135.77, 135.81, 138.09, 138.14, 140.0, 144.7, 147.7, 150.8, 155.6, 155.8, 169.5, 169.8. ES-MS m/z 630 (M+H). Anal. Calcd. for C38H42F3N3O2.0.4CH2Cl2: C, 69.49; H, 6.50; N, 6.33; F, 8.59. Found. C, 69.34; H, 6.56; N, 6.39; F, 8.63.
EXAMPLE 14




COMPOUND 14: 3,5-Dichloro-N-(3-{4-[(3-cyano-phenoxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.55-1.01 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.16-1.26 (m, 1H), 1.47-1.58 (m, 1H), 1.60-1.84 (m, 2H), 1.87-2.05 (m, 2H), 2.31-2.46 (m, 1H), 2.64-2.93 (m, 3H), 3.28-3.40 (m, 1H), 3.81-3.93 (m, 1H), 4.31 and 4.33 (d, 1H, J=6.8 Hz), 6.90-6.95 (m, 1H), 6.98 (s, 1H), 7.17-7.33 (m, 4H), 7.60 (d, 2H, J=8.1 Hz), 8.52 and 8.55 (s, 2H), 9.05 and 9.13 (br s, 1H). 13C NMR (CDCl3) δ 13.11 and 13.15, 28.19 and 28.42, 29.03 and 29.13, 30.12 and 30.18, 39.84 and 39.88, 42.58 and 42.64, 43.64 and 43.74, 51.57 and 51.61, 59.99 and 60.06, 83.84 and 83.98, 113.06 and 113.07, 118.29, 119.15, 120.31 and 120.34, 123.70 (q, J=272 Hz), 124.79 and 124.84, 125.59 (q, J=3.9 Hz), 126.74 and 126.77, 129.11 and 129.13, 130.20 (q, J=32.5 Hz), 130.30, 142.65, 143.25 and 143.27, 147.39 and 147.40, 157.64 and 157.72, 161.23 and 161.25. ESI-MS m/z 605 (MH)+, 607 (MH+2)+. Anal. Calcd. for C30H29Cl2F3N4O2: C, 59.51; H, 4.83; N, 9.25; Cl, 11.71; F, 9.41. Found. C, 59.17; H, 4.85; N, 9.27; Cl, 11.76; F, 9.52.
EXAMPLE 15




COMPOUND 15: 3,5-Dichloro-N-(3-{4-[ethylideneaminooxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure C with 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.39 mmol), then general procedure I with the resulting amine followed by using general procedure J afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethyl-phenyl)-methanol as a colourless syrup (195 mg, 42% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (225 mg, 1.17 mmol) and the amine from above (195 mg, 0.59 mmol) afforded 3,5-dichloro-N-(3-{4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide as a white solid (203 mg, 69%).
To a solution of the alcohol from above (203 mg, 0.40 mmol), N-hydroxyphthalimide (98 mg, 0.60 mmol) and Ph3P (158 mg, 0.60 mmol) in THF (3 mL) cooled to 0° C. was added DIAD (119 μL, 0.60 mmol) dropwise. The reaction mixture was stirred at room temperature for 3.5 hours to afford 3,5-dichloro-N-(3-{4-[(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide as a white solid (75 mg, 29%) after work-up and purification.
Using general procedure D with the above substrate (75 mg, 0.12 mmol) and then using general procedure A with the resulting amine and acetaldehyde (6 μL, 0.11 mmol) afforded COMPOUND 15 (28 mg, 45% over 2 steps). 1H NMR (CDCl3) δ 0.38-0.81 (m, 2H), 0.93-0.97 (m, 3H), 1.06-1.20 (m, 1H), 1.45-1.57 (m, 2H), 1.72-2.02 (m, 6H), 2.27-2.46 (m, 1H), 2.59-2.90 (m, 3H), 3.25-3.40 (m, 1H), 3.81-3.96 (m, 1H), 4.27-4.37 (m, 1H), 6.60-6.73, 7.41-7.30 (m, 1H), 7.15-7.22 (m, 2H), 7.56 (d, 2H, J=8.1 Hz), 8.57 (s, 2H), 8.98, 9.14, 9.27 (br s, 1H). 13C NMR (CDCl3) δ 12.03, 13.16, 13.29, 15.21, 28.45, 28.66, 28.84, 29.29, 29.57, 29.88, 29.97, 30.24, 30.45, 40.28, 40.37, 41.11, 41.34, 43.92, 51.81, 52.00, 60.40, 60.58, 60.72, 87.64, 88.36, 124.17 (q, J=272 Hz), 125.17, 127.31, 129.13, 129.34 (q, J=32 Hz), 143.34, 145.18, 147.61, 147.77, 161.44, 161.57. ES-MS m/z 545 (M+H). Anal. Calcd. for C25H29N4Cl2F3O2.0.1H2O.0.2CH2Cl2: C, 53.65; H, 5.29; N, 9.93; Cl, 15.08; F, 10.10. Found. C, 53.76; H, 5.29; N, 9.77; Cl, 15.07; F, 9.89.
EXAMPLE 16




COMPOUND 16: 2,6-Dimethyl-N-(3 (R)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
To a solution of (−)-DIP-chlorideTM (3.45 g, 10.8 mmol) in THF (6 mL) at 0° C. was added a solution of 4-(4-trifluoromethylbenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.92 g, 5.38 mmol) in THF (2 mL). The mixture was stirred at room temperature for 18 hours. Aqueous work-up and purification gave 4(S)-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (ee 82% determined by Mosher ester) as a white crystalline solid (989 mg, 51%) and 4(S)-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine (ee 82% determined by Mosher ester after conversion to 4-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester) as a white crystalline solid (571 mg, 41%). 4(S)-[Hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine (1.00 g) was recrystallized (EtOAc/hexane) five times to provide a white solid (0.64 g) with 97% ee. 4(S)-[Hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine and 4(S)-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester could be interconverted by protection and deprotection of the Boc group in quantitative yield.
To a solution of 4(S)-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (314 mg, 0.875 mmol), phenol (210 mg, 2.01 mmol) and Ph3P (383 mg, 1.31 mmol) in THF (8 mL) at room temperature was added DIAD (0.258 mL, 1.31 mmol) dropwise. The mixture was stirred at room temperature for 6 hours. Work-up and purification gave 4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white foam (347 mg, 91%).
Using general procedure C, the above amine (347 mg, 0.798 mmol) gave 4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine (ee 96.3% determined by chiral HPLC) as a colorless oil (267 mg, 100%).
Using general procedure G, methyl-(S)-lactate (63 mg, 0.61 mmol) gave the mesylate as a colorless oil. A solution of the above amine (135 mg, 0.403 mmol) in dry CH3CN (1.5 mL) was added to the above mesylate followed by 2,2,6,6-tetramethylpiperidine (77 mg, 0.54 mmol). The mixture was heated at reflux for 3.5 hours. Aqueous work-up and purification gave the methyl ester, which was subsequently reduced with LiAlH4 (1.0M in THF, 0.48 mL, 0.48 mmol) to give 2(R)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-propan-1-ol (de 94% determined by chiral HPLC) as a colorless oil (103 mg, 65% over 2 steps) after a Feiser work-up and purification.
Using general procedure G, the above alcohol (102 mg, 0.260 mmol) gave the chloride, which was subsequently dissolved in DMSO (1.5 mL) followed by the addition of NaCN (26 mg, 0.52 mmol). The reaction was heated at 140° C. for 1 hour. Aqueous work-up and purification gave the nitrile, which was subsequently reduced with BH3-THF (1.0M in THF, 0.63 mL, 0.63 mmol) in THF (1.5 mL) at reflux and treated with MeOH then ethylenediamine (0.5 mL) to give 3(R)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colorless oil (59 mg, 57% over 2 steps) after work-up and purification.
Using general procedure E, the above amine (59 mg, 0.15 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (40 mg, 0.17 mmol) gave COMPOUND 16 as a white foam (87 mg, 97%). 1H NMR (CDCl3) δ 0.55-0.65 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 0.94-1.02 (m, 1H), 1.50-1.60 (m, 2H), 1.65-1.80 (m, 1H), 1.89 (t, 2H, J=12 Hz), 2.20 (d, 1H, J=12 Hz), 2.38-2.44 (m, 1H), 2.43 (s, 6H), 2.75 (d, 2H, J=9.9 Hz), 2.85 (m, 1H), 3.32 (m, 1H), 3.82-3.90 (m, 1H), 4.10 (d, 1H, J=8.1 Hz), 6.47 (d, 2H, J=8.1 Hz), 6.80 (t, 1H, J=6.3 Hz), 6.96 (t, 2H, J=8.0 Hz), 7.12 (d, 2H, J=7.8 Hz), 7.38 (s, 2H), 7.46 (d, 4H, J=8.1 Hz), 8.62 (d, 2H, J=6.0 Hz), 8.79 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 19.4, 28.2, 29.9, 30.7, 39.9, 43.0, 43.8, 52.2, 60.7, 83.6, 115.7, 121.1, 121.3, 124.2 (q, J=308 Hz), 125.3, 125.4, 125.8, 126.9, 129.3, 129.9 (q, J=32 Hz), 135.4, 137.7, 139.6, 144.2, 147.3, 150.4, 157.6, 169.2. ES-MS m/z 616 (M+H). Anal. Calcd. for C37H40F3N3O2.04CH2Cl2: C, 69.14; H, 6.33; N, 6.47; F, 8.77. Found. C, 69.12; H, 6.43; N, 6.44; F, 8.66.
EXAMPLE 17




COMPOUND 17: 2,6-Dimethyl-N-(3(S)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
To a solution of 4(S)-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 16) (314 mg, 0.875 mmol), phenol (210 mg, 2.01 mmol) and Ph3P (383 mg, 1.31 mmol) in THF (8 mL) at room temperature was added DIAD (0.258 mL, 1.31 mmol) dropwise. Standard work-up and purification gave 4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white foam (347 mg, 91%).
Using general procedure C, the above carbamate (347 mg, 0.798 mmol) gave 4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine (ee 96.3% determined by chiral HPLC) as a colorless oil (267 mg, 100%).
Using general procedure G, methyl-(R)-lactate (63 mg, 0.61 mmol) gave the mesylate as a colorless oil. A solution of the above amine (135 mg, 0.403 mmol) in dry CH3CN (1.5 mL) was added to the above mesylate followed by 2,2,6,6-tetramethylpiperidine (77 mg, 0.54 mmol). The mixture was heated at reflux for 3 hours. Work-up and purification gave the methyl ester, which was subsequently reduced with LiAlH4 (1.0M in THF, 0.40 mL, 0.40 mmol) to give 2(S)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-propan-1-ol (de 89% determined by chiral HPLC) as a colorless oil (71 mg, 51% over 2 steps) following a Feiser work-up and purification.
Using general procedure G the above alcohol (71 mg, 0.18 mmol) gave the chloride, which was subsequently dissolved in DMSO (1 mL) followed by the addition of NaCN (18 mg, 0.36 mmol). The reaction was heated at 140° C. for 1 hour. Work-up and purification gave the nitrile, which was subsequently reduced with BH3-THF (1.0M, 0.41 mL, 0.41 mmol) in THF (1 mL) at reflux and treated with MeOH then ethylenediamine (0.5 mL) to give 3(R)-{4(R)-[phenoxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colorless oil (43.5 mg, 59% over 2 steps) after work-up and purification.
Using general procedure E, the above amine (43 mg, 0.11 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (29 mg, 0.13 mmol) gave COMPOUND 17 as a white foam (64 mg, 98%). 1H NMR (CDCl3) δ 0.76-0.90 (m, 1H), 0.96 (d, 3H, J=6.3 Hz), 1.05 (d, 1H, J=11.7 Hz), 1.49-1.60 (m, 2H), 1.77-1.84 (m, 1H), 2.01 (t, 2H, J=10.7 Hz), 2.31 (t, 1H, J=10.8 Hz), 2.42 (s, 6H), 2.63 (d, 1H, J=8.4 Hz), 2.80-2.90 (m, 2H), 3.32 (t, 1H, J=11.6 Hz), 3.83-3.93 (m, 1H), 4.15 (d, 1H, J=7.8 Hz), 6.49 (d, 2H, J=7.8 Hz), 6.82 (t, 1H, J=7.4 Hz), 6.98 (t, 2H, J=8.0 Hz), 7.12 (d, 2H, J=7.8 Hz), 7.34 (s, 2H), 7.41-7.47 (m, 4H), 8.60 (d, 2H, J=6.0 Hz), 8.80 (br s, 1H). 13C NMR (CDCl3) δ 13.3, 19.4, 28.6, 29.2, 30.6, 39.9, 43.1, 43.9, 52.1, 60.5, 83.8, 115.9, 121.2, 121.3, 124.2 (q, J=308 Hz), 125.3, 125.4, 125.8, 126.8, 129.3, 129.9 (q, J=32 Hz), 135.3, 137.7, 139.6, 144.2, 147.4, 150.4, 157.7, 169.3. ES-MS m/z 616 (M+H). Anal. Calcd. for C37H40F3N3O2.0.4CH2Cl2: C, 69.14; H, 6.33; N, 6.47; F, 8.77. Found. C, 69.10; H, 6.47; N, 6.37; F, 8.58.
Scheme 2 describes the preparation of Examples 18-20, using general procedures E, and reagents listed below.















Example
R1COOH







18
2,4-dimethyl-1-oxy-nicotinic acid


19
2,6-dimethylbenzoic acid


20
4,6-dimethyl-pyrimidine-5-carboxylic acid









EXAMPLE 18




COMPOUND 18: N-(3-{4-[(6-Chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
To a suspension of NaH (60% in mineral oil, 56 mg, 1.4 mmol) in DMF (2.3 mL) was added 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.696 mmol) followed by 2,6-dichloropyridine (309 mg, 2.09 mmol). The mixture was heated to 90° C. for 2 h then concentrated in vacuo. Aqueous work-up and purification gave 4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a colourless foam (313 mg, 95%).
Using general procedure C with the carbamate from above (313 mg, 0.665 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (121 mg, 0.557 mmol) and then using general procedure D gave a 1:1 diastereomeric mixture of 3-{4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colourless oil (48 mg, 39% over 3 steps).
COMPOUND 18 was isolated as a white solid. 1H NMR (CDCl3) δ 0.42-0.86 (m, 2H), 0.95, 0.96 (d, 3H, J=6.6 Hz), 1.08-1.18 (m, 1H), 1.45-1.55 (m, 1H), 1.63-1.83 (m, 2H), 1.87-2.06 (m, 2H), 2.27-2.45 (m, 1H), 2.31, 2.32 (s, 3H), 2.49 (s, 3H), 2.56-2.87 (m, 3H), 3.23-3.35 (m, 1H), 3.79-3.90 (m, 1H), 5.20, 5.23 (d, 1H, J=9.3 Hz), 6.62, 6.64 (d, 1H, J=3.6 Hz), 6.85 (dd, 1H, J=7.5, 1.2 Hz), 7.05, 7.09 (d, 1H, J=6.6 Hz), 7.43-7.52 (m, 3H), 7.54-7.61 (m, 2H), 8.35 (d, 1H, J=6.3 Hz), 9.31 (br s, 1H). 13C NMR (CDCl3) δ 13.73, 15.54, 15.63, 28.78, 29.36, 29.56, 30.15, 30.91, 40.23, 41.91, 41.98, 44.23, 52.13, 52.19, 60.62, 81.11, 81.24, 109.79, 117.21, 125.46, 125.73, 128.12, 130.04, 133.56, 133.72, 137.23, 139.07, 141.32, 143.94, 146.11, 148.49, 162.85, 165.69. ES-MS m/z 591 (M+H). Anal. Calcd. for C30H34N4ClO3F3.0.8CH4O: C, 59.99; H, 6.08; N, 9.08; Cl, 5.75; F, 9.24. Found. C, 59.85; H, 6.11; N, 9.24; Cl, 5.61; F, 9.55.
EXAMPLE 19




COMPOUND 19: N-(3-{4-[(6-Chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.24-0.86 (m, 2H), 0.87-0.99 (m, 3H), 1.41-2.02 (m, 6H), 2.22-2.46 (m, 7H), 2.50-2.88 (m, 3H), 3.19-3.34 (m, 1H), 3.80-3.94 (m, 1H), 5.04, 5.07 (d, 1H, J=6.3 Hz), 6.57 (d, 1H, J=8.1 Hz), 6.84 (dd, 1H, J=7.2, 0.9 Hz), 7.06 (d, 1H, J=7.5 Hz), 7.11 (d, 1H, J=7.5 Hz), 7.30-7.41 (m, 3H), 7.43-7.49 (m, 1H), 7.43-7.49 (m, 1H), 7.55 (d, 2H, J=8.1 Hz), 8.93, 9.00 (br s, 1H). ES-MS m/z 574 (M+H).
EXAMPLE 20




COMPOUND 20: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.43-0.85 (m, 2H), 0.95, 0.96 (d, 3H, J=6.3 Hz), 1.08-1.21 (m, 1H), 1.44-2.04 (m, 5H), 2.30-2.47 (m, 1H), 2.53, 2.54 (s, 6H), 2.59-2.87 (m, 3H), 3.24-3.36 (m, 1H), 3.81-3.93 (m, 1H), 5.12, 5.23 (d, 1H, J=7.8 Hz), 6.64 (dd, 1H, J=10.5, 8.4 Hz), 6.82 (dd, 1H, J=7.2, 2.1 Hz), 7.37-7.51 (m, 3H), 7.55 (d, 2H, J=8.1 Hz), 9.12, 9.19 (s, 1H), 8.96, 9.27 (br s, 1H). ES-MS m/z 576 (M+H).
Scheme 3 describes the preparation of Examples 21-40, using various general procedures previously described, and reagents listed below.
















Example
R3*
R2—Hal







21a
Br
2-bromopyridine


22b
CF3
2-bromopyridine


23b
CF3
6-chloro-2-picoline


24b
CF3
2-chloro-6-ethylpyridine




(Choppin, Sabine; et al., Org. Lett., 2, 6, 2000,




803-806)


25c
CF3
2,6-difluoropyridine


26c
CF3
2-chloro-6-(trifluoromethyl)pyridine


27c
CF3
2-chloro-6-cyanopyridine




(Sakamoto, Takao; et al., Chem. Pharm. Bull.,




33, 2, 1985, 565-571)


28c
SO2Me
2-bromo-6-picoline


29c
SO2Me
2,6-dichloropyridine


30c
SO2Me
2,6-difluoropyridine


31b
OCF3
2-bromo-6-picoline


32a
OCF3
2,6-difluoropyridine


33a
OCF3
2,6-dichloropyridine


34c
SO2NHMe
2-bromo-6-picoline


35c
Br
2-chloropyridine


36a
Br
2-bromo-3-picoline


37b
CF3
2-bromo-4-picoline


38b
CF3
2-bromo-3-picoline


39c
CF3
2,3-dichloropyridine


40c
CF3
2,4-dichloropyridine




(Choppin, Sabine; et al., Eur. J. Org. Chem.,




3, 2001, 603-606)





aiii) general procedure I, iv) BH3—Me2S, THF, reflux


biii) general procedure I, iv) general procedure J


ciii) 2-(3-oxo-butyl-isoindole-1,3-dione, general procedure B, iv) general procedure D






EXAMPLE 21




COMPOUND 21: N-(3-{4-[(4-Bromo-phenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.43-0.83 (m, 1H), 0.96 (d, 3H, J=6.3 Hz), 1.17-1.28 (m, 1H), 1.45-1.57 (m, 1H), 1.59-2.06 (m, 5H), 2.30-2.47 (m, 1H), 2.61-2.92 (m, 3H), 3.26-3.40 (m, 1H), 3.80-3.94 (m, 1H), 5.34 (d, 1H, J=8.1 Hz), 6.65 (dd, 1H, J=8.4, 0.9 Hz), 6.78-6.83 (m, 1H), 7.10 and 7.11 (d, 2H, J=8.4 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.49-7.56 (m, 1H), 8.06-8.10 (m, 1H), 8.56 and 8.57 (s, 2H), 9.16 and 9.33 (br s, 1H). 13C NMR (CDCl3) δ 13.18 and 13.23, 28.52 and 28.68, 29.28 and 29.48, 29.85 and 30.24, 40.21, 41.78, 43.77 and 43.85, 51.94 and 52.09, 60.52 and 60.66, 79.22, 111.02 and 111.06, 116.93, 121.27, 128.82 and 128.85, 129.01 and 129.04, 131.29, 138.59, 139.32 and 139.33, 146.90, 147.66, 161.48 and 161.59, 162.92 and 162.95. ESI-MS m/z 591 (MH)+, 593 (MH+2)+, 595 (MH+4)+. Anal. Calcd. for C27H29BrCl2N4O2: C, 54.75; H, 4.93; N, 9.46; Cl, 11.97. Found. C, 54.54; H, 5.01; N, 9.42; Cl, 12.05.
EXAMPLE 22




COMPOUND 22: 3,5-Dichloro-N-(3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.49-1.01 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.14-1.26 (m, 1H), 1.45-1.55 (m, 1H), 1.62-2.04 (m, 4H), 2.30-2.45 (m, 1H), 2.61-2.90 (m, 3H), 3.27-3.38 (m, 1H), 3.83-3.94 (m, 1H), 5.45 (d, 1H, J=7.8 Hz), 6.68 (dd, 1H, J=8.4, 0.8 Hz), 6.79-6.83 (m, 1H), 7.34 (dd, 2H, J=8.1, 3.3 Hz), 7.50-7.57 (m, 3H), 8.06-8.09 (m, 1H), 8.57 (s, 2H), 9.11, 9.27 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.62, 28.96, 29.07, 29.80, 30.33, 30.68, 40.61, 40.71, 42.33, 44.20, 44.29, 52.31, 52.45, 60.89, 60.98, 79.57, 111.44, 111.48, 117.45, 124.49 (q, J=272 Hz), 127.75, 129.48, 129.95 (q, J=32 Hz), 139.07, 143.73, 144.91, 147.29, 148.07, 161.87, 161.96, 163.26. ES-MS m/z 581 (M+H). Anal. Calcd. for C28H29N4Cl2O2F3.0.06CH2Cl2: C, 57.46; H, 5.00; N, 9.55; Cl, 12.81; F, 9.72. Found. C, 57.33; H, 4.97; N, 9.57; Cl, 12.71; F, 9.62.
EXAMPLE 23




COMPOUND 23: 3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ0.37-1.02 (m, 2H), 0.95 (dd, 3H, J=6.6, 1.8 Hz), 1.09-1.18 (m, 1H), 1.43-1.55 (m, 1H), 1.63-2.04 (m, 4H), 2.27-2.46 (m, 1H), 2.39 (s, 3H), 2.58-2.90 (m, 3H), 3.25-3.39 (m, 1H), 3.80-3.95 (m, 1H), 5.29 (dd, 1H, J=8.4, 1.8 Hz), 6.44 (d, 1H, J=8.4 Hz), 6.65 (d, 1H, J=7.2 Hz), 7.32-7.42 (m, 3H), 7.53 (d, 2H, J=8.1 Hz), 8.56, 8.58 (s, 2H), 9.27, 9.44 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.21, 13.31, 24.05, 28.60, 28.98, 29.38, 29.74, 29.83, 30.22, 40.30, 40.42, 41.69, 43.73, 51.92, 52.09, 60.55, 60.74, 79.41, 107.24, 116.06, 124.13 (q, J=272 Hz), 125.05, 125.10, 127.60, 129.14, 129.50 (q, J=32 Hz), 138.88, 143.40, 144.66, 147.65, 156.30, 161.41, 161.56, 162.20. ES-MS m/z 595 (M+H). Anal. Calcd. for C29H31Cl2F3N4O2: C, 58.49; H, 5.25; N, 9.41; Cl, 11.91; F, 9.57. Found. C, 58.32; H, 5.19; N, 9.37; Cl, 12.11; F, 9.35.
EXAMPLE 24




COMPOUND 24: 3,5-Dichloro-N-(3-{4-[(6-ethyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.39-0.82 (m, 3H), 0.95 (m, 7H), 1.13 (m, 8H), 1.50 (m, 2H), 1.69-2.05 (m, 8H), 2.38 (m, 2H), 2.57-2.90 (m, 10H), 3.32 (m, 2H), 3.88 (m, 2H), 5.30 (d, 2H, J=7.5 Hz), 6.46 (2d, 2H, J=8.1 Hz), 6.64 (2d, 2H, J=7.5 Hz), 7.33 (d, 2H, J=7.8 Hz), 7.34 (d, 2H, J=7.8 Hz), 7.42 (m, 2H), 7.53 (d, 4H, J=7.8 Hz), 8.55 (s, 2H), 8.57 (s, 2H), 9.23 (d, 1H, J=5.7 Hz), 9.41 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 13.19, 13.29, 28.63, 29.01, 29.39, 29.81, 29.89, 30.33, 30.81, 40.27, 40.40, 41.76, 43.84, 51.94, 52.09, 60.54, 60.74, 79.48, 107.58, 114.77, 125.00, 125.05, 127.56, 127.60, 129.15, 138.88, 143.40, 144.94, 147.65, 161.25, 161.41, 161.59, 162.26. ES-MS m/z 609 (M+H). Anal. Calcd. for C30H33N4Cl2F3O2: C, 59.12; H, 5.46; N, 9.19; Cl, 11.63; F, 9.35. Found. C, 59.00; H, 5.56; N, 9.10; Cl, 11.80; F, 9.17.
EXAMPLE 25




COMPOUND 25: 3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.43-0.83 (m, 3H), 0.97 (m, 7H), 1.17 (m, 2H), 1.50 (m, 2H), 1.66-2.03 (m, 8H), 2.37 (m, 2H), 2.64 (m, 1H), 2.80 (m, 5H), 3.33 (m, 2H), 3.87 (m, 2H), 5.30 (m, 2H), 6.43 (m, 2H), 6.54 (m, 2H), 7.34 (m, 4H), 7.60 (m, 6H), 8.62 (s, 4H), 9.12 (d, 1H, J=4.8 Hz), 9.31 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.28, 28.55, 28.66, 29.29, 29.42, 29.85, 30.30, 40.22, 40.36, 41.62, 43.67, 43.79, 51.82, 51.98, 60.50, 60.64, 80.29, 100.49, 100.96, 107.23, 122.23, 125.27, 125.32, 125.84, 127.51, 129.10, 129.71, 130.14, 142.80, 142.90, 143.34, 143.58, 147.78, 160.27, 161.47, 161.60, 161.85, 162.03, 163.47. ES-MS m/z 599 (M+H). Anal. Calcd. for C28H28N4Cl2F4O2: C, 56.10; H, 4.71; N, 9.35; Cl, 11.83; F, 12.68. Found. C, 56.05; H, 4.75; N, 9.30; Cl, 12.00; F, 12.43.
EXAMPLE 26




COMPOUND 26: 3,5-Dichloro-N-(3-{4-[(4-trifluoromethyl-phenyl)-(6-trifluoromethyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.34-0.82 (m, 3H), 0.95 (m, 7H), 1.11 (m, 2H), 1.50 (m, 2H), 1.67-2.06 (m, 8H), 2.39 (m, 2H), 2.63 (m, 1H), 2.74-2.91 (m, 5H), 3.32 (m, 2H), 3.87 (m, 2H), 5.33 (m, 2H), 6.86 (m, 2H), 7.19 (m, 2H), 7.37 (m, 4H), 7.54 (d, 4H, J=8.1 Hz), 7.67 (m, 2H), 8.56 (s, 2H), 8.58 (s, 2H), 9.17 (d, 1H, J=6.3 Hz), 9.40 (d, 1H, J=4.2 Hz). 13C NMR (CDCl3) δ 13.19, 13.32, 28.42, 29.04, 29.18, 29.70, 29.86, 30.34, 40.22, 40.40, 41.16, 43.64, 51.74, 51.90, 60.46, 60.73, 80.66, 113.60, 114.58, 125.15, 125.20, 127.88, 129.12, 139.73, 143.32, 143.47, 147.65, 161.41, 161.63, 162.68. ES-MS m/z 649 (M+H). Anal. Calcd. for C29H28N4Cl2F6O2: C, 53.63; H, 4.35; N, 8.63; Cl, 10.92; F, 17.55. Found. C, 53.63; H, 4.36; N, 8.81; Cl, 11.06; F, 17.44.
EXAMPLE 27




COMPOUND 27: 3,5-Dichloro-N-(3-{4-[(6-cyano-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.47-0.78 (m, 3H), 0.92 (m, 7H), 1.19 (m, 2H), 1.51 (m, 2H), 1.69-2.04 (m, 8H), 2.38 (m, 2H), 2.65 (m, 1H), 2.73-2.88 (m, 5H), 3.33 (m, 2H), 3.86 (m, 2H), 5.41 (m, 2H), 6.93 (d, 2H, J=8.4 Hz), 7.26 (m, 2H), 7.35 (m, 4H), 7.56 (d, 4H, J=8.1 Hz), 7.65 (m, 2H), 8.59 (s, 2H), 8.61 (s, 2H), 9.03 (d, 1H, J=4.8 Hz), 9.12 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.26, 28.51, 28.68, 29.24, 29.44, 30.09, 30.30, 40.16, 40.23, 41.41, 43.71, 43.80, 51.72, 60.41, 60.48, 80.58, 116.09, 117.09, 122.53, 125.33, 127.57, 129.08, 130.28, 139.50, 143.16, 143.25, 147.66, 147.70, 161.49, 161.56, 162.99. ES-MS m/z 628 (M+Na). Anal. Calcd. for C29H28N5Cl2F3O2: C, 57.43; H, 4.65; N, 11.55; Cl, 11.69; F, 9.40. Found. C, 57.20; H, 4.65; N, 11.54; Cl, 11.50; F, 9.20.
EXAMPLE 28




COMPOUND 28: 3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
A mixture of 4-(4-bromo-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.68 g, 10.0 mmol), NaSMe (1.05 g, 15.0 mmol) and DMF (100 mL) was heated at 75° C. for 3 hours to give 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.37 g, 100%) following work-up.
To solution of the above sulfide (1.2 g, 3.58 mmol) in MeOH (58 mL) cooled to 0° C. was added OXONE® (4.40 g, 7.15 mmol) and the mixture was stirred at 0° C. for 4 hours to afford 4-(4-methanesulfonyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (802 mg, 61%) after basic work-up and purification.
The above ketone (810 mg, 2.20 mmol) was reduced with NaBH4 (84 mg, 2.20 mmol) to afford 4-[hydroxy-(4-methanesulfonyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (760 mg, 94%) as a white foam after work-up and purification.
COMPOUND 28 was isolated as a white foam. 1H NMR (CDCl3) δ 0.39-0.84 (m, 1H), 0.94, 0.96 (d, 3H, J=6.7 Hz), 1.07-1.17 (m, 1H), 1.42-1.59 (m, 1H), 1.59-1.83 (m, 3H), 1.88-2.01 (m, 2H), 2.25-2.46 (m, 1H), 2.39 (s, 3H), 2.59-2.93 (m, 3H), 3.03 (s, 3H), 3.20-3.41 (m, 1H), 3.77-3.95 (m, 1H), 5.32 (d, 1H, J=7.0 Hz), 6.43-6.49 (m, 1H), 6.66 (d, 1H, J=7.0 Hz), 7.36-7.46 (m, 3H), 7.84 (d, 2H, J=8.3 Hz), 8.57, 8.59 (s, 2H), 9.22, 9.38 (br s, 1H). 13C NMR (CDCl3) δ 13.22, 13.31, 24.04, 28.57, 28.83, 29.35, 29.75, 30.22, 40.25, 40.36, 41.65, 43.71, 44.41, 51.83, 52.01, 53.45, 60.49, 60.67, 79.11, 107.32, 116.17, 127.24, 128.19, 129.13, 138.96, 139.34, 143.37, 147.20, 147.63, 156.24, 161.38, 161.54, 162.00. ES-MS m/z 607 (M+H). Anal. Calcd. for C29H34Cl2N4O4S.0.3CH2Cl2.0.4H2O: C, 55.14; H, 5.59; N, 8.78; Cl, 14.44; S, 5.02. Found. C, 55.31; H, 5.71; N, 8.97; Cl, 14.23; S, 4.92.
EXAMPLE 29




COMPOUND 29: 3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-methanesulfonyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.33-0.85 (m, 2H), 0.94 (d, 3H, J=6.1 Hz), 1.06-1.21 (m, 1H), 1.41-1.60 (m, 1H), 1.61-1.99 (m, 4H), 2.25-2.46 (m, 1H), 2.55-2.89 (m, 3H), 3.03 (s, 3H), 3.23-3.42 (m, 1H), 3.76-3.92 (m, 1H), 5.29-5.38 (m, 1H), 6.60 (d, 1H, J=8.2 Hz), 6.85 (d, 1H, J=7.4 Hz), 7.36-7.55 (m, 3H), 7.85 (d, 2H, J=8.3 Hz), 8.61, 8.62 (s, 2H), 9.08, 9.29 (br s, 1H). 13C NMR (CDCl3) δ 13.64, 13.71, 28.86, 29.02, 29.60, 29.80, 30.25, 30.76, 40.49, 40.64, 41.82, 44.05, 44.15, 44.78, 52.09, 52.26, 60.69, 60.87, 80.50, 109.58, 117.38, 127.80, 128.60, 129.49, 140.14, 141.37, 143.72, 146.41, 148.13, 148.60, 161.83, 161.99, 162.62. ES-MS m/z 649 (M+Na). Anal. Calcd. for C28H31Cl3N4O4S.0.6CH2Cl2.0.1H2O: C, 50.61; H, 4.81; N, 8.25; Cl, 21.94; S, 4.72. Found. C, 50.45; H, 4.73; N, 8.21; Cl, 22.10; S, 4.65.
EXAMPLE 30




COMPOUND 30: 3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-methanesulfonyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.41-0.93 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.10-1.21 (m, 1H), 1.47-2.02 (m, 5H), 2.28-2.49 (m, 1H), 2.57-2.90 (m, 3H), 3.03 (s, 3H), 3.24-3.42 (m, 1H), 3.78-3.92 (m, 1H), 5.27-5.37 (m, 1H), 6.45 (d, 1H, J=7.6 Hz), 6.57 (d, 1H, J=7.8 Hz), 7.41, 7.43 (d, 2H, J=3.9 Hz), 7.57-7.70 (m, 1H), 7.88 (d, 2H, J=8.2 Hz), 8.62 (s, 2H), 9.06, 9.25 (br s, 1H). 13C NMR (CDCl3) δ 13.65, 14.59, 21.46, 28.91, 29.66, 30.31, 30.73, 40.54, 40.67, 42.01, 44.05, 44.17, 44.79, 52.13, 52.30, 60.80, 60.93, 80.44, 101.03, 101.50, 107.67, 127.85, 128.45, 129.48, 140.19, 143.30, 143.41, 143.71, 146.42, 148.15, 160.61, 161.85, 161.97, 162.23, 163.81. ES-MS m/z 609 (M+H). Anal. Calcd. for C28H31Cl2FN4O4S.0.1CH2Cl2.0.1H2O: C, 54.45; H, 5.11; N, 9.04; Cl, 12.58; F, 3.07; S, 5.17. Found. C, 54.45; H, 5.17; N, 8.88; Cl, 12.71; F, 2.88; S, 4.98.
EXAMPLE 31




COMPOUND 31: 3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 1-bromo-4-(trifluoromethoxy)benzene (1.88 g, 7.80 mmol) in THF (16 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 4.1 mL, 7.8 mmol), and the solution was stirred at −78° C. for 30 minutes. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 7.03 mmol) in THF (2 mL) was added dropwise, and the mixture was stirred at −78° C. for 45 minutes then allowed to warm to room temperature over 1 h. Work-up and purification gave 4-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (1.75 g, 66%).
COMPOUND 31 was isolated as a white solid. 1H NMR (CDCl3) δ 0.29-0.80 (m, 1H), 0.94, 0.96 (d, 3H, J=2.3 Hz), 1.08-1.17 (m, 1H), 1.43-1.56 (m, 1H), 1.62-2.05 (m, 5H), 2.26-2.40 (m, 1H), 2.41 (s, 3H), 2.57-2.92 (m, 3H), 3.22-3.41 (m, 1H), 3.79-3.96 (m, 1H), 5.19, 5.21 (d, 1H, J=3.5 Hz), 6.42 (d, 1H, J=8.3 Hz), 6.65 (d, 1H, J=5.6 Hz), 7.11 (d, 2H, J=8.2 Hz), 7.22-7.29 (m, 2H), 7.36-7.43 (m, 1H), 8.56, 8.58 (s, 2H), 9.36, 9.56 (br s, 1H). 13C NMR (CDCl3) δ 13.59, 13.70, 24.46, 28.99, 29.50, 29.78, 30.02, 30.36, 30.56, 40.71, 40.84, 42.11, 44.13, 52.30, 52.46, 53.82, 60.95, 61.15, 79.71, 107.58, 116.36, 119.11, 120.91, 122.51, 129.08, 129.52, 139.23, 139.53, 143.80, 148.02, 148.75, 156.69, 161.78, 161.96, 162.69. ES-MS m/z 611 (M+H). Anal. Calcd. for C29H31Cl2F3N4O3: C, 56.96; H, 5.11; N, 9.16; Cl, 11.6; F, 9.32. Found. C, 57.04; H, 5.14; N, 9.20; Cl, 11.77; F, 9.39.
EXAMPLE 32




COMPOUND 32: 3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.35-1.02 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.10-1.21 (m, 1H), 1.44-1.57 (m, 1H), 1.61-2.06 (m, 4H), 2.28-2.47 (m, 1H), 2.59-2.92 (m, 3H), 3.25-3.40 (m, 1H), 3.80-3.94 (m, 1H), 5.23 and 5.24 (d, 1H, J=8.0 Hz), 6.41-6.45 (m, 1H), 6.52 (d, 1H, J=7.8 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.25 and 7.27 (d, 2H, J=8.4 Hz), 7.56-7.65 (m, 1H), 8.63 (s, 2H), 9.21 and 9.43 (br s, 1H). 13C NMR (CDCl3) δ 13.17 and 13.24, 28.44 and 28.71, 29.19 and 29.48, 29.64 and 30.19, 40.13 and 40.29, 41.46 and 41.51, 43.57 and 43.71, 51.72 and 51.89, 60.40 and 60.57, 80.09 and 80.12, 100.52 (d, J=35.2 Hz), 107.17 and 107.20 (d, J=5.1 Hz), 120.34 (q, J=258 Hz), 120.66, 128.57, 128.98 and 129.02, 138.06 and 138.09, 142.73 (d, J=8.2 Hz), 143.26 and 143.29, 147.72, 148.55 (q, J=2.1 Hz), 161.80 and 161.82 (d, J=241 Hz), 161.42 and 161.58, 161.87 and 162.05. ESI-MS m/z 615 (MH)+, 617 (MH+2)+. Anal. Calcd. for C28H28Cl2F4N4O3: C, 54.64; H, 4.59; N, 9.10; Cl, 11.52. Found. C, 54.53; H, 4.61; N, 9.01; Cl, 11.63.
EXAMPLE 33




COMPOUND 33: 3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-trifluoromethoxy-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.29-1.01 (m, 2H), 0.956 and 0.960 (d, 3H, J=6.6 Hz), 1.07-1.18 (m, 1H), 1.44-2.05 (m, 5H), 2.29-2.47 (m, 1H), 2.57-2.92 (m, 3H), 3.24-3.40 (m, 1H), 3.80-3.95 (m, 1H), 5.23 and 5.26 (d, 1H, J=6.8 Hz), 6.56 and 6.57 (d, 1H, J=8.1 Hz), 6.85 and 6.86 (d, 1H, J=7.5 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.24-7.29 (m, 2H), 7.47 and 7.48 (dd, 1H, J=8.1, 7.4 Hz), 8.66 (s, 2H), 9.27 and 9.52 (br s, 1H). 13C NMR (CDCl3) δ 13.17 and 13.27, 28.43 and 28.84, 29.19 and 29.61, 29.62 and 30.24, 40.16 and 40.32, 41.33 and 41.39, 43.57 and 43.70, 51.74 and 51.93, 60.42 and 60.64, 80.17 and 80.22, 109.08 and 109.11, 116.68 and 116.71, 120.30 (q, J=261 Hz), 120.63, 128.73, 129.03 and 129.07, 138.04 and 138.07, 140.77, 143.31 and 143.33, 147.73 and 147.75, 148.20 and 148.22, 148.58 (q, J=1.3 Hz), 161.40 and 161.58, 162.46. ESI-MS m/z 631 (MH)+, 633 (MH+2)+, 635 (MH+4)+. Anal. Calcd. for C28H28Cl3F3N4O3: C, 53.22; H, 4.47; N, 8.87; Cl, 16.83. Found. C, 53.30; H, 4.45; N, 8.82; Cl, 16.71.
EXAMPLE 34




COMPOUND 34: 3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-methylsulfamoyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-bromo-N-methyl-benzenesulfonamide (Marvel; Smith, J. Am. Chem. Soc., 45, 1923, 2697) (1.00 g, 4.00 mmol) in THF (35 mL) at −78° C. was added MeLi (4.00 mmol) and the solution was stirred at −78° C. for 15 minutes. n-BuLi (1.95M in hexanes, 2.05 mL, 4.00 mmol) was then added. After the solution was stirred at −78° C. for 45 minutes, TMEDA (1.20 mL, 8.00 mmol) was added followed by a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.76 g, 22.30 mmol) in THF (5 mL), and the mixture was stirred at −78° C. for 1 hour. Work-up and purification gave 4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (622 mg, 41%) as a white foam.
COMPOUND 34 was isolated as a white foam. 1H NMR (CDCl3) δ 0.42-0.84 (m, 1H), 0.96 (d, 3H, J=6.4 Hz), 1.09-1.21 (m, 1H), 1.41-1.59 (m, 1H), 1.65-2.02 (m, 5H), 2.28-2.50 (m, 1H), 2.38 (s, 3H), 2.64 (d, 3H, J=4.8 Hz), 2.70-2.94 (m, 3H), 3.23-3.44 (m, 1H), 3.79-3.95 (m, 1H), 4.48-4.56 (m, 1H), 5.33 (d, 1H, J=8.2 Hz), 6.46 (d, 1H, J=8.0 Hz), 6.66 (d, 1H, J=7.3 Hz), 7.37-7.47 (m, 3H), 7.76 (d, 2H, J=7.9 Hz), 8.56, 8.57 (s, 2H), 9.23, 9.40 (br s, 1H). 13C NMR (CDCl3) δ 13.59, 13.69, 14.59, 21.45, 24.43, 28.91, 29.22, 29.80, 30.07, 30.19, 30.65, 40.60, 42.10, 44.17, 52.26, 52.42, 60.85, 61.03, 79.56, 107.70, 116.51, 127.44, 128.33, 129.53, 138.71, 139.32, 143.76, 146.33, 148.01, 156.63, 161.82, 161.97, 162.48. ES-MS m/z 611 (M+H). Anal. Calcd. for C29H35Cl2N5O4S.0.3C4H8O2.0.4H2O: C, 55.44; H, 5.89; N, 10.70; S, 4.90. Found. C, 55.41; H, 5.80; N, 10.81; S, 4.67.
EXAMPLE 35




COMPOUND 35: N-(3-{4-[(R)-4-Bromophenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}butyl)-3,5-dichloro-isonicotinamide
To a solution of (+)-DIP-chlorideTM (6.42 g, 20.0 mmol) in THF (10 mL) at 0° C. was added 4-(4-bromobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.68 g, 10.0 mmol). The mixture was stirred at room temperature for 29 hours to give (R)-4-[(4-bromophenyl)-hydroxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (ee 82% determined by both chiral HPLC and Mosher ester) as a crystalline solid (2.22 g, 54%) following work-up and purification. This material was recrystallized (CH2Cl2/hexane) five times to provide a white solid (1.27 g, 35%) with 95% ee.
COMPOUND 35 was isolated as a white foam. 1H NMR (CDCl3) δ 0.45-85 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 1.22 (br d, 1H, J=12 Hz), 1.51 (m, 1H), 1.66-1.98 (m, 5H), 2.30-2.45 (m, 1H), 2.60-2.90 (m, 3H), 3.31 (m, 1H), 3.80-3.90 (m, 1H), 5.33 (d, 1H, J=7.1 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.80 (m, 1H), 7.09 and 7.10 (d, 2H, J=8.1 Hz), 7.40 (d, 2H, J=8.4 Hz), 7.48-7.55 (m, 1H), 8.08 (t, 1H, J=2.4 Hz), 8.56 and 8.56 (s, 2H), 9.17 and 9.34 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.2, 13.3, 28.6, 28.7, 29.4, 29.6, 29.9, 30.2, 40.2, 40.3, 41.8, 43.8, 43.9, 51.9, 52.1, 60.5, 60.6, 79.3, 111.0, 116.9, 121.3, 128.8, 129.1, 131.3, 138.6, 139.4, 143.3, 146.9, 147.7, 161.5, 161.6, 163.0. ES-MS m/z 593 (M+H). Anal. Calcd. for C27H29BrCl2N4O2.0.3CH2Cl2: C, 53.07; H, 4.83; N, 9.07; Br, 12.93; Cl, 14.92. Found. C, 53.13; H, 4.80; N, 9.02; Br, 12.83; Cl, 14.78.
EXAMPLE 36




COMPOUND 36: N-(3-{4-[(4-Bromo-phenyl)-(3-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Off-white foam. 1H NMR (CDCl3) δ 0.45-1.12 (m, 2H), 0.97 (d, 3H, J=5.4 Hz), 1.17-1.28 (m, 1H), 1.45-1.58 (m, 1H), 1.66-1.85 (m, 2H), 1.88-2.09 (m, 2H), 2.16 (s, 3H), 2.25-2.47 (m, 1H), 2.61-2.93 (m, 3H), 3.25-3.42 (m, 1H), 3.75-3.92 (m, 1H), 5.42 and 5.45 (d, 1H, J=6.6 Hz), 6.71 (apparent t, 1H, J=5.6 Hz), 7.11 and 7.13 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=7.2 Hz), 7.39 (d, 2H, J=8.4 Hz), 7.90 (s, 1H), 8.54 (s, 2H), 8.96 and 9.19 (br s, 1H). 13C NMR (CDCl3) δ 13.10 and 13.23, 15.88 and 15.89, 28.39 and 29.03, 28.94 and 29.54, 29.91 and 30.50, 39.90 and 40.04, 41.72 and 41.77, 43.94, 51.77 and 52.01, 60.22 and 60.44, 78.76 and 78.81, 116.73 and 116.74, 120.42 and 120.45, 121.17, 128.81 and 128.85, 128.90 and 128.94, 131.20, 138.46 and 138.48, 139.63 and 139.66, 143.14 and 143.16, 143.96, 147.65, 160.96 and 160.98. ESI-MS m/z 605 (MH)+, 607 (MH+2)+, 609 (MH+4)+. Anal. Calcd. for C28H31BrCl2N4O2.0.2CH2Cl2: C, 54.33; H, 5.08; N, 8.99; Br, 12.82. Found. C, 54.51; H, 5.17; N, 8.72; Br, 12.44.
EXAMPLE 37




COMPOUND 37: 3,5-Dichloro-N-(3-{4-[(4-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ0.5-1.06 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.18-1.26 (m, 1H), 1.45-1.56 (m, 1H), 1.62-1.87 (m, 3H), 1.89-2.03 (m, 1H), 2.28 (s, 3H), 2.29-2.43 (m, 1H), 2.61-2.89 (m, 3H), 3.27-3.37 (m, 1H), 3.83-3.93 (m, 1H), 5.46 (d, 1H, J=7.8 Hz), 6.50 (s, 1H), 6.64 (d, 1H, J=5.1 Hz), 7.32 (dd, 2H, J=8.1, 2.1 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.92 (dd, 1H, J=5.4, 2.4 Hz), 8.57, 8.57 (s, 2H), 9.10, 9.25 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.24, 20.87, 28.45, 28.72, 29.26, 29.46, 29.99, 30.31, 40.25, 40.34, 41.99, 43.82, 43.92, 51.98, 52.11, 60.55, 60.62, 77.03, 111.18, 118.61, 124.54 (q, J=270 Hz), 125.10, 127.30, 129.08, 129.50 (q, J=32 Hz), 143.34, 144.68, 146.41, 147.70, 150.04, 161.51, 161.60, 163.17. ES-MS m/z 595 (M+H). Anal. Calcd. for C29H31N4O2Cl2F3: C, 58.49; H, 5.25; N, 9.41; Cl, 11.91; F, 9.57. Found. C, 58.69; H, 5.21; N, 9.46; Cl, 11.71; F, 9.63.
EXAMPLE 38




COMPOUND 38: 3,5-Dichloro-N-(3-{4-[(3-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.45-1.11 (m, 2H), 0.95, 0.96 (d, 3H, J=6.6 Hz), 1.15-1.26 (m, 1H), 1.46-1.57 (m, 1H), 1.66-1.83 (m, 2H), 1.89-2.07 (m, 2H), 2.18 (s, 3H), 2.29-2.47 (m, 1H), 2.60-2.91 (m, 3H), 3.26-3.40 (m, 1H), 3.79-3.94 (m, 1H), 5.49, 5.51 (d, 1H, J=8.4 Hz), 6.71-6.75 (m, 1H), 7.33-7.38 (m, 3H), 7.53 (d, 2H, J=8.1 Hz), 7.89-7.93 (m, 1H), 8.56 (s, 2H), 8.92, 9.17 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.17, 13.30, 15.92, 28.64, 29.10, 29.29, 29.67, 29.95, 30.57, 40.09, 40.25, 41.91, 41.98, 43.94, 51.80, 52.05, 60.31, 60.53, 77.04, 116.90, 120.44, 124.13 (q, J=272 Hz), 125.07, 125.12, 127.45, 128.99, 129.04, 129.52 (q, J=32 Hz), 138.61, 143.27, 144.01, 144.84, 147.70, 160.93, 161.47, 161.65. ES-MS m/z 595 (M+H). Anal. Calcd. for C29H31N4O2Cl2F3.0.1H2O.0.1CH2Cl2: C, 57.70; H, 5.22; N, 9.25; Cl, 12.88; F, 9.41. Found. C, 57.54; H, 5.27; N, 9.27; Cl, 13.25; F, 9.18.
EXAMPLE 39




COMPOUND 39: 3,5-Dichloro-N-(3-{4-[(3-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.46-1.08 (m, 2H), 0.96, 0.97 (d, 3H, J=6.6 Hz), 1.16-1.27 (m, 1H), 1.47-1.61 (m, 1H), 1.72-2.09 (m, 4H), 2.30-2.50 (m, 1H), 2.61-2.93 (m, 3H), 3.25-3.40 (m, 1H), 3.81-3.97 (m, 1H), 5.40, 5.44 (d, 1H, J=8.4 Hz), 6.78-6.83 (m, 1H), 7.35-7.40 (m, 2H), 7.54-7.61 (m, 3H), 7.96-7.99 (m, 1H), 8.54, 8.55 (s, 2H), 9.03, 9.24 (br s, 1H). 13C NMR (CDCl3) δ 13.57, 13.68, 28.98, 29.30, 29.62, 29.84, 30.33, 30.88, 40.52, 40.67, 42.15, 42.23, 44.18, 52.18, 52.39, 60.78, 60.97, 80.91, 81.03, 118.14, 118.72, 124.46 (q, J=272 Hz), 125.56, 125.60, 127.78, 127.82, 129.47, 130.18 (q, J=32 Hz), 138.80, 143.70, 144.34, 145.02, 148.03, 158.51, 161.82, 161.99. ES-MS m/z 615 (M+H). Anal. Calcd. for C28H28N4Cl3F3O2: C, 54.60; H, 4.58; N, 9.10; Cl, 17.27; F, 9.25. Found. C, 54.57; H, 4.59; N, 9.09; Cl, 16.97; F, 9.32.
EXAMPLE 40




COMPOUND 40: 3,5-Dichloro-N-(3-{4-[(4-chloro-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.45-0.91 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.15-1.27 (m, 2H), 1.46-2.04 (m, 4H), 2.30-2.45 (m, 1H), 2.62-2.90 (m, 3H), 3.27-3.38 (m, 1H), 3.83-3.94 (m, 1H), 5.40 (d, 1H, J=8.1 Hz), 6.73 (s, 1H), 6.84 (d, 1H, J=4.8 Hz), 7.29-7.33 (m, 2H), 7.55 (d, 2H, J=8.1 Hz), 7.95-7.99 (m, 1H), 8.58 (s, 2H), 9.14, 9.29 (br s, 1H). 13C NMR (CDCl3) δ 13.24, 28.59, 29.37, 29.96, 30.28, 30.94, 40.26, 41.77, 43.72, 51.90, 52.03, 60.56, 79.95, 111.24, 117.88, 122.25 (q, J=272 Hz), 125.26, 127.34, 129.13, 129.81 (q, J=32 Hz), 143.34, 143.95, 145.55, 147.56, 147.68, 161.46, 163.66. ES-MS m/z 615 (M+H).
EXAMPLE 41




COMPOUND 41: 6-[(1-{3-[(3,5-Dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-trifluoromethyl-phenyl)-methoxy]-pyridine-2-carboxylic acid methyl ester
To saturated HCl/MeOH (4 mL) at 0° C. was added a solution of COMPOUND 27 (165 mg, 0.272 mmol) in MeOH (1 mL), and the mixture was stirred at room temperature for 45 minutes. Work-up and purification gave a 1:1 diastereomeric mixture of COMPOUND 41 (122 mg, 70%). 1H NMR(CDCl3) δ0.35-0.62 (m, 2H), 0.70-0.83 (m, 1H), 0.95 (m, 7H), 1.12 (m, 2H), 1.49 (m, 2H), 1.67-2.05 (m, 8H), 2.29-2.46 (m, 2H), 2.61 (m, 1H), 2.73-2.89 (m, 5H), 3.32 (m, 2H), 3.86 (m, 2H), 3.98 (s, 6H), 5.42 (d, 2H, J=8.7 Hz), 6.85 (m, 2H), 7.42 (m, 4H), 7.53 (d, 4H, J=8.1 Hz), 7.64 (m, 4H), 8.62 (s, 2H), 8.63 (s, 2H), 9.20 (d, 1H, J=5.7 Hz), 9.41 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.22, 13.32, 28.45, 28.96, 29.22, 29.77, 30.28, 40.22, 40.35, 41.21, 43.66, 43.74, 51.83, 52.00, 52.54, 60.46, 60.65, 80.23, 115.00, 118.85, 125.10, 127.96, 129.03, 139.33, 143.29, 143.84, 145.36, 147.79, 161.47, 161.63, 162.42, 165.39. ES-MS m/z 641 (M+H). Anal. Calcd. for C30H31N4Cl2F3O4.0.2CH2Cl2: C, 55.25; H, 4.82; N, 8.53; Cl, 12.96; F, 8.68. Found. C, 55.10; H, 4.76; N, 8.44; Cl, 13.27; F, 8.46.
EXAMPLE 42




COMPOUND 42: 3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[(4-bromo-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 4.33 mmol) and zinc cyanide (305 mg, 2.60 mmol) in DMF (20 mL) under nitrogen was added DPPF (48 mg, 0.087 mmol) and Pd2(dba)3 (40 mg, 0.043 mmol). The resulting suspension was warmed to 130° C. and stirred for 5 hours. Standard work-up and purification gave 4-[(4-cyano-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 79%) as a yellow solid.
Using general procedure C with the above carbamate (1.2 g, 2.95 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (1.2 g, 5.60 mmol) followed by general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-methyl-pyridin-2-yloxy)-methyl]-benzonitrile (500 mg, 40% over 4 steps) as a white foam.
Using general procedure F, 3,5-dichloroisonicotinic acid (301 mg, 1.58 mmol) and the above amine (300 mg, 0.79 mmol) gave a diastereomeric mixture of COMPOUND 42 (285 mg, 65%) as a white foam. 1H NMR (CDCl3) δ 0.38-0.82 (m, 1H), 0.96 (d, 3H, J=6.5 Hz), 1.09-1.22 (m, 1H), 1.40-2.03 (m, 5H), 2.27-2.50 (m, 1H), 2.37 (s, 3H), 2.57-2.93 (m, 4H), 3.23-3.43 (m, 1H), 3.79-3.97 (m, 1H), 5.25-5.34 (m, 1H), 6.45 (d, 1H, J=9.0 Hz), 6.65 (d, 1H, J=7.4 Hz), 7.28-7.36 (m, 2H), 7.37-7.45 (m, 1H), 7.56 (d, 2H, J=8.4 Hz), 8.56, 8.57 (s, 2H), 9.14, 9.32 (br s, 1H). 13C NMR (CDCl3) δ 11.17, 11.25, 21.96, 26.51, 26.75, 27.28, 27.78, 28.23, 38.20, 39.57, 41.68, 50.01, 58.46, 58.63, 77.18, 105.28, 109.10, 114.14, 116.77, 125.90, 127.11, 129.94, 136.90, 141.32, 144.19, 145.58, 154.18, 159.49, 159.93. ES-MS m/z 553 (M+H). Anal. Calcd. for C29H31Cl2N5O2.0.2CH2Cl2.0.3H2O: C, 61.01; H, 5.61; N, 12.19; Cl, 14.80. Found. C, 61.03; H, 5.61; N, 11.96; Cl, 14.91.
EXAMPLE 43




COMPOUND 43: 3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-(4-cyano-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 2.78 mmol) in DMF (14 mL) was added NaH (60% in mineral oil, 278 mg, 6.95 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Dichloropyridine (1.23 g, 8.34 mmol) was added and the mixture was heated at 70° C. for 3 hours. Standard work-up and purification afforded 4-[(4-bromo-phenyl)-(6-chloro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off white solid (1.28 g, 96%).
The above bromide (1.10 g, 2.28 mmol), Zn(CN)2 (161 mg, 1.37 mmol), DPPF (126 mg, 0.23 mmol) and degassed DMF (12 mL) were flushed with N2 and heated to 60° C. Pd2(dba)3 (104 mg, 0.11 mmol) was added and the mixture was heated at 130° C. overnight. Work-up and purification afforded 4-[(6-chloro-pyridin-2-yloxy)-(4-cyano-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (236 mg, 24%) and 4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 21%) as pale yellow solids.
Using general procedure C with 4-[(6-chloro-pyridin-2-yloxy)-(4-cyano-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (236 mg, 0.55 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (203 mg, 0.93 mmol) and then using general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-chloro-pyridin-2-yloxy)-methyl]-benzonitrile as a colourless syrup (65 mg, 37% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (77 mg, 0.40 mmol) and the amine from above (80 mg, 0.20 mmol) afforded COMPOUND 43 (98 mg, 85%). 1H NMR (CDCl3) δ 0.38-1.00 (m, 2H), 0.95 (d, 3H, J=6.3 Hz), 1.10-1.17 (m, 1H), 1.45-1.56 (m, 1H), 1.66-2.03 (m, 4H), 2.29-2.45 (m, 1H), 2.59-2.90 (m, 3H), 3.26-3.39 (m, 1H), 3.79-3.93 (m, 1H), 5.29-5.32 (m, 1H), 6.59 (dd, 1H, J=8.1, 1.5 Hz), 6.86 (dd, 1H, J=7.5, 1.5 Hz), 7.32-7.36 (m, 2H), 7.46-7.52 (m, 1H), 7.59 (d, 2H, J=7.8 Hz), 8.62 (s, 2H), 9.09, 9.30 (br s, 1H). 13C NMR (CDCl3) δ 13.24, 13.31, 28.46, 28.65, 29.20, 29.44, 29.82, 30.34, 40.16, 40.31, 41.33, 43.63, 43.74, 51.75, 51.92, 60.40, 60.56, 80.22, 109.13, 111.59, 117.01, 118.67, 128.00, 129.09, 132.16, 140.96, 143.33, 145.01, 147.74, 148.21, 161.42, 161.57, 162.19. ES-MS m/z 572 (M+H). Anal. Calcd. for C28H28N5Cl3O2.0.1CH2Cl2: C, 58.05; H, 4.89; N, 12.05; Cl, 19.51. Found. C, 58.08; H, 4.93; N, 11.95; Cl, 19.27.
EXAMPLE 44




COMPOUND 44: 3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure C with 4-[(4-cyano-phenyl)-(6-cyano-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 43) (200 mg, 0.48 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (168 mg, 0.77 mmol) and then using general procedure D afforded 6-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-cyano-phenyl)-methoxy]-pyridine-2-carbonitrile as a colourless syrup (40 mg, 22% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (40 mg, 0.21 mmol) and the amine from above (40 mg, 0.10 mmol) afforded COMPOUND 44 (27 mg, 47%). 1H NMR (CDCl3) δ 0.49-0.97 (m, 2H), 0.96 (d, 3H, J=6.3 Hz), 1.15-1.23 (m, 1H), 1.45-1.56 (m, 1H), 1.67-1.89 (m, 3H), 1.91-2.06 (m, 1H), 2.30-2.45 (m, 1H), 2.62-2.90 (m, 3H), 3.28-3.39 (m, 1H), 3.80-3.91 (m, 1H), 5.38-5.42 (m, 1H), 6.94 (d, 1H, J=8.1 Hz), 7.26-7.36 (m, 3H), 7.61 (d, 2H, J=7.8 Hz), 7.64-7.70 (m, 1H), 8.57, 8.60 (s, 2H), 8.90, 8.99 (br s, 1H). 13C NMR (CDCl3) δ 13.27, 28.55, 29.21, 29.30, 30.23, 30.42, 40.07, 40.13, 41.39, 43.77, 43.84, 51.68, 51.76, 60.30, 80.45, 111.81, 116.06, 116.11, 116.98, 118.55, 122.67, 127.90, 129.09, 130.27, 132.24, 139.63, 143.24, 144.59, 147.64, 161.47, 161.52, 162.83. ES-MS m/z 563 (M+H). Anal. Calcd. for C29H28N6Cl2O2.0.1CH2Cl2: C, 61.11; H, 4.97; N, 14.69; Cl, 13.64. Found. C, 60.96; H, 5.03; N, 14.39; Cl, 13.81.
EXAMPLE 45




COMPOUND 45: 3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.36 g, 3.67 mmol) in DMF (18 mL) was added NaH (60% in mineral oil, 367 mg, 9.17 mmol) and the mixture was stirred at room temperature for 10 minutes. 2,6-Difluoropyridine (1.00 mL, 11.0 mmol) was added and the mixture was heated at 70° C. overnight. Work-up and purification gave 4-[(4-bromo-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (1.60 g, 94%).
The above bromide (1.60 g, 3.44 mmol), Zn(CN)2 (242 mg, 2.06 mmol), DPPF (382 mg, 0.69 mmol) and degassed DMF (17 mL) were flushed with N2. Pd2(dba)3 (311 mg, 0.34 mmol) was added and the mixture was heated at 130° C. overnight. Aqueous work-up and purification afforded 4-[(4-cyano-phenyl)-(6-fluoro-pyridin-2-yloxy)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (1.12 mg, 78%).
Using general procedure C with the above substrate (1.12 g, 2.72 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (893 mg, 4.11 mmol) followed by general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-fluoro-pyridin-2-yloxy)-methyl]-benzonitrile as a colourless syrup (270 mg, 27% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (216 mg, 1.12 mmol) and the amine from above (215 mg, 0.56 mmol) afforded COMPOUND 45 (203 mg, 65%). 1H NMR (CDCl3) δ 0.44-0.98 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.13-1.21 (m, 1H), 1.47-1.57 (m, 1H), 1.63-2.04 (m, 4H), 2.30-2.44 (m, 1H), 2.62-2.88 (m, 3H), 3.28-3.39 (m, 1H), 3.82-3.93 (m, 1H), 5.27-5.31 (m, 1H), 6.43-6.47 (m, 1H), 6.56 (d, 1H, J=7.8 Hz), 7.33, 7.34 (d, 2H, J=8.1 Hz), 7.58-7.65 (m, 3H), 8.62 (s, 2H), 9.04-9.23 (br s, 1H). 13C NMR (CDCl3) δ 13.28, 28.51, 29.22, 29.28, 29.88, 30.32, 40.14, 40.27, 41.50, 41.54, 43.65, 43.78, 51.73, 51.89, 60.38, 60.50, 80.11, 100.64, 101.11, 107.25, 111.58, 118.65, 127.85, 129.05, 129.09, 132.17, 142.91, 143.02, 143.31, 145.02, 147.72, 161.44, 161.56, 161.78 (d, J=242 Hz), 161.79. ES-MS m/z 556 (M+H). Anal. Calcd. for C28H28N5Cl2FO2.0.1H2O.0.16CH2Cl2: C, 59.17; H, 5.03; N, 12.25; Cl, 14.34; F, 3.32. Found. C, 59.21; H, 5.08; N, 12.37; Cl, 14.36; F, 3.15.
EXAMPLE 46




COMPOUND 46: N-(3-{4-[(4-Carbamoyl-phenyl)-(6-methyl-pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
To a solution of COMPOUND 42 (100 mg, 0.18 mmol) in MeOH (2 mL) was added 10% NaOH (2 mL). The resulting mixture was heated at 50° C. overnight. Work-up and purification afforded a diastereomeric mixture of COMPOUND 46 (32 mg, 31%) as a white foam. 1H NMR (CDCl3) δ 0.32-0.82 (m, 1H), 0.93-0.98 (m, 3H), 1.17-1.26 (m, 2H), 1.41-1.57 (m, 1H), 1.69-1.81 (m, 2H), 1.89-1.98 (m, 2H), 2.26-2.49 (m, 1H), 2.37 (s, 3H), 2.61-2.92 (m, 3H), 3.22-3.41 (m, 1H), 3.78-3.96 (m, 1H), 5.31 (d, 1H, J=7.5 Hz), 5.62, 6.27 (br s, 2H), 6.42 (d, 1H, J=7.8 Hz), 6.64 (d, 1H, J=7.5 Hz), 7.27-7.33 (m, 2H), 7.35-7.43 (m, 1H), 7.70 (d, 2H, J=7.9 Hz), 8.53, 8.55 (s, 2H), 9.26, 9.43 (br s, 1H). 13C NMR (CDCl3) δ 13.21, 13.32, 24.05, 28.33, 29.01, 29.10, 29.70, 29.89, 30.16, 40.30, 40.40, 41.71, 43.81, 51.98, 52.15, 60.56, 60.76, 79.56, 107.22, 116.02, 127.27, 127.45, 129.11, 132.52, 138.86, 143.35, 144.54, 147.54, 156.28, 161.42, 161.58, 162.24, 169.40. ES-MS m/z 572 (M+H). Anal. Calcd. for C29H33Cl2N5O3.0.5CH2Cl2.0.3H2O: C, 57.30; H, 5.64; N, 11.33; Cl, 17.20. Found. C, 57.17; H, 5.65; N, 11.26; Cl, 17.27.
EXAMPLE 47




COMPOUND 47: 4-[(1-{3-[(3,5-Dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(6-methyl-pyridin-2-yloxy)-methyl]-benzoic acid methyl ester
To a solution of COMPOUND 42 (40 mg, 0.07 mmol) in HCl/MeOH (3 mL), was added H2O (3 drops). The resulting mixture was heated at 80° C. overnight to afford a diastereomeric mixture of COMPOUND 47 (22 mg, 51%) as a white foam following work-up and purification. 1H NMR (CDCl3) δ 0.37-0.82 (m, 1H), 0.87-1.02 (m, 3H), 1.07-1.23 (m, 1H), 1.44-1.58 (m, 1H), 1.63-2.00 (m, 5H), 2.28-2.47 (m, 1H), 2.37 (s, 3H), 2.53-2.94 (m, 3H), 3.22-3.40 (m, 1H), 3.76-3.93 (m, 1H), 3.88 (s, 3H), 5.27 (d, 1H, J=8.0 Hz), 6.42 (d, 1H, J=8.5 Hz), 6.63 (d, 1H, J=7.1 Hz), 7.27-7.32 (m, 2H), 7.38, 7.39 (dd, 1H, J=7.6, 7.6 Hz), 7.94 (d, 2H, J=8.4 Hz), 8.56, 8.57 (s, 2H), 9.24, 9.39 (br s, 1H). 13C NMR (CDCl3) δ 13.58, 13.69, 24.42, 28.95, 29.36, 29.74, 30.15, 30.28, 30.60, 40.69, 40.79, 42.09, 44.14, 52.46, 60.97, 61.16, 80.11, 107.57, 116.38, 127.63, 127.67, 129.50, 129.62, 129.82, 139.21, 143.75, 146.18, 148.04, 156.68, 161.81, 161.97, 162.66, 167.31. ES-MS m/z 585 (M+H). Anal. Calcd. for C29H34Cl2N4O4.0.3CH2Cl2: C, 59.56; H, 5.71; N, 9.17. Found. C, 59.39; H, 5.76; N, 8.91.
EXAMPLE 48




COMPOUND 48: N-(3-{4-[(4-Bromo-phenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 3-{4-[(4-bromo-phenyl)-(pyridin-2-yloxy)-methyl]-piperidin-1-yl}-butylamine (see EXAMPLE 21) (116 mg, 0.28 mmol) and 2,4-dimethyl-1-oxynicotinic acid (61 mg, 0.36 mmol) gave COMPOUND 48 as a pale yellow foam (144 mg, 92%). 1H NMR (CDCl3) δ 0.62-1.00 (m, 1H), 0.96 (d, 3H, J=6.9 Hz), 1.22-1.32 (m, 1H), 1.47-1.58 (m, 1H), 1.61-2.07 (m, 5H), 2.28 and 2.29 (s, 3H), 2.32-2.49 (m, 1H), 2.44 (s, 3H), 2.58-2.84 (m, 3H), 3.26-3.38 (m, 1H), 3.72-3.84 (m, 1H), 5.34 and 5.37 (d, 1H, J=8.3 Hz), 6.68-6.71 (m, 1H), 6.77-6.82 (m, 1H), 6.88 and 6.92 (d, 1H, J=6.5 Hz), 7.195 and 7.203 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.4 Hz), 7.49-7.56 (m, 1H), 8.04-8.07 (m, 1H), 8.10 and 8.12 (d, 1H, J=5.1 Hz), 9.01 (br s, 1H). 13C NMR (CDCl3) δ 13.28 and 13.32, 14.86 and 14.88, 18.26 and 18.28, 28.48 and 28.60, 29.03 and 29.16, 31.52 and 31.58, 38.95 and 38.96, 42.03 and 42.06, 44.61, 51.24 and 51.27, 58.75 and 58.79, 79.35 and 79.41, 111.05, 116.73, 120.98, 124.70, 128.77, 131.06, 133.97, 136.82, 137.86, 138.47, 139.42 and 139.43, 145.32 and 145.37, 146.64 and 146.66, 162.88, 165.18 and 165.21. ESI-MS m/z 567 (MH)+, 569 (MH+2)+. Anal. Calcd. for C29H35BrN4O3.1.0CH2Cl2: C, 55.23; H, 5.72; N, 8.59; Br, 12.25. Found. C, 55.48; H, 5.81; N, 8.66; Br, 11.98.
EXAMPLE 49




COMPOUND 49: 2,6-Dimethyl-4-pyridin-4-yl-N-(3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-benzamide
Using general procedure E, 3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (75 mg, 0.18 mmol) (see EXAMPLE 22) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (46 mg, 0.20 mmol) gave COMPOUND 49 as a white solid (56 mg, 50%). 1H NMR (CDCl3) δ 0.46-1.09 (m, 2H), 0.94 (dd, 3H, J=6.6, 3.6 Hz), 1.44-2.05 (m, 5H), 2.24-2.46 (m, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.54-2.89 (m, 4H), 3.23-3.40 (m, 1H), 3.77-3.94 (m, 1H), 5.23-5.31 (m, 1H), 6.60 (dd, 1H, J=8.4, 3.6 Hz), 6.54 (dd, 1H, J=11.7, 4.8 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.36-7.44 (m, 5H), 5.54-5.57 (m, 2H), 7.84, 7.79 (dd, 1H, J=4.8, 1.2 Hz), 8.57, 8.73 (d, 1H, J=5.7 Hz), 8.61, 8.63 (s, 2H). 13C NMR (CDCl3) δ 13.22, 13.39, 19.40 (2 carbons), 28.23, 28.80, 29.09, 29.77, 30.52, 31.09, 39.72, 39.85, 42.21, 43.98, 51.97, 52.14, 60.25, 60.55, 79.55, 79.63, 111.01, 116.96, 121.67, 124.05 (q, J=272 Hz), 124.91, 124.95, 126.05, 126.07, 127.25, 129.46 (q, J=32 Hz), 135.18, 138.06, 138.16, 138.54, 139.39, 144.59, 144.67, 146.64, 147.88, 150.27, 162.79, 162.82, 169.26, 169.52. ES-MS m/z 617 (M+H). Anal. Calcd. for C36H39F3N4O2: C, 68.76; H, 6.36; N, 8.88; F, 9.04. Found. C, 68.54; H, 6.31; N, 8.75; F, 9.26.
EXAMPLE 50




COMPOUND 50: 2,6-Dimethyl-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
Using general procedure E, 3-{4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (see EXAMPLE 23) (40 mg, 0.10 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (24 mg, 0.11 mmol) afforded COMPOUND 50 (30 mg, 50%). 1H NMR (CDCl3) δ 0.50-1.10 (m, 2H), 0.95, 0.96 (d, 3H, J=6.1 Hz), 1.47-2.06 (m, 5H), 2.20, 2.22 (s, 3H), 2.26-2.45 (m, 1H), 2.42 (s, 6H), 2.56-2.87 (m, 4H), 3.24-3.41 (m, 1H), 3.76-3.94 (m, 1H), 5.16, 5.23 (d, 1H, J=8.1 Hz), 6.29 (dd, 1H, J=8.4, 4.5 Hz), 6.57 (dd, 1H, J=7.5, 2.7 Hz), 7.18-7.24 (m, 3H), 7.36-7.40 (m, 4H), 7.50 (d, 2H, J=4.8 Hz), 8.35, 8.47 (br s, 1H), 8.61-8.64 (m, 2H). 13C NMR (CDCl3) δ 13.17, 13.39, 19.42, 23.99, 24.03, 28.26, 28.90, 29.08, 29.87, 30.78, 31.32, 39.58, 39.69, 42.28, 44.06, 44.16, 51.95, 52.10, 60.03, 60.38, 79.67, 79.83, 106.97, 107.01, 116.03, 121.47, 124.06 (q, J=272 Hz), 124.88, 124.92, 125.93, 127.35, 129.43 (q, J=32 Hz), 135.25, 137.90, 137.97, 138.77, 139.38, 144.73, 147.70, 150.32, 156.19, 162.20, 169.26, 169.54. ES-MS m/z 631 (M+H). Anal. Calcd. for C37H41F3N4O2: C, 70.06; H, 6.58; N, 8.83; F, 8.98. Found. C, 70.15; H, 6.50; N, 8.79; F, 8.78.
EXAMPLE 51




COMPOUND 51: 2,6-Dimethyl-N-(3 (R)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
To a solution of 4(S)-[(4-trifluoromethyl-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 16) (443 mg, 1.23 mmol), 2-hydroxy-6-methylpyridine (269 mg, 2.47 mmol) and Ph3P (646 mg, 2.47 mmol) in THF (10 mL) at room temperature was added DIAD (0.49 mL, 2.47 mmol) dropwise. The mixture was stirred at room temperature for 2 hours to give 4(R)-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white foam (416 mg, 75%) following work-up and purification.
Using general procedure C, the above carbamate (560 mg, 1.24 mmol) gave (R)-2-methyl-6-[piperidin-4-yl-(4-trifluoromethyl-phenyl)-methoxy]-pyridine (ee 96.5% determined by chiral HPLC) as a colorless oil (436 mg, 100%).
Using general procedure G, methyl-(S)-lactate (98 mg, 0.944 mmol) gave (S)-2-methanesulfonyloxy-propionic acid methyl ester as a colorless oil (172 mg, 100%).
A solution of the above piperidine (240 mg, 0.629 mmol) in dry CH3CN (2 mL) was added to the above mesylate followed by 2,2,6,6-tetramethylpiperidine (127 mg, 0.900 mmol). The mixture was heated at reflux for 15 hours to give the methyl ester (263 mg, 0.603 mmol), which was subsequently reduced with LiAlH4 (1.0 M in THF, 0.905 mL, 0.905 mmol) in Et2O (4 mL) to give 2(R)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-propan-1-ol (de 95% determined by chiral HPLC) as a colorless oil (209 mg, 75% over 2 steps) following a Feiser work-up and purification.
Using general procedure G the above alcohol (195 mg, 0.478 mmol) gave the chloride, which was subsequently dissolved in DMSO (2.5 mL) followed by the addition of NaCN (47 mg, 0.95 mmol). The reaction was heated at 140° C. for 1 hour to give the nitrile (140 mg, 0.336 mmol), which was subsequently reduced with BH3-THF (1.0M in THF, 1.01 mL, 1.01 mmol) in THF (2 mL) at reflux and treated with MeOH then ethylenediamine (1 mL) to give 3(R)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colorless oil (121 mg, 64% over 2 steps) following work-up and purification.
Using general procedure E, the above amine (58 mg, 0.14 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (37.5 mg, 0.165 mmol) gave COMPOUND 51 as a white foam (80.8 mg, 93%). 1H NMR (CDCl3) δ 0.55-0.65 (m, 1H), 0.94 (d, 3H, J=6.3 Hz), 1.04 (br d, 2H, J=10.5 Hz), 1.45-1.80 (m, 3H), 1.87-2.01 (m, 2H), 2.19 (s, 3H), 2.36-2.41 (m, 1H), 2.41 (s, 6H), 2.69-2.82 (m, 3H), 3.20-3.35 (m, 1H), 3.80-3.90 (m, 1H), 5.18 (d, 1H, J=8.4 Hz), 6.28 (d, 1H, J=8.1 Hz), 6.55 (d, 1H, J=7.2 Hz), 7.17-7.29 (m, 3H), 7.35-7.40 (m, 4H), 7.48 (d, 2H, J=6.0 Hz), 8.35 (br s, 1H), 8.60 (d, 2H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.5, 19.8, 24.4, 28.6, 30.2, 31.7, 39.9, 42.6, 44.5, 52.5, 60.7, 80.2, 107.4, 116.4, 121.9, 125.3, 126.4, 127.7, 129.8 (q, J=32 Hz), 135.6, 138.4, 139.2, 139.7, 145.1, 148.1, 150.7, 156.6, 162.5, 169.7. ES-MS m/z 632 (M+H). Anal. Calcd. for C37H41F3N4O2.0.4CH2Cl2: C, 67.58; H, 6.34; N, 8.43; F, 8.57. Found. C, 67.46; H, 6.35; N, 8.27; F, 8.31.
EXAMPLE 52




COMPOUND 52: 2,6-Dimethyl-N-(3(S)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-4-pyridin-4-yl-benzamide
Using general procedure G, methyl-(R)-lactate (98 mg, 0.944 mmol) gave the mesylate as a colorless oil (172 mg, 100%).
A solution of (R)-2-methyl-6-[piperidin-4-yl-(4-trifluoromethyl-phenyl)-methoxy]-pyridine (see EXAMPLE 51) (240 mg, 0.629 mmol) in dry CH3CN (2 mL) was added to the above mesylate followed by 2,2,6,6-tetramethylpiperidine (127 mg, 0.900 mmol). The mixture was heated at reflux for 15 hours to give the methyl ester (212 mg, 0.486 mmol), which was subsequently reduced with LiAlH4 (1.0 M in THF, 0.73 mL, 0.73 mmol) in Et2O (2.5 mL) to give 2(S)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-propan-1-ol (de 87% determined by chiral HPLC) as a colorless oil (183 mg, 76% over 2 steps) following a Feiser work-up and purification.
Using general procedure G, the above alcohol (172 mg, 0.422 mmol) gave the chloride, which was subsequently dissolved in DMSO (2 mL) followed by the addition of NaCN (41 mg, 0.84 mmol). The reaction was heated at 140° C. for 1 hour to give the nitrile (128 mg, 0.307 mmol), which was subsequently reduced with BH3-THF (1.0M in THF, 0.92 mL, 0.92 mmol) in THF (1.8 mL) at reflux and treated with MeOH then ethylenediamine (1 mL) to give 3(S)-{4(R)-[(6-methylpyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colorless oil (109 mg, 61% over 2 steps) following work-up and purification.
Using general procedure E, the above amine (65 mg, 0.14 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (42 mg, 0.19 mmol) gave COMPOUND 52 as a white foam (95 mg, 98%). 1H NMR (CDCl3) δ 0.72-1.09 (m, 3H), 0.95 (d, 3H, J=6.3 Hz), 1.48-1.85 (m, 3H), 1.93-2.04 (m, 2H), 2.21 (s, 3H), 2.30 (t, 1H, J=10.6 Hz), 2.40 (s, 6H), 2.59 (d, 1H, J=10.8 Hz), 2.76-2.86 (m, 2H), 3.31-3.40 (m, 1H), 3.75-3.83 (m, 1H), 5.24 (d, 1H, J=8.1 Hz), 6.29 (d, 1H, J=8.1 Hz), 6.56 (d, 1H, J=7.2 Hz), 7.18-7.29 (m, 3H), 7.34-7.39 (m, 4H), 7.48 (d, 2H, J=6.0 Hz), 8.47 (br s, 1H), 8.60 (d, 2H, J=5.7 Hz). 13C NMR (CDCl3) δ 13.8, 19.8, 24.4, 29.3, 29.4, 31.2, 40.0, 42.7, 44.6, 52.3, 60.4, 80.0, 107.4, 116.4, 121.9, 125.3, 126.3, 127.7, 129.8 (q, J=32 Hz), 135.6, 138.3, 139.2, 139.8, 145.1, 148.1, 150.7, 156.6, 162.6, 170.0. ES-MS m/z 653 (M+Na). Anal. Calcd. for C37H41F3N4O2.0.4CH2Cl2: C, 67.58; H, 6.34; N, 8.43; F, 8.57. Found. C, 67.74; H, 6.38; N, 8.25; F, 8.34.
EXAMPLE 53




COMPOUND 53: 3,5-Dichloro-N-(3-{4-methyl-4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-1)-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To 4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 1.82 mmol) in DMF (14 mL) was added to NaH (60% in mineral oil, 153 mg, 6.37 mmol) and the mixture was heated at 50° C. for 30 minutes. MeI (0.47 mL, 7.64 mmol) was added and the mixture was heated at 50° C. for an additional 3 hours to afford 4-methyl-4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (390 mg, 58%) following work-up and purification.
The ketone from above (390 mg, 1.05 mmol) in MeOH (5 mL) was reduced with NaBH4 (79 mg, 2.1 mmol) to afford a white solid (348 mg) after work-up.
To the alcohol from above (310 mg, 0.83 mmol) in DMF (4.0 mL) was added NaH (60% in mineral oil, 83 mg, 2.08 mmol) and the mixture was stirred at room temperature for 10 minutes. 6-Chloro-2-picoline (0.27 mL, 2.50 mmol) was added and the mixture heated at 70° C. for 3.5 hours. Standard work-up and purification afforded 4-methyl-4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (263 mg, 54% over 2 steps).
Using general procedure C with the above substrate (260 mg, 0.56 mmol), then general procedure I with the resulting amine and then using general procedure J afforded 3-{4-methyl-4-[(6-methyl-pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a colourless syrup (124 mg, 51% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (62 mg, 0.32 mmol) and the amine from above (70 mg, 0.16 mmol) afforded COMPOUND 53 (53 mg, 54%). 1H NMR (CDCl3) δ 0.82, 0.83 (s, 3H), 0.84-1.00 (m, 1H), 1.03 (d, 3H, J=5.7 Hz), 1.04-1.29 (m, 2H), 1.34-1.59 (m, 2H), 1.72-1.89 (m, 1H), 2.20-2.34 (m, 1H), 2.35 (s, 3H), 2.46-2.63 (m, 2H), 2.66-2.87 (m, 1H), 2.80-2.90 (m, 1H), 3.29-3.40 (m, 1H), 3.85-3.96 (m, 1H), 5.30-5.45 (m, 1H), 6.45 (d, 1H, J=8.1 Hz), 6.64 (d, 1H, J=7.2 Hz), 7.24-7.28 (m, 2H), 7.38-7.44 (m, 1H), 7.50 (d, 2H, J=8.1 Hz), 8.55, 8.56 (s, 2H), 9.38, 9.46 (br s, 1H). 13C NMR (CDCl3) δ 13.33, 13.39, 17.73, 24.08, 29.74, 29.99, 34.82, 35.11, 35.21, 36.21, 40.28, 40.34, 41.45, 45.70, 60.50, 60.56, 81.87, 107.26, 116.07, 124.16 (q, J=272 Hz), 124.41, 124.46, 128.34, 129.08, 129.47, 138.83, 142.86, 143.36, 147.63, 156.33, 161.51, 161.58, 162.15. ES-MS m/z 609 (M+H). Anal. Calcd. for C30H33N4Cl2F3O2: C, 59.12; H, 5.46; N, 9.19; Cl, 11.63; F, 9.35. Found. C, 58.92; H, 5.44; N, 9.08; Cl, 11.89; F, 9.23.
Scheme 4 describes the preparation of Examples 54-59, using various general procedures previously described, and reagents listed below.
















Example
R3
R2—Hal







54




2,6-difluoropyridine


 


55




2,6-dichloropyridine


 


56




2,6-dichloropyridine


 


57




2,6-difluoropyridine


 


58




2-chloro-6-methylpyridine


 


59




2-chloro-6-methylpyridine









EXAMPLE 54




COMPOUND 54: 3,5-Dichloro-N-(3-{4-[(6-fluoro-pyridin-2-yloxy)-thiazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
2-(Trimethylsilyl)thiazole (1.0 g, 6.36 mmol) and 4-formyl-cyclohexanecarboxylic acid tert-butyl ester (1.63 g, 7.63 mmol) were stirred at room temperature for 4 hours. THF (50 mL) and TBAF (1M in THF, 7.6 mL, 7.6 mmol) were added and the mixture stirred for an additional hour. Standard work-up and purification afforded 4-(hydroxy-thiazol-2-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a beige syrup (940 mg, 50%).
COMPOUND 54 was isolated as a white foam. 1H NMR (CDCl3) δ 0.62-0.86 (m, 1H), 0.96 (d, 3H, J=6.6 Hz), 0.99-1.17 (m, 1H), 1.46-1.65 (m, 2H), 1.68-2.14 (m, 4H), 2.34-2.52 (m, 1H), 2.64-2.91 (m, 3H), 3.23-3.41 (m, 1H), 3.78-3.94 (m, 1H), 5.86 (dd, 1H, J=6.7, 3.1 Hz), 6.50 (dd, 1H, J=7.9, 5.4 Hz), 6.63 (d, 1H, J=7.9 Hz), 7.25 (d, 1H, J=3.0 Hz), 7.63-7.75 (m, 2H), 8.53 (s, 2H), 8.98 (br s, 1H). 13C NMR (CDCl3) δ 13.61, 14.59, 28.05, 28.75, 28.83, 29.46, 30.67, 40.56, 41.66, 44.26, 52.21, 60.89, 101.53, 102.00, 107.71, 119.41, 129.29, 143.15, 143.49, 143.59, 148.09, 160.60, 161.88, 162.03, 163.81, 169.51, 169.67. ES-MS m/z 539 (M+H). Anal. Calcd. for C24H26Cl2FN5O2S.0.4H2O: C, 52.83; H, 4.95; N, 12.83; Cl, 12.99; S, 5.88. Found. C, 52.91; H, 4.99; N, 12.54; Cl, 13.28; S, 5.49.
EXAMPLE 55




COMPOUND 55: 3,5-Dichloro-N-(3-{4-[(6-chloro-pyridin-2-yloxy)-thiazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.62-1.13 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.44-1.62 (m, 2H), 1.66-1.87 (m, 2H), 1.96-2.20 (m, 2H), 2.34-2.49 (m, 1H), 2.62-2.90 (m, 3H), 3.21-3.39 (m, 1H), 3.76-3.94 (m, 1H), 5.91 (dd, 1H, J=6.4, 3.0 Hz), 6.67 (d, 1H, J=8.5 Hz), 6.92 (d, 1H, J=7.5 Hz), 7.25 (d, 1H, J=2.9 Hz), 7.51-7.58 (m, 1H), 7.73 (d, 1H, J=3.2 Hz), 8.53, 8.54 (s, 2H), 8.94 (br s, 1H). 13C NMR (CDCl3) δ 13.63, 14.59, 28.08, 28.76, 28.86, 29.46, 30.73, 40.49, 41.50, 44.33, 52.17, 60.80, 109.59, 109.64, 117.84, 119.47, 129.27, 141.51, 143.09, 143.50, 148.06, 148.63, 162.00, 162.49, 169.42, 169.56. ES-MS m/z 556 (M+H). Anal. Calcd. for C24H26Cl3N5O2S.0.2CH2Cl2.0.3H2O: C, 50.53; H, 4.71; N, 12.13; Cl, 20.88; S, 5.55. Found. C, 50.35; H, 4.81; N, 11.76; Cl, 20.76; S, 5.37.
EXAMPLE 56




COMPOUND 56: 3,5-Dichloro-N-(3-{4-[(6-chloropyridin-2-yloxy)-oxazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of oxazole (420 mg, 6.08 mmol) in THF (15 mL) was added BH3-THF (1.0M in THF, 6.69 mL, 6.69 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to −78° C., t-BuLi (1.7M, 4.29 mL, 7.30 mmol) was introduced to the mixture and stirred at this temperature for 30 min. 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 6.08 mmol) was added dropwise and the mixture was stirred at −78° C. for 3 hours. Work-up and purification gave 4-(hydroxy-oxazol-2-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (1.227 g, 71%).
COMPOUND 56 was isolated as a white foam. 1H NMR (CDCl3) δ 0.55-1.04 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.42-1.63 (m, 3H), 1.72-1.82 (m, 2H), 2.01-2.09 (m, 1H), 2.43 (td, 1H, J=11.4, 2.1 Hz), 2.70-2.88 (m, 3H), 3.39 (m, 1H), 3.84 (m, 1H), 5.67 (d, 1H, J=6.3 Hz), 6.69 (d, 1H, J=8.1 Hz), 6.92 (d, 1H, J=7.5 Hz), 7.04 (s, 1H), 7.55 (t, 1H, J=7.8 Hz), 7.57 (s, 1H), 8.55 and 8.56 (s, 2H), 8.79 (br s, 1H). 13C NMR (CDCl3) δ 13.66, 13.70, 28.3, 28.5, 28.9, 29.1, 40.3, 44.4, 44.5, 51.8, 51.9, 60.4, 60.5, 73.6, 73.7, 109.5, 109.6, 117.7, 127.6, 129.2, 139.1, 141.5, 143.4, 148.0, 148.1, 148.5, 162.0, 162.1, 162.2, 162.9. ES-MS m/z 540 (M+H). Anal. Calcd. for C24H26Cl3N5O3.0.5H2O.0.1C6H14: C, 53.26; H, 5.14; N, 12.58; Cl, 19.11. Found. C, 53.10; H, 5.05; N, 12.45; Cl, 18.83.
EXAMPLE 57




COMPOUND 57: 3,5-Dichloro-N-(3-{4-[(6-fluoropyridin-2-yloxy)-oxazol-2-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.55-1.04 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.41-1.63 (m, 3H), 1.80 (m, 2H), 2.01-2.09 (m, 1H), 2.44 (t, 1H, J=11.4 Hz), 2.70-2.89 (m, 3H), 3.35 (m, 1H), 3.84 (m, 1H), 5.60 (d, 1H, J=7.5 Hz), 6.50 (d, 1H, J=7.2 Hz), 6.64 (d, 1H, J=8.4 Hz), 7.05 (s, 1H), 7.57 (s, 1H), 7.68 (q, 1H, J=8.1 Hz), 8.55 and 8.56 (s, 2H), 8.85 (br s, 1H). 13C NMR (CDCl3) δ 13.7, 28.3, 28.4, 28.9, 29.0, 30.7, 30.8, 40.2, 44.4, 51.8, 51.9, 60.4, 60.5, 73.61, 73.65, 101.4, 101.8, 107.6, 127.6, 129.2, 139.1, 143.4, 143.5, 148.03, 148.07, 161.8, 162.05, 162.09 (d, J=241 Hz), 163.7. ES-MS m/z 523 (M+H). Anal. Calcd. for C24H26Cl2FN5O3.0.3H2O: C, 54.62; H, 5.08; N, 13.27; Cl, 13.43; F, 3.60. Found. C, 54.82; H, 5.06; N, 13.09; Cl, 13.14; F, 3.44.
EXAMPLE 58




COMPOUND 58: 3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-pyridin-3-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a cold (−78° C.) solution of 2-bromo pyridine (800 mg, 5.06 mmol) in freshly distilled THF (15 mL) was added LDA (2.0 M, 2.8 mL, 6.5 mmol). The mixture was stirred under N2 for 30 min. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was added slowly to maintain the bath temperature below −70° C. The reaction was stirred at below −70° C. for 30 min, warmed to −20° C. within 60 min, and quenched with saturated aqueous NH4Cl (10 mL). Work-up and purification gave 4-[(2-bromo-pyridin-3-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 50%) as a colourless oil.
To a solution of the above alcohol (470 mg, 1.27 mmol) in MeOH (4 ml) in a Parr flask was added 10% Pd/C (80 mg) under N2. The mixture was hydrogenated at room temperature under 1.5 atm H2 for 1 h. 3N NaOH (5 mL) was added and the mixture was extracted with CHCl3 (20 mL×2). The combined organic solution was filtered through a short pad of Celite® to give 4-(hydroxy-pyridin-3-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester (270 mg, 72%) as a colourless oil.
COMPOUND 58 was isolated as a white foam. 1H NMR (CDCl3) δ 0.48-0.80 (m, 2H), 0.96 (d, 3H, J=6.0 Hz), 1.15-1.25 (m, 1H), 1.30-2.05 (m, 5H), 2.25-2.50 (m, 4H), 2.80-2.98 (m, 3H), 3.25-3.54 (m, 1H), 3.75-3.98 (m, 1H), 5.25-5.28 (m, 1H), 6.43 (d, 1H, J=9.0 Hz), 6.65 (d, 1H, J=6.0 Hz), 7.20-7.25 (m, 1H), 7.30-7.48 (m, 1H), 7.59 (d, 1H, J=6.0 Hz), 8.45 (d, 1H, J=6.0 Hz), 8.50 (d, 1H, J=3.0 Hz), 8.55 (s, 1H), 8.58 (s, 1H), 9.25 (s, 0.5H), 9.48 (s, 0.5H). 13C NMR (CDCl3) δ 13.62, 13.71, 24.42, 28.82, 29.35, 29.58, 30.20, 30.60, 40.53, 40.61, 41.78, 42.69, 44.17, 52.17, 52.32, 60.80, 60.97, 78.19, 78.24, 107.72, 116.45, 123.65, 129.47, 135.27, 136.35, 139.28, 143.69, 148.03, 149.17, 149.67, 156.65, 161.90, 162.04, 162.45. ES-MS m/z 550 (M+Na). Anal. Calcd. for C27H31Cl2N5O2.0.5CH2Cl2.0.3C4H8O2: C, 57.70; H, 5.80; N, 11.72; Cl, 17.80. Found. C, 57.61; H, 5.70; N, 11.97; Cl, 17.63.
EXAMPLE 59




COMPOUND 59: 3,5-Dichloro-N-(3-{4-[(6-methyl-pyridin-2-yloxy)-pyridin-4-yl-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
To a cold (−90° C.) solution of 3-bromo pyridine (741 mg, 4.7 mmol) in freshly distilled THF (18 ml) was added LDA (2.0M, 2.6 mL, 5.2 mmol). The mixture was stirred under N2 for 20 min. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was added slowly to maintain the bath temperature below −80° C. The reaction was continued at below −80° C. for 30 min, warmed to −20° C. within 30 min and quenched with saturated aqueous NH4Cl (10 mL). Work-up and purification gave 4-[(3-bromo-pyridin-4-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 70%) as colourless oil.
To a solution of the above alcohol (610 mg, 1.6 mmol) in MeOH (5 mL) in a Parr flask was added 10% Pd/C (100 mg) under N2. The mixture was hydrogenated at room temperature under 1.5 atm H2 for 1 h. 3N NaOH (5 mL) was added and the mixture was extracted with CHCl3 (20 mL×2). The solution was filtered through a short pad of Celite® to give the 4-(hydroxy-pyridin-4-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester (380 mg, 81%) as a colourless oil.
COMPOUND 59 was isolated as a white foam. 1H NMR (CDCl3) δ 0.80-1.05 (m, 2H), 0.97 (d, 3H, J=12.0 Hz), 1.20-1.25 (m, 1H), 1.50-1.60 (m, 1H), 1.59 (s, 3H), 1.80-2.10 (m, 4H), 2.27-2.50 (m, 2H), 2.36 (s, 3H), 2.80-2.99 (m, 3H), 3.25-3.48 (m, 1H), 3.74-3.96 (m, 1H), 5.31 (d, 1H, J=9.0 Hz)), 6.44 (d, 1H, J=9.0 Hz), 6.63 (d, 1H, J=6.0 Hz), 7.11 (d, 1H, J=6.0 Hz), 7.36-7.42 (m, 1H), 8.46 (d, 2H, J=6.0 Hz), 8.50 (s, 1H), 8.53 (s, 1H), 9.15 (s, 0.5H), 9.25 (s, 0.5H). 13C NMR (CDCl3) δ 13.60, 13.66, 24.40, 28.88, 29.66, 30.31, 30.68, 40.57, 41.79, 44.18, 52.32, 52.46, 60.86, 61.01, 78.92, 107.67, 116.61, 122.58, 122.64, 129.50, 139.35, 143.70, 148.03, 150.03, 156.64, 161.30, 162.36. ES-MS m/z 550 (M+Na). Anal. Calcd. for C27H31Cl2N5O2.0.05CH2Cl2-0.4C4H8O2: C, 60.59; H, 6.09; N, 12.33; Cl, 13.11. Found. C, 60.60; H, 6.06; N, 12.40; Cl, 13.21.
EXAMPLE 60




COMPOUND 60: N-(3-{4-[(4-Bromo-phenyl)-(thiazol-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure 1,4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-piperidine (Palani A., et al. J. Med. Chem., 2002, 45, 3143-3160) (3.26 g, 10.4 mmol) gave the nitrile (1.37 g, 3.62 mmol), which was subsequently reduced with BH3-Me2S (2.0M in THF, 8.0 mL, 16 mmol) in THF (30 mL) at reflux and treated with MeOH then 6M HCl (16 mL) to give the crude amine following standard work-up.
The resulting colourless oil was dissolved into EtOAc (6 mL) and 6M HCl (18 mL) and the solution was stirred at room temperature for a further 21 hours. The reaction was made basic by the addition of 20% NaOH and was extracted with CH2Cl2 (25 mL×5). The organic solution was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification gave the ketone-amine (628 mg, 1.85 mmol), which was subsequently reduced with NaBH4 (215 mg, 5.68 mmol) in MeOH (10 mL) to give the crude amino-alcohol as a white foam (552 mg, 44% over 2 steps) following work-up.
To a 0° C. solution of this material and NEt3 (0.34 mL, 2.4 mmol) in CH2Cl2 (11 mL) under nitrogen was added TFAA (0.30 mL, 2.1 mmol) and the reaction was stirred at 0° C. for 30 minutes. Standard work-up and purification gave N-(3-{4-[(4-bromo-phenyl)-hydroxy-methyl]-piperidin-1-yl}-butyl)-2,2,2-trifluoro-acetamide as a white foam (455 mg, 64%).
To a mixture of the above TFA-alcohol (206 mg, 0.47 mmol) and NaH (60% in mineral oil, 45 mg, 1.1 mmol) in DMF (1.8 mL) under nitrogen was added 2-bromothiazole (0.06 mL, 0.7 mmol) and the reaction was stirred at 60° C. for 2 hours to give N-(3-{4-[(4-bromo-phenyl)-(thiazol-2-yloxy)-methyl]-piperidin-1-yl}-butyl)-2,2,2-trifluoro-acetamide as a brown oil (81.2 mg, 33%) following work-up and purification.
A solution of the above acetamide (81.2 mg, 0.16 mmol) and K2CO3 (114 mg, 0.82 mmol) in MeOH (2 mL) and H2O (0.5 mL) was stirred at room temperature for 6 hours to give 3-{4-[(4-bromo-phenyl)-(thiazol-2-yloxy)-methyl]-piperidin-1-yl}-butylamine as a colourless oil (40.3 mg, 60%) following standard work-up and purification.
Using general procedure F, 3,5-dichloroisonicotinic acid (28 mg, 0.14 mmol) and the above primary amine (40.3 mg, 0.095 mmol) gave a diastereomeric mixture of COMPOUND 60 as a white foam (25.8 mg, 45%). 1H NMR (CDCl3) δ 0.42-1.03 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.16-1.25 (m, 1H), 1.46-1.56 (m, 1H), 1.64-2.04 (m, 4H), 2.30-2.44 (m, 1H), 2.60-2.91 (m, 3H), 3.26-3.38 (m, 1H), 3.81-3.92 (m, 1H), 5.09 and 5.10 (d, 1H, J=7.8 Hz), 6.62 and 6.63 (d, 1H, J=2.9 Hz), 7.05-7.10 (m, 3H), 7.45 (d, 2H, J=8.4 Hz), 8.59 (s, 2H), 8.99 and 9.13 (br s, 1H). 13C NMR (CDCl3) δ 13.23, 28.36 and 28.53, 29.12 and 29.42, 30.06 and 30.34, 40.14 and 40.24, 41.81, 43.66 and 43.77, 51.77 and 51.85, 60.48 and 60.52, 86.40 and 86.46, 111.23, 122.13 and 122.16, 128.70 and 128.75, 129.03 and 129.05, 131.60, 137.01, 137.45, 143.26 and 143.28, 147.72, 161.47 and 161.54, 173.96 and 173.98. ESI-MS m/z 597 (MH)+, 599 (MH+2)+, 601 (MH+4)+. Anal. Calcd. for C25H27BrCl2N4O2S.0.6CH2Cl2: C, 47.35; H, 4.38; N, 8.63; Br, 12.31. Found. C, 47.36; H, 4.56; N, 8.67; Br, 12.15.
EXAMPLE 61




COMPOUND 61: 3,5-Dichloro-N-(3-{4-[(thiazol-2-yloxy)-(4-trifluoro-methyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure C, 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (907 mg, 2.54 mmol) gave piperidin-4-yl-(4-trifluoromethyl-phenyl)-methanone as a white solid (635 mg, 97%).
Using general procedure I, the crude secondary amine (631 mg, 2.45 mmol) gave the nitrile (338 mg, 1.04 mmol), which was subsequently reduced with BH3-Me2S (2.0M in THF, 3.0 mL, 6.0 mmol) in THF (10 mL) at reflux and treated with MeOH then 6M HCl (6 mL) to give [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethyl-phenyl)-methanol as a white foam (269 mg, 70% over 2 steps) following work-up and purification.
A solution of the amino alcohol (269 mg, 0.81 mmol) and NEt3 (0.17 mL, 1.2 mmol) in CH2Cl2 (5.5 mL) was cooled to 0° C. under nitrogen and TFAA (0.17 mL, 1.2 mmol) was added. The reaction was stirred at 0° C. for 1 hour to give 2,2,2-trifluoro-N-(3-{4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-acetamide as a pale yellow foam (302 mg, 87%) following standard work-up and purification.
To a solution of the above alcohol (302 mg, 0.71 mmol) and 2-bromothiazole (0.10 mL, 1.1 mmol) in DMF (2.5 mL) under nitrogen was added NaH (60% in mineral oil, 86 mg, 2.2 mmol). The mixture was warmed to 60° C. and stirred for 2 hours to give 2,2,2-trifluoro-N-(3-{4-[(thiazol-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butyl)-acetamide as a light brown oil (98.4 mg, 27%) following work-up and purification.
A mixture of the trifluoroacetamide (98.4 mg, 0.19 mmol) and K2CO3 (130 mg, 0.94 mmol) in MeOH (2.5 mL) and H2O (0.5 mL) was stirred at room temperature for 4 hours. Standard work-up and purification gave 3-{4-[(thiazol-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine as a yellow oil (63.7 mg, 81%).
Using general procedure F, 3,5-dichloroisonicotinic acid (37 mg, 0.19 mmol) and the primary amine (63.7 mg, 0.15 mmol) gave a diastereomeric mixture of COMPOUND 61 as a white powder (49.0 mg, 54%). 1H NMR (CDCl3) δ 0.51-1.07 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.17-1.27 (m, 1H), 1.47-1.60 (m, 1H), 1.68-2.05 (m, 4H), 2.31-2.45 (m, 1H), 2.62-2.92 (m, 3H), 3.28-3.40 (m, 1H), 3.81-3.93 (m, 1H), 5.25 (d, 1H, J=8.1 Hz), 6.63 and 6.64 (d, 1H, J=3.6 Hz), 7.05 and 7.06 (d, 1H, J=3.6 Hz), 7.33 (d, 2H, J=7.8 Hz), 7.59 (d, 2H, J=7.8 Hz), 8.60 (s, 2H), 8.89 and 9.02 (br s, 1H). 13C NMR (CDCl3) δ 13.19 and 13.21, 28.28 and 28.40, 29.13, 30.13 and 30.34, 40.03 and 40.12, 41.88 and 41.90, 43.64 and 43.79, 51.68 and 51.74, 60.33, 86.09 and 86.12, 111.33, 123.90 (q, J=272 Hz), 125.37 (q, J=3.9 Hz), 127.20 and 127.25, 128.99 and 129.02, 130.20 and 130.23 (q, J=32.4 Hz), 136.93, 142.52 (q, J=1.3 Hz), 143.21 and 143.24, 147.69, 161.44 and 161.48, 173.82 and 173.84. ESI-MS m/z 587 (MH)+, 589 (MH+2)+. Anal. Calcd. for C26H27Cl2F3N4O2S: C, 53.16; H, 4.63; N, 9.54; Cl, 12.07. Found. C, 52.83; H, 4.71; N, 9.40; Cl, 12.07.
Scheme 5 describes the preparation of Examples 62-79, using various general procedures previously described, and reagents listed below.
















Example
R3*
R2—CH2Br







62
Br
3-chlorobenzyl bromide


63
CN
benzyl bromide


64
CN
3-fluorobenzyl bromide


65
CN
3-chlorobenzyl bromide


66
CN
3-methylbenzyl bromide


67
CF3
benzyl bromide


68
CF3
3-fluorobenzyl bromide


69
CF3
3-chlorobenzyl bromide


70
OCF3
benzyl bromide


71
OCF3
3-methylbenzyl bromide


72
SMe
3-fluorobenzyl bromide


73
SMe
3-chlorobenzyl bromide


74
SMe
3-methylbenzyl bromide


75
SO2Me
3-chlorobenzyl bromide


76
SO2Me
3-methylbenzyl bromide


77
OMe
3-fluorobenzyl bromide


78
OMe
3-chlorobenzyl bromide


79
SO2NHMe
benzyl bromide









EXAMPLE 62




COMPOUND 62: N-(3-{4-[(4-Bromo-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, 4-bromoaniline (1.23 g, 7.13 mmol) and 1-Boc-4-piperidone (1.42 g, 7.13 mmol) afforded 4-(4-bromo-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.5 g, 53%).
COMPOUND 62 was isolated as a white solid. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.2 Hz), 1.07-1.30 (m, 1H), 1.46-1.61 (m, 1H), 1.66-1.91 (m, 4H), 2.18 (t, 1H, J=11.4 Hz), 2.57 (t, 1H, J=11.4 Hz), 2.73-2.99 (m, 3H), 3.34 (t, 1H, J=10.1 Hz), 3.60 (t, 1H, J=11.4 Hz), 3.79 (s, 2H), 3.79-3.93 (m, 1H), 6.43 (d, 2H, J=8.7 Hz), 7.00-7.31 (m, 6H), 8.48 (s, 2H), 8.91 (s, 1H). 13C NMR (CDCl3) δ 13.8, 29.6, 30.1, 30.7, 40.6, 42.9, 43.9, 48.7, 49.4, 52.4, 56.3, 60.7, 109.6, 115.3, 124.7, 126.5, 127.5, 129.5, 130.3, 132.3, 135.0, 142.0, 143.6, 147.7, 148.0, 161.8. ES-MS m/z 625 (M+2)+. Anal. Calcd. for C28H30N4Cl3OBr.0.4CH2Cl2: C, 51.78; H, 4.71; N, 8.50; Cl, 20.45. Found. C, 51.85; H, 4.69; N, 8.40; Cl, 20.37.
EXAMPLE 63




COMPOUND 63: N-(3-{4-[Benzyl-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Willoughby, Christopher A.; Bioorg. Med. Chem. Lett., 13, 3, 2003, 427-432) (311 mg, 1.55 mmol), 4-bromobenzonitrile (237 mg, 1.30 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), (±)-BINAP (48 mg, 0.077 mmol) and t-BuONa (136 mg, 1.42 mmol) in freshly degassed toluene (4.5 mL) was stirred at 85° C. under argon for 2 hours. Work-up and purification gave 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as an orange solid (324 mg, 83%).
COMPOUND 63 was isolated as a white powder. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.03-1.17 (m, 1H), 1.19-1.33 (m, 1H), 1.52-1.62 (m, 1H), 1.73-1.87 (m, 3H), 2.16-2.25 (m, 1H), 2.55-2.63 (m, 1H), 2.78-2.98 (m, 3H), 3.30-3.42 (m, 1H), 3.67-3.78 (m, 1H), 3.81-3.91 (m, 1H), 3.98 (s, 2H), 6.56 (d, 2H, J=8.7 Hz), 7.12 (d, 2H, J=6.9 Hz), 7.23-7.39 (m, 5H), 8.47 (s, 2H), 8.66 (br s, 1H). 13C NMR (CDCl3) δ 13.34, 29.30, 30.07, 30.41, 39.85, 43.43, 48.23, 51.69, 55.53, 59.88, 98.15, 112.33, 120.25, 125.68, 127.02, 128.66, 128.94, 133.41, 137.82, 143.05, 147.55, 151.23, 161.40. ESI-MS m/z 536 (MH)+, 538 (MH+2)+. Anal. Calcd. for C29H31Cl2N5O.0.1CH2Cl2: C, 64.13; H, 5.77; N, 12.85; Cl, 14.31. Found. C, 64.08; H, 5.72; N, 12.52; Cl, 14.36.
EXAMPLE 64




COMPOUND 64: 3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.02-1.15 (m, 1H), 1.32-1.18 (m, 1H), 1.51-1.62 (m, 1H), 1.73-1.87 (m, 3H), 2.17-2.26 (m, 1H), 2.55-2.64 (m, 1H), 2.79-2.99 (m, 3H), 3.32-3.42 (m, 1H), 3.68-3.78 (m, 1H), 3.80-3.90 (m, 1H), 3.96 (s, 2H), 6.55 (d, 2H, J=8.9 Hz), 6.79-6.85 (m, 1H), 6.92-6.99 (m, 2H), 7.27-7.35 (m, 1H), 7.39 (d, 2H, J=8.9 Hz), 8.48 (s, 2H), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 29.34, 30.26, 30.53, 39.84, 43.48, 47.95, 51.68, 55.59, 59.84, 98.69, 112.44, 112.76 (d, J=21.9 Hz), 114.05 (d, J=21.1 Hz), 120.10, 121.36 (d, J=2.8 Hz), 129.00, 130.34 (d, J=8.5 Hz), 133.51, 140.92 (d, J=6.3 Hz), 143.08, 147.57, 151.05, 161.41, 163.15 (d, J=246 Hz). ESI-MS m/z 554 (MH)+, 556 (MH+2)+. Anal. Calcd. for C29H30Cl2FN5O.0.3H2O: C, 62.21; H, 5.51; N, 12.51; Cl, 12.66. Found. C, 62.26; H, 5.48; N, 12.26; Cl, 12.85.
EXAMPLE 65




COMPOUND 65: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR(CDCl3) δ 1.01-1.15 (m, 1H), 1.03 (d, 3H, J=6.6 Hz), 1.17-1.31 (m, 1H), 1.52-1.67 (m, 1H), 1.73-1.86 (m, 3H), 2.17-2.25 (m, 1H), 2.55-2.64 (m, 1H), 2.81-2.97 (m, 3H), 3.32-3.42 (m, 1H), 3.67-3.90 (m, 2H), 3.95 (s, 2H), 6.56 (d, 2H, J=9.0 Hz), 7.01-7.06 (m, 1H), 7.11 (s, 1H), 7.21-7.31 (m, 2H), 7.39 (d, 2H, J=9.0 Hz), 8.49 (s, 2H), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.39, 29.36, 30.34, 30.49, 40.02, 43.45, 47.99, 51.79, 55.60, 60.05, 98.92, 112.47, 120.11, 123.99, 125.88, 127.43, 129.08, 130.09, 133.61, 134.80, 140.32, 143.14, 147.64, 151.08, 161.41. ESI-MS m/z 570 (MH)+, 572 (MH+2)+, 574 (MH+4)+. Anal. Calcd. for C29H30Cl3N5O.0.4H2O.0.2C4H10O: C, 60.36; H, 5.58; N, 11.81. Found. C, 60.36; H, 5.27; N, 11.56.
EXAMPLE 66




COMPOUND 66: 3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.02-1.16 (m, 1H), 1.18-1.32 (m, 1H), 1.51-1.65 (m, 1H), 1.72-1.86 (m, 3H), 2.16-2.24 (m, 1H), 2.35 (s, 3H), 2.55-2.63 (m, 1H), 2.78-2.97 (m, 3H), 3.31-3.41 (m, 1H), 3.67-3.77 (m, 1H), 3.80-3.90 (m, 1H), 3.94 (s, 2H), 6.56 (d, 2H, J=8.9 Hz), 6.88-6.94 (m, 2H), 7.07 (d, 1H, J=7.5 Hz), 7.21 (dd, 1H, J=7.5, 7.5 Hz), 7.37 (d, 2H, J=8.9 Hz), 8.48 (s, 2H), 8.68 (br s, 1H). 13C NMR (CDCl3) δ 13.31, 21.43, 29.25, 30.18, 30.47, 39.77, 43.47, 48.29, 51.64, 55.49, 59.74, 98.01, 112.29, 120.26, 122.71, 126.26, 127.73, 128.50, 128.91, 133.38, 137.86, 138.33, 143.03, 147.52, 151.33, 161.41. ESI-MS m/z 550 (MH)+, 552 (MH+2)+. Anal. Calcd. for C30H33Cl2N5O.0.1CH2Cl2: C, 64.67; H, 5.99; N, 12.53; Cl, 13.95. Found. C, 64.56; H, 5.92; N, 12.49; Cl, 13.56.
EXAMPLE 67




COMPOUND 67: N-(3-{4-[Benzyl-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, 4-trifluoromethylaniline (2.02 g, 12.5 mmol) and 1-Boc-4-piperidone (2.5 g, 12.5 mmol) afforded 4-(4-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.71 g, 40%).
COMPOUND 67 was isolated as a white solid. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.5 Hz), 1.00-1.33 (m, 2H), 1.48-1.67 (m, 1H), 1.71-1.95 (m, 3H), 2.21 (t, 1H, J=11.3 Hz), 2.60 (t, 1H, J=11.9 Hz), 2.77-3.01 (m, 3H), 3.29-2.43 (m, 1H), 3.66-3.80 (m, 1H), 3.82-3.93 (m, 1H), 3.94 (s, 2H), 6.60 (d, 2H, J=8.8 Hz), 7.11-7.39 (m, 7H), 8.48 (s, 2H), 8.82 (s, 1H). 13C NMR (CDCl3) δ 13.8, 29.7, 30.7, 40.6, 43.9, 48.9, 52.4, 56.0, 60.7, 112.4, 126.3, 126.8, 127.3, 129.1, 129.4, 139.1, 148.1, 151.1, 161.9. ES-MS t/z 580 (M+2)+. Anal. Calcd. for C29H31N4Cl2OF3.0.2CH2Cl2: C, 58.80; H, 5.31; N, 9.39. Found. C, 58.95; H, 5.32; N, 9.27.
EXAMPLE 68




COMPOUND 68: 3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.97-1.12 (m, 1H), 1.03 (d, 3H, J=6.6 Hz), 1.15-1.29 (m, 1H), 1.51-1.61 (m, 1H), 1.73-1.88 (m, 3H), 2.17-2.27 (m, 1H), 2.56-2.65 (m, 1H), 2.79-2.99 (m, 3H), 3.31-3.41 (m, 1H), 3.68-3.78 (m, 1H), 3.82-3.91 (m, 1H), 3.91 (s, 2H), 6.58 (d, 2H, J=8.7 Hz), 6.84-6.99 (m, 3H), 7.24-7.38 (m, 1H), 7.36 (d, 2H, J=8.7 Hz), 8.48 (s, 2H), 8.79 (br d, 1H). 13C NMR (CDCl3) δ 13.34, 29.27, 30.29, 30.39, 39.96, 43.46, 48.08 (d, J=1.7 Hz), 51.80, 55.53, 60.03, 112.02, 112.82 (d, J=21.7 Hz), 113.84 (d, J=21.2 Hz), 118.46 (q, J=32.8 Hz), 121.45 (d, J=2.9 Hz), 124.71 (q, J=270 Hz), 126.43 (q, J=3.8 Hz), 128.99, 130.19 (d, J=8.7 Hz), 141.70 (d, J=6.7 Hz), 143.12, 147.55, 150.50 (q, J=1.1 Hz), 161.38, 163.14 (d, J=247 Hz). ESI-MS m/z 597 (MH)+, 599 (MH+2)+. Anal. Calcd. for C29H30Cl2F4N4O.0.3H2O: C, 57.78; H, 5.12; N, 9.29; Cl, 11.76; F, 12.60. Found. C, 57.91; H, 5.06; N, 9.22; Cl, 11.84; F, 12.25.
EXAMPLE 69




COMPOUND 69: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ0.96-1.29 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.46-1.51 (m, 1H), 1.72-1.88 (m, 3H), 2.16-2.26 (m, 1H), 2.56-2.66 (m, 1H), 2.78-2.99 (m, 3H), 3.30-3.42 (m, 1H), 3.66-3.78 (m, 1H), 3.82-3.93 (m, 3H), 6.58 (d, 2H, J=8.7 Hz), 7.06 (d, 1H, J=6.6 Hz), 7.15 (s, 1H), 7.21-7.30 (m, 2H), 7.36 (d, 2H, J=8.7 Hz), 8.49 (s, 2H), 8.80 (br s, 1H). 13C NMR (CDCl3) δ 13.41, 29.31, 31.40, 40.09, 43.50, 48.18, 51.90, 55.57, 60.17, 122.09, 118.62 (q, J=32 Hz), 124.13, 124.43, 124.84 (q, J=270 Hz), 126.00, 126.55 (q, J=3 Hz), 127.24, 129.08, 130.01, 134.70, 141.13, 143.18, 147.64, 150.57, 161.45. ES-MS m/z 613 (M+H). Anal. Calcd. for C29H30N4Cl3OF3.0.1CH2Cl2: C, 56.15; H, 4.89; N, 9.00; Cl, 18.23. Found. C, 55.86; H, 4.82; N, 8.94; Cl, 18.03.
EXAMPLE 70




COMPOUND 70: N-(3-{4-[Benzyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, 4-trifluoromethoxy-phenylamine (354 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (692 mg, 96%) as a white crystalline solid.
COMPOUND 70 was isolated as a white foam. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.18-1.25 (m, 2H), 1.51-1.58 (m, 2H), 1.72-1.82 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.58 (t, 1H, J=11.4 Hz), 2.80-2.96 (m, 3H), 3.34 (t, 1H, J=11.4 Hz), 3.63 (t, 1H, J=11.4 Hz), 3.85 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=8.7 Hz), 7.17-7.35 (m, 5H), 8.47 (s, 2H), 8.96 (br s, 1H). 13C NMR (CDCl3) δ 13.7, 29.6, 30.7, 40.4, 44.0, 49.3, 52.4, 56.3, 60.6, 113.8, 121.1 (q, J=254 Hz), 122.5, 126.4, 127.2, 129.0, 129.4, 139.7, 140.4, 143.6, 147.8, 148.0, 161.9. ES-MS m/z 596 (M+H). Anal. Calcd. for C29H31Cl2F3N4O2: C, 57.98; H, 5.47; N, 8.90; Cl, 13.51; F, 9.05. Found. C, 58.07; H, 5.33; N, 9.03; Cl, 13.21; F, 8.91.
EXAMPLE 71




COMPOUND 71: 3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.95-1.26 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.81-1.85 (m, 3H), 2.18 (t, 1H, J=11.4 Hz), 2.36 (s, 3H), 2.58 (t, 1H, J=11.4 Hz), 2.79-2.95 (m, 3H), 3.30-3.38 (m, 1H), 3.58-3.67 (m, 1H), 3.83 (s, 2H), 3.84-3.89 (m, 1H), 6.53 (d, 2H, J=9.3 Hz), 6.96-7.07 (m, 5H), 7.18-7.24 (m, 1H), 8.48 (s, 2H), 8.95 (br s, 1H). 13C NMR (CDCl3) δ 13.76, 21.94, 29.61, 30.68, 30.76, 40.63, 43.90, 49.33, 52.51, 56.25, 60.78, 113.66, 119.37, 122.55, 123.47, 126.98, 127.97, 128.86, 129.41, 138.63, 139.75, 140.33, 143.58, 147.88, 148.08, 161.89. ES-MS m/z 609 (M+H). Anal. Calcd. for C30H33N4Cl2O2F3: C, 59.12; H, 5.46; N, 9.19; Cl, 11.63; F, 9.35. Found. C, 59.25; H, 5.52; N, 9.09; Cl, 11.46; F, 9.44.
EXAMPLE 72




COMPOUND 72: 3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 4-(methylthio)aniline (250 μL, 2.01 mmol) and 1-Boc-4-piperidone (400 mg, 2.01 mmol) afforded 4-(4-methylsulfanyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (502 mg, 77%).
COMPOUND 72 was isolated as a white solid. 1H NMR (CDCl3) δ 0.96-1.18 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.53-1.58 (m, 1H), 1.74-1.81 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.38 (s, 3H), 2.58 (t, 1H, J=10.5 Hz), 2.79-2.96 (m, 3H), 3.30-3.38 (m, 1H), 3.63-3.67 (m, 1H), 3.81 (s, 2H), 3.86-3.92 (m, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.88-7.01 (m, 3H), 7.16 (d, 2H, J=8.4 Hz), 7.26-7.33 (m, 1H), 8.48 (s, 2H), 8.98 (br s, 1H). 13C NMR (CDCl3) δ 13.79, 19.11, 29.69, 30.71, 30.81, 40.58, 43.92, 48.80, 52.45, 56.24, 60.72, 113.47 (d, J=22 Hz), 114.06 (d, J=21 Hz), 114.37, 122.08, 124.85, 129.45, 130.46 (d, J=8 Hz), 131.37, 143.08 (d, J=6 Hz), 143.60, 147.45, 148.02, 161.85, 163.60 (d, J=246 Hz). ES-MS m/z 575 (M+H). Anal. Calcd. for C29H33N4OSCl2F.0.1CH2Cl2: C, 59.84; H, 5.73; N, 9.59; S, 5.49; Cl, 13.35; F, 3.25. Found. C, 59.57; H, 5.77; N, 9.35; S, 5.30; Cl, 13.75; F, 3.12.
EXAMPLE 73




COMPOUND 73: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.53-1.58 (m, 1H), 1.78-1.81 (m, 3H), 2.18 (t, 1H, J=11.4 Hz), 2.38 (s, 3H), 2.58 (t, 1H, J=10.8 Hz), 2.79-2.96 (m, 3H), 3.31-3.59 (m, 1H), 3.59-3.65 (m, 1H), 3.79 (s, 2H), 3.86-3.90 (m, 1H), 6.52 (d, 2H, J=8.7 Hz), 7.07-7.28 (m, 6H), 8.49 (s, 2H), 8.97 (br s, 1H). 13C NMR (CDCl3) δ 13.78, 19.09, 29.63, 30.70, 40.57, 43.92, 48.85, 52.46, 56.18, 60.74, 114.37, 124.72, 124.95, 126.59, 127.41, 129.46, 130.24, 131.37, 131.62, 134.95, 142.43, 143.59, 147.44, 148.04, 161.86. ES-MS m/z 591 (M+H). Anal. Calcd. for C29H33N4OSCl3: C, 58.84; H, 5.62; N, 9.46; S, 5.42; Cl, 17.97. Found. C, 59.03; H, 5.75; N, 9.27; S, 5.29; Cl, 17.74.
EXAMPLE 74




COMPOUND 74: 3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.98-1.23 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.53-1.58 (m, 1H), 1.76-1.82 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.35 (s, 3H), 2.38 (s, 3H), 2.58 (t, 1H, J=11.4 Hz), 2.78-2.96 (m, 3H), 3.31-3.38 (m, 1H), 3.59-3.65 (m, 1H), 3.81 (s, 2H), 3.86-3.91 (m, 1H), 6.53 (d, 2H, J=8.7 Hz), 6.96-7.05 (m, 3H), 7.15-7.22 (m, 3H), 8.48 (s, 2H), 9.00 (br s, 1H). 13C NMR (CDCl3) δ 13.78, 19.31, 21.96, 30.69, 30.77, 40.61, 43.94, 49.20, 52.54, 56.00, 60.78, 114.06, 123.52, 124.11, 127.03, 127.87, 128.79, 129.41, 131.57, 138.53, 140.04, 143.57, 147.91, 148.07, 161.91. ES-MS m/z 571 (M+H). Anal. Calcd. for C30H36N4OSCl2: C, 63.04; H, 6.35; N, 9.80; S, 5.61; Cl, 12.40. Found. C, 62.95; H, 6.36; N, 9.60; S, 5.40; Cl, 12.51.
EXAMPLE 75




COMPOUND 75: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 1-Boc-4-piperidone (2.01 g, 10.09 mmol) and 4-(methanesulfonyl)aniline hydrochloride (1.69 g, 8.13 mmol) afforded 4-(4-methanesulfonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.44 g, 50%).
COMPOUND 75 was isolated as a white solid. 1H NMR (CDCl3) δ 0.97-1.30 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 1.57-1.58 (m, 1H), 1.73-1.82 (m, 3H), 2.23 (t, 1H, J=11.4 Hz), 2.61 (t, 1H, J=11.1 Hz), 2.82-2.93 (m, 3H), 2.99 (s, 3H), 3.34-3.42 (m, 1H), 3.76-3.87 (m, 2H), 3.96 (s, 2H), 6.61 (d, 2H, J=8.7 Hz), 7.05 (d, 1H, J=6.9 Hz), 7.12 (s, 1H), 7.26-7.32 (m, 2H), 7.66 (d, 2H, J=8.7 Hz), 8.50 (s, 2H), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.44, 29.38, 30.38, 30.51, 40.06, 43.47, 44.97, 48.10, 51.83, 55.78, 60.11, 112.11, 124.07, 125.91, 127.47, 129.11, 129.27, 130.13, 134.83, 140.30, 147.67, 152.01, 161.43. ES-MS m/z 623 (M+H). Anal. Calcd. for C29H33N4Cl3O3S.0.2CH2Cl2: C, 54.71; H, 5.25; N, 8.74; Cl, 18.80; S, 5.00. Found. C, 54.49; H, 5.32; N, 8.61; Cl, 18.60; S, 5.14.
EXAMPLE 76




COMPOUND 76: 3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 1.02-1.32 (m, 2H), 1.03 (d, 3H, J=6.3 Hz), 1.55-1.58 (m, 1H), 1.75-1.84 (m, 3H), 2.22 (t, 1H, J=11.7 Hz) 2.36 (s, 3H), 2.61 (t, 1H, J=11.7 Hz), 2.81-2.93 (m, 3H), 2.98 (s, 3H), 3.36-3.42 (m, 1H), 3.75-3.96 (m, 2H), 3.96 (s, 2H), 6.63 (d, 2H, J=8.7 Hz), 6.91-6.93 (m, 2H), 7.08 (d, 1H, J=7.2 Hz), 7.20 (d, 1H, J=6.9 Hz), 7.64 (d, 2H, J=8.4 Hz), 8.49 (s, 2H), 8.70 (br s, 1H). 13C NMR (CDCl3) δ 13.42, 21.56, 29.34, 30.36, 30.47, 40.10, 43.47, 44.98, 48.49, 51.90, 55.73, 60.18, 111.99, 122.85, 126.40, 126.84, 127.90, 128.64, 129.15, 137.90, 138.49, 143.15, 147.70, 152.34, 161.48. ES-MS m/z 603 (M+H). Anal. Calcd. for C30H36N4Cl2O3S.0.2CH2Cl2.0.3H2O: C, 57.94; H, 5.96; N, 8.95; Cl, 13.59; S, 5.12. Found. C, 58.31; H, 6.12; N, 8.98; Cl, 13.22; S, 4.92.
EXAMPLE 77




COMPOUND 77: 3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
COMPOUND 77 was isolated as a white solid. 1H NMR (CDCl3) δ 0.94-1.20 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.50-1.56 (m, 1H), 1.78-1.82 (m, 3H), 2.14 (t, 1H, J=12.0 Hz), 2.55 (t, 1H, J=12.0 Hz), 2.78-2.93 (m, 3H), 3.29-3.48 (m, 2H), 3.71 (s, 3H), 3.76 (s, 2H), 3.85-3.91 (m, 1H), 6.57 (d, 2H, J=7.5 Hz), 6.72 (d, 2H, J=7.5 Hz), 6.86-6.96 (m, 2H), 7.01 (d, 1H, J=7.5 Hz), 7.22-7.30 (m, 1H), 8.47 (s, 2H), 9.09 (br s, 1H). 1H NMR (CDCl3) δ 13.75, 29.79, 30.60, 30.93, 40.69, 43.91, 49.83, 52.51, 56.02, 57.71, 60.86, 113.74, 114.02, 114.96, 116.55, 117.09, 122.48, 129.42, 130.17, 130.28, 143.04, 143.66, 143.75, 148.02, 152.81, 161.88, 165.18. ES-MS m/z 559 (M+H). Anal. Calcd. for C29H33N4Cl2O2F: C, 62.25; H, 5.94; N, 10.01; Cl, 12.67; F, 3.40. Found. C, 62.08; H, 5.97; N, 9.95; Cl, 12.60; F, 3.27.
EXAMPLE 78




COMPOUND 78: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.94-1.18 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.51-1.56 (m, 1H), 1.78-1.81 (m, 3H), 2.14 (t, 1H, J=10.8 Hz), 2.54 (d, 1H, J=11.1 Hz), 2.78-2.95 (m, 3H), 3.29-3.47 (m, 2H), 3.71 (s, 3H), 3.74 (s, 2H), 3.85-3.92 (m, 1H), 6.57 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.10-7.12 (m, 1H), 7.17-7.23 (m, 3H), 8.48 (s, 2H), 9.09 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 29.37, 30.18, 30.52, 40.30, 43.49, 49.46, 52.10, 55.62, 57.26, 60.47, 114.58, 116.67, 124.75, 126.64, 126.83, 129.03, 129.65, 134.37, 142.63, 143.20, 147.62, 152.43, 161.48. ES-MS m/z 575 (M+H). Anal. Calcd. for C29H33N4Cl3O2: C, 60.48; H, 5.77; N, 9.73; Cl, 18.47. Found. C, 60.49; H, 5.81; N, 9.64; Cl, 18.45.
EXAMPLE 79




COMPOUND 79: N-(3-{4-Benzyl-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, 4-amino-N-methyl-benzenesulfonamide (Andrewes; King; Walker, Proc. R. Soc. London B., 133, 1946, 20-30) (320 mg, 1.72 mmol) and 1-Boc-4-piperidone (377 mg, 1.89 mmol) afforded a white solid (440 mg).
COMPOUND 79 was isolated as a white solid. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.08-1.28 (m, 2H), 1.56 (m, 1H), 1.78 (m, 3H), 2.22 (t, 1H, J=11.4 Hz), 2.58 (d, 3H, J=5.4 Hz), 2.60 (m, 1H), 2.80-2.96 (m, 3H), 2.36 (m, 1H), 3.71-3.88 (m, 2H), 3.99 (s, 2H), 4.31 (q, 1H, J=5.4 Hz), 6.60 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=6.9 Hz), 7.23-7.36 (m, 3H), 7.57 (d, 2H, J=9.0 Hz), 8.47 (s, 2H), 8.72 (br s, 1H). 13C NMR (CDCl3) δ 13.43, 29.31, 30.33, 30.47, 39.97, 43.56, 48.48, 51.78, 53.47, 55.68, 59.99, 111.93, 124.79, 125.83, 127.05, 128.71, 129.06, 138.17, 143.13, 147.63, 151.63, 161.52. ES-MS m/z 604 (M+H). Anal. Calcd. for C29H35N5Cl2O3S.0.4CH2Cl2: C, 55.30; H, 5.65; N, 10.97; Cl, 15.55; S, 5.02. Found. C, 55.18; H, 5.51; N, 10.80; Cl, 15.73; S, 5.00.
EXAMPLE 80




COMPOUND 80: Methanesulfonic acid 4-[benzyl-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
Using general procedure H, 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 77) (612 mg, 2.00 mmol) and benzyl bromide (410 mg, 2.40 mmol) gave 4-[benzyl-(4-methoxyphenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (688 mg, 87%).
Using general procedure C with the above carbamate (303 mg, 0.765 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (320 mg, 1.47 mmol) and then using general procedure D gave [1-(3-amino-1-methylpropyl)-piperidin-4-yl]-benzyl-(4-methoxy-phenyl)-amine as a colorless oil (190 mg, 68% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (184 mg, 0.959 mmol) and the above amine (176 mg, 0.479 mmol) gave N-(3-{4-[benzyl-(4-methoxyphenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide as a white foam (243 mg, 94%).
To a solution of the above substrate (124 mg, 0.229 mmol) in CH2Cl2 (2 mL) cooled to −78° C. was added BBr3 (1.0M in CH2Cl2, 0.92 mL, 0.92 mmol). The mixture was warmed to room temperature and stirred for 1 hour. 6N HCl was added and the mixture stirred at room temperature overnight to afford N-(3-{4-[benzyl-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide as a white solid (107 mg, 89%) following basic work-up and purification.
Using general procedure G, the above alcohol (43 mg, 0.082 mmol) afforded COMPOUND 80 as a white solid (42 mg, 80%). 1H NMR (CDCl3) δ 0.88-1.25 (m, 2H), 1.28 (d, 3H, J=6.3 Hz), 1.57 (m, 1H), 1.82 (m, 3H), 2.19 (t, 1H, J=10.8 Hz), 2.59 (t, 1H, J=11.1 Hz), 2.81-2.96 (m, 3H), 3.06 (s, 3H), 3.35 (m, 1H), 3.64 (m, 1H), 3.86 (m, 3H), 6.54 (d, 2H, J=9.0 Hz), 7.02 (d, 2H, J=9.0 Hz), 7.18 (d, 2H, J=7.2 Hz), 7.22-7.35 (m, 3H), 8.47 (s, 2H), 8.93 (br s, 1H). 13C NMR (CDCl3) δ 13.36, 29.21, 30.34, 36.78, 40.10, 43.55, 48.85, 52.05, 55.88, 60.29, 113.49, 122.69, 125.99, 126.20, 126.65, 126.86, 128.61, 129.01, 139.14, 139.90, 143.16, 147.65, 147.73, 161.50. ES-MS m/z 605 (M+H). Anal. Calcd. for C29H34N4Cl2O4S.CH2Cl2.0.3H2O: C, 53.71; H, 5.45; N, 8.46; Cl, 17.14; S, 4.84. Found. C, 53.61; H, 5.34; N, 8.32; Cl, 17.21; S, 4.90.
EXAMPLE 81




COMPOUND 81: N-(3-{4-[Benzyl-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, benzylamine (1.2 mL, 11 mmol) and 1-Boc-4-piperidone (2.0 g, 10 mmol) gave 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.93 g, 100%).
A solution of the above amine (500 mg, 1.72 mmol), 1-iodo-4-nitrobenzene (408 mg, 1.64 mmol), Pd2(dba)3, (±)BINAP and toluene was purged with N2 and then heated to 100° C. for 24 h to afford 4-[benzyl-(4-nitro-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (250 mg, 37%) following aqueous work-up and purification.
Using general procedure C with the above carbamate (100 mg, 0.24 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (107 mg, 0.49 mmol) and then using general procedure D afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-(4-nitro-phenyl)-amine (79 mg, 86% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (60 mg, 0.31 mmol) and the above amine (79 mg, 0.21 mmol) afforded COMPOUND 81 as a yellow solid (45 mg, 38%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.09-1.36 (m, 2H), 1.55-1.60 (m, 1H), 1.76-1.91 (m, 3H), 2.27 (t, 1H, J=11.4 Hz), 2.61 (t, 1H, J=11.4 Hz), 2.82-2.97 (m, 3H), 3.33-3.41 (m, 1H), 3.77-3.87 (m, 2H), 4.07 (s, 2H), 6.55 (d, 2H, J=9.6 Hz), 7.12 (d, 2H, J=7.2 Hz), 7.27-7.37 (m, 3H), 8.02 (d, 2H, J=8.4 Hz), 8.48 (s, 2H), 8.56 (br s, 1H). 13C NMR (CDCl3) δ 13.80, 29.89, 30.81, 30.96, 40.38, 43.87, 48.91, 52.18, 56.55, 60.42, 111.75, 126.14, 126.49, 127.68, 129.25, 129.44, 137.78, 137.96, 143.52, 148.08, 153.62, 161.86. ES-MS m/z 556 (M+H). Anal. Calcd. for C28H31N5Cl2O3.0.6CH2Cl2.0.2C4H10O: C, 56.75; H, 5.54; N, 11.25; Cl, 18.23. Found. C, 56.71; H, 5.33; N, 11.17; Cl, 18.05.
EXAMPLE 82




COMPOUND 82: 3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 3-chlorobenzylamine (0.27 mL, 2.2 mmol) and 1-Boc-4-piperidone (484 mg, 2.4 mmol) afforded 4-(3-chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (640 mg, 89%).
The above secondary amine (640 mg, 1.80 mmol), 1-iodo-4-nitrobenzene (899 mg, 3.61 mmol), sodium tert-butoxide (243 mg, 2.53 mmol), (+/−) BINAP (224 mg, 0.36 mmol), Pd2(dba)3 (165 mg, 0.18 mmol) and toluene (4.0 mL) were flushed with N2 for 5 minutes. The mixture was heated at 100° C. overnight to afford an orange/brown solid (500 mg) following aqueous work-up and purification.
Using general procedure C with the above substrate, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (427 mg, 1.97 mmol) and then using general procedure D afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-chloro-benzyl)-(4-nitro-phenyl)-amine as a yellow solid (215 mg, 29% over 4 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (46 mg, 0.24 mmol) and the above amine (50 mg, 0.12 mmol) afforded COMPOUND 82 as a yellow solid (61 mg, 86%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.06-1.35 (m, 2H), 1.52-1.63 (m, 1H), 1.73-1.89 (m, 3H), 2.18-2.28 (m, 1H), 2.56-2.67 (m, 1H), 2.80-3.00 (m, 3H), 3.32-3.44 (m, 1H), 3.74-3.90 (m, 2H), 4.03 (s, 2H), 6.54 (d, 2H, J=7.00 Hz), 7.00-7.05 (m, 1H), 7.10 (s, 1H), 7.23-7.32 (m, 2H), 8.04 (d, 2H, J=9.3 Hz), 8.46-8.54 (m, 3H). 13C NMR (CDCl3) δ 13.45, 29.49, 30.38, 30.65, 39.86, 43.50, 48.16, 51.64, 56.15, 59.81, 111.42, 124.00, 125.88, 126.11, 127.55, 129.07, 130.19, 134.86, 137.80, 139.84, 143.11, 147.64, 153.03, 161.47. ES-MS m/z 590 (M+H). Anal. Calcd. for C28H30N5Cl3O3.0.3CH2Cl2: C, 55.14; H, 5.00; N, 11.36; Cl, 20.71. Found. C, 55.34; H, 4.92; N, 11.32; Cl, 20.66.
EXAMPLE 83




COMPOUND 83: N-(3-{4-[Benzyl-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
Using general procedure A, 1-Boc-4-piperidone (1.00 g, 5.03 mmol) and 4-amino-N,N-dibenzyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2002, 64-68) (1.53 g, 4.34 mmol) afforded 4-(4-dibenzylsulfamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.27 g, 55%).
Using general procedure H with the above aniline (970 mg, 1.81 mmol) and benzyl bromide (0.66 mL, 5.52 mmol) followed by general procedure C afforded N,N-dibenzyl-4-(benzyl-piperidin-4-yl-amino)-benzenesulfonamide as a white solid (679 mg, 72% over 2 steps).
Using general procedure B with the above amine (679 mg, 1.29 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (877 mg, 4.04 mmol) and then using general procedure D afforded 4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-N,N-dibenzyl-benzenesulfonamide as a white solid (461 mg, 60% over 2 steps).
To the above amine (122 mg, 0.204 mmol) was added conc. H2SO4 (2 mL) and the mixture was stirred at room temperature for 1.5 hours. The mixture was poured onto ice ( ̃20 mL), neutralized with Na2CO3 (s,  ̃5 g), diluted with H2O (20 mL) and extracted with CH2Cl2 (5×25 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzenesulfonamide as a yellow solid (66 mg, 78%).
Using general procedure F, 3,5-dichloroisonicotinic acid (87 mg, 0.45 mmol) and the above amine (58 mg, 0.14 mmol) afforded the desired product and N-{3-[4-(benzyl-{4-[(3,5-dichloro-pyridine-4-carbonyl)-sulfamoyl]-phenyl}-amino)-piperidin-1-yl]-butyl}-3,5-dichloro-isonicotinamide.
To the above amide in THF (1 mL) was added 6N HCl (1 mL) and the mixture was heated at 60° C. overnight to afford COMPOUND 83 as a white solid (27 mg, 29% over 2 steps) following work-up and purification. 1H NMR (CDCl3) δ 0.96-1.32 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.51-1.57 (m, 1H), 1.75-1.90 (m, 3H), 2.22 (t, 1H, J=11.7 Hz), 2.61 (t, 1H, J=10.8 Hz), 2.81-2.97 (m, 3H), 3.32-3.40 (m, 1H), 3.71-3.79 (m, 1H), 3.84-3.90 (m, 1H), 3.98 (s, 2H), 4.60 (s, 2H), 6.60 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=7.2 Hz), 7.29-7.36 (m, 3H), 7.65 (d, 2H, J=9.0 Hz), 8.48 (s, 2H), 8.71 (br s, 1H). 13C NMR (CDCl3) δ 13.80, 29.75, 30.76, 30.87, 40.44, 43.91, 48.84, 52.26, 56.15, 60.51, 112.35, 126.24, 127.49, 128.69, 129.13, 129.44, 138.45, 143.54, 148.05, 152.01, 161.89. ES-MS m/z 590 (M+H). Anal. Calcd. for C28H35N5O3SCl2.0.9CH2Cl2.0.4H2O: C, 51.48; H, 5.32; N, 10.39; S, 4.76; Cl, 19.98. Found. C, 51.37; H, 5.18; N, 10.04; S, 4.58; Cl, 20.37.
EXAMPLE 84




COMPOUND 84: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-fluoro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 3-fluorobenzylamine (0.25 mL, 2.2 mmol) and 1-Boc-4-piperidone (482 mg, 2.4 mmol) afforded 4-(3-fluoro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (620 mg, 91%).
The above secondary amine (620 mg, 2.0 mmol), 1-iodo-4-nitrobenzene (996 mg, 4.0 mmol), sodium tert-butoxide (269 mg, 2.8 mmol), (+/−) BINAP (246 mg, 0.4 mmol), Pd2(dba)3 (183 mg, 0.2 mmol) and toluene (4.0 mL) were flushed with N2 for 5 minutes. The mixture was heated at 100° C. overnight to afford 4-[(3-fluoro-benzyl)-(4-nitro-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an orange/brown solid (354 mg,  ̃41%) following aqueous work-up and purification.
Using general procedure C with the above substrate (354 mg, 0.82 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (356 mg, 1.64 mmol) and then using general procedure D afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-fluoro-benzyl)-(4-nitro-phenyl)-amine as a yellow solid (198 mg, 60% over 3 steps).
Using general procedure E, the above amine (50 mg, 0.13 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (21 mg, 0.14 mmol) afforded COMPOUND 84 as a yellow solid (57 mg, 85%). 1H NMR (CDCl3) δ 0.96-1.29 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.52-1.61 (m, 1H), 1.70-1.85 (m, 3H), 2.16-2.28 (m, 1H), 2.52 (s, 6H), 2.55-2.66 (m, 1H), 2.74-2.95 (m, 3H), 3.29-3.41 (m, 1H), 3.72-3.88 (m, 2H), 4.09 (s, 2H), 6.55 (d, 2H, J=9.0 Hz), 6.85-7.03 (m, 3H), 7.27-7.36 (m, 1H), 8.04 (d, 2H, J=9.0 Hz), 8.26 (br s, 1H), 8.92 (s, 1H). 13C NMR (CDCl3) δ 13.48, 21.97, 29.34, 30.35, 31.01, 39.83, 43.53, 48.25, 51.72, 56.12, 59.95, 111.32, 112.90 (d, J=22 Hz), 114.23 (d, J=21 Hz), 121.47, 126.16, 130.48 (d, J=8 Hz), 130.81, 137.80, 140.60 (d, J=7 Hz), 153.19, 157.63, 163.12, 163.21 (d, J=247 Hz), 166.33. ES-MS m/z 535 (M+H). Anal. Calcd. for C29H35N6O3F.0.8CH2Cl2: C, 59.40; H, 6.12; N, 13.95; F, 3.15. Found. C, 59.26; H, 6.02; N, 13.98; F, 3.15.
EXAMPLE 85




COMPOUND 85: 4-((3-Chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid methyl ester
Using general procedure A, methyl 4-aminobenzoate (380 mg, 2.51 mmol) and 1-Boc-4-piperidone (500 g, 2.51 mmol) afforded 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (643 mg, 77%).
Using general procedure H, the above aniline (590 mg, 1.77 mmol) and 3-chlorobenzyl bromide (348 μL, 2.65 mmol) afforded 4-[(3-chloro-benzyl)-(4-methoxycarbonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (452 mg, 56%).
Using general procedure C with the above carbamate (452 mg, 0.98 mmol), then using general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (428 mg, 1.97 mmol) followed by general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-chloro-benzyl)-amino]-benzoic acid methyl ester (295 mg, 70% over 3 steps).
Using general procedure E, the above amine (295 mg, 0.69 mmol) and 2,6-dimethylbenzoic acid (113 mg, 0.75 mmol) afforded COMPOUND 85 as a white solid (290 mg, 75%). 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.3 Hz), 1.00-1.21 (m, 2H), 1.48-1.54 (m, 1H), 1.70-1.76 (m, 3H), 2.17 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=10.8 Hz), 2.74-2.90 (m, 3H), 3.23-3.31 (m, 1H), 3.66-3.75 (m, 1H), 3.78-3.90 (m, 1H), 3.80 (s, 3H), 3.86 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.95-7.01 (m, 3H), 7.06-7.11 (m, 2H), 7.20-7.23 (m, 2H), 7.80 (d, 2H, J=8.7 Hz), 8.35 (br s, 1H). 13C NMR (CDCl3) δ 13.59, 13.85, 19.54, 29.41, 29.81, 30.69, 31.34, 34.02, 40.18, 43.95, 48.56, 49.10, 51.94, 52.41, 53.87, 56.16, 58.61, 60.87, 112.04, 118.42, 124.59, 126.55, 126.95, 127.43, 127.78, 128.88, 130.24, 131.35, 131.75, 132.13, 134.42, 134.89, 138.98, 141.94, 152.30, 167.51, 170.29. ES-MS m/z 562 (M+H). Anal. Calcd. for C33H40N3ClO3.0.2CH2Cl2: C, 68.86; H, 7.03; N, 7.26. Found. C, 68.73; H, 7.00; N, 7.26.
EXAMPLE 86




COMPOUND 86: N-[3-(4-{(3-Chloro-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
Using general procedure K, COMPOUND 85 (273 mg, 0.485 mmol) afforded 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (280 mg).
Using general procedure E, the above acid (40 mg) and morpholine (71 μL, 0.080 mmol) gave COMPOUND 86 as a white solid (24 mg, 53%). 1H NMR (CDCl3) δ 0.91-1.21 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.49-1.54 (m, 1H), 1.70-1.74 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.24-3.31 (m, 1H), 3.62-3.65 (m, 9H), 3.82 (s, 2H), 3.83-3.88 (m, 1H), 6.53 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.01-7.11 (m, 3H), 7.19-7.25 (m, 4H), 8.35-8.36 (m, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.33, 30.65, 31.34, 40.20, 43.98, 46.15, 48.66, 52.50, 56.20, 60.90, 67.35, 112.45, 123.18, 124.66, 126.60, 127.36, 127.75, 128.87, 129.79, 130.20, 134.41, 134.87, 138.96, 142.35, 150.27, 170.30, 171.16. ES-MS m/z 617 (M+H). Anal. Calcd. for C36N45N4ClO3.0.2CH2Cl2: C, 68.56; H, 7.21; N, 8.83. Found. C, 68.65; H, 7.21; N, 8.90.
EXAMPLE 87




COMPOUND 87: N-(3-{4-[(3-Chloro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and dimethylamine (2.0M in THF, 56 μL, 0.11 mmol) afforded COMPOUND 87 as a white solid (31 mg, 71%). 1H NMR (CDCl3) δ 0.89-1.20 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.70-1.83 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=12.0 Hz), 2.74-2.90 (m, 3H), 3.03 (s, 6H), 3.24-3.31 (m, 1H), 3.62-3.69 (m, 1H), 3.81 (s, 2H), 3.84-3.91 (m, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.12 (m, 3H), 7.21-7.28 (m, 4H), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.32, 30.67, 31.31, 40.24, 43.98, 48.67, 52.54, 56.18, 60.96, 112.31, 124.37, 124.68, 126.63, 127.30, 127.77, 128.88, 129.70, 130.16, 134.41, 134.83, 138.96, 142.53, 149.98, 170.32, 172.18. ES-MS m/z 575 (M+H). Anal. Calcd. for C34H43N4ClO2.0.5CH2Cl2: C, 67.09; H, 7.18; N, 9.07. Found. C, 66.75; H, 7.12; N, 8.94.
EXAMPLE 88




COMPOUND 88: N-[3-(4-{(3-Chloro-benzyl)-[4-(methoxy-methyl-carbamoyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and N,O-dimethylhydroxylamine hydrochloride (11 mg, 0.11 mmol) afforded COMPOUND 88 as a white solid (36 mg, 84%). 1H NMR (CDCl3) δ 0.91-1.21 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.71-1.88 (m, 3H), 2.17 (t, 1H, J=11.4 Hz), 2.30 (s, 6H), 2.56 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.24-3.30 (m, 1H), 3.30 (s, 3H), 3.57 (s, 3H), 3.65-3.72 (m, 1H), 3.84 (s, 2H), 3.84-3.90 (m, 1H), 6.52 (d, 2H, J=8.7 Hz), 6.96 (d, 2H, J=7.5 Hz), 7.02-7.11 (m, 3H), 7.21-7.26 (m, 2H), 7.62 (d, 2H, J=8.4 Hz), 8.39 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.54, 29.37, 30.69, 31.32, 34.49, 40.23, 43.97, 48.64, 52.50, 56.07, 60.93, 61.16, 111.89, 121.77, 124.65, 126.60, 127.34, 127.77, 128.88, 130.19, 131.09, 134.41, 134.85, 138.97, 142.35, 150.90, 169.94, 170.31. ES-MS m/z 591 (M+H). Anal. Calcd. for C34H43N4ClO3.0.3CH2Cl2: C, 66.84; H, 7.13; N, 9.09. Found. C, 66.87; H, 7.06; N, 8.94.
EXAMPLE 89




COMPOUND 89: N-(3-{4-[(3-Chloro-benzyl)-(4-phenylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E, 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (40 mg, 0.074) and aniline (8 μL, 0.08 mmol) afforded COMPOUND 89 as a white solid (32 mg, 71%). 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.51-1.55 (m, 1H), 1.72-1.76 (m, 3H), 2.19 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 3H), 3.25-3.32 (m, 1H), 3.67-3.75 (m, 1H), 3.87 (s, 2H), 3.87-3.93 (m, 1H), 6.57 (d, 2H, J=8.7 Hz), 6.95-7.12 (m, 6H), 7.23-7.32 (m, 4H), 7.60 (d, 2H, J=7.8 Hz), 7.68 (d, 2H, J=8.4 Hz), 7.76 (s, 1H), 8.35 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.55, 29.42, 30.70, 31.35, 40.22, 43.96, 48.59, 52.47, 56.25, 60.92, 112.50, 120.35, 122.88, 124.35, 124.61, 126.60, 127.47, 127.78, 128.89, 129.13, 129.37, 130.27, 134.44, 134.95, 138.80, 138.97, 142.01, 151.51, 165.65, 170.31. ES-MS m/z 623 (M+H). Anal. Calcd. for C38H43N4ClO2.0.2CH2Cl2: C, 71.65; H, 6.83; N, 8.75. Found. C, 71.64; H, 6.81; N, 8.84.
EXAMPLE 90




COMPOUND 90: N-(3-{4-[(4-Carbamoyl-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E (Wang, W.; McMurray, J. S. Tetrahedron Lett., 1999, 40, 2501-2504) 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (90 mg, 0.16 mmol) and NH4Cl (22 mg, 0.41 mmol) gave COMPOUND 90 as a white solid (64.1 mg, 0.12 mmol, 71%). 1H NMR (CDCl3) δ 0.95-1.09 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.10-1.25 (m, 1H), 1.48-1.58 (m, 1H), 1.68-1.83 (m, 3H), 2.13-2.24 (m, 1H), 2.31 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.23-3.34 (m, 1H), 3.64-3.76 (m, 1H), 3.83-3.93 (m, 1H), 3.85 (s, 2H), 5.67 (br s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.94-7.04 (m, 3H), 7.06-7.13 (m, 2H), 7.20-7.27 (m, 2H), 7.61 (d, 2H, J=8.4 Hz), 8.34 (br d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.37, 19.05, 28.90, 30.19, 30.84, 39.72, 43.48, 48.09, 51.94, 55.68, 60.37, 111.78, 120.97, 124.13, 126.10, 126.93, 127.29, 128.40, 129.07, 129.77, 133.95, 134.40, 138.46, 141.59, 151.10, 169.07, 169.83. ESI-MS m/z 547 (MH)+, 549 (MH+2)+. Anal. Calcd. for C32H39ClN4O2.0.7CH2Cl2.0.3H2O: C, 64.18; H, 6.75; N, 9.15; Cl, 13.90. Found. C, 64.11; H, 6.58; N, 9.11; Cl, 13.99.
EXAMPLE 91




COMPOUND 91: N-(3-{4-[Benzyl-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
Using general procedure H with 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 85) (1.0 g) and benzylbromide (0.54 mL, 4.50 mmol) and then using general procedure C afforded 4-(benzyl-piperidin-4-yl-amino)-benzoic acid methyl ester as a white solid (620 mg, 63% over 2 steps).
Using general procedure B with the above secondary amine (620 mg, 1.91 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (830 mg, 3.82 mmol) and then using general procedure D afforded 4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzoic acid methyl ester as a white solid (120 mg, 16% over 2 steps).
Using general procedure E with the above amine (120 mg, 0.30 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (76 mg, 0.33 mmol) and then using general procedure K afforded 4-(benzyl-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a yellow solid (160 mg, 88% over 2 steps).
Using general procedure E, the above acid (60 mg, 0.10 mmol) and dimethylamine (2M, 153 μL, 0.31 mmol) afforded COMPOUND 91 as a white solid (49 mg, 78%). 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.0 Hz), 1.00-1.33 (m, 2H), 1.49-1.60 (m, 1H), 1.68-1.82 (m, 3H), 2.11-2.23 (m, 1H), 2.39 (s, 6H), 2.49-2.60 (m, 1H), 2.71-2.92 (m, 3H), 3.01 (s, 6H), 3.25-3.37 (m, 1H), 3.60-3.72 (m, 1H), 3.79-3.92 (m, 3H), 6.47 (d, 2H, J=8.1 Hz), 6.86-6.92 (m, 2H), 7.12-7.19 (m, 3H), 7.23 (d, 2H, J=8.1 Hz), 7.29 (s, 2H), 7.45 (d, 2H, J=3.9 Hz), 8.26 (br s, 1H), 8.63 (d, 2H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.83, 19.75, 29.40, 30.81, 31.64, 40.05, 44.16, 48.65, 52.47, 56.10, 60.59, 112.07, 121.91, 123.95, 126.25, 126.47, 127.03, 128.83, 129.71, 135.63, 138.47, 139.63, 139.91, 148.03, 150.14, 150.75, 169.76, 172.25. ES-MS m/z 618 (M+H). Anal. Calcd. for C39H47N5O2.1.0CH2Cl2: C, 68.36; H, 7.03; N, 9.97. Found. C, 68.16; H, 7.02; N, 10.04.
EXAMPLE 92




COMPOUND 92: N-(3-{4-[Benzyl-(4-carbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
Using general procedure E, 4-(benzyl-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 91) (60 mg, 0.10 mmol) and ammonium chloride (22 mg, 0.41 mmol) afforded COMPOUND 92 as a white solid (43 mg, 71%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5.7 Hz), 1.06-1.35 (m, 2H), 1.51-1.62 (m, 1H), 1.69-1.86 (m, 3H), 2.13-2.31 (m, 1H), 2.40 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.20-3.40 (m, 2H), 3.62-3.71 (m, 1H), 3.89 (s, 2H), 5.79 (br s, 2H), 6.49 (d, 2H, J=8.1 Hz), 6.84-6.93 (m, 2H), 7.12-7.22 (m, 3H), 7.25-7.33 (m, 2H), 7.41-7.48 (m, 2H), 7.57 (d, 2H, J=8.1 Hz), 8.20 (br s, 1H), 8.60-8.67 (m, 2H). 13C NMR (CDCl3) δ 13.45, 19.34, 29.05, 30.40, 31.30, 39.60, 43.73, 48.18, 51.98, 55.72, 60.12, 111.66, 120.60, 121.49, 125.76, 126.06, 126.75, 128.51, 129.11, 135.24, 138.06, 139.02, 139.21, 147.61, 150.35, 151.34, 169.08, 169.34. ES-MS m/z 590 (M+H).
Scheme 6 describes the preparation of Examples 93-95, using general procedure E, and reagents listed below.















Example
R1COOH







93
2,4-dimethyl-1-oxy-nicotinic acid


94
2,6-dimethyl-4-pyridin-4-yl-benzoic acid


95
4,6-dimethyl-pyrimidine-5-carboxylic acid









EXAMPLE 93




COMPOUND 93: N-(3-{4-[(4-Cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White foam. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.6 Hz), 1.21-1.48 (m, 2H), 1.56-1.69 (m, 1H), 1.74-1.88 (m, 3H), 2.20-2.28 (m, 1H), 2.29 (s, 3H), 2.39 (s, 3H), 2.54-2.63 (m, 1H), 2.76-2.94 (m, 3H), 3.35-3.47 (m, 1H), 3.65-3.81 (m, 2H), 4.26 (s, 2H), 6.60 (d, 2H, J=8.9 Hz), 6.84-7.03 (m, 4H), 7.27-7.34 (m, 1H), 7.40 (d, 2H, J=8.9 Hz), 7.96 (d, 1H, J=6.6 Hz), 8.38 (br s, 1H). ESI-MS m/z 530 (MH)+.
EXAMPLE 94




COMPOUND 94: N-(3-{4-[(4-Cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.08-1.35 (m, 2H), 1.56-1.62 (m, 1H), 1.74-1.85 (m, 3H), 2.20 (t, 1H, J=12.0 Hz), 2.40 (s, 6H), 2.58 (t, 1H, J=10.8 Hz), 2.78-2.95 (m, 3H), 3.32-3.37 (m, 1H), 3.65-3.73 (m, 1H), 3.82-3.86 (m, 1H), 3.89 (s, 2H), 6.50 (d, 2H, J=8.7 Hz), 6.58 (d, 1H, J=9.6 Hz), 6.64 (d, 1H, J=7.5 Hz), 6.84-6.90 (m, 1H), 7.11-7.19 (m, 1H), 7.31 (s, 2H), 7.37 (d, 2H, J=8.4 Hz), 7.47 (d, 2H, J=5.1 Hz), 7.95 (br s, 1H), 8.67 (d, 2H, J=4.8 Hz). ES-MS m/z 590 (M+H).
EXAMPLE 95




COMPOUND 95: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.3 Hz), 1.53-1.67 (m, 2H), 1.69-1.85 (m, 4H), 2.16-2.27 (m, 1H), 2.52-2.27 (m, 1H), 2.76-2.96 (m, 3H), 3.39-3.50 (m, 1H), 3.66-3.86 (m, 2H), 4.58 (s, 2H), 6.65 (d, 2H, J=8.4 Hz), 6.88-6.99 (m, 2H), 7.03 (d, 1H, J=7.5 Hz), 7.22-7.37 (m, 2H), 7.42 (d, 2H, J=8.4 Hz), 8.02 (br s, 1H), 8.30 (d, 1H, J=3.6 Hz), 8.53 (dd, 1H, J=8.7, 8.7 Hz). ES-MS m/z 515 (M+H).
Scheme 7 describes the preparation of Examples 96-99, using various general procedures previously described, and reagents listed below.















Example
R1COOH







96
4,6-dimethyl-pyrimidine-5-carboxylic acid


97
2,6-dimethylbenzoic acid


98
2,4-dimethyl-1-oxy-nicotinic acid


99
4-methylnicotinic acid









EXAMPLE 96




COMPOUND 96: 4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid
Using general procedure A, 4-(4-aminophenoxy)-benzoic acid methyl ester (Fokin; et al., Chem. Abstr., 72, 12294, 1970) (556 mg, 2.29 mmol) and 1-Boc-4-piperidone (478 mg, 2.40 mmol) gave 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (917 mg, 94%) as a crystalline solid.
Using general procedure H, the above aniline (550 mg, 1.29 mmol) and benzyl bromide (265 mg, 1.55 mmol) gave 4-{benzyl-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (660 mg, 99%) as a colorless oil.
Using general procedure C with the above carbamate (660 mg, 1.28 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (522 mg, 2.40 mmol) and then using general procedure D gave 4-(4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-phenoxy)-benzoic acid methyl ester (341 mg, 56% over 3 steps) as a colorless oil.
COMPOUND 96 was isolated as an off-white solid. 1H NMR (CDCl3) δ 1.15 (d, 3H, J=5.4 Hz), 1.61-1.79 (m, 3H), 1.82-2.17 (m, 3H), 2.39-2.52 (m, 1H), 2.48 (s, 6H), 2.67-2.79 (m, 1H), 2.95-3.14 (m, 2H), 3.21-3.47 (m, 2H), 3.56-3.77 (m, 2H), 4.11-4.22 (m, 2H), 6.69 (d, 2H, J=7.8 Hz), 6.78-6.88 (m, 4H), 7.16-7.31 (m, 5H), 7.68 (d, 2H, J=7.5 Hz), 8.74 (br s, 1H), 8.86 (s, 1H). ES-MS m/z 608 (M+H).
EXAMPLE 97




COMPOUND 97: 4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-benzoic acid
White solid. 1H NMR (CD3OD) δ 1.40 (d, 3H, J=6.6 Hz), 1.80-1.93 (m, 1H), 1.96-2.21 (m, 5H), 2.29 (s, 6H), 3.12-3.26 (m, 2H), 3.36-3.60 (m, 5H), 4.03-4.14 (m, 1H), 4.44 (s, 2H), 6.82-6.89 (m, 6H), 7.04 (d, 2H, J=7.5 Hz), 7.14-7.21 (m, 2H), 7.24-7.30 (m, 4H), 7.90 (d, 2H, J=8.4 Hz). ES-MS m/z 606 (M+H).
EXAMPLE 98




COMPOUND 98: 4-{4-[Benzyl-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid
Beige solid. 1H NMR (MeOH-d4) δ1.19 (d, 3H, J=6.6 Hz), 1.65-1.87 (m, 3H), 1.92-2.05 (m, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.58-2.68 (m, 1H), 2.74-2.84 (m, 1H), 2.95-3.12 (m, 3H), 3.38-3.58 (m, 2H), 3.78-3.89 (m, 1H), 4.40 (s, 2H), 6.76-6.87 (m, 6H), 7.14-7.21 (m, 1H), 7.23-7.31 (m, 5H), 7.81-7.91 (m, 2H), 8.23 (d, 1H, J=6.0 Hz). ESI-MS m/z 623 (MH)+.
EXAMPLE 99




COMPOUND 99: 4-{4-[Benzyl-(1-{1-methyl-3-[(4-methyl-pyridine-3-carbonyl)-amino]-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid
White solid. 1H NMR (CD3OD) δ 1.34 (d, 3H, J=6.6 Hz), 1.75-1.87 (m, 1H), 1.94-2.20 (m, 5H), 2.45 (s, 3H), 2.97-3.19 (m, 2H), 3.39-3.60 (m, 5H), 3.94-4.06 (m, 1H), 4.41 (s, 2H), 6.77-6.86 (m, 6H), 7.12-7.28 (m, 5H), 7.33 (d, 1H, J=5.1 Hz), 7.87 (d, 2H, J=8.1 Hz), 8.43 (d, 1H, J=4.2 Hz), 8.52 (s, 1H). ES-MS m/z 593 (M+H).
EXAMPLE 100




COMPOUND 100: 4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzyl]-benzoic acid
A solution of 4-(4-nitro-benzoyl)-benzoic acid (Dinsmore, Christopher J.; et al., Bioorg. Med. Chem. Lett., 7, 10, 1997, 1345-1348) (4.00 g, 14.7 mmol) and sulfuric acid (1.2 mL) in MeOH (40 mL) was heated at reflux for 18 h. The mixture was filtered and after work-up gave 4-(4-nitro-benzoyl)-benzoic acid methyl ester as a yellow solid (3.97 g, 94%).
The above substrate (3.23 g, 11.3 mmol) in MeOH (40 mL) was flushed with N2 in a Parr flask. 10% Pd/C (200 mg) was added and the mixture was hydrogenated at 45 psi H2 for 20 h. The mixture was filtered through Celite® and concentrated to give 4-(4-amino-benzyl)-benzoic acid methyl ester as pink crystals (660 mg, 24%) and 4-[(4-amino-phenyl)-hydroxy-methyl]-benzoic acid methyl ester as yellow crystals (2.07 g, 71%) following purification.
Using general procedure A, 4-(4-amino-benzyl)-benzoic acid methyl ester (0.66 g, 2.7 mmol) and 1-Boc-4-piperidone (545 mg, 2.74 mmol) gave 4-[4-(4-methoxycarbonyl-benzyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (434 mg, 36%).
Using general procedure H, the above amine (434 mg, 1.02 mmol) and benzyl bromide (0.18 mL, 1.5 mmol) gave 4-{benzyl-[4-(4-methoxycarbonyl-benzyl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (444 mg, 84%).
Using general procedure C with the carbamate from above (444 mg, 0.863 mmol), and then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (375 mg, 1.73 mmol) and then using general procedure D gave 4-(4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzyl)-benzoic acid methyl ester as a yellow oil (146 mg, 35% over 3 steps).
Using general procedure E, the above amine (124 mg, 0.255 mmol) and 2,6-dimethylbenzoic acid (46 mg, 0.31 mmol) gave 4-[4-(benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzyl]-benzoic acid methyl ester as a yellow foam (133 mg, 84%).
Using general procedure K, the above methyl ester (106 mg, 0.172 mmol) gave COMPOUND 100 as a yellow foam (100 mg, 96%). 1H NMR (CD3OD) δ 1.34 (d, 3H, J=6.3 Hz), 1.76-2.18 (m, 6H), 2.26 (s, 6H), 3.06 (m, 2H), 3.30-3.57 (m, 5H), 3.81 (s, 2H), 3.99 (m, 1H), 4.24 (s, 2H), 6.67 (d, 2H, J=8.4 Hz), 6.94 (d, 2H, J=8.1 Hz), 7.01 (d, 2H, J=7.5 Hz), 7.13 (m, 8H), 7.81 (d, 2H, J=7.8 Hz). 13C NMR (CDCl3) δ 13.15, 19.67, 27.34, 27.96, 31.79, 37.91, 41.27, 45.13, 50.13, 51.34, 54.91, 59.36, 114.18, 126.62, 126.98, 127.80, 128.82, 128.92, 129.85, 130.06, 130.29, 130.92, 134.35, 138.23, 140.59, 146.48, 147.58, 171.27, 171.81. ES-MS t/z 604 (M+H). Anal. Calcd. for C39H45N3O3.0.6CH2Cl2: C, 72.64; H, 7.11; N, 6.42. Found. C, 72.30; H, 7.11; N, 6.45.
EXAMPLE 101




COMPOUND 101: 4-[4-(Benzyl-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoyl]-benzoic acid
Using general procedure A, 4-[(4-amino-phenyl)-hydroxy-methyl]-benzoic acid methyl ester (see EXAMPLE 100) (1.40 g, 5.44 mmol) and 1-Boc-4-piperidone (1.63 g, 8.18 mmol) gave 4-{4-[hydroxy-(4-methoxycarbonyl-phenyl)-methyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester as a pale solid (2.04 g, 85%).
Using general procedure H, the above amine (2.04 g, 4.63 mmol) and benzyl bromide (0.77 mL, 6.5 mmol) gave the alcohol (444 mg, 0.837 mmol), which was subsequently oxidized with MnO2 (85%, 856 mg, 8.37 mmol) in CH2Cl2 (8.4 mL) to give 4-{benzyl-[4-(4-methoxycarbonyl-benzoyl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (381 mg, 13% over 2 steps) following filtration through Celite®.
Using general procedure C with the carbamate from above (381 mg, 0.721 mmol), then general procedure I with the resulting amine followed by general procedure J gave the crude primary amine that was used in the next reaction without purification.
The above substrate (249 mg) and MnO2 (85%, 227 mg, 2.21 mmol) in CH2Cl2 (9 mL) were stirred at room temperature for 4 days. The mixture was filtered through Celite®V and concentrated to give 4-(4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzoyl)-benzoic acid methyl ester as a yellow foam (92 mg, 25% over 4 steps) following purification.
Using general procedure E with the above amine (46 mg, 0.092 mmol) and 2,6-dimethylbenzoic acid (17 mg, 0.11 mmol) followed by general procedure K with the resulting ester gave COMPOUND 101 as a yellow powder (22 mg, 48% over 2 steps). 1H NMR (CDCl3+CD3OD) δ 1.05 (d, 3H, J=5.7 Hz), 1.52 (m, 3H), 1.76-1.97 (m, 3H), 2.19 (s, 6H), 2.39 (m, 1H), 2.67 (m, 1H), 2.91 (m, 3H), 3.26 (m, 1H), 3.61 (m, 1H), 3.85 (m, 1H), 4.11 (s, 2H), 6.54 (d, 2H, J=8.1 Hz), 6.89 (d, 2H, J=7.2 Hz), 7.02 (m, 3H), 7.16 (m, 3H), 7.53 (m, 4H), 7.95 (d, 2H, J=6.9 Hz). 13C NMR (CDCl3+CD3OD) δ 13.20, 19.10, 28.29, 29.09, 31.02, 38.54, 44.54, 51.27, 55.08, 59.79, 111.77, 125.19, 125.99, 127.06, 127.53, 128.75, 128.89, 129.02, 129.31, 133.02, 134.06, 137.80, 137.95, 138.65, 141.26, 152.68, 171.24, 173.21, 195.46. ES-MS m/z 618 (M+H). Anal. Calcd. for C39H43N3O4.0.8CH2Cl2: C, 69.71; H, 6.56; N, 6.13. Found. C, 69.61; H, 6.48; N, 6.05.
EXAMPLE 102




COMPOUND 102: 4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzyl}-benzoic acid
Using general procedure E with 4-(4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzyl-amino}-benzyl)-benzoic acid methyl ester (see EXAMPLE 100) (79 mg, 0.16 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (30 mg, 0.20 mmol) followed by general procedure K with the resulting ester gave COMPOUND 102 as a yellow powder (59 mg, 70% over 2 steps). 1H NMR (CDCl3+CD3OD) δ 1.20 (d, 3H, J=6.0 Hz), 1.68 (m, 1H), 1.90 (m, 4H), 2.13 (m, 1H), 2.40 (s, 6H), 2.61 (m, 1H), 2.81 (m, 1H), 3.09-3.37 (m, 4H), 3.54 (m, 1H), 3.80 (m, 3H), 4.23 (s, 2H), 6.55 (d, 2H, J=7.8 Hz), 6.90 (d, 2H, J=7.8 Hz), 7.09 (m, 7H), 7.71 (d, 2H, J=7.5 Hz), 8.77 (s, 1H). 1H NMR (CDCl3+CD3OD) δ 12.71, 21.99, 27.18, 27.54, 31.62, 37.35, 41.10, 45.34, 50.14, 51.13, 54.40, 58.93, 114.26, 126.48, 126.91, 128.73, 128.87, 129.96, 130.02, 130.82, 131.69, 140.33, 146.24, 147.43, 157.34, 163.70, 167.59, 172.17. ES-MS m/z 606 (M+H). Anal. Calcd. for C37H43N5O3.0.7CH2Cl2: C, 68.07; H, 6.73; N, 10.53. Found. C, 68.09; H, 6.66; N, 10.49.
Scheme 8 describes the preparation of Examples 103-124, using various general procedures previously described, and reagents listed below.
















Example
R3*
R1COOH







103
Br
3,5-dichloroisonicotinic acid


104
CF3
3,5-dichloroisonicotinic acid


105
SMe
3,5-dichloroisonicotinic acid


106
CN
3,5-dichloroisonicotinic acid


107
COOMe
3,5-dichloroisonicotinic acid


108
Cl
3,5-dichloroisonicotinic acid


109
CONMe2
2,6-dimethylbenzoic acid


110
CONMe2
2,6-dimethyl-4-pyridin-4-yl-benzoic acid


111
NHCOMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


112
NHCOMe
2,6-dimethylbenzoic acid


113
O(CH2)2OMe
2,6-dimethylbenzoic acid


114
O(CH2)2OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


115
OCH2CONHNH2
2,6-dimethylbenzoic acid


116
OCH2CONHNH2
4,6-dimethyl-pyrimidine-5-carboxylic acid


117
OH
2,6-dimethylbenzoic acid


118
NHSO2Me
4,6-dimethyl-pyrimidine-5-carboxylic acid


119
OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


120
OMe
2,6-dimethylbenzoic acid


121
OMe
2,4-dimethyl-1-oxy-nicotinc acid


122
OCF3
2,6-dimethylbenzoic acid


123
OCF3
4,6-dimethyl-pyrimidine-5-carboxylic acid


124
OCF3
2,4-dimethyl-1-oxy-nicotinc acid









EXAMPLE 103




COMPOUND 103: N-(3-{4-[(4-Bromo-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.07-1.28 (m, 1H), 1.49-1.61 (m, 1H), 1.65-1.89 (m, 4H), 2.19 (t, 1H, J=11.3 Hz), 2.58 (t, 1H, J=11.3 Hz), 2.76-2.98 (m, 3H), 3.36 (t, 1H, J=10.0 Hz), 3.61 (t, 1H, J=11.7 Hz), 3.84 (s, 2H), 3.82-3.92 (m, 1H), 6.42 (d, 2H, J=6.6 Hz), 7.20 (d, 2H, J=8.8 Hz), 7.40-7.58 (m, 4H), 8.45 (s, 2H), 8.79 (s, 1H). 13C NMR (CDCl3) δ 13.8, 29.8, 30.8, 40.5, 43.9, 48.5, 52.3, 56.7, 60.6, 110.2, 113.2, 115.4, 115.7, 119.2, 129.5, 129.8, 130.1, 131.2, 132.4, 141.5, 143.6, 147.3, 148.0, 161.8. ES-MS m/z 616 (M+2)+. Anal. Calcd. for C29H30N5Cl2OBr.0.2CH2Cl2: C, 55.46; H, 4.85; N, 11.07; Cl, 13.45. Found. C, 55.69; H, 4.98; N, 10.95; Cl, 13.38.
EXAMPLE 104




COMPOUND 104: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White powder. 1H NMR (CDCl3) δ 0.98-1.12 (m, 1H), 1.04 (d, 3H, J=6.6 Hz), 1.15-1.29 (m, 1H), 1.52-1.63 (m, 1H), 1.74-1.88 (m, 3H), 2.18-2.27 (m, 1H), 2.57-2.60 (m, 1H), 2.80-2.99 (m, 3H), 3.32-3.43 (m, 1H), 3.70-3.92 (m, 2H), 3.95 (s, 2H), 6.56 (d, 2H, J=8.7 Hz), 7.38 (d, 2H, J=8.7 Hz), 7.43-7.49 (m, 3H), 7.54-7.59 (m, 1H), 8.48 (s, 2H), 8.67 (br s, 1H). 13C NMR (CDCl3) δ 13.36, 29.33, 30.34, 30.49, 39.87, 43.47, 47.88, 51.73, 55.72, 59.88, 112.19, 112.77, 118.68, 119.02 (q, J=32.6 Hz), 124.65 (q, J=270 Hz), 126.58 (q, J=3.7 Hz), 129.07, 129.44, 129.49, 130.53, 130.82, 140.55, 143.14, 147.50, 150.20 (q, J=1.2 Hz), 161.33. ESI-MS m/z 604 (MH)+, 606 (MH+2)+. Anal. Calcd. for C30H30Cl2F3N5O.0.3H2O: C, 59.08; H, 6.05; N, 11.48; Cl, 11.63. Found. C, 59.13; H, 5.10; N, 11.22; Cl, 11.87.
EXAMPLE 105




COMPOUND 105: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.97-1.21 (m, 2H), 1.02 (d, 2H, J=6.6 Hz), 1.51-1.57 (m, 1H), 1.78-1.82 (m, 3H), 2.19 (t, 1H, J=11.4 Hz), 2.39 (s, 3H), 2.59 (t, 1H, J=10.8 Hz), 2.80-2.96 (m, 3H), 3.31-3.39 (m, 1H), 3.60-3.67 (m, 1H), 3.84 (s, 2H), 3.84-3.89 (m, 1H), 6.50 (d, 2H, J=9.0 Hz), 7.16 (d, 2H, J=8.7 Hz), 7.42-7.58 (m, 4H), 8.47 (s, 2H), 8.87 (br s, 1H). 13C NMR (CDCl3) δ 13.41, 18.52, 29.38, 30.33, 30.51, 40.21, 43.49, 48.18, 52.02, 56.23, 60.32, 112.70, 113.99, 114.38, 118.91, 125.33, 129.15, 129.36, 129.82, 130.70, 130.85, 141.44, 143.26, 146.59, 147.58, 161.38. ES-MS m/z 582 (M+H). Anal. Calcd. for C30H33N5OSCl2.0.4H2O: C, 61.09; H, 5.78; N, 11.87; S, 5.44; Cl, 12.02. Found. C, 61.05; H, 5.74; N, 12.13; S, 5.22; Cl, 12.20.
EXAMPLE 106




COMPOUND 106: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 4-aminobenzonitrile (1.19 g, 10.1 mmol) and 1-Boc-4-piperidone (2.05 g, 10.3 mmol) gave 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.58 g, 52%).
COMPOUND 106 was isolated as a white powder. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.6 Hz), 1.03-1.16 (m, 1H), 1.19-1.32 (m, 1H), 1.52-1.63 (m, 1H), 1.74-1.87 (m, 3H), 2.19-2.27 (m, 1H), 2.57-2.66 (m, 1H), 2.79-3.00 (m, 3H), 3.34-3.44 (m, 1H), 3.71-3.89 (m, 2H), 4.01 (s, 2H), 6.54 (d, 2H, J=9.0 Hz), 7.39-7.52 (m, 5H), 7.56-7.61 (m, 1H), 8.46 (br s, 1H), 8.48 (s, 2H). 13C NMR (CDCl3) δ 13.35, 29.35, 30.25, 30.64, 39.64, 43.46, 47.74, 51.50, 55.67, 59.55, 99.15, 112.49, 112.83, 118.55, 119.88, 129.03, 129.27, 129.60, 130.40, 130.95, 133.59, 139.84, 143.04, 147.47, 150.77, 161.34. ESI-MS m/z 561 (MH)+, 563 (MH+2)+. Anal. Calcd. for C30H30Cl2N6O.0.4CH2Cl2: C, 61.32; H, 5.21; N, 14.11; Cl, 16.67. Found. C, 61.27; H, 5.11; N, 13.74; Cl, 16.64.
EXAMPLE 107




COMPOUND 107: 4-[(3-Cyano-benzyl)-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester
White solid. 1H NMR (CDCl3) δ 0.97-1.25 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.54-1.59 (m, 1H), 1.69-1.82 (m, 3H), 2.23 (t, 1H, J=11.1 Hz), 2.61 (t, 1H, J=10.8 Hz), 2.81-2.96 (m, 3H), 3.33-3.41 (m, 1H), 3.76-3.87 (m, 2H), 3.83 (s, 3H), 3.99 (s, 2H), 6.52 (d, 2H, J=9.0 Hz), 7.43-7.49 (m, 3H), 7.54-7.61 (m, 1H), 7.82 (d, 2H, J=9.0 Hz), 8.47 (s, 2H), 8.64 (br s, 1H). 13C NMR (CDCl3) δ 13.83, 29.87, 30.90, 40.42, 43.08, 43.90, 48.26, 52.03, 52.22, 56.09, 60.44, 112.21, 113.26, 119.13, 129.54, 129.92, 130.98, 131.28, 131.87, 140.95, 143.59, 147.99, 151.78, 161.80, 167.39. ES-MS m/z 595 (M+2). Anal. Calcd. for C31H33N5Cl2O3.0.4CH2Cl2: C, 60.01; H, 5.42; N, 11.14. Found. C, 59.91; H, 5.38; N, 10.84.
EXAMPLE 108




COMPOUND 108: 3,5-Dichloro-N-(3-{4-[(4-chloro-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, 4-chloroaniline (640 mg, 5.0 mmol) and 1-Boc-4-piperidone (1.0 g, 5.0 mmol) afforded 4-(4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.21 g, 78%).
COMPOUND 108 was isolated as a white solid. 1H NMR (CDCl3) δ 0.94-1.22 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.53-1.57 (m, 1H), 1.78-1.82 (m, 3H), 2.19 (t, 1H, J=11.4 Hz), 2.59 (t, 1H, J=10.8 Hz), 2.80-2.96 (m, 3H), 3.32-3.40 (m, 1H), 3.57-3.65 (m, 1H), 3.83 (s, 2H), 3.83-3.90 (m, 1H), 6.47 (d, 2H, J=8.7 Hz), 7.08 (d, 2H, J=8.4 Hz), 7.46 (m, 3H), 7.54 (br s, 1H), 8.46 (s, 2H), 8.82 (br s, 1H). 13C NMR (CDCl3) δ 13.41, 29.36, 30.40, 40.11, 43.51, 48.16, 51.93, 56.41, 60.17, 112.72, 114.89, 118.85, 122.69, 129.13, 129.41, 129.75, 130.78, 141.16, 143.22, 146.54, 147.56, 161.38. ES-MS m/z 570 (M+H). Anal. Calcd. for C29H30N5Cl3O.0.1CH2Cl2.0.1C3H7NO: C, 60.18; H, 5.31; N, 12.17; Cl, 19.34. Found. C, 60.26; H, 5.41; N, 12.04; Cl, 19.05.
EXAMPLE 109




COMPOUND 109: N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure A, 4-amino-N,N-dimethyl-benzamide (Schiemenz, G. P.; Stein, G., Tetrahedron, 26, 1970, 2007-2026) (619 mg, 3.77 mmol) and 1-Boc-4-piperidone (901 mg, 4.52 mmol) gave 4-(4-dimethylcarbamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.31 g).
COMPOUND 109 was isolated as a white solid. 1H NMR (CDCl3) δ 0.93-1.21 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.51-1.55 (m, 1H), 1.70-1.75 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.57 (t, 1H, J=11.7 Hz), 2.75-2.91 (m, 3H), 3.03 (s, 6H), 3.25-3.33 (m, 1H), 3.64-3.71 (m, 1H), 3.82-3.91 (m, 1H), 3.86 (s, 2H), 6.50 (d, 2H, J=8.4 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.02-7.07 (m, 1H), 7.25-7.28 (m, 2H), 7.41-7.42 (m, 3H), 7.52-7.55 (m, 1H), 8.29 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.55, 29.42, 30.73, 31.40, 40.17, 43.98, 48.31, 52.46, 56.43, 60.85, 112.56, 113.02, 119.29, 124.95, 127.70, 128.80, 129.72, 130.20, 131.00, 131.14, 134.51, 139.03, 142.01, 149.62, 170.23, 172.05. ES-MS m/z 566 (M+H). Anal. Calcd. for C35H43N5O2.0.3CH2Cl2: C, 71.71; H, 7.43; N, 11.85. Found. C, 71.57; H, 7.46; N, 11.63.
EXAMPLE 110




COMPOUND 110: N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
White solid. 1H NMR (CDCl3) δ 0.97-1.27 (m, 5H), 1.53-1.60 (m, 1H), 1.70-1.98 (m, 3H), 2.16-2.24 (m, 1H), 2.40 (s, 6H), 2.54-2.61 (m, 1H), 2.77-2.93 (m, 3H), 3.02 (s, 6H), 3.31-3.38 (m, 1H), 3.65-3.73 (m, 1H), 3.85 (br s, 3H), 6.45 (d, 2H, J=8.1 Hz), 7.08-7.10 (m, 1H), 7.22-7.31 (m, 6H), 7.42-7.48 (m, 3H), 8.10 (br s, 1H), 8.65 (s, 2H). 13C NMR (CDCl3) δ 13.83, 19.77, 29.49, 30.80, 31.74, 39.94, 44.15, 48.15, 52.31, 56.36, 60.42, 112.49, 113.00, 119.16, 121.74, 125.06, 126.34, 129.74, 129.93, 130.88, 130.94, 131.38, 135.76, 138.36, 139.67, 141.74, 147.78, 149.52, 150.91, 169.66, 171.99. ES-MS m/z 643 (M+H). Anal. Calcd. for C40H46N6O2.1.2CH2Cl2: C, 66.44; H, 6.55; N, 11.28. Found. C, 66.43; H, 6.55; N, 11.24.
EXAMPLE 111




COMPOUND 111: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, N-(4-amino-phenyl)-acetamide (Gowda, D. Channe; Gowda, Shankare, Indian J. Chem. Sect., 39, 9, 2000, 709-711) (675 mg, 4.49 mmol) and 1-Boc-4-piperidone (938 mg, 4.71 mmol) gave 4-(4-acetylamino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (923 mg, 62%).
COMPOUND 111 was isolated as a white foam. 1H NMR (CDCl3) δ 0.85-1.08 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.49-1.59 (m, 1H), 1.75-1.79 (m, 3H), 2.12 (s, 3H), 2.17 (t, 1H, J=10.8 Hz), 2.51 (s, 6H), 2.57 (t, 1H, J=12.0 Hz), 2.74-2.85 (m, 3H), 3.29-3.36 (m, 1H), 3.54-3.61 (m, 1H), 3.83-3.89 (m, 3H), 6.52 (d, 2H, J=8.4 Hz), 6.99 (br s, 1H), 7.22-7.26 (m, 2H), 7.40-7.45 (m, 1H), 7.51-7.56 (m, 3H), 8.65-8.67 (m, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 12.18, 20.62, 22.81, 27.99, 29.08, 29.53, 38.59, 42.42, 47.16, 50.58, 54.71, 55.41, 111.09, 113.09, 117.69, 120.69, 127.71, 128.00, 128.70, 129.26, 129.55, 129.81, 140.60, 143.81, 145.99, 156.16, 161.77, 165.04, 167.13. ES-MS m/z 554 (M+H). Anal. Calcd. for C32H39N7O2.0.9H2O: C, 67.44; H, 7.22; N, 17.20. Found. C, 67.47; H, 7.15; N, 17.09.
EXAMPLE 112




COMPOUND 112: N-(3-{4-[(4-Acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White foam. 1H NMR (CDCl3) δ 0.94-1.18 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.50-1.59 (m, 1H), 1.69-1.83 (m, 3H), 2.11 (s, 3H), 2.15 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.55 (t, 1H, J=11.1 Hz), 2.74-2.90 (m, 3H), 3.24-3.31 (m, 1H), 3.53-3.59 (m, 1H), 3.76 (s, 2H), 3.85-3.90 (m, 1H), 6.50 (d, 2H, J=8.7 Hz), 6.92-7.03 (m, 4H), 7.21 (d, 2H, J=8.7 Hz), 7.42-7.44 (m, 3H), 7.51 (br s, 1H), 8.40-8.42 (m, 1H). 13C NMR (CDCl3) δ 13.84, 19.54, 24.46, 29.40, 30.69, 31.25, 40.26, 44.01, 48.66, 52.54, 57.36, 60.92, 112.76, 114.70, 119.42, 122.40, 127.68, 128.81, 129.32, 129.60, 130.47, 130.84, 131.48, 134.45, 138.93, 142.67, 145.52, 168.88, 170.35. ES-MS m/z 552 (M+H). Anal. Calcd. for C34H41N5O2.0.7H2O: C, 72.36; H, 7.57; N, 12.41. Found. C, 72.36; H, 7.44; N, 12.30.
EXAMPLE 113




COMPOUND 113: N-[3-(4-{(3-Cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
Using general procedure A, 4-(2-methoxy-ethoxy)-phenylamine (Ishidate; Maruyoma, Chem. Abstr., 1952, 8810) (1.15 g, 6.84 mmol) and 1-Boc-4-piperidone (1.36 g, 6.83 mmol) afforded 4-[4-(2-methoxy-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (2.08 g, 86%).
COMPOUND 113 was isolated as a white solid. 1H NMR (CDCl3) δ 0.88-1.16 (m, 2H), 0.98 (d, 3H, J=6.3 Hz), 1.49-1.54 (m, 1H), 1.69-1.78 (m, 3H), 2.11 (t, 1H, J=11.4 Hz), 2.30 (s, 6H), 2.52 (t, 1H, J=10.8 Hz), 2.72-2.88 (m, 3H), 3.22-3.31 (m, 1H), 3.37-3.45 (m, 1H), 3.41 (s, 3H), 3.68 (t, 2H, J=4.8 Hz), 3.71 (s, 2H), 3.85-3.89 (m, 1H), 4.00 (t, 2H, J=4.5 Hz), 6.52 (d, 2H, J=8.1 Hz), 6.74 (d, 2H, J=7.8 Hz), 6.91-6.96 (m, 3H), 7.38-7.50 (m, 4H), 8.45-8.46 (m, 1H). 13C NMR (CDCl3) δ 13.39, 19.14, 29.08, 30.34, 30.91, 39.87, 43.61, 48.78, 52.20, 58.08, 59.16, 60.57, 67.76, 71.15, 112.33, 115.56, 116.60, 119.07, 127.25, 128.35, 129.02, 130.35, 130.39, 131.27, 134.05, 138.63, 142.54, 142.72, 151.65, 169.87. ES-MS m/z 569 (M+H). Anal. Calcd. for C35H44N4O3: C, 73.91; H, 7.80; N, 9.85. Found. C, 73.67; H, 7.81; N, 9.76.
EXAMPLE 114




COMPOUND 114: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
White solid. 1H NMR (CDCl3) δ 0.86-1.10 (m, 2H), 1.00 (d, 3H, J=5.7 Hz), 1.54 (d, 1H, J=12.0 Hz), 1.74-1.78 (m, 3H), 2.14 (t, 1H, J=12.0 Hz), 2.50 (s, 6H), 2.54 (t, 1H, J=12.0 Hz), 2.72-2.84 (m, 3H), 3.27-3.38 (m, 2H), 3.36 (s, 3H), 3.68 (t, 2H, J=4.2 Hz), 3.82 (m, 3H), 4.01 (t, 2H, J=4.5 Hz), 6.54 (d, 2H, J=8.1 Hz), 6.74 (d, 2H, J=8.1 Hz), 7.37-7.42 (m, 1H), 7.47-7.54 (m, 3H), 8.72 (br s, 1H), 8.82 (s, 1H). 13C NMR (CDCl3) δ 13.39, 21.95, 29.24, 30.45, 30.63, 40.10, 43.58, 49.13, 52.06, 57.80, 59.17, 60.38, 67.76, 71.14, 112.40, 115.62, 116.59, 117.10, 119.06, 129.13, 130.38, 130.48, 130.87, 131.37, 142.10, 142.52, 152.00, 157.53, 163.05, 166.32. ES-MS m/z 571 (M+H). Anal. Calcd. for C33H42N6O3.0.3CH2Cl2: C, 67.08; H, 7.20; N, 14.10. Found. C, 67.26; H, 7.35; N, 14.19.
EXAMPLE 115




COMPOUND 115: N-(3-{4-[(3-Cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure A, (4-amino-phenoxy)-acetic acid methyl ester (Oguchi, Minoru; et al., J. Med. Chem., 43, 16, 2000, 3052-3066) (860 mg, 4.72 mmol) and 1-Boc-4-piperidone (941 mg, 4.72 mmol) afforded 4-[4-(2-oxo-propoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.66 g, 96%).
COMPOUND 115 was isolated as a white solid. 1H NMR (CDCl3) δ 0.86-1.91 (m, 5H), 1.51-1.55 (m, 1H), 1.70-1.74 (m, 3H), 2.09-2.19 (m, 1H), 2.30 (s, 6H), 2.51-2.58 (m, 1H), 2.76-2.87 (m, 3H), 3.25-3.32 (m, 1H), 3.44-3.50 (m, 1H), 3.74 (s, 2H), 3.86 (br s, 3H), 4.45 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.0 Hz), 6.91-7.00 (m, 3H), 7.38-7.52 (m, 4H), 7.71 (s, 1H), 8.37 (br s, 1H). 13C NMR (CDCl3) δ 13.78, 19.57, 29.39, 30.65, 31.42, 40.17, 44.09, 48.96, 52.52, 58.12, 60.87, 68.04, 112.89, 116.00, 116.48, 127.67, 128.79, 129.56, 130.61, 130.90, 131.52, 134.48, 142.55, 144.05, 150.13, 169.29. ES-MS m/z 583 (M+H). Anal. Calcd. for C34H42N6O3.0.3CH2Cl2.0.2C6H14: C, 68.17; H, 7.32; N, 13.44. Found. C, 68.22; H, 7.31; N, 13.35.
EXAMPLE 116




COMPOUND 116: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.87-1.01 (m, 5H), 1.52-1.57 (m, 1H), 1.75-1.78 (m, 3H), 2.10-2.17 (m, 1H), 2.49 (s, 6H), 2.49-2.58 (m, 1H), 2.73-2.84 (m, 3H), 3.24-3.42 (m, 2H), 3.85-3.88 (m, 5H), 4.47 (s, 2H), 6.55 (d, 2H, J=7.5 Hz), 6.71 (d, 2H, J=7.5 Hz), 7.39-7.55 (m, 4H), 7.88 (br s, 1H), 8.66 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.79, 22.30, 29.58, 30.74, 31.07, 38.68, 40.41, 44.00, 49.61, 52.40, 57.91, 60.67, 68.07, 112.86, 115.97, 117.36, 119.38, 129.62, 130.61, 130.98, 131.20, 131.64, 142.16, 143.73, 150.65, 157.88, 163.44, 166.66, 169.27. ES-MS m/z 585 (M+H). Anal. Calcd. for C32H40N8O3.0.3CH2Cl2.0.08C6H14: C, 63.80; H, 6.81; N, 18.16. Found. C, 63.66; H, 6.85; N, 18.14.
EXAMPLE 117




COMPOUND 117: N-(3-{4-[(3-Cyano-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure A, 1-Boc-4-piperidone (2.52 g, 12.66 mmol) and acetic acid 4-amino-phenyl ester (Bargota, Rakesh S.; et al., Bioorg. Med. Chem. Lett., 13, 10, 2003, 1623-1626) (2.95 g, 19.52 mmol) afforded 4-(4-acetoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.41 g, 76%).
COMPOUND 117 was isolated as a white solid. 1H NMR (CDCl3) δ 0.92-1.13 (m, 2H), 0.98 (d, 3H, J=6.3 Hz), 1.50-1.54 (m, 1H), 1.69-1.73 (m, 3H), 2.11 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.51 (t, 1H, J=11.1 Hz), 2.72-2.88 (m, 3H), 3.24-3.37 (m, 2H), 3.69 (s, 2H), 3.87-3.90 (m, 1H), 4.80 (br s, 1H), 5.30 (s, 1H), 6.49 (d, 2H, J=8.4 Hz), 6.63 (d, 2H, J=8.1 Hz), 6.93-6.96 (m, 3H), 7.36-7.51 (m, 4H), 8.48 (br s, 1H). 13C NMR (CDCl3) δ 13.38, 19.14, 29.08, 30.29, 30.83, 36.56, 39.93, 43.64, 48.99, 52.15, 58.49, 60.52, 112.26, 115.95, 117.52, 119.10, 127.26, 128.42, 128.98, 130.32, 130.53, 131.40, 134.05, 138.42, 142.17, 142.59, 148.97, 170.09. ES-MS m/z 511 (M+H). Anal. Calcd. for C32H38N4O2.0.8H2O: C, 73.45; H, 7.59; N, 10.71. Found. C, 73.52; H, 7.51; N, 11.06.
EXAMPLE 118




COMPOUND 118: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methanesulfonylamino-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 4-nitroaniline (5.04 g, 36.5 mmol) in CH2Cl2 (100 ml) cooled to 0° C. were added Et3N (6.61 mL, 47.4 mmol) and MsCl (3.39 mL, 43.8 mmol) and the mixture was stirred at room temperature overnight to give dimethanesulfonyl-(4-nitro-phenyl)-amine as a yellow solid (10.46 g, 98%) following work-up.
The above substrate (9.2 g, 31 mmol), MeOH (100 mL) and 1N NaOH (150 mL) were stirred at room temperature for 2 hours to give N-(4-nitro-phenyl)-methanesulfonamide as a yellow solid (6.35 g, 94%) following an acidic work-up.
Using general procedure H, the above substrate (1.51 g, 6.98 mmol) and bromomethyl methyl ether (0.86 mL, 10.5 mmol) gave N-methoxymethyl-N-(4-nitro-phenyl)-methanesulfonamide (1.75 g, 96%).
A solution of the above substrate (1.72 g, 6.60 mmol) in MeOH (40 ml) was flushed with N2 in a Parr flask. 10% Pd/C (175 mg) was added and the mixture was hydrogenated at 30 psi H2 for 1 hour. The mixture was filtered through Celite®, the cake was rinsed with MeOH and the combined filtrate was concentrated under reduced pressure to give N-(4-amino-phenyl)-N-methoxymethyl-methanesulfonamide as a white solid (1.47 g, 97%).
Using general procedure A, the above aniline (1.47 g, 6.38 mmol) and 1-Boc-4-piperidone (1.33 g, 6.70 mmol) afforded 4-[4-(methanesulfonyl-methoxymethyl-amino)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.17 g, 83%).
COMPOUND 118 was isolated as a white foam. 1H NMR (CDCl3) δ 0.86-1.15 (m, 2H), 1.02 (d, 3H, J=5.4 Hz), 1.49-1.58 (m, 1H), 1.75-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.58 (t, 1H, J=11.7 Hz), 2.75-2.92 (m, 3H), 2.92 (s, 3H), 3.33-3.37 (m, 1H), 3.59-3.65 (m, 1H), 3.76-3.88 (m, 1H), 3.89 (s, 2H), 6.09 (br s, 1H), 6.51 (d, 2H, J=7.8 Hz), 7.05 (d, 2H, J=7.5 Hz), 7.46-7.55 (m, 4H), 8.60 (br s, 1H), 8.88 (s, 1H). 13C NMR (CDCl3) δ 13.86, 22.33, 29.57, 30.78, 31.11, 39.18, 40.45, 43.95, 48.76, 52.33, 56.55, 60.61, 112.99, 114.44, 119.34, 125.71, 126.68, 129.81, 130.19, 131.10, 131.28, 141.87, 147.25, 157.91, 163.53, 166.66. ES-MS m/z 590 (M+H). Anal. Calcd. for C31H39N7O3S.0.3H2O.0.3CH2Cl2: C, 60.57; H, 6.53; N, 15.80; S, 5.17. Found. C, 60.63; H, 6.64; N, 15.66; S, 5.12.
EXAMPLE 119




COMPOUND 119: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
COMPOUND 119 was isolated as a white solid. 1H NMR (CDCl3) δ 0.80-1.13 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.49-1.57 (m, 1H), 1.71-1.81 (m, 3H), 2.07-2.19 (m, 1H), 2.47-2.59 (m, 1H), 2.52 (s, 6H), 2.70-2.90 (m, 3H), 3.25-3.46 (m, 2H), 3.72 (s, 3H), 3.80 (s, 2H), 3.82-3.92 (m, 1H), 6.57 (d, 2H, J=9.3 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.37-7.58 (m, 4H), 8.75 (br s, 1H), 8.83 (s, 1H). ES-MS m/z 527 (M+H).
EXAMPLE 120




COMPOUND 120: N-(3-{4-[(3-Cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.87-1.19 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.47-1.58 (m, 1H), 1.48-1.66 (m, 3H), 2.06-2.17 (m, 1H), 2.31 (s, 6H), 2.46-2.58 (m, 1H), 2.70-2.91 (m, 3H), 3.21-3.46 (m, 2H), 3.65-3.74 (m, 5H), 3.84-3.95 (m, 1H), 6.55 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.7 Hz), 6.89-7.01 (m, 3H), 7.35-7.52 (m, 4H), 8.44 (br s, 1H). ES-MS m/z 525 (M+H).
EXAMPLE 121




COMPOUND 121: N-(3-{4-[(3-Cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.94-1.28 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.51-1.63 (m, 1H), 1.71-1.85 (m, 3H), 2.10-2.20 (m, 1H), 2.29 (s, 3H), 2.44 (s, 3H), 2.47-2.58 (m, 1H), 2.71-2.89 (m, 3H), 3.28-3.50 (m, 2H), 3.72 (s, 3H), 3.73-3.84 (m, 1H), 3.99 (m, 2H), 6.61 (d, 2H, J=8.7 Hz), 6.73 (d, 2H, J=8.7 Hz), 6.84 (d, 1H, J=6.6 Hz), 7.41 (dd, 1H, J=7.8, 7.2 Hz), 7.55 (s, 1H), 7.60 (d, 1H, J=7.8 Hz), 7.92 (d, 1H, J=6.6 Hz), 8.66 (br s, 1H). ES-MS m/z 542 (M+H).
EXAMPLE 122




COMPOUND 122: N-(3-{4-[(3-Cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure A, 4-(trifluoromethoxy)aniline (2.09 g, 11.8 mmol) and 1-Boc-4-piperidone (2.6 g, 13.0 mmol) afforded 4-(4-trifluoromethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.56 g, 60%).
COMPOUND 122 was isolated as a white solid. 1H NMR (CDCl3) δ 0.91-1.23 (m, 2H), 1.00 (d, 3H, J=6.4 Hz), 1.47-1.57 (m, 1H), 1.69-1.81 (m, 3H), 2.16 (t, 1H, J=11.7 Hz), 2.31 (s, 6H), 2.56 (t, 1H, J=12.0 Hz), 2.74-2.91 (m, 3H), 3.25-3.33 (m, 1H), 3.55-3.65 (m, 1H), 3.81 (s, 2H), 3.82-3.92 (m, 1H), 6.49 (d, 2H, J=8.8 Hz), 6.93-7.05 (m, 5H), 7.40-7.46 (m, 3H), 7.51-7.56 (m, 1H), 8.31 (br s, 1H). ES-MS m/z 579 (M+H).
EXAMPLE 123




COMPOUND 123: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.88-1.15 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.48-1.57 (m, 1H), 1.71-1.81 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.58 (t, 1H, J=11.4 Hz), 2.75-2.89 (m, 3H), 3.29-3.37 (m, 1H), 3.58-3.65 (m, 1H), 3.82-3.89 (m, 1H), 3.90 (s, 2H), 6.50 (d, 2H, J=9.3 Hz), 7.00 (d, 2H, J=8.4 Hz), 7.43-7.58 (m, 4H), 8.56 (br s, 1H), 8.87 (s, 1H). ES-MS m/z 581 (M+H).
EXAMPLE 124




COMPOUND 124: N-(3-{4-[(3-Cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CD3OD) δ 1.12-1.20 (m, 3H), 1.35-1.39 (m, 1H), 1.64-1.78 (m, 3H), 1.90-1.96 (m, 3H), 2.34 (s, 3H), 2.46 (s, 3H), 2.89-3.07 (m, 3H), 3.42-3.58 (m, 2H), 3.87-3.96 (m, 1H), 4.51 (s, 2H), 6.76 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.6 Hz), 7.30 (d, 1H, J=7.3 Hz), 7.49 (d, 1H, J=7.0 Hz), 7.57-7.62 (m, 3H), 8.25 (d, 1H, J=6.2 Hz). ES-MS m/z 596 (M+H).
EXAMPLE 125




COMPOUND 125: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 105) (484 mg, 1.1 mmol) in MeOH (20 mL) cooled to 0° C. was added OXONE® (680 mg, 1.1 mmol) and the mixture was stirred at 0° C. for 1.5 hours. Work-up and purification afforded 4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (166 mg, 32%) as a white solid and 4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (264 mg, 53%) as a white solid.
Using general procedure C with 4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (260 mg, 0.57 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (270 mg, 1.2 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methanesulfinyl-phenyl)-amino]-methyl}-benzonitrile as a white solid (133 mg, 55% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (117 mg, 0.61 mmol) and the above amine (130 mg, 0.31 mmol) afforded COMPOUND 125 as a white solid (77 mg, 42%). 1H NMR (CDCl3) δ 1.01-1.24 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 1.55-1.60 (m, 1H), 1.79-1.82 (m, 3H), 2.23 (t, 1H, J=11.7 Hz), 2.62 (t, 1H, J=11.4 Hz), 2.67 (s, 3H), 2.82-2.97 (m, 3H), 3.33-3.40 (m, 1H), 3.76-3.86 (m, 2H), 3.96 (s, 2H), 6.62 (d, 2H, J=8.4 Hz), 7.43-7.56 (m, 5H), 8.47 (s, 2H), 8.65 (br s, 1H). 13C NMR (CDCl3) δ 13.46, 26.45, 30.46, 30.53, 40.02, 43.52, 43.70, 47.97, 51.84, 53.44, 55.91, 60.05, 112.89, 113.18, 118.78, 126.69, 129.17, 129.54, 130.62, 130.93, 132.46, 140.53, 143.23, 147.59, 150.32, 161.39. ES-MS m/z 598 (M+H). Anal. Calcd. for C30H33N5Cl2O2S.0.5CH2Cl2: C, 57.15; H, 5.35; N, 10.92; Cl, 16.59; S, 5.00. Found. C, 57.22; H, 5.27; N, 10.98; Cl, 16.30; S, 4.93.
EXAMPLE 126




COMPOUND 126: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure C with 4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 125) (166 mg, 0.35 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (147 mg, 0.68 mmol) and then using general procedure D gave 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methanesulfonyl-phenyl)-amino]-methyl}-benzonitrile as a white solid (94 mg, 61% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (79 mg, 0.41 mmol) and the above amine (91 mg, 0.21 mmol) afforded COMPOUND 126 as a white solid (70 mg, 55%). 1H NMR (CDCl3) δ 1.02-1.31 (m, 2H), 1.04 (d, 3H, J=6.3 Hz), 1.54-1.59 (m, 1H), 1.77-1.81 (m, 3H), 2.24 (t, 1H, J=11.4 Hz), 2.63 (t, 1H, J=11.1 Hz), 2.83-2.94 (m, 3H), 2.99 (s, 3H), 3.36-3.41 (m, 1H), 3.78-3.85 (m, 2H), 4.03 (s, 2H), 6.59 (d, 2H, J=8.4 Hz), 7.40-7.60 (m, 4H), 7.67 (d, 2H, J=8.4 Hz), 8.48 (br s, 3H). 13C NMR (CDCl3) δ 13.46, 29.46, 30.41, 30.66, 39.91, 43.50, 44.99, 47.86, 51.72, 53.44, 55.91, 59.90, 112.20, 113.00, 118.69, 127.95, 129.16, 129.38, 129.72, 130.55, 131.08, 139.85, 143.17, 147.61, 151.69, 161.40. ES-MS m/z 614 (M+H). Anal. Calcd. for C30H33N5Cl2O3S.0.5CH2Cl2: C, 55.75; H, 5.22; N, 10.66; Cl, 16.19; S, 4.88. Found. C, 55.85; H, 5.18; N, 10.69; Cl, 15.95; S, 4.85.
EXAMPLE 127




COMPOUND 127: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
4-Amino-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 63) (400 mg, 2.0 mmol) and 3-cyanobenzaldehyde (262 mg, 2.0 mmol) in MeOH (6 mL) were stirred at room temperature overnight. NaBH4 (151 mg, 4.0 mmol) was added and the mixture was stirred for an additional 30 minutes to give the crude material after work-up.
The above secondary amine (480 mg), 1-iodo-4-nitrobenzene (416 mg, 1.67 mmol), sodium tert-butoxide (205 mg, 2.13 mmol), (+/−) BINAP (93 mg, 0.15 mmol), Pd2(dba)3 (70 mg, 0.076 mmol) and toluene (3.5 mL) were flushed with N2 for 5 minutes. The mixture was heated at 100° C. for 20 hours. A second aliquot of 1-iodo-4-nitrobenzene (416 mg, 1.67 mmol) was added and the mixture heated at 100° C. for 3 days to afford 4-[(3-cyano-benzyl)-(4-nitro-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (170 mg, 26%) after aqueous work-up and purification.
Using general procedure C with the above substrate (170 mg, 0.39 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (129 mg, 0.59 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-nitro-phenyl)-amino]-methyl}-benzonitrile as a yellow solid (41 mg, 26% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (38 mg, 0.20 mmol) and the above amine (41 mg, 0.10 mmol) afforded COMPOUND 127 as a yellow solid (38 mg, 66%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.06-1.37 (m, 2H), 1.52-1.61 (m, 1H), 1.73-1.89 (m, 3H), 2.19-2.30 (m, 1H), 2.57-2.68 (m, 1H), 2.80-3.00 (m, 3H), 3.33-3.46 (m, 1H), 3.76-3.89 (m, 2H), 4.10 (s, 2H), 6.52 (d, 2H, J=9.0 Hz), 7.37-7.62 (m, 4H), 8.05 (d, 2H, J=8.7 Hz), 8.34 (br s, 1H), 8.48 (s, 2H). 13C NMR (CDCl3) δ 13.47, 29.57, 30.42, 30.80, 39.74, 43.52, 47.99, 51.57, 56.27, 59.64, 111.52, 113.06, 118.55, 126.17, 129.14, 129.32, 129.78, 130.46, 131.17, 138.11, 139.46, 143.13, 147.60, 152.75, 161.43. ES-MS m/z 581 (M+H). Anal. Calcd. for C29H30N6Cl2O3.0.1CH2Cl2: C, 59.24; H, 5.16; N, 14.24; Cl, 13.22. Found. C, 59.10; H, 5.19; N, 14.13; Cl, 13.39.
EXAMPLE 128




COMPOUND 128: 3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure K with COMPOUND 107 (36 mg, 0.06 mmol) followed by general procedure E with the resulting acid and dimethylamine (2.0M in THF, 31 μL, 0.062 mmol) afforded COMPOUND 128 as a white solid (18 mg, 50% over 2 steps). 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.29 (d, 3H, J=5.7 Hz), 1.54-1.58 (m, 1H), 1.71-1.80 (m, 3H), 2.17-2.25 (m, 1H), 2.56-2.64 (m, 1H), 2.81-2.95 (m, 3H), 3.03 (s, 6H), 3.33-3.40 (m, 1H), 3.70-3.87 (m, 2H), 3.92 (s, 2H), 6.51 (d, 2H, J=8.7 Hz), 7.26-7.28 (m, 2H), 7.46-7.55 (m, 4H), 8.47 (s, 2H), 8.76 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 29.79, 30.85, 40.47, 43.94, 48.36, 52.30, 56.17, 60.52, 112.38, 112.61, 113.15, 119.26, 125.14, 129.54, 129.75, 129.84, 130.05, 131.11, 131.17, 141.47, 147.98, 149.42, 172.01. ES-MS m/z 607 (M+H). Anal. Calcd. for C32H36N6Cl2O2.0.6CH2Cl2: C, 59.46; H, 5.69; N, 12.76. Found. C, 59.52; H, 5.64; N, 12.41.
EXAMPLE 129




COMPOUND 129: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (300 mg, 0.71 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (119 mg, 0.78 mmol) followed by general procedure K with the resulting ester afforded 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a white solid (260 mg, 74%).
Using general procedure E, the above acid (50 mg, 0.09 mmol) and dimethylamine (2M, 167 μL, 0.33 mmol) afforded COMPOUND 129 as a white solid (45 mg, 87%). 1H NMR (CDCl3) δ 0.86-1.17 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.51-1.62 (m, 1H), 1.71-1.83 (m, 3H), 2.14-2.25 (m, 1H), 2.51 (s, 6H), 2.54-2.64 (m, 1H), 2.71-2.92 (m, 3H), 3.04 (s, 6H), 3.24-3.39 (m, 1H), 3.65-3.91 (m, 2H), 3.96 (s, 2H), 6.51 (d, 2H, J=8.7 Hz), 7.25-7.31 (m, 2H), 7.42-7.58 (m, 4H), 8.56 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.85, 22.36, 29.60, 30.83, 31.11, 40.50, 43.90, 48.46, 52.40, 56.09, 60.73, 112.45, 113.10, 118.24, 125.16, 129.79, 130.14, 131.18, 141.68, 149.59, 157.98, 163.52, 166.64, 172.02. ES-MS m/z 568 (M+H). Anal. Calcd. for C33H41N7O2.0.1CH2Cl2.0.2H2O: C, 68.57; H, 7.23; N, 16.91. Found. C, 68.77; H, 7.38; N, 16.51.
EXAMPLE 130




COMPOUND 130: N-(3-{4-[(3-Cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (200 mg, 0.48 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (87 mg, 0.52 mmol) followed by general procedure K with the resulting ester afforded 4-[(3-cyano-benzyl)-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a yellow solid (180 mg, 70%).
Using general procedure E, the above acid (50 mg, 0.09 mmol) and dimethylamine (2M, 138 μL, 0.28 mmol) afforded COMPOUND 130 as a white solid (36 mg, 60%). 1H NMR (CDCl3) δ 0.97 (d, 3H, J=6.6 Hz), 1.15-1.40 (m, 2H), 1.47-1.62 (m, 1H), 1.68-1.86 (m, 3H), 2.12-2.32 (m, 1H), 2.23 (s, 3H), 2.26 (s, 3H), 2.46-2.56 (m, 1H), 2.67-2.85 (m, 3H), 2.97 (s, 6H), 3.28-3.41 (m, 1H), 3.54-3.76 (m, 2H), 4.21 (s, 2H), 6.49 (d, 2H, J=9.0 Hz), 6.80 (d, 1H, J=6.6 Hz), 7.22 (d, 2H, J=7.8 Hz), 7.34-7.53 (m, 4H), 7.84 (d, 1H, J=6.6 Hz), 8.59 (br s, 1H). 13C NMR (CDCl3) δ 13.93, 15.54, 18.84, 29.87, 30.71, 32.38, 39.45, 44.63, 48.66, 51.89, 56.41, 59.20, 112.50, 112.97, 119.33, 124.92, 125.27, 129.76, 129.84, 130.13, 131.03, 131.39, 134.48, 137.27, 138.30, 141.88, 145.88, 149.71, 165.75, 172.08. ES-MS m/z 583 (M+H).
EXAMPLE 131




COMPOUND 131: N-[3-(4-{(3-Cyano-benzyl)-[4-(piperidine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
Using general procedure F with 2,6-dimethylbenzoic acid (93 mg, 0.62 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (107 mg, 64% over 2 steps).
Using general procedure E, the above acid (49 mg, 0.090 mmol) and piperidine (15 μL, 0.14 mmol) afforded COMPOUND 131 as a white solid (33 mg, 59%). 1H NMR (CDCl3) δ 0.94-1.20 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.56-1.81 (m, 10H), 2.18 (t, 1H, J=11.7 Hz), 2.31 (s, 6H), 2.57 (t, 1H, J=12.0 Hz), 2.75-2.92 (m, 3H), 3.25-3.32 (m, 1H), 3.52 (br s, 4H), 3.64-3.71 (m, 1H), 3.85 (s, 2H), 3.85-3.91 (m, 1H), 6.50 (d, 2H, J=8.4 Hz), 6.95 (d, 2H, J=4.5 Hz), 7.03-7.08 (m, 1H), 7.22-7.26 (m, 2H), 7.42-7.46 (m, 3H), 7.54 (d, 1H, J=7.2 Hz), 8.29 (br s, 1H). 13C NMR (CDCl3) δ 13.43, 19.15, 24.70, 26.13, 29.02, 30.33, 31.00, 39.77, 43.59, 48.06, 52.07, 56.04, 60.45, 112.26, 112.60, 118.91, 124.75, 127.30, 128.40, 129.08, 129.31, 129.81, 130.59, 130.76, 134.11, 138.64, 141.67, 149.18, 169.83, 170.51. ES-MS m/z 606 (M+H). Anal. Calcd. for C38H47N5O2.0.4CH2Cl2: C, 72.09; H, 7.53; N, 10.95. Found. C, 72.46; H, 7.53; N, 11.04.
EXAMPLE 132




COMPOUND 132: N-(3-{4-[(3-Cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (30 mg, 0.056 mmol) and methylamine hydrochloride (19 mg, 0.28 mmol) afforded COMPOUND 132 as a white solid (22 mg, 72%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.3 Hz), 1.15-1.26 (m, 1H), 1.52-1.75 (m, 4H), 2.15-2.37 (m, 2H), 2.31 (s, 6H), 2.59 (t, 1H, J=11.1 Hz), 2.76-2.88 (m, 3H), 2.96 (d, 3H, J=4.2 Hz), 3.20-3.33 (m, 1H), 3.67-3.74 (m, 1H), 3.85-3.89 (m, 1H), 3.89 (s, 2H), 5.91 (br s, 1H), 6.52 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.2 Hz), 7.04-7.09 (m, 1H), 7.41-7.46 (m, 3H), 7.54-7.57 (m, 3H), 8.25 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.54, 27.07, 29.47, 30.73, 31.40, 40.13, 43.97, 48.36, 52.39, 56.37, 60.80, 112.55, 113.05, 119.20, 123.36, 127.70, 128.80, 128.86, 129.76, 130.13, 131.07, 134.52, 139.01, 141.73, 150.81, 168.13, 170.24. ES-MS m/z 552 (M+H). Anal. Calcd. for C34H41N5O2.0.9H2O: C, 71.90; H, 7.60; N, 12.33. Found. C, 71.72; H, 7.71; N, 12.72.
EXAMPLE 133




COMPOUND 133: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure E with 4,6-dimethyl-pyrimidine-5-carboxylic acid (71 mg, 0.46 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester gave 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a brown solid (105 mg, 64% over 2 steps).
Using general procedure E, the above acid (52 mg, 0.10 mmol) and methylamine hydrochloride (32 mg, 0.48 mmol) afforded COMPOUND 133 as a white solid (31 mg, 58%) after an aqueous work-up. 1H NMR (CDCl3) δ 0.91-1.13 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.49-1.64 (m, 1H), 1.76-1.79 (m, 3H), 2.21 (t, 1H, J=11.1 Hz), 2.51 (s, 6H), 2.60 (t, 1H, J=11.4 Hz), 2.75-2.90 (m, 3H), 2.96 (d, 3H, J=4.8 Hz), 3.29-3.38 (m, 1H), 3.70-3.87 (m, 2H), 3.87 (s, 2H), 5.95-5.96 (m, 1H), 6.53 (d, 2H, J=8.7 Hz), 7.43-7.59 (m, 6H), 8.52-8.53 (m, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 12.49, 20.94, 25.65, 28.26, 29.34, 29.88, 38.83, 42.64, 47.03, 50.79, 54.67, 58.99, 111.06, 111.67, 117.80, 122.08, 127.52, 128.45, 128.65, 129.75, 140.01, 149.41, 156.51, 162.09, 165.30, 166.72. ES-MS m/z 554 (M+H). Anal. Calcd. for C32H39N7O2.0.4CH2Cl2: C, 66.22; H, 6.83; N, 16.68. Found. C, 66.17; H, 7.14; N, 16.53.
EXAMPLE 134




COMPOUND 134: N-[3-(4-{(3-Cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
Using general procedure E, 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 131) (60 mg, 0.11 mmol) and piperazine (29 mg, 0.33 mmol) afforded COMPOUND 134 as a white solid (23 mg, 34%). 1H NMR (CDCl3) δ 0.98-1.18 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.55 (m, 1H), 1.70-1.82 (m, 3H), 2.18 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.58 (t, 1H, J=11.1 Hz), 2.76-2.92 (m, 7H), 3.26-3.33 (m, 1H), 3.58-3.72 (m, 5H), 3.87 (m, 3H), 6.51 (d, 2H, J=8.7 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.03-7.08 (m, 1H), 7.23-7.26 (m, 2H), 7.42-7.47 (m, 3H), 7.55 (d, 1H, J=6.6 Hz), 8.26 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.55, 29.41, 30.70, 31.42, 40.14, 43.98, 46.66, 48.43, 52.45, 56.42, 60.83, 112.64, 113.03, 119.29, 124.40, 127.70, 128.79, 129.72, 130.18, 131.01, 131.12, 134.51, 139.03, 141.94, 149.74, 170.22, 171.00. ES-MS m/z 607 (M+H). Anal. Calcd. for C37H46N6O2.CH2Cl2: C, 70.10; H, 7.36; N, 13.12. Found. C, 69.89; H, 7.48; N, 13.02.
EXAMPLE 135




COMPOUND 135: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 133) (54 mg, 0.10 mmol) and piperazine (26 mg, 0.30 mmol) afforded COMPOUND 135 as a white solid (19 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.13 (m, 2H), 1.03 (d, 3H, J=6.3 Hz), 1.49-1.79 (m, 5H), 2.20 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.60 (t, 1H, J=10.8 Hz), 2.76-2.86 (m, 7H), 3.29-3.37 (m, 1H), 3.58-3.72 (m, 4H), 3.82-3.88 (m, 1H), 3.96 (s, 2H), 6.52 (d, 2H, J=8.7 Hz), 7.25-7.26 (m, 2H), 7.44-7.56 (m, 4H), 8.54 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.46, 21.97, 29.16, 30.38, 30.82, 39.97, 41.22, 42.71, 43.57, 46.25, 48.11, 51.94, 55.66, 60.20, 112.14, 112.70, 118.91, 124.15, 129.38, 129.45, 129.70, 130.77, 130.90, 141.23, 149.34, 157.56, 163.12, 166.27, 170.60. ES-MS m/z 609 (M+H). Anal. Calcd. for C35H44N8O2.0.5CH2Cl2.0.1H2O: C, 65.29; H, 6.98; N, 17.16. Found. C, 65.22; H, 7.12; N, 16.78.
EXAMPLE 136




COMPOUND 136: 4,6-Dimethyl-pyrimidine-5-carboxylic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
Using general procedure E, 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-hydroxy-phenyl)-amino]-methyl}-benzonitrile (see EXAMPLE 117) (929 mg, 2.43 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (1.11 g, 7.28 mmol) afforded COMPOUND 136 as a white solid (1.036 g, 65%). 1H NMR (CDCl3) δ 0.94-1.13 (m, 2H), 1.03 (d, 3H, J=6.3 Hz), 1.50-1.59 (m, 1H), 1.78-1.85 (m, 3H), 2.20 (t, 1H, J=11.7 Hz), 2.52 (s, 6H), 2.59 (t, 1H, J=12.0 Hz), 2.65 (s, 6H), 2.70-2.87 (m, 3H), 3.31-3.38 (m, 1H), 3.63-3.67 (m, 1H), 3.85-3.89 (m, 1H), 3.93 (s, 2H), 6.61 (d, 2H, J=9.0 Hz), 7.03 (d, 2H, J=9.0 Hz), 7.44-7.59 (m, 4H), 8.56 (br s, 1H), 8.87 (s, 1H), 9.01 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.35, 23.40, 29.61, 30.81, 31.18, 40.42, 43.97, 48.84, 52.41, 56.90, 60.63, 113.10, 114.30, 114.54, 119.27, 122.20, 126.52, 129.81, 130.23, 131.14, 131.29, 141.81, 141.97, 147.02, 157.95, 158.63, 163.49, 164.86, 166.55, 166.66. ES-MS m/z 647 (M+H). Anal. Calcd. for C37H42N8O3.0.8H2O: C, 67.21; H, 6.65; N, 16.95. Found. C, 67.20; H, 6.46; N, 16.70.
EXAMPLE 137




COMPOUND 137: Acetic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester
To a solution of COMPOUND 117 (51 mg, 0.10 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 137 as a white solid (48 mg, 85%) following work-up and purification. 1H NMR (CDCl3) δ 0.97-1.18 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.24 (s, 3H), 2.31 (s, 6H), 2.55 (t, 1H, J=10.5 Hz), 2.74-2.87 (m, 3H), 3.24-3.31 (m, 1H), 3.57-3.63 (m, 1H), 3.77 (s, 2H), 3.85-3.91 (m, 1H), 6.51 (d, 2H, J=8.4 Hz), 6.84 (d, 2H, J=8.1 Hz), 6.93-7.05 (m, 3H), 7.43-7.52 (m, 4H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 14.53, 20.27, 22.20, 30.06, 31.46, 32.06, 40.96, 44.70, 49.60, 53.28, 57.84, 61.68, 113.66, 115.15, 120.06, 123.21, 128.42, 129.52, 130.36, 131.08, 131.64, 132.01, 135.21, 139.77, 143.16, 143.23, 147.35, 170.96, 171.27. ES-MS m/z 533 (M+H). Anal. Calcd. for C34H40N4O3.0.6H2O: C, 72.47; H, 7.37; N, 9.94. Found. C, 72.38; H, 7.25; N, 9.83.
EXAMPLE 138




COMPOUND 138: Acetic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
To a solution of COMPOUND 136 (870 mg, 1.39 mmol) in MeOH (14 mL) was added 10N NaOH (1.4 mL, 14 mmol) and the mixture was heated at 40° C. overnight to afford 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide as a pink solid (400 mg, 53%) following an acidic work-up and purification.
To a solution of the above phenol (45 mg, 0.087 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (0.02 mL, 0.21 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 138 as a white solid (43 mg, 80%) following work-up and purification. 1H NMR (CDCl3) δ 0.82-1.12 (m, 5H), 1.54-1.58 (m, 1H), 1.76-1.79 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.25 (s, 3H), 2.51 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.74-2.86 (m, 3H), 3.30-3.36 (m, 1H), 3.56-3.62 (m, 1H), 3.82-3.87 (m, 1H), 3.89 (s, 2H), 6.53 (d, 2H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 7.41-7.46 (m, 1H), 7.52-7.55 (m, 3H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 12.37, 20.06, 20.93, 28.06, 29.26, 29.75, 38.92, 42.58, 47.57, 50.96, 55.43, 59.14, 111.59, 113.16, 117.91, 121.16, 128.32, 128.89, 129.64, 129.83, 129.94, 140.71, 141.26, 145.13, 156.53, 162.07, 165.32, 169.07. ES-MS m/z 555 (M+H). Anal. Calcd. for C32H38N6O3.0.8CH2Cl2: C, 63.27; H, 6.41; N, 13.50. Found. C; 63.46; H, 6.39; N, 13.29.
EXAMPLE 139




COMPOUND 139: Carbonic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester methyl ester
To a solution of COMPOUND 117 (43 mg, 0.083 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by methyl chloroformate (14 μL, 0.19 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 139 as a white solid (41 mg, 86%) following work-up and purification. 1H NMR (CDCl3) δ 0.91-1.14 (m, 2H), 1.00 (d, 3H, J=6.0 Hz), 1.50-1.55 (m, 1H), 1.70-1.74 (m, 3H), 2.15 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.91 (m, 3H), 3.24-3.32 (m, 1H), 3.57-3.63 (m, 1H), 3.78 (s, 2H), 3.86 (s, 3H), 3.86-3.90 (m, 1H), 6.51 (d, 2H, J=8.1 Hz), 6.92-7.05 (m, 5H), 7.43-7.53 (m, 4H), 8.37-8.38 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.54, 29.34, 30.72, 31.34, 40.23, 43.96, 48.84, 52.54, 55.68, 57.14, 60.94, 112.96, 114.36, 119.30, 122.04, 127.69, 128.78, 129.65, 130.33, 130.94, 131.25, 134.49, 139.04, 142.38, 143.01, 146.78, 155.24, 170.23. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.5H2O: C, 70.69; H, 7.15; N, 9.70. Found. C, 70.64; H, 7.02; N, 9.65.
EXAMPLE 140




COMPOUND 140: Carbonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester methyl ester
To a solution of COMPOUND 138 (41 mg, 0.080 mmol) in CH2Cl2 (2 mL) were added Et3N (0.04 mL, 0.29 mmol) followed by methyl chloroformate (15 μL, 0.19 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 140 as a white solid (33 mg, 66%) following work-up and purification. 1H NMR (CDCl3) δ 0.90-1.14 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.53-1.59 (m, 1H), 1.76-1.79 (m, 3H), 2.17 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.57 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.33-3.39 (m, 1H), 3.56-3.61 (m, 1H), 3.86-3.89 (m, 6H), 6.53 (d, 2H, J=9.0 Hz), 6.95 (d, 2H, J=8.4 Hz), 7.44-7.46 (m, 1H), 7.52-7.55 (m, 4H), 8.60 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.35, 29.58, 30.79, 31.13, 40.45, 43.97, 48.93, 52.42, 55.70, 56.89, 60.65, 113.04, 114.45, 119.31, 122.12, 129.76, 130.28, 131.09, 131.32, 142.01, 143.22, 146.71, 155.19, 157.95, 163.49, 166.69. ES-MS m/z 571 (M+H). Anal. Calcd. for C32H38N6O4.0.7CH2Cl2: C, 62.33; H, 6.30; N, 13.34. Found. C, 62.25; H, 6.34; N, 13.44.
EXAMPLE 141




COMPOUND 141: Diethyl-carbamic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (40 mg, 0.29 mmol) followed by diethylcarbamoyl chloride (20 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 141 as a white solid (35 mg, 67%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.01 (m, 1H), 1.00 (d, 3H, J=5.7 Hz), 1.10-1.18 (m, 7H), 1.50-1.58 (m, 1H), 1.70-1.73 (m, 3H), 2.14 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=11.4 Hz), 2.73-2.88 (m, 3H), 3.15-3.36 (m, 5H), 3.50-3.56 (m, 1H), 3.74 (s, 2H), 3.87-3.93 (m, 1H), 6.51 (d, 2H, J=7.2 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.95-6.99 (m, 3H), 7.41-7.50 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.80, 14.59, 19.53, 29.33, 30.74, 31.32, 36.87, 40.26, 42.17, 42.56, 43.96, 48.78, 52.59, 57.57, 60.99, 112.84, 114.95, 119.36, 122.75, 127.68, 128.77, 129.55, 130.48, 130.83, 131.43, 134.47, 139.03, 142.64, 143.52, 146.07, 155.18, 170.24. ES-MS m/z 610 (M+H). Anal. Calcd. for C37H47N5O3.0.8H2O: C, 71.19; H, 7.85; N, 11.22. Found. C, 71.09; H, 7.68; N, 11.16.
EXAMPLE 142




COMPOUND 142: N-(3-{4-[(4-Amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
To a solution of COMPOUND 112 (59 mg, 0.11 mmol) in MeOH (1 mL) was added 6N HCl (2 mL) and the solution was stirred at room temperature for 26 hours to afford COMPOUND 142 as a white solid (36 mg, 67%) following a basic work-up and purification. 1H NMR (CDCl3) δ 0.91-1.12 (m, 2H), 0.98 (d, 3H, J=6.0 Hz), 1.51 (m, 1H), 1.68-1.75 (m, 3H), 2.09 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.49 (t, 1H, J=10.8 Hz), 2.71-2.83 (m, 3H), 3.22-3.34 (m, 2H), 3.67 (s, 2H), 3.88 (m, 1H), 6.50 (m, 4H), 6.93 (m, 3H), 7.34-7.48 (m, 4H), 8.48 (br s, 1H). 13C NMR (CDCl3) δ 13.36, 19.14, 29.10, 30.33, 30.92, 39.85, 43.62, 48.98, 52.18, 58.75, 60.55, 112.21, 116.34, 118.09, 127.24, 128.35, 128.91, 130.24, 130.63, 131.00, 131.49, 134.03, 138.60, 138.93, 141.24, 142.75, 169.89. ES-MS m/z 510 (M+H). Anal. Calcd. for C32H39N5O.0.1CH2Cl2.0.2C6H14: C, 74.70; H, 7.91; N, 13.08. Found. C, 74.89; H, 7.77; N, 13.20.
EXAMPLE 143




COMPOUND 143: [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid tert-butyl ester
Using general procedure A, (4-amino-phenoxy)-acetic acid tert-butyl ester (Renodon-Corniere, Axelle; et al., J. Med. Chem., 45, 4, 2002, 944-954) (4.84 g, 21.6 mmol) and 1-Boc-4-piperidone (3.4 g, 17.1 mmol) afforded 4-(4-tert-butoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, 95%).
Using general procedure H, the above aniline (6.6 mg, 14.9 mmol) and 3-cyanobenzyl bromide (3.1 g, 15.8 mmol) afforded 4-[(4-tert-butoxycarbonylmethoxy-phenyl)-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (6.78 g, 87%).
The above carbamate (5.1 g, 9.74 mmol) was treated with a solution of EtOAc (40 mL) saturated with HCl. The mixture was stirred at room temperature for 3 h then concentrated under reduced pressure to give the crude material after work-up.
Using general procedure B with the above amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (3.38 g, 15.6 mmol) and then using general procedure D afforded {4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-acetic acid tert-butyl ester (800 mg, 44%).
Using general procedure E, the above amine (440 mg, 0.89 mmol) and 2,6-dimethylbenzoic acid (148 mg, 0.99 mmol) afforded COMPOUND 143 as a white solid (430 mg, 77%). 1H NMR (CDCl3) δ 0.87-1.15 (m, 2H), 0.96 (d, 3H, J=6.0 Hz), 1.43 (s, 9H), 1.43-1.51 (m, 1H), 1.67-1.75 (m, 3H), 2.10 (t, 1H, J=11.4 Hz), 2.28 (s, 6H), 2.49 (t, 1H, J=11.4 Hz), 2.70-2.86 (m, 3H), 3.21-3.28 (m, 1H), 3.38-3.45 (m, 1H), 3.70 (s, 2H), 3.81-3.85 (m, 1H), 3.36 (s, 2H), 6.50 (d, 2H, J=8.1 Hz), 6.68 (d, 2H, J=7.8 Hz), 6.91-6.97 (m, 3H), 7.34-7.47 (m, 4H), 8.46 (br s, 1H). ES-MS m/z 625 (M+H).
EXAMPLE 144




COMPOUND 144: {4-[(Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester
Using general procedure E, {4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-acetic acid tert-butyl ester (see EXAMPLE 143) (356 mg, 0.72 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (121 mg, 0.80 mmol) afforded COMPOUND 144 as a white solid (340 mg, 75%). 1H NMR (CDCl3) δ 0.93-1.15 (m, 5H), 1.39 (s, 9H), 1.45-50 (m, 1H), 1.69-1.73 (m, 3H), 2.09 (t, 1H, J=11.1 Hz), 2.43 (s, 6H), 2.47-2.51 (m, 1H), 3.67-3.77 (m, 3H), 3.26-3.43 (m, 2H), 3.63-3.74 (m, 1H), 3.82 (s, 2H), 4.33 (s, 2H), 6.49 (d, 2H, J=7.8 Hz), 6.66 (d, 2H, J=7.8 Hz), 7.32-7.48 (m, 4H), 8.63 (br s, 1H), 8.76 (s, 1H). ES-MS m/z 627 (M+H).
EXAMPLE 145




COMPOUND 145: Dimethyl-carbamic acid 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenyl ester
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (36 mg, 0.26 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 145 as a white solid (41 mg, 84%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.50-1.58 (m, 1H), 1.70-1.81 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=12.0 Hz), 2.73-3.05 (m, 9H), 3.23-3.28 (m, 1H), 3.51-5.56 (m, 1H), 3.75 (s, 2H), 3.87-3.93 (m, 1H), 6.50 (d, 2H, J=7.8 Hz), 6.86 (d, 2H, J=8.1 Hz), 6.93-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42-8.44 (m, 1H). 13C NMR (CDCl3) δ 13.80, 19.53, 29.34, 30.75, 31.32, 36.75, 36.87, 37.04, 38.99, 40.24, 43.97, 48.81, 52.57, 57.43, 60.97, 112.84, 114.79, 119.36, 122.74, 127.68, 128.77, 129.57, 130.45, 130.83, 131.40, 134.47, 139.04, 142.64, 143.47, 146.18, 155.88, 162.90, 170.23. ES-MS m/z 582 (M+H). Anal. Calcd. for C35H43N5O3.1.0H2O: C, 70.09; H, 7.56; N, 11.68. Found. C, 70.35; H, 7.56; N, 11.95.
EXAMPLE 146




COMPOUND 146: Dimethyl-carbamic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
To a solution of COMPOUND 138 (43 mg, 0.084 mmol) in DMF (1 mL) were added K2CO3 (38 mg, 0.27 mmol) followed by dimethylcarbamoyl chloride (15 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 146 as a white solid (27 mg, 53%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.13 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.59 (m, 1H), 1.75-1.79 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=10.5 Hz), 2.73-2.88 (m, 3H), 2.98 (s, 3H), 3.05 (s, 3H), 3.28-3.36 (m, 1H), 3.53-3.60 (m, 1H), 3.83-3.87 (m, 1H), 3.87 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.88 (d, 2H, J=9.0 Hz), 7.40-7.45 (m, 1H), 7.50-7.56 (m, 3H), 8.65-8.66 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 14.72, 23.24, 30.49, 31.68, 32.01, 37.66, 37.95, 41.32, 44.90, 49.82, 53.32, 58.14, 61.53, 113.83, 115.91, 120.24, 123.71, 130.55, 131.32, 131.88, 132.15, 132.37, 143.13, 144.63, 146.97, 156.73, 158.83, 164.36, 167.61. ES-MS m/z 584 (M+H). Anal. Calcd. for C33H41N7O3.1.4H2O: C, 65.09; H, 7.25; N, 16.10. Found. C, 65.27; H, 6.88; N, 15.76.
EXAMPLE 147




COMPOUND 147: [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid methyl ester
To a solution of COMPOUND 117 (102 mg, 0.20 mmol) in DMF (1 mL) were added K2CO3 (86 mg, 0.62 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 147 as a tan solid (97 mg, 82%) following work-up and purification. 1H NMR (CDCl3) δ 0.90-1.13 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.49-1.54 (m, 1H), 1.69-1.81 (m, 3H), 2.12 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.53 (t, 1H, J=11.7 Hz), 2.73-2.88 (m, 3H), 3.24-3.31 (m, 1H), 3.41-3.49 (m, 1H), 3.71 (s, 2H), 3.78 (s, 3H), 3.86-3.90 (m, 1H), 4.52 (s, 2H), 6.51 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.4 Hz), 6.94-7.00 (m, 3H), 7.42-7.50 (m, 4H), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.79, 19.51, 29.43, 30.68, 31.28, 40.19, 44.01, 49.03, 52.51, 58.07, 60.86, 66.52, 112.73, 116.20, 116.37, 119.42, 127.62, 128.72, 129.51, 130.61, 130.78, 131.56, 134.42, 139.02, 142.79, 143.83, 150.85, 162.90, 170.14, 170.22. ES-MS m/z 583 (M+H). Anal. Calcd. for C35H422N4O4.0.3H2O: C, 71.48; H, 7.30; N, 9.53. Found. C, 71.42; H, 7.23; N, 9.40.
EXAMPLE 148




COMPOUND 148: {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester
To a solution of COMPOUND 138 (105 mg, 0.205 mmol) in DMF (1 mL) were added K2CO3 (87 mg, 0.63 mmol) followed by methyl bromoacetate (40 μL, 0.42 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 148 as a tan solid (81 mg, 66%) following work-up and purification. 1H NMR (CDCl3) δ 0.86-1.03 (m, 5H), 1.52-1.60 (m, 1H), 1.74-1.78 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.59 (m, 1H), 2.72-2.88 (m, 3H), 3.29-3.48 (m, 2H), 3.78-3.83 (m, 6H), 4.53 (s, 2H), 6.53 (d, 2H, J=8.4 Hz), 6.75 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 1H), 7.49-7.54 (m, 3H), 8.71 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 11.37, 19.90, 27.17, 28.32, 28.69, 37.93, 41.60, 46.92, 49.93, 50.15, 55.37, 58.15, 64.12, 110.38, 113.84, 114.32, 116.98, 127.17, 128.17, 128.50, 128.83, 129.20, 139.97, 141.27, 148.72, 155.46, 161.02, 164.27, 167.71. ES-MS m/z 585 (M+H). Anal. Calcd. for C33H40N6O4.0.7H2O: C, 66.36; H, 6.99; N, 14.07. Found. C, 66.32; H, 6.83; N, 13.71.
EXAMPLE 149




COMPOUND 149: [4-((3-Cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-acetic acid
To a solution of COMPOUND 143 in CH2Cl2 (2 mL) was added anisole (0.1 mL, 0.92 mmol) followed by TFA (2 mL) and the solution was stirred at room temperature for 90 minutes to afford COMPOUND 149 as a white solid (200 mg, 52%) after a basic work-up and purification. 1H NMR (CD3OD) δ 1.29 (d, 3H, J=6.3 Hz), 1.76-1.89 (m, 5H), 2.07-2.28 (m, 1H), 2.28 (s, 6H), 2.86-3.03 (m, 2H), 3.19-3.27 (m, 3H), 3.37-3.51 (m, 2H), 3.67-3.75 (m, 1H), 4.19 (s, 2H), 4.24 (s, 2H), 6.76 (s, 4H), 7.02 (d, 2H, J=7.5 Hz), 7.11-7.16 (m, 1H), 7.36-7.41 (m, 1H), 7.48-7.55 (m, 3H). 13C NMR (CD3OD) δ 12.82, 18.45, 27.43, 31.16, 36.74, 46.73, 49.61, 50.48, 56.06, 59.61, 67.86, 112.19, 115.51, 118.98, 119.18, 127.52, 128.96, 129.51, 130.55, 130.77, 132.17, 134.23, 137.73, 142.53, 142.92, 152.96, 172.43, 176.24. ES-MS m/z 569 (M+H). Anal. Calcd. for C34H40N4O4.0.6CH2Cl2: C, 67.06; H, 6.70; N, 9.04. Found. C, 66.95; H, 6.64; N, 8.91.
EXAMPLE 150




COMPOUND 150: {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid
To a solution of COMPOUND 144 in CH2Cl2 (2 mL) was added anisole (0.1 mL, 0.92 mmol) followed by TFA (2 mL) and the solution was stirred at room temperature for 2 h to afford COMPOUND 150 as a white solid (210 mg, 70%) following work-up and purification. 1H NMR (CDCl3) δ 1.21 (m, 3H), 1.62-1.71 (m, 5H), 2.17 (m, 1H), 2.43 (s, 6H), 2.58 (m, 1H), 2.82 (m, 1H), 3.03-3.07 (m, 2H), 3.44-3.52 (m, 4H), 3.67-3.72 (m, 1H), 3.93-3.99 (m, 1H), 4.12 (s, 2H), 6.46 (m, 2H), 6.66 (m, 2H), 7.26-7.39 (m, 4H), 8.58 (br s, 1H), 8.82 (s, 1H). 13C NMR (CDCl3) δ 12.35, 22.47, 25.26, 27.15, 31.92, 36.99, 44.70, 50.89, 54.47, 58.49, 67.56, 112.73, 115.53, 116.55, 119.35, 129.79, 130.30, 130.68, 130.99, 131.49, 142.57, 152.35, 157.67, 163.47, 167.77, 175.61. ES-MS m/z 571 (M+H). Anal. Calcd. for C32H38N6O4.1.3CH2Cl2: C, 58.72; H, 6.01; N, 12.34. Found. C, 58.81; H, 6.08; N, 12.28.
EXAMPLE 151




COMPOUND 151: N-(3-{4-[(3-Cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure A, 4-amino-N-benzyl-N-methyl-benzenesulfonamide (Mikhura, I. V.; et al., Russ. J. Org. Chem., 36, 1, 2000, 64-68) (852 mg, 3.09 mmol) and 1-Boc-4-piperidone (677 mg, 3.40 mmol) afforded 4-[4-(benzyl-methyl-sulfamoyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (796 mg, 64%).
Using general procedure H with the above amine (790 mg, 1.72 mmol) and α-bromo-m-tolunitrile (660 mg, 3.37 mmol) and then using general procedure C gave N-benzyl-4-[(3-cyano-benzyl)-piperidin-4-yl-amino]-N-methyl-benzenesulfonamide as a white foam (202 mg, 25% over 2 steps).
The above amine (100 mg, 0.21 mmol) and conc. H2SO4 (2 mL) were stirred at room temperature for 2 hours. The mixture was poured over ice, neutralized with 10N NaOH to pH-12 and extracted with CHCl3 (2×20 mL) and EtOAc (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 4-[(3-cyano-benzyl)-piperidin-4-yl-amino]-N-methyl-benzenesulfonamide as a white solid (31 mg, 38%) following purification.
Using general procedure B with the above amine (160 mg, 0.417 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (181 mg, 0.833 mmol) and then using general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-N-methyl-benzenesulfonamide as a white solid (105 mg, 55% over 2 steps).
Using general procedure E, the above amine (42 mg, 0.092 mmol) and 2,6-dimethylbenzoic acid (15 mg, 0.10 mmol) gave COMPOUND 151 as a white solid (49 mg, 89%). 1H NMR (CDCl3) δ 0.98-1.24 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.53 (m, 1H), 1.70-1.75 (m, 3H), 2.19 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.56-2.61 (m, 4H), 2.76-2.92 (m, 3H), 3.30 (t, 1H, J=10.8 Hz), 3.72 (t, 1H, J=10.2 Hz), 3.81-3.87 (m, 1H), 3.94 (s, 2H), 4.40 (d, 1H, J=4.98 Hz), 6.55 (d, 2H, J=8.4 Hz), 6.96 (d, 2H, J=7.2 Hz), 7.05-7.10 (m, 1H), 7.38-7.48 (m, 3H), 7.55-7.60 (m, 3H), 8.16 (br s, 1H). 13C NMR (CDCl3) δ 13.49, 19.17, 29.08, 29.35, 30.28, 31.08, 39.67, 43.55, 48.01, 51.87, 56.04, 60.29, 112.11, 112.79, 118.77, 125.78, 127.33, 128.43, 129.23, 129.56, 130.61, 130.86, 134.16, 138.63, 140.64, 151.25, 169.83. ES-MS m/z 588 (M+H). Anal. Calcd. for C33H41N5O3S.0.3CH2Cl2: C, 65.22; H, 6.84; N, 11.42; S, 5.23. Found. C, 65.36; H, 6.84; N, 11.21; S, 5.13.
EXAMPLE 152




COMPOUND 152: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-N-methyl-benzenesulfonamide (see EXAMPLE 151) (63 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (23 mg, 0.15 mmol) gave COMPOUND 152 as a white solid (72 mg, 89%). 1H NMR (CDCl3) δ 1.00-1.17 (m, 2H), 1.02 (d, 3H, J=5.4 Hz), 1.55 (m, 1H), 1.74-1.78 (m, 3H), 2.21 (t, 1H, J=10.5 Hz), 2.50 (s, 6H), 2.58-2.62 (m, 4H), 2.75-2.85 (m, 3H), 3.34 (m, 1H), 3.77 (m, 2H), 4.05 (s, 2H), 4.44 (d, 1H, J=4.2 Hz), 6.56 (d, 2H, J=8.1 Hz), 7.47-7.72 (m, 5H), 8.35 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.52, 21.97, 28.92, 29.32, 30.31, 31.00, 39.75, 43.60, 48.08, 51.64, 55.73, 59.82, 112.00, 112.78, 118.79, 125.81, 129.25, 129.48, 129.64, 130.70, 130.88, 130.95, 140.36, 151.29, 157.53, 163.15, 166.30. ES-MS m/z 590 (M+H). Anal. Calcd. for C31H39N7O3S.0.6CH2Cl2: C, 59.24; H, 6.32; N, 15.30; S, 5.00. Found. C, 59.35; H, 6.37; N, 15.18; S, 4.87.
EXAMPLE 153




COMPOUND 153: N-[3-(4-{(3-Cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (33 μL, 0.24 mmol) was added cyclopropanecarbonyl chloride (17 μL, 0.18 mmol) and the solution was stirred at room temperature for 4 hours to afford COMPOUND 153 as a white solid (69 mg, 100%) following work-up and purification. 1H NMR (CDCl3) δ 0.75-0.83 (m, 2H), 1.01 (m, 6H), 1.01-1.16 (m, 1H), 1.42-1.61 (m, 2H), 1.61-1.77 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.28 (t, 1H, J=11.1 Hz), 3.54 (m, 1H), 3.76 (s, 2H), 3.85 (m, 1H), 6.50 (d, 2H, J=6.49 (d, 2H, J=8.4 Hz), 6.91-6.99 (m, 3H), 7.24 (d, 2H, J=9.3 Hz), 7.36-7.44 (m, 4H), 7.50 (br s, 1H), 8.40 (br s, 1H). 13C NMR (CDCl3) δ 7.98, 8.39, 13.77, 15.72, 19.54, 29.29, 30.57, 31.31, 40.14, 44.03, 48.66, 52.46, 57.39, 60.82, 112.78, 114.85, 119.40, 122.01, 127.67, 128.79, 129.56, 129.66, 130.50, 130.82, 131.47, 134.45, 138.91, 142.66, 145.31, 170.35, 172.09. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.0.3CH2Cl2: C, 72.28; H, 7.28; N, 11.61. Found. C, 72.57; H, 7.38; N, 11.30.
EXAMPLE 154




COMPOUND 154: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
To a solution of COMPOUND 111 (880 mg, 1.59 mmol) in MeOH (10 mL) was added 6N HCl (20 mL) and the solution was stirred at room temperature for 18 hours and heated at 40° C. for 3 hours to give 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide as a white solid (813 mg, 100%) following a basic work-up.
To a solution of the above aniline (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added cyclopropanecarbonyl chloride (14 μL, 0.15 mmol) and the solution was stirred at room temperature for 16 hours to afford COMPOUND 154 as a white solid (56 mg, 96%) following work-up and purification. 1H NMR (CDCl3) δ 0.74-0.79 (m, 2H), 0.98-1.15 (m, 7H), 1.43 (m, 1H), 1.56 (m, 1H), 1.74-1.79 (m, 3H), 2.19 (m, 1H), 2.50 (s, 6H), 2.58 (m, 1H), 2.75-2.87 (m, 3H), 3.32 (m, 1H), 3.57 (m, 1H), 3.82 (m, 1H), 3.89 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.26 (m, 3H), 7.39-7.44 (m, 1H), 7.49-7.53 (m, 3H), 8.64 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 7.64, 13.36, 15.44, 21.95, 29.04, 30.17, 30.77, 39.86, 43.64, 48.46, 51.94, 56.68, 60.10, 112.48, 114.66, 118.98, 121.61, 129.27, 129.43, 130.06, 130.58, 130.84, 131.12, 141.85, 144.86, 157.51, 163.09, 166.38, 171.62. ES-MS m/z 580 (M+H). Anal. Calcd. for C34H41N7O2.0.45CH2Cl2: C, 66.96; H, 6.83; N, 15.87. Found. C, 66.99; H, 7.02; N, 15.55.
EXAMPLE 155




COMPOUND 155: N-[3-(4-{(3-Cyano-benzyl)-[4-(3,3-dimethyl-ureido)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
A mixture of COMPOUND 142 (61 mg, 0.12 mmol), K2CO3 (50 mg, 0.36 mmol) and dimethylcarbamoyl chloride (23 μL, 0.24 mmol) in DMF (1 mL) was stirred at room temperature for 76 hours to afford COMPOUND 155 as a white solid (53 mg, 76%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.17 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.49-1.59 (m, 1H), 1.69-1.78 (m, 3H), 2.14 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=10.8 Hz), 2.73-2.85 (m, 3H), 2.98 (s, 6H), 3.27 (t, 1H, J=10.5 Hz), 3.52 (m, 1H), 3.73 (s, 2H), 3.90 (m, 1H), 6.04 (s, 1H), 6.50 (d, 2H, J=8.1 Hz), 6.94-6.99 (m, 3H), 7.09 (d, 2H, J=8.1 Hz), 7.39-7.58 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.38, 30.74, 31.29, 36.79, 40.28, 43.97, 48.67, 52.61, 57.72, 61.01, 112.75, 115.27, 119.44, 122.87, 127.66, 128.76, 129.49, 130.39, 130.59, 130.76, 131.54, 134.46, 139.03, 142.81, 144.99, 156.69, 170.24. ES-MS m/z 581 (M+H). Anal. Calcd. for C35H44N6O2.0.2CH2Cl2: C, 70.73; H, 7.49; N, 14.06. Found. C, 70.74; H, 7.57; N, 13.74.
EXAMPLE 156




COMPOUND 156: N-[3-(4-{(3-Cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added TFAA (21 μL, 0.15 mmol) and the solution was stirred at room temperature for 2.5 hours to afford COMPOUND 156 as a white solid (54 mg, 89%) following work-up and purification. 1H NMR (CDCl3) δ 1.00-1.25 (m, 5H), 1.52-1.61 (m, 1H), 1.70-1.76 (m, 3H), 2.17 (m, 1H), 2.30 (s, 6H), 2.57 (m, 1H), 2.75-2.87 (m, 3H), 3.29 (m, 1H), 3.61 (m, 1H), 3.81-3.90 (m, 3H), 6.52 (d, 2H, J=6.9 Hz), 6.94-6.99 (m, 3H), 7.26-7.31 (m, 2H), 7.42 (s, 3H), 7.53 (br s, 1H), 7.81 (s, 1H), 8.34 (br s, 1H). 13C NMR (CDCl3) δ 13.82, 19.51, 29.43, 30.71, 31.29, 40.23, 43.95, 48.49, 52.50, 57.03, 60.91, 112.94, 114.14, 116.17 (q, J=300 Hz), 119.30, 122.70, 125.87, 127.67, 128.79, 129.70, 130.29, 130.98, 131.28, 134.49, 138.95, 142.15, 146.85, 154.99 (q, J=37 Hz), 170.26. ES-MS m/z 606 (M+H). Anal. Calcd. for C34H38N5O2F3.0.2CH2Cl2: C, 65.97; H, 6.22; N, 11.25; F, 9.15. Found. C, 66.21; H, 6.26; N, 11.16; F, 9.05.
EXAMPLE 157




COMPOUND 157: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
To a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (see EXAMPLE 154) (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) and Et3N (28 μL, 0.20 mmol) was added TFAA (21 μL, 0.15 mmol) and the solution was stirred at room temperature for 3 hours. Standard work-up and purification afforded COMPOUND 157 as a white solid (57 mg, 94%). 1H NMR (CDCl3) δ 0.88-1.15 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.57 (m, 1H), 1.74-1.80 (m, 3H), 2.19 (t, 1H, J=12.0 Hz), 2.51 (s, 6H), 2.59 (t, 1H, J=11.4 Hz), 2.75-2.86 (m, 3H), 3.33 (m, 1H), 3.63 (m, 1H), 3.84-3.92 (m, 1H), 3.92 (s, 2H), 6.55 (d, 2H, J=8.4 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.43-7.52 (m, 4H), 7.76 (s, 1H), 8.58 (br s, 1H), 8.87 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.31, 29.63, 30.80, 31.09, 40.45, 43.95, 48.59, 52.36, 56.68, 60.63, 113.00, 114.16, 116.28 (q, J=289 Hz), 119.27, 121.70, 126.01, 129.80, 130.21, 131.12, 131.30, 141.76, 146.82, 154.93 (q, J=37 Hz), 157.91, 163.50, 166.66. ES-MS m/z 608 (M+H). Anal. Calcd. for C32H36N7O2F3.0.3CH2Cl2: C, 61.27; H, 5.83; N, 15.49; F, 9.00. Found. C, 61.33; H, 5.90; N, 15.36; F, 8.74.
EXAMPLE 158




COMPOUND 158: N-(3-{4-[(3-Cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in toluene (1 mL) was added phosgene (20% in toluene, 82 μL, 0.15 mmol) and the resultant slurry was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 mL). To the solution were added ammonium chloride (33 mg, 0.62 mmol) and DIPEA (120 μL, 0.69 mmol) and the mixture was stirred at room temperature for 17 hours to afford COMPOUND 158 as a white solid (24 mg, 36%) following work-up and purification. 1H NMR (CDCl3) δ 1.00-1.15 (m, 5H), 1.55 (m, 1H), 1.71 (m, 3H), 2.16 (m, 1H), 2.30 (s, 6H), 2.56 (m, 1H), 2.75-2.87 (m, 3H), 3.29 (m, 1H), 3.57 (m, 1H), 3.79-3.90 (m, 3H), 4.63 (s, 2H), 6.41 (s, 1H), 6.50 (d, 2H, J=7.8 Hz), 6.92-7.04 (m, 5H), 7.43 (s, 3H), 7.52 (br s, 1H), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.41, 30.68, 31.30, 40.24, 43.99, 48.69, 52.49, 57.30, 60.85, 112.86, 114.97, 119.39, 125.05, 127.70, 128.84, 129.63, 130.41, 130.90, 131.39, 134.47, 138.87, 142.42, 146.09, 158.05, 170.39. ES-MS m/z 553 (M+H). Anal. Calcd. for C33H40N6O2.0.85CH2Cl2.0.1C6H14: C, 65.31; H, 6.86; N, 13.27. Found. C, 65.38; H, 6.66; N, 13.07.
EXAMPLE 159




COMPOUND 159: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (see EXAMPLE 154) (54 mg, 0.10 mmol) in toluene (1 mL) was added phosgene (20% in toluene, 82 μL, 0.15 mmol) and the resultant slurry was stirred at room temperature for 3.5 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in DMF (1 mL). To the solution were added ammonium chloride (28 mg, 0.53 mmol) and DIPEA (110 μL, 0.64 mmol) and the mixture was stirred at room temperature for 25 hours. Standard work-up and purification afforded COMPOUND 159 as a white solid (23 mg, 39%). 1H NMR (CDCl3) δ0.90-1.10 (m, 5H), 1.54 (d, 1H, J=13.5 Hz), 1.74-1.83 (m, 3H), 2.17 (t, 1H, J=11.1 Hz), 2.50 (s, 6H), 2.56 (t, 1H, J=11.1 Hz), 2.73-2.84 (m, 3H), 3.31 (m, 1H), 3.56 (m, 1H), 3.82-3.89 (m, 1H), 3.89 (s, 2H), 4.72 (s, 2H), 6.51 (d, 2H, J=8.1 Hz), 6.58 (s, 1H), 7.05 (d, 2H, J=8.1 Hz), 7.41-7.56 (m, 4H), 8.62 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.44, 21.94, 29.21, 30.42, 30.73, 40.05, 43.58, 48.57, 51.99, 53.45, 56.55, 60.24, 112.55, 117.73, 118.98, 125.26, 128.41, 129.36, 129.93, 130.67, 130.88, 131.02, 141.60, 145.94, 157.52, 157.75, 163.11, 166.29. ES-MS m/z 555 (M+H). Anal. Calcd. for C31H38N8O2.0.8CH2Cl2: C, 61.34; H, 6.41; N, 18.00. Found. C, 61.52; H, 6.49; N, 17.93.
EXAMPLE 160




COMPOUND 160: N-[3-(4-{(3-Cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,6-dimethyl-benzamide
To a solution of COMPOUND 142 (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) was added 2-chloro-ethylchloroformate (12 μL, 0.12 mmol) followed by Et3N (21 μL, 0.15 mmol) and the solution was stirred at room temperature for 18.5 hours to afford the crude substrate after work-up.
To the above substrate (70 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 15 mg, 0.25 mmol) and the mixture was heated at 90° C. for 2.5 hours to afford COMPOUND 160 as a white solid (52 mg, 90%) following work-up and purification. 1H NMR (CDCl3) δ 0.98-1.20 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.60 (m, 1H), 1.70-1.78 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.56 (t, 1H, J=11.1 Hz), 2.75-2.91 (m, 3H), 3.28 (t, 1H, J=11.7 Hz), 3.58 (m, 1H), 3.77 (s, 2H), 3.86-3.93 (m, 1H), 3.95 (t, 2H, J=7.8 Hz), 4.43 (t, 2H, J=7.8 Hz), 6.56 (d, 2H, J=8.4 Hz), 6.92-7.03 (m, 3H), 7.26 (m, 2H), 7.43 (m, 3H), 7.52 (br s, 1H), 8.37 (br S, 1H). 13C NMR (CDCl3) δ 13.43, 19.14, 29.01, 30.32, 30.95, 39.82, 43.59, 45.79, 48.17, 52.14, 53.46, 60.53, 61.32, 112.51, 114.31, 118.96, 120.69, 127.27, 128.37, 128.83, 129.23, 130.01, 130.51, 130.96, 134.08, 138.64, 142.01, 145.28, 155.73, 169.83. ES-MS m/z 580 (M+H). Anal. Calcd. for C35H41N5O3.0.2CH2Cl2: C, 70.85; H, 6.99; N, 11.74. Found. C, 70.89; H, 7.07; N, 11.57.
EXAMPLE 161




COMPOUND 161: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
To a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-amino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (see EXAMPLE 154) (51 mg, 0.10 mmol) in CH2Cl2 (1 mL) was added 2-chloro-ethylchloroformate (12 μL, 0.12 mmol) followed by Et3N (21 μL, 0.15 mmol) and the solution was stirred at room temperature for 18.5 hours to afford the crude substrate after work-up.
To the above substrate (73 mg) in DMF (2 mL) was added NaH (60% in mineral oil, 15 mg, 0.25 mmol) and the mixture was heated at 90° C. for 2 hours to afford COMPOUND 161 as a white solid (49 mg, 84%) following work-up and purification. 1H NMR (CDCl3) δ 0.90-1.10 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.54-1.61 (m, 1H), 1.77 (m, 3H), 2.18 (t, 1H, J=11.7 Hz), 2.51 (s, 6H), 2.58 (t, 1H, J=11.4 Hz), 2.74-2.86 (m, 3H), 3.30 (m, 1H), 3.60 (m, 1H), 3.88 (m, 3H), 3.97 (t, 2H, J=8.1 Hz), 4.44 (t, 2H, J=8.4 Hz), 6.57 (d, 2H, J=9.0 Hz), 7.28 (d, 2H, J=10.5 Hz), 7.41-7.46 (m, 1H), 7.51-7.57 (m, 3H), 8.65 (m, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.46, 21.95, 29.24, 30.40, 30.75, 40.01, 43.62, 45.75, 48.28, 51.99, 56.62, 60.21, 61.32, 112.57, 114.40, 118.96, 120.62, 129.07, 129.33, 129.96, 130.64, 130.89, 131.02, 141.65, 145.15, 155.69, 157.51, 163.09, 166.29. ES-MS m/z 582 (M+H). Anal. Calcd. for C33H39N7O3.0.15CH2Cl2: C, 66.98; H, 6.66; N, 16.49. Found. C, 67.03; H, 6.70; N, 16.27.
EXAMPLE 162




COMPOUND 162: 4-{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (440 mg, 1.07 mmol) and 3-cyanobenzyl bromide (314 mg, 1.6 mmol) afforded 4-{(3-cyano-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 90%).
Using general procedure C with the above substrate (520 mg, 0.96 mmol), then general procedure B with 2-(3-oxo-butyl)-isoindole-1,3-dione (413 mg, 1.90 mmol) and then using general procedure D afforded 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid methyl ester as a white solid (218 mg, 44% over 3 steps).
Using general procedure E with the above primary amine (80 mg, 0.16 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (26 mg, 0.17 mmol) followed by general procedure K afforded COMPOUND 162 as a white solid (25 mg, 25% over 2 steps). 1H NMR (CD3OD) δ 1.40 (d, 3H, J=6.0 Hz), 1.78-1.94 (m, 1H), 2.03-2.15 (m, 4H), 2.15-2.29 (m, 1H), 2.48 (s, 6H), 3.06-3.27 (m, 2H), 3.32-3.61 (m, 5H), 3.99-4.12 (m, 1H), 4.46 (s, 2H), 6.80 (d, 2H, J=8.4 Hz), 6.86 (s, 4H), 7.38-7.46 (m, 1H), 7.49-7.61 (m, 3H), 7.87 (d, 2H, J=8.1 Hz), 8.86 (s, 1H). 13C NMR (CD3OD) δ 14.19, 22.40, 28.54, 28.70, 32.64, 38.07, 51.10 (2 carbons), 56.32, 61.15, 113.81, 117.56, 118.92, 120.25, 122.70, 130.25, 131.05, 131.85, 132.08 (2 carbons), 132.90, 133.18, 143.95, 146.90, 149.93, 158.66, 163.43, 165.09, 169.54, 173.58. ES-MS m/z 633 (M+H). Anal. Calcd. for C37H40N6O4.1.2CH2Cl2: C, 62.45; H, 5.82; N, 11.44. Found. C, 62.56; H, 5.95; N, 11.40.
EXAMPLE 163




COMPOUND 163: 4-{4-[{1-[3-(2-Chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 162) (80 mg, 0.16 mmol) and 2-chloro-6-methyl benzoic acid (29 mg, 0.17 mmol) followed by general procedure K afforded COMPOUND 163 as a white solid (42 mg, 41% over 2 steps). 1H NMR (CD3OD) δ 1.39 (d, 3H, J=6.6 Hz), 1.79-2.07 (m, 3H), 2.08-2.21 (m, 3H), 2.34 (s, 3H), 3.06-3.26 (m, 2H), 3.34-3.64 (m, 5H), 3.98-4.10 (m, 1H), 4.48 (s, 2H), 6.86 (d, 2H, J=8.4 Hz), 6.92 (s, 4H), 7.19-7.30 (m, 3H), 7.44-7.51 (m, 1H), 7.55-7.65 (m, 3H), 7.91 (d, 2H, J=8.4 Hz). 13C NMR (CD3OD) δ 14.26, 19.87, 28.36, 28.48, 32.53, 37.62, 51.11, 56.02, 61.37, 113.82, 117.65, 119.02, 120.25, 122.79, 128.23, 128.90, 130.28, 131.07, 131.75, 131.85, 131.92, 132.11, 133.03, 133.18, 138.02, 138.59, 143.83, 146.92, 149.84, 163.81, 171.08, 172.17. ES-MS m/z 651 (M+H). Anal. Calcd. for C38H39N4ClO4.0.5CH2Cl2.1.7H2O: C, 63.84; H, 6.04; N, 7.74; Cl, 9.79. Found. C, 63.70; H, 6.08; N, 7.64; Cl, 9.92.
EXAMPLE 164




COMPOUND 164: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 85) (331 mg, 0.99 mmol) and 3-(bromomethyl)benzonitrile (300 mg, 1.53 mmol) gave impure product as a white foam (299 mg).
Using general procedure C with the impure carbamate, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (252 mg, 1.16 mmol) and then using general procedure D gave 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester as a white foam (146 mg, 35% over 4 steps).
Using general procedure E with the primary amine (73 mg, 0.17 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (37 mg, 0.24 mmol) followed by general procedure K with the resulting ester gave 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a beige solid (43.4 mg, 46% over 2 steps).
Using general procedure E, the crude carboxylic acid (43.4 mg, 0.080 mmol) and NH4Cl (11 mg, 0.21 mmol) gave COMPOUND 164 as an off-white foam (23.7 mg, 55%). 1H NMR (CDCl3) δ 0.98-1.21 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.51-1.62 (m, 1H), 1.70-1.86 (m, 3H), 2.17-2.28 (m, 1H), 2.51 (s, 6H), 2.55-2.66 (m, 1H), 2.72-2.93 (m, 3H), 3.30-3.40 (m, 1H), 3.70-3.87 (m, 2H), 4.04 (s, 2H), 5.80 (br s, 2H), 6.55 (d, 2H, J=8.6 Hz), 7.43-7.57 (m, 4H), 7.63 (d, 2H, J=8.6 Hz), 8.47 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.45, 21.91, 29.26, 30.36, 30.80, 39.90, 43.53, 47.97, 51.81, 55.64, 60.06, 111.94, 112.71, 118.75, 121.60, 129.22, 129.46, 129.58, 130.67, 130.78, 130.83, 140.79, 150.87, 157.53, 163.09, 166.23, 168.84. ESI-MS m/z 540 (MH)+. Anal. Calcd. for C31H37N7O2.0.8CH2Cl2: C, 62.86; H, 6.40; N, 16.14. Found. C, 62.61; H, 6.59; N, 16.27.
EXAMPLE 165




COMPOUND 165: N-(3-{4-[(4-Carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2-chloro-6-methyl-benzamide
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 164) (73 mg, 0.17 mmol) and 2-chloro-6-methylbenzoic acid (43 mg, 0.25 mmol) followed by general procedure K with the resulting ester gave 4-[{1-[3-(2-chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-(3-cyano-benzyl)-amino]-benzoic acid as a beige solid (44.5 mg, 46% over 2 steps).
Using general procedure E, the crude carboxylic acid (44.5 mg, 0.080 mmol) and NH4Cl (12 mg, 0.22 mmol) gave COMPOUND 165 as a white foam (20.9 mg, 47%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.0 Hz), 1.03-1.17 (m, 1H), 1.19-1.32 (m, 1H), 1.49-1.60 (m, 1H), 1.70-1.88 (m, 3H), 2.16-2.26 (m, 1H), 2.36 (s, 3H), 2.54-2.65 (m, 1H), 2.78-2.99 (m, 3H), 3.27-3.39 (m, 1H), 3.70-3.91 (m, 2H), 3.98 (s, 2H), 5.79 (br s, 2H), 6.54 (d, 2H, J=8.6 Hz), 7.04-7.14 (m, 3H), 7.36-7.48 (m, 3H), 7.52-7.58 (m, 1H), 7.62 (d, 2H, J=8.6 Hz), 8.33 (br s, 1H). 13C NMR (CDCl3) δ 13.38, 19.32, 29.27, 30.33, 30.84, 39.82, 43.54, 47.96, 51.87, 55.96, 60.17, 112.06, 112.71, 118.69, 121.50, 126.54, 128.39, 129.18, 129.43, 129.63, 130.56, 130.72, 137.19, 137.54, 141.05, 150.86, 166.71, 168.83. ESI-MS m/z 558 (MH)+, 560 (MH+2)+. Anal. Calcd. for C32H36ClN5O2.0.9CH2Cl2: C, 62.27; H, 6.00; N, 11.04. Found. C, 62.25; H, 5.94; N, 11.04.
EXAMPLE 166




COMPOUND 166: N-(3-{4-[(4-Carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (100 mg, 0.24 mmol) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (59 mg, 0.26 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-4-pyridin-4-yl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (92 mg, 58% over 2 steps).
Using general procedure E, the above acid (44 mg, 0.07 mmol) and ammonium chloride (15 mg, 0.0.28 mmol) afforded COMPOUND 166 as a white solid (31 mg, 71%). 1H NMR (CDCl3) δ 0.92-1.32 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.51-1.62 (m, 1H), 1.69-1.83 (m, 3H), 2.14-2.27 (m, 1H), 2.39 (s, 6H), 2.53-2.64 (m, 1H), 2.74-2.95 (m, 3H), 3.29-3.41 (m, 1H), 3.67-3.88 (m, 2H), 3.90 (s, 2H), 5.81 (br s, 2H), 6.47 (d, 2H, J=8.4 Hz), 7.10 (d, 1H, J=7.5 Hz), 7.18 (s, 1H), 7.22-7.33 (m, 3H), 7.41-7.49 (m, 3H), 7.60 (d, 2H, J=7.8 Hz), 8.02 (br s, 1H), 8.65 (d, 2H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.50, 19.37, 29.20, 30.43, 31.42, 39.48, 43.75, 47.70, 51.83, 55.93, 59.92, 111.95, 112.70, 118.65, 121.33, 121.58, 125.95, 129.26, 129.43, 130.39, 130.65, 135.39, 137.95, 139.29, 140.94, 147.37, 150.53, 150.83, 168.88, 169.26. ES-MS m/z 615 (M+H). Anal. Calcd. for C38H42N6O2.1.2H2O: C, 65.69; H, 6.24; N, 11.73. Found. C, 65.94; H, 6.24; N, 11.70.
EXAMPLE 167




COMPOUND 167: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 129) (50 mg, 0.09 mmol) and morpholine (29 μL, 0.33 mmol) afforded COMPOUND 167 as a white solid (48 mg, 87%). 1H NMR (CDCl3) δ 0.84-1.18 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.50-1.60 (m, 1H), 1.70-1.84 (m, 3H), 2.14-2.26 (m, 1H), 2.51 (s, 6H), 2.53-2.65 (m, 1H), 2.71-2.92 (m, 3H), 3.27-3.39 (m, 1H), 3.57-3.92 (m, 10H), 3.96 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.25-7.30 (m, 2H), 7.43-7.59 (m, 4H), 8.54 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.36, 29.54, 30.83, 31.12, 40.49, 43.87, 48.45, 52.39, 56.04, 60.76, 67.36, 77.61, 112.53, 113.14, 123.98, 129.89, 130.08, 131.17, 141.51, 149.88, 157.99, 163.53, 166.57, 171.00. ES-MS m/z 610 (M+H). Anal. Calcd. for C35H43N7O3.0.2CH2Cl2.0.1H2O: C, 67.26; H, 6.99; N, 15.60. Found. C, 67.44; H, 7.12; N, 15.30.
EXAMPLE 168




COMPOUND 168: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl 1-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide
Using general procedure A, 4-amino-N,N-dibenzyl-benzenesulfonamide (see EXAMPLE 83) (4.30 g, 12.20 mmol) and 1-Boc-4-piperidone (4.86 g, 24.40 mmol) afforded 4-(4-dibenzylsulfamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (3.84 g, 59%).
Using general procedure H, the amine (1.37 g, 2.56 mmol) and α-bromo-m-tolunitrile (1.51 g, 7.68 mmol) afforded a yellow oil as a mixture of starting amine/product (1:1).
Using general procedure C with the above amine, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (313 mg, 1.44 mmol) and then using general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-N,N-dibenzyl-benzenesulfonamide as a white foam (170 mg, 11% over 4 steps).
Using general procedure E, the amine (126 mg, 0.20 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (40 mg, 0.26 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-dibenzylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide as a pale yellow foam (146 mg, 100%).
A solution of the above amine (146 mg, 0.19 mmol) in H2SO4 (conc) (1.5 mL) was stirred for 1 h. Then the mixture was poured into ice (20 mL), basified with Na2CO3 (s) to pH-9, and extracted with CH2Cl2 (12×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford COMPOUND 168 as a pale yellow foam (48 mg, 44%) after purification. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.3 Hz), 1.11-1.25 (m, 1H), 1.54-1.59 (m, 4H), 2.22 (t, 1H, J=11.4 Hz), 2.50 (s, 6H), 2.60 (t, 1H, J=11.1 Hz), 2.75-2.90 (m, 3H), 3.34 (br s, 1H), 3.71-3.83 (m, 2H), 4.06 (s, 2H), 4.85 (s, 2H), 6.56 (d, 2H, J=8.7 Hz), 7.46-7.57 (m, 4H), 7.66 (d, 2H, J=8.7 Hz), 8.32 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.38, 21.97, 29.28, 30.34, 30.92, 39.88, 43.55, 47.97, 51.75, 53.45, 60.01, 112.06, 112.85, 118.76, 128.52, 129.09, 129.36, 129.51, 129.65, 130.71, 130.86, 130.98, 140.23, 151.23, 151.57, 163.16, 166.28. ES-MS m/z 598 [M+H]+. Anal. Calcd. for C30H37N7O3S.0.9CH2Cl2: C, 56.91; H, 6.00; N, 15.03; S, 4.92. Found. C, 56.83; H, 6.03; N, 14.88; S, 4.87.
EXAMPLE 169




COMPOUND 169: Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
Using general procedure A, 4-aminophenol (2.0 g, 18.3 mmol) and 1-Boc-4-piperidone (3.64 mg, 18.3 mmol) gave the alcohol which was subsequently treated with TBDMSCl (2.76 g, 18.3 mmol), imidazole (1.50 g, 22 mmol) and DMF (40 mL) to afford 4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 63% over 2 steps) following work-up and purification.
Using general procedure H, the above aniline (2.1 g, 5.16 mmol) and 3-cyanobenzyl bromide (1.52 g, 7.74 mmol) gave 4-[[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 100%).
Using general procedure C with the above carbamate (2.7 g, 5.16 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (2.24 g, 10.3 mmol) and then using general procedure D afforded 3-({[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amino}-methyl)-benzonitrile (810 mg, 32% over 3 steps).
To the above amine (810 mg, 1.64 mmol) in CH2Cl2 (20 mL) was added Boc2O (360 mg, 1.65 mmol) and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure and the residue was dissolved in THF (10 mL) and TBAF (10M in THF, 2.0 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated under reduced pressure to give (3-{4-[(3-cyano-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (740 mg, 94% over 2 steps) following work-up and purification.
Using general procedure G with the above alcohol (740 mg, 1.55 mmol) followed by general procedure C afforded methanesulfonic acid 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenyl ester (360 mg, 51% over 2 steps).
Using general procedure E, the above amine (120 mg, 0.26 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (44 mg, 0.29 mmol) afforded COMPOUND 169 as a white solid (92 mg, 60%). 1H NMR (CDCl3) δ 0.88-1.15 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.53-1.60 (m, 1H), 1.75-1.79 (m, 3H), 2.18 (t, 1H, J=12.0 Hz), 2.51 (s, 6H), 2.58 (t, 1H, J=12.0 Hz), 2.58-2.86 (m, 3H), 3.07 (s, 3H), 3.28-3.37 (m, 1H), 3.59-3.66 (m, 1H), 3.82-3.89 (m, 1H), 3.91 (s, 2H), 6.52 (d, 2H, J=8.4 Hz), 7.06 (d, 2H, J=8.4 Hz), 7.44-7.56 (m, 4H), 8.54 (br s, 1H), 8.87 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.35, 29.54, 30.79, 31.12, 37.26, 40.49, 43.89, 48.80, 52.40, 56.63, 60.74, 114.32, 123.35, 129.87, 130.11, 131.20, 141.60, 147.71, 157.97, 163.52, 166.63. ES-MS m/z 591 (M+H). Anal. Calcd. for C31H38N6O4S.0.2CH2Cl2: C, 61.66; H, 6.37; N, 13.83; S, 5.28. Found. C, 61.80; H, 6.39; N, 13.82; S, 5.24.
EXAMPLE 170




COMPOUND 170: Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester
Using general procedure E, methanesulfonic acid 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-phenyl ester (see EXAMPLE 169) (120 mg, 0.26 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (53 mg, 0.32 mmol) afforded COMPOUND 170 as a white solid (110 mg, 69%). 1H NMR (CDCl3) δ 1.02-1.28 (m, 5H), 1.53-1.63 (m, 1H), 1.78-1.82 (m, 3H), 2.21 (t, 1H, J=12.0 Hz), 2.29 (s, 3H), 2.44 (s, 3H), 2.58 (t, 1H, J=12.0 Hz), 2.76-2.85 (m, 3H), 3.08 (s, 3H), 3.37 (m, 1H), 3.65-3.77 (m, 2H), 4.12 (s, 2H), 6.55 (d, 2H, J=7.8 Hz), 6.88 (d, 1H, J=6.3 Hz), 7.06 (d, 2H, J=8.1 Hz), 7.44-7.62 (m, 4H), 7.97 (d, 1H, J=6.3 Hz), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.96, 15.44, 18.86, 29.89, 30.56, 32.71, 37.22, 39.11, 44.86, 49.10, 51.67, 56.93, 58.72, 112.98, 114.19, 119.31, 123.28, 125.34, 129.87, 130.11, 131.07, 131.31, 134.98, 137.37, 138.14, 140.73, 141.90, 145.80, 147.91, 165.75. ES-MS m/z 606 (M+H). Anal. Calcd. for C32H39N5O5S.0.6CH2Cl2: C, 59.62; H, 6.17; N, 10.66; S, 4.88. Found. C, 59.43; H, 6.22; N, 10.46; S, 4.79.
EXAMPLE 171




COMPOUND 171: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 1-CBZ-4-piperidone (3.00 g, 12.86 mmol) and 2-(4-amino-benzyl)-isoindole-1,3-dione (Vamecq, Joseph; et al., J. Med. Chem., 43, 7, 2000, 1311-1319) (1.62 g, 6.42 mmol), then general procedure H with the resulting amine and 3-cyanobenzyl bromide (1.68 g, 8.59 mmol) and then using general procedure D afforded 4-[(4-aminomethyl-phenyl)-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (1.95 g, 67% over 3 steps).
To a solution of the above amine (462 mg, 1.02 mmol) in CH2Cl2 (10 mL) were added Et3N (0.45 mL, 3.23 mmol) followed by acetic anhydride (0.20 mL, 2.12 mmol) and the mixture was stirred at room temperature overnight to afford 4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (463 mg, 91%) following work-up and purification.
To a solution of the above substrate (445 mg, 0.90 mmol) in EtOH (9 mL) were added ammonium formate (695 mg, 11.01 mmol) followed by 10% Pd/C (215 mg) and the mixture was stirred at room temperature for 2 hours. Standard work-up and purification afforded N-{4-[(3-cyano-benzyl)-piperidin-4-yl-amino]-benzyl}-acetamide as a white solid (154 mg, 47%).
Using general procedure B with the above amine (146 mg, 0.403 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (285 mg, 1.31 mmol) and then using general procedure D afforded N-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzyl}-acetamide as a white solid (108 mg, 62% over 2 steps).
Using general procedure E, the above amine (48 mg, 0.11 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (27 mg, 0.18 mmol) afforded COMPOUND 171 as a white solid (49 mg, 72%). 1H NMR (CDCl3) δ 0.87-1.25 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.54-1.59 (m, 1H), 1.75-1.78 (m, 3H), 1.98 (s, 3H), 2.18 (t, 1H, J=12.3 Hz), 2.50 (s, 6H), 2.58 (t, 1H, J=11.4 Hz), 2.73-2.85 (m, 3H), 3.27-3.35 (m, 1H), 3.50-3.66 (m, 1H), 3.80-3.90 (m, 1H), 3.90 (s, 2H), 4.28 (d, 2H, J=4.5 Hz), 5.69 (br s, 1H), 6.52 (d, 2H, J=7.5 Hz), 7.08 (d, 2H, J=7.5 Hz), 7.42-7.58 (m, 4H), 8.65 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.46, 20.27, 21.31, 21.92, 23.25, 29.20, 30.43, 30.74, 33.96, 38.09, 40.03, 43.18, 43.60, 44.85, 45.52, 48.45, 51.14, 52.01, 52.17, 53.46, 56.16, 56.92, 60.23, 112.53, 113.92, 118.99, 124.70, 127.38, 127.88, 128.39, 128.54, 129.31, 129.90, 130.61, 130.89, 130.96, 138.18, 139.71, 141.72, 147.53, 157.48, 162.95, 163.07, 166.25, 166.43, 169.74. ES-MS m/z 568 (M+H). Anal. Calcd. for C33H41N7O2.2.0H2O: C, 65.65; H, 7.51; N, 16.24. Found. C, 65.78; H, 7.16; N, 16.05.
EXAMPLE 172




COMPOUND 172: N-(3-{4-[[4-(Acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, N-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzyl}-acetamide (see EXAMPLE 171) (51 mg, 0.12 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (29 mg, 0.18 mmol) afforded COMPOUND 172 as a white solid (27 mg, 33%). 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.53-1.61 (m, 1H), 1.71-1.81 (m, 3H), 1.99 (s, 3H), 2.16-2.25 (m, 1H), 2.29 (s, 3H), 2.46 (s, 3H), 2.57 (t, 1H, J=12.6 Hz), 2.74-2.84 (m, 3H), 3.31-3.38 (m, 1H), 3.58-3.81 (m, 2H), 7.09 (s, 2H), 4.28 (d, 2H, J=4.5 Hz), 5.73 (br s, 1H), 6.54 (d, 2H, J=7.2 Hz), 3.87 (d, 1H, J=6.0 Hz), 7.07 (d, 2H, J=7.2 Hz), 7.45-7.53 (m, 3H), 7.63 (d, 1H, J=7.5 Hz), 7.98 (d, 1H, J=6.0 Hz), 8.47 (br s, 1H). 13C NMR (CDCl3) δ 13.90, 15.54, 18.82, 20.62, 21.73, 23.67, 29.86, 30.73, 32.22, 35.13, 38.21, 39.60, 43.56, 44.58, 48.99, 51.52, 52.02, 56.85, 59.43, 112.86, 114.30, 119.42, 125.23, 127.63, 128.23, 128.76, 129.11, 129.66, 129.75, 130.30, 130.94, 131.54, 134.44, 137.24, 138.32, 142.29, 145.90, 148.00, 165.72, 170.17. ES-MS m/z 583 (M+H). Anal. Calcd. for C34H42N6O3.1.3CH2Cl2: C, 61.17; H, 6.49; N, 12.12. Found. C, 61.32; H, 6.45; N, 11.88.
EXAMPLE 173




COMPOUND 173: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
A mixture of 4′-aminoacetophenone (1.45 g, 10.7 mmol), ethylene glycol (2.00 g, 32.2 mmol), and p-TsOH.H2O (2.45 g, 12.9 mmol) in toluene (30 mL) were heated to reflux under a Dean-Stark trap for 3.5 h. Basic work-up and purification gave 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine as colourless crystals (0.67 g, 35%).
Using general procedure A, the amine from above (388 mg, 2.16 mmol) and I-Boc-4-piperidone (518 mg, 2.60 mmol) gave 4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (283 mg, 36%).
Using general procedure H, the above aniline (690 mg, 1.90 mmol) and 3-cyanobenzyl bromide (1.12 g, 5.71 mmol) afforded a beige solid (907 mg).
A solution of the above carbamate (907 mg) in 6N HCl (20 mL) was heated at 40° C. for 2 hours to give 3-{[(4-acetyl-phenyl)-piperidin-4-yl-amino]-methyl}-benzonitrile as a white solid (410 mg, 65% over 2 steps) following basic work-up and purification.
Using general procedure B with the above amine (410 mg, 1.23 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (670 mg, 3.1 mmol) and then using general procedure D afforded a pale brown solid.
To the above amine in THF (4 mL) was added Boc2O (350 mg, 1.60 mmol) and the mixture was stirred at room temperature for 1 hour to afford (3-{4-[(4-acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester as a white solid (271 mg, 44% over 3 steps) following work-up and purification.
Using general procedure C, the above substrate (270 mg, 0.54 mmol) gave 3-({(4-acetyl-phenyl)-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-amino}-methyl)-benzonitrile as a white solid (209 mg, 97%).
Using general procedure E, the above amine (104 mg, 0.26 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (59 mg, 0.39 mmol) afforded COMPOUND 173 as a white solid (102 mg, 73%). 1H NMR (CDCl3) δ 0.97-1.15 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.55-1.60 (m, 1H), 1.76-1.79 (m, 3H), 2.22 (t, 1H, J=12.0 Hz), 2.48 (s, 3H), 2.52 (s, 6H), 2.61 (t, 1H, J=12.0 Hz), 2.76-2.95 (m, 3H), 3.30-3.39 (m, 1H), 3.78-3.85 (m, 2H), 4.04 (s, 2H), 6.54 (d, 2H, J=8.4 Hz), 7.45-7.55 (m, 4H), 7.79 (d, 2H, J=8.4 Hz), 8.44 (br s, 1H), 8.92 (s, 1H). 13C NMR (CDCl3) δ 13.89, 22.34, 26.42, 29.75, 30.79, 31.35, 40.20, 43.98, 48.33, 52.13, 56.05, 60.30, 111.99, 113.17, 119.13, 127.14, 129.94, 131.08, 131.26, 140.99, 152.12, 157.93, 163.50, 166.68. ES-MS m/z 539 (M+H). Anal. Calcd. for C32H38N6O2.0.5CH2Cl2: C, 67.17; H, 6.76; N, 14.46. Found. C, 66.97; H, 6.89; N, 14.80.
EXAMPLE 174




COMPOUND 174: N-(3-{4-[(4-Acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 3-({(4-acetyl-phenyl)-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-amino}-methyl)-benzonitrile (see EXAMPLE 173) (102 mg, 0.25 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (63 mg, 0.38 mmol) afforded COMPOUND 174 as a white solid (85 mg, 61%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=5.1 Hz), 1.14-1.39 (m, 2H), 1.53-1.62 (m, 1H), 1.79-1.83 (m, 3H), 2.26 (t, 1H, J=12.3 Hz), 2.30 (s, 3H), 2.42 (s, 3H), 2.48 (s, 3H), 2.61 (t, 1H, J=11.4 Hz), 2.77-2.90 (m, 3H), 3.40 (br s, 1H), 3.70-3.83 (m, 2H), 4.28 (s, 2H), 6.57 (d, 2H, J=7.5 Hz), 6.89 (d, 1H, J=6.0 Hz), 7.44-7.60 (m, 4H), 7.83 (d, 2H, J=7.8 Hz), 7.98 (d, 1H, J=6.0 Hz), 8.36 (br s, 1H). 13C NMR (CDCl3) δ 13.99, 15.49, 18.87, 26.42, 30.05, 30.71, 32.71, 39.19, 44.72, 48.57, 51.67, 56.44, 58.79, 112.04, 113.12, 119.18, 125.32, 127.03, 129.95, 129.98, 131.10, 131.18, 134.85, 137.35, 138.18, 141.20, 145.84, 152.26, 165.75. ES-MS m/z 554 (M+H). Anal. Calcd. for C33H39N5O3.0.9CH2Cl2: C, 64.62; H, 6.53; N, 11.11. Found. C, 64.80; H, 6.51; N, 11.15.
EXAMPLE 175




COMPOUND 175: {4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoylamino}-acetic acid methyl ester
Using general procedure E, 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid (see EXAMPLE 129) (100 mg, 0.26 mmol) and glycine methyl ester hydrochloride (46 mg, 0.37 mmol) afforded COMPOUND 175 as a white solid (65 mg, 57%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.04-1.26 (m, 2H), 1.46-1.62 (m, 1H), 1.67-1.86 (m, 3H), 2.14-2.27 (m, 1H), 2.51 (s, 6H), 2.56-2.65 (m, 1H), 2.70-2.93 (m, 3H), 3.28-3.38 (m, 2H), 3.47-3.53 (m, 1H), 3.67-3.89 (m, 2H), 3.96-4.07 (m, 3H), 4.20, 4.21 (s, 2H), 6.43-6.59 (m, 3H), 7.42-7.58 (m, 4H), 7.64 (d, 3H, J=8.1 Hz), 8.49 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.50, 14.75, 21.97, 25.65, 28.42, 29.32, 30.43, 30.82, 36.04, 36.33, 39.99, 41.65, 43.55, 44.41, 48.02, 51.89, 52.40, 53.80, 55.71, 56.68, 60.17, 111.77, 112.07, 112.78, 118.78, 122.09, 128.89, 129.50, 129.65, 130.72, 130.84, 131.65, 140.87, 150.78, 157.58, 158.34, 163.12, 166.28, 166.90, 170.80, 181.11. ES-MS m/z 612 (M+H).
EXAMPLE 176




COMPOUND 176: N-[3-(4-{(3-Cyano-benzyl)-[4-(1-methoxyimino-ethyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide
A mixture of COMPOUND 174 (59 mg, 0.11 mmol), NaOAc (170 mg, 2.1 mmol) and methoxylamine hydrochloride (89 mg, 1.1 mmol) in MeOH (1.2 mL) was stirred at room temperature for 3 days to afford COMPOUND 176 as a white solid (51 mg, 83%) following work-up and purification. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.3 Hz), 1.02-1.26 (m, 2H), 1.53-1.60 (m, 1H), 1.78-1.82 (m, 3H), 2.147 (s, 3H), 2.22 (t, 1H, J=11.4 Hz), 2.29 (s, 3H), 2.46 (s, 3H), 2.59 (t, 1H, J=11.7 Hz), 2.75-2.88 (m, 3H), 3.36-3.38 (m, 1H), 3.68-3.81 (m, 2H), 3.94 (s, 3H), 4.13 (s, 2H), 6.55 (d, 2H, J=8.7 Hz), 6.87 (d, 1H, J=6.9 Hz), 7.44-7.53 (m, 5H), 7.61 (d, 1H, J=7.5 Hz), 7.98 (d, 1H, J=6.3 Hz), 8.41 (br s, 1H). 13C NMR (CDCl3) δ 12.73, 13.96, 15.46, 18.86, 29.99, 30.69, 32.66, 39.23, 44.83, 48.66, 51.77, 56.60, 58.83, 62.05, 112.23, 112.92, 113.20, 119.31, 125.30, 126.01, 127.62, 129.75, 130.20, 130.59, 130.95, 131.37, 134.90, 137.37, 138.16, 142.13, 145.84, 149.25, 154.72, 156.74. ES-MS m/z 582 (M+H). Anal. Calcd. for C34H42N6O3.0.4CH2Cl2: C, 67.00; H, 6.99; N, 13.63. Found. C, 67.17; H, 7.03; N, 13.59.
Scheme 9 describes the preparation of Examples 177-192, using various general procedures previously described, and reagents listed below.
















Example
R3—NH2
R1COOH







177
5-aminoindole
2,6-dimethylbenzoic acid


178
5-aminoindole
4,6-dimethyl-pyrimidine-5-carboxylic acid


179
3,4-(methylenedioxy)aniline
4,6-dimethyl-pyrimidine-5-carboxylic acid


180
3,4-(methylenedioxy)aniline
2,6-dimethylbenzoic acid


181
5-amino-2,3-dihydro-benzofuran
4,6-dimethyl-pyrimidine-5-carboxylic acid



(Wright, Stephen W.; et al.,



Tetrahedron Lett., 37, 27, 1996,



4631-4634)


182
5-amino-2,3-dihydro-benzofuran
2,6-dimethylbenzoic acid


183
5-amino-1,3-dihydro-isobenzofuran
2,6-dimethylbenzoic acid



(Clark, R. L.; et al., J. Med.



Chem., 21, 1978, 965-978)


184
benzofuran-5-ylamine (Abramenko,
4,6-dimethyl-pyrimidine-5-carboxylic acid



P. I.; et al., Chem. Heterocycl.



Cmpd., 11, 1975, 1358-1361)


185
benzofuran-5-ylamine
2,6-dimethylbenzoic acid


186
4-aminoveratole
4,6-dimethyl-pyrimidine-5-carboxylic acid


187
4-aminoveratole
2,6-dimethylbenzoic acid


188
1,4-benzodioxan-6-amine
4,6-dimethyl-pyrimidine-5-carboxylic acid


189
1,4-benzodioxan-6-amine
2-chloro-6-methylbenzoic acid


190
1,4-benzodioxan-6-amine
2,6-dimethylbenzoic acid


191
6-methoxy-pyridin-3-ylamine
4,6-dimethyl-pyrimidine-5-carboxylic acid



(Nishikawa, Yoshinori; et al., J.



Med. Chem., 32, 3, 1989, 583-593)


192
6-methoxy-pyridin-3-ylamine
2,6-dimethylbenzoic acid









EXAMPLE 177




COMPOUND 177: N-(3-{4-[(3-Cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.89-1.17 (m, 2H), 0.99 (d, 3H, J=5.4 Hz), 1.52 (d, 1H, J=13.8 Hz), 1.75-1.78 (m, 3H), 2.07-2.15 (m, 1H), 2.32 (s, 6H), 2.48-2.56 (m, 1H), 2.73-2.94 (m, 3H), 3.25-3.41 (m, 2H), 3.78 (s, 2H), 3.88 (br s, 1H), 6.33 (s, 1H), 6.66 (d, 1H, J=8.7 Hz), 6.90-6.95 (m, 4H), 7.07 (s, 1H), 7.15 (d, 1H, J=8.7 Hz), 7.32-7.37 (m, 1H), 7.43-7.50 (m, 2H), 7.55 (s, 1H), 8.26 (s, 1H), 8.59 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 19.15, 29.14, 30.39, 30.87, 39.88, 43.68, 49.45, 52.21, 59.82, 60.57, 101.80, 108.43, 111.43, 112.09, 114.97, 119.23, 124.82, 127.28, 128.35, 128.41, 128.83, 130.16, 130.81, 131.71, 134.02, 138.53, 142.44, 142.98, 170.01. ES-MS m/z 534 (M+H). Anal. Calcd. for C34H39N5O.0.7CH2Cl2: C, 70.26; H, 6.86; N, 11.81. Found. C, 70.35; H, 6.84; N, 11.98.
EXAMPLE 178




COMPOUND 178: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.87-1.15 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.54 (d, 1H, J=12.0 Hz), 1.79-1.83 (m, 3H), 2.13 (t, 1H, J=12.0 Hz), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.72-2.87 (m, 3H), 3.27-3.41 (m, 2H), 3.83-3.88 (m, 1H), 3.88 (s, 2H), 6.37 (s, 1H), 6.67 (d, 1H, J=8.1 Hz), 6.94 (s, 1H), 7.12 (s, 1H), 7.18 (d, 1H, J=8.7 Hz), 7.34-7.39 (m, 1H), 7.45 (d, 1H, J=7.5 Hz), 7.57-7.61 (m, 2H), 8.09 (br s, 1H), 8.81 (s, 1H), 8.84 (br s, 1H). 13C NMR (CDCl3) δ 13.37, 21.94, 29.45, 30.55, 40.21, 43.59, 50.07, 52.09, 59.63, 60.47, 102.10, 109.44, 111.41, 112.21, 115.62, 119.20, 124.79, 128.39, 128.95, 130.33, 130.84, 131.14, 131.82, 142.22, 142.49, 157.52, 163.04, 166.35. ES-MS m/z 536 (M+H). Anal. Calcd. for C32H37N7O.0.3CH2Cl2: C, 69.13; H, 6.75; N, 17.47. Found. C, 69.38; H, 6.86; N, 17.48.
EXAMPLE 179




COMPOUND 179: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.82-1.10 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.48-1.55 (m, 1H), 1.75 (m, 3H), 2.12 (t, 1H, J=11.7 Hz), 2.45-2.56 (m, 1H), 2.50 (s, 6H), 2.71-2.86 (m, 3H), 3.26-3.40 (m, 2H), 3.79 (s, 2H), 3.79-3.88 (m, 1H), 5.84 (s, 2H), 6.02 (d, 1H, J=8.4 Hz), 6.24 (s, 1H), 6.59 (d, 1H, J=8.4 Hz), 7.38-7.55 (m, 3H), 8.71 (m, 1H), 8.82 (s, 1H). 1H NMR (CDCl3) δ 13.42, 21.93, 29.35, 30.52, 30.63, 40.12, 43.56, 49.34, 52.00, 58.30, 60.33, 98.77, 100.83, 108.34, 112.43, 119.04, 129.16, 130.33, 130.53, 130.88, 131.35, 140.59, 141.85, 143.92, 148.39, 157.52, 163.04, 166.27. ES-MS m/z 541 (M+H). Anal. Calcd. for C31H36N6O3.0.9CH2Cl2: C, 62.09; H, 6.17; N, 13.62. Found. C, 62.29; H, 6.05; N, 13.84.
EXAMPLE 180




COMPOUND 180: N-(3-{4-[Benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.89-1.21 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.49-1.55 (m, 1H), 1.69-1.81 (m, 3H), 2.11 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.52 (t, 1H, J=11.1 Hz), 2.73-2.89 (m, 3H), 3.23-3.47 (m, 2H), 3.69 (s, 2H), 3.86-3.92 (m, 1H), 5.83 (s, 2H), 6.00 (dd, 1H, J=8.4, 1.8 Hz), 6.23 (s, 1H), 6.58 (d, 1H, J=8.4 Hz), 6.93-7.00 (m, 3H), 7.37-7.52 (m, 4H), 8.43 (m, 1H). 13C NMR (CDCl3) δ 13.38, 19.14, 29.09, 30.34, 30.92, 39.83, 43.59, 48.95, 52.13, 58.60, 60.52, 98.45, 100.76, 107.87, 108.30, 112.38, 119.05, 127.24, 128.35, 129.06, 130.35, 130.40, 131.25, 134.05, 138.62, 140.25, 142.23, 144.13, 148.34, 169.85. ES-MS m/z 539 (M+H). Anal. Calcd. for C33H38N4O3.0.4CH2Cl2: C, 70.05; H, 6.83; N, 9.78. Found. C, 70.30; H, 6.77; N, 9.85.
EXAMPLE 181




COMPOUND 181: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.87-1.07 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.54 (d, 1H, J=12.3 Hz), 1.74-1.78 (m, 3H), 2.12 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.50-2.56 (m, 1H), 2.67-2.86 (m, 3H), 3.09 (t, 2H, J=8.4 Hz), 3.30 (m, 2H), 3.79 (s, 2H), 3.79-3.88 (m, 1H), 4.47 (t, 2H, J=8.4 Hz), 6.42 (d, 1H, J=8.4 Hz), 6.56-6.59 (m, 2H), 7.37-7.42 (m, 1H), 7.47-7.55 (m, 3H), 8.77 (br s, 1H), 8.82 (s, 1H). 13C NMR (CDCl3) δ 13.39, 21.92, 29.35, 30.25, 30.51, 30.63, 40.06, 43.60, 49.74, 51.95, 58.95, 60.28, 71.07, 109.15, 112.28, 114.95, 117.11, 119.11, 127.79, 129.06, 130.43, 130.59, 130.86, 131.60, 142.19, 142.51, 153.85, 157.49, 163.01, 166.30. ES-MS m/z 539 (M+H). Anal. Calcd. for C32H38N6O2.0.5CHCl3: C, 65.24; H, 6.48; N, 14.04. Found. C, 65.19; H, 6.55; N, 13.93.
EXAMPLE 182




COMPOUND 182: N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.88-1.17 (m, 2H), 0.98 (d, 3H, J=6.3 Hz), 1.51 (d, 1H, J=13.8 Hz), 1.66-1.81 (m, 3H), 2.10 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.50 (t, 1H, J=10.8 Hz), 2.72-2.88 (m, 3H), 3.09 (t, 2H, J=8.4 Hz), 3.24-3.31 (m, 2H), 3.69 (s, 2H), 3.86-3.90 (m, 1H), 4.46 (t, 2H, J=8.4 Hz), 6.39 (d, 1H, J=8.7 Hz), 6.56 (m, 2H), 6.92-6.97 (m, 3H), 7.35-7.48 (m, 4H), 8.45 (s, 1H). 13C NMR (CDCl3) δ 12.41, 18.16, 28.15, 29.32, 29.94, 38.86, 42.66, 48.25, 51.17, 52.50, 58.24, 59.54, 70.05, 108.11, 111.27, 113.35, 115.45, 118.17, 126.26, 126.76, 127.37, 127.99, 129.32, 129.62, 130.52, 133.05, 137.63, 141.63, 141.79, 152.48, 169.90. ES-MS m/z 537 (M+H). Anal. Calcd. for C34H40N4O2.0.3C6H14.0.1CH2Cl2: C, 75.51; H, 7.84; N, 9.81. Found. C, 75.44; H, 7.85; N, 9.81.
EXAMPLE 183




COMPOUND 183: N-(3-{4-[(3-Cyano-benzyl)-(1,3-dihydro-isobenzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.93-1.20 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.51-1.55 (m, 1H), 1.71-1.84 (m, 3H), 2.17 (t, 1H, J=11.4 Hz), 2.31 (s, 6H), 2.57 (t, 1H, J=11.7 Hz), 2.75-2.91 (m, 3H), 3.29 (t, 1H, J=11.4 Hz), 3.56-3.64 (m, 1H), 3.81 (s, 2H), 3.86-3.92 (m, 1H), 4.98 (s, 4H), 6.43-6.47 (m, 2H), 6.93-7.05 (m, 4H), 7.39-7.52 (m, 3H), 8.36 (m, 1H). 13C NMR (CDCl3) δ 13.83, 19.54, 29.37, 30.74, 31.36, 40.22, 44.01, 48.87, 52.56, 57.41, 60.92, 73.58, 74.03, 106.40, 112.93, 113.68, 119.37, 121.96, 127.68, 128.67, 128.77, 129.61, 130.38, 130.89, 131.30, 134.49, 139.05, 141.09, 142.52, 148.51, 170.23. ES-MS m/z 537 (M+H). Anal. Calcd. for C34H40N4O2.0.4C6H14.0.1CH2Cl2: C, 75.63; H, 7.96; N, 9.67. Found. C, 75.41; H, 7.90; N, 9.70.
EXAMPLE 184




COMPOUND 184: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.94-1.12 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.47-1.57 (m, 1H), 1.74-1.83 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.56 (t, 1H, J=11.4 Hz), 2.74-2.85 (m, 3H), 3.32 (t, 1H, J=11.1 Hz), 3.48 (m, 1H), 3.82-3.90 (m, 1H), 3.90 (s, 2H), 6.59 (s, 1H), 6.67 (dd, 1H, J=9.0, 1.5 Hz), 7.28 (m, 1H), 7.37-7.58 (m, 5H), 8.74 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.41, 21.94, 29.33, 30.52, 30.64, 40.09, 43.61, 49.54, 52.03, 58.73, 60.32, 106.43, 107.32, 107.99, 111.56, 112.38, 114.87, 119.05, 128.09, 129.14, 130.48, 130.88, 131.48, 142.05, 144.55, 145.51, 149.53, 157.51, 163.05, 166.30. ES-MS m/z 537 (M+H). Anal. Calcd. for C32H36N6O2.0.4CH2Cl2: C, 68.20; H, 6.50; N, 14.73. Found. C, 68.32; H, 6.48; N, 14.74.
EXAMPLE 185




COMPOUND 185: N-(3-{4-[Benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.97-1.21 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.53 (m, 1H), 1.66-1.78 (m, 3H), 2.14 (t, 1H, J=10.8 Hz), 2.32 (s, 6H), 2.54 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.28 (t, 1H, J=11.4 Hz), 3.45-3.52 (m, 1H), 3.79 (s, 2H), 3.87-3.93 (m, 1H), 6.58 (s, 1H), 6.66 (d, 1H, J=8.7 Hz), 6.77 (s, 1H), 6.94-7.00 (m, 3H), 7.26 (m, 1H), 7.36-7.41 (m, 1H), 7.46-7.51 (m, 4H), 8.47 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.55, 29.53, 30.79, 31.33, 40.26, 44.04, 49.56, 52.60, 59.43, 60.96, 106.81, 107.80, 111.89, 112.73, 114.91, 119.49, 127.66, 128.45, 128.76, 129.44, 130.77, 130.89, 131.79, 134.46, 139.03, 142.87, 145.13, 145.86, 149.69, 170.27. ES-MS m/z 535 (M+H). Anal. Calcd. for C34H38N4O2.0.1CH2Cl2: C, 75.40; H, 7.09; N, 10.31. Found. C, 75.68, H, 7.13; N, 10.37.
EXAMPLE 186




COMPOUND 186: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.88-1.09 (m, 5H), 1.49-1.58 (m, 1H), 1.76-1.80 (m, 3H), 2.11-2.18 (m, 1H), 2.52 (s, 6H), 2.52-2.58 (m, 1H), 2.74-2.86 (m, 3H), 3.32-3.40 (m, 2H), 3.68-3.86 (m, 1H), 3.73 (s, 3H), 3.78 (s, 3H), 3.81 (s, 2H), 6.16-6.22 (m, 2H), 6.68 (d, 1H, J=8.7 Hz), 7.39-7.44 (m, 1H), 7.49-7.56 (m, 3H), 8.74 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.77, 22.29, 29.73, 30.81, 31.14, 40.30, 44.07, 49.60, 52.32, 56.26, 56.78, 58.52, 60.51, 102.59, 108.38, 112.76, 112.97, 119.38, 129.54, 130.78, 130.91, 131.23, 131.78, 142.45, 142.97, 143.30, 149.95, 157.83, 163.45, 166.72. ES-MS m/z 557 (M+H). Anal. Calcd. for C32H40N6O3.0.8CH2Cl2: C, 63.07; H, 6.71; N, 13.45. Found. C, 62.95; H, 6.60; N, 13.46.
EXAMPLE 187




COMPOUND 187: N-(3-{4-[(3-Cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.90-1.19 (m, 5H), 1.49-1.54 (m, 1H), 1.71-1.75 (m, 3H), 2.12 (t, 1H, J=10.5 Hz), 2.31 (s, 6H), 2.52 (t, 1H, J=10.8 Hz), 2.74-2.94 (m, 3H), 3.24-3.44 (m, 2H), 3.76 (s, 5H), 3.85 (s, 3H), 3.84-3.92 (m, 1H), 6.13 (d, 1H, J=8.7 Hz), 6.19 (s, 1H), 6.66 (d, 1H, J=7.8 Hz), 6.92 (br s, 3H), 7.36-7.50 (m, 4H), 8.45 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.55, 30.78, 31.33, 40.25, 44.04, 49.21, 52.61, 56.22, 56.81, 58.72, 60.96, 102.01, 107.64, 112.78, 112.99, 119.41, 127.64, 128.74, 129.45, 130.08, 130.80, 131.66, 134.45, 139.02, 142.60, 142.92, 143.51, 149.97, 170.25. ES-MS m/z 555 (M+H). Anal. Calcd. for C34H42N4O3.0.6CH2Cl2: C, 68.61; H, 7.19; N, 9.25. Found. C, 68.81; H, 7.14; N, 9.31.
EXAMPLE 188




COMPOUND 188: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide
Pale yellow foam. 1H NMR (CDCl3) δ 0.80-1.10 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.49-1.59 (m, 1H), 1.69-1.83 (m, 3H), 2.09-2.20 (m, 1H), 2.44-2.60 (m, 1H), 2.51 (s, 6H), 2.69-2.90 (m, 3H), 3.25-3.37 (m, 1H), 3.39-3.50 (m, 1H), 3.79 (s, 2H), 3.82-3.91 (m, 1H), 4.14-4.24 (m, 4H), 6.06-6.16 (m, 2H), 6.66 (d, 1H, J=8.7 Hz), 7.39-7.46 (m, 1H), 7.48-7.58 (m, 3H), 8.74 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.32, 21.83, 29.12, 30.35, 30.53, 40.01, 43.47, 48.72, 51.94, 57.18, 60.22, 64.08, 64.59, 103.86, 108.27, 112.33, 117.39, 118.98, 129.08, 130.05, 130.40, 130.78, 131.07, 136.16, 142.02, 143.13, 143.75, 157.42, 162.94, 166.18. ESI-MS m/z 555 (MH)+. Anal. Calcd. for C32H38N6O3.H2O: C, 67.11; H, 7.04; N, 14.67. Found: C, 67.00; H, 6.68; N, 14.40.
EXAMPLE 189




COMPOUND 189: 2-Chloro-N-(3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide
Off-white powder. 1H NMR (CDCl3) δ 0.91-1.05 (m, 1H), 0.99 (d, 3H, J=6.6 Hz), 1.08-1.22 (m, 1H), 1.47-1.58 (m, 1H), 1.68-1.84 (m, 3H), 2.08-2.17 (m, 1H), 2.35 (s, 3H), 2.48-2.58 (m, 1H), 2.74-2.97 (m, 3H), 3.24-3.35 (m, 1H), 3.39-3.50 (m, 1H), 3.73 (s, 2H), 3.84-3.95 (m, 1H), 4.12-4.22 (m, 4H), 6.06-6.15 (m, 2H), 6.65 (d, 1H, J=8.7 Hz), 6.96-7.05 (m, 2H), 7.10 (d, 1H, J=6.9 Hz), 7.38-7.46 (m, 3H), 7.48-7.53 (m, 1H), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.26, 19.24, 29.14, 30.26, 30.60, 39.95, 43.48, 48.57, 52.05, 57.54, 60.36, 64.06, 64.58, 103.83, 108.26, 112.32, 117.35, 118.94, 126.44, 128.25, 129.05, 129.32, 130.08, 130.33, 130.55, 130.99, 136.02, 137.01, 137.55, 142.32, 143.23, 143.70, 166.65. ESI-MS m/z 573 (MH)+, 575 (MH+2)+. Anal. Calcd. for C33H37ClN4O3.0.2H2O.0.1CH2Cl2: C, 67.93; H, 6.48; N, 9.57; Cl, 7.27. Found: C, 67.72; H, 6.44; N, 9.54; Cl, 7.58.
EXAMPLE 190




COMPOUND 190: N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White foam. 1H NMR (CDCl3) δ 0.86-1.16 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.46-1.57 (m, 1H), 1.65-1.82 (m, 3H), 2.07-2.17 (m, 1H), 2.31 (s, 6H), 2.47-2.58 (m, 1H), 2.69-2.91 (m, 3H), 3.21-3.33 (m, 1H), 3.37-3.49 (m, 1H), 3.69 (s, 2H), 3.84-3.94 (m, 1H), 4.11-4.22 (m, 4H), 6.05-6.14 (m, 2H), 6.64 (d, 1H, J=8.7 Hz), 6.89-7.01 (m, 3H), 7.37-7.53 (m, 4H), 8.45 (br s, 1H). 13C NMR (CDCl3) δ 13.27, 19.02, 28.88, 30.20, 30.76, 39.74, 43.48, 48.46, 52.07, 57.45, 60.45, 64.04, 64.58, 103.60, 108.05, 112.26, 117.31, 118.98, 127.14, 128.25, 128.98, 130.07, 130.26, 131.00, 133.94, 135.90, 138.52, 142.37, 143.26, 143.69, 169.73. ESI-MS m/z 553 (MH)+. Anal. Calcd. for C34H40N4O3.0.2CH2Cl2: C, 72.10; H, 7.15; N, 9.83. Found: C, 71.87; H, 7.07; N, 9.71.
EXAMPLE 191




COMPOUND 191: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.85-1.17 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.62 (m, 1H), 1.72-1.83 (m, 3H), 2.06-2.18 (m, 1H), 2.39-2.58 (m, 1H), 2.51 (s, 6H), 2.71-2.91 (m, 3H), 3.26-3.39 (m, 2H), 3.79-3.90 (m, 6H), 6.58 (d, 1H, J=9.0 Hz), 6.98 (d, 1H, J=8.4 Hz), 7.38-7.56 (m, 5H), 8.57 (br s, 1H), 8.80 (s, 1H). 13C NMR (CDCl3) δ 13.42, 21.95, 29.32, 30.37, 30.76, 40.03, 43.55, 49.16, 51.87, 53.33, 58.43, 60.20, 110.78, 112.59, 118.92, 128.79, 129.31, 130.37, 130.75, 130.85, 131.45, 134.93, 138.93, 141.19, 157.51, 158.12, 163.06, 166.28. ES-MS m/z 528 (M+H). Anal. Calcd. for C30H37N7O2.0.1CH2Cl2: C, 67.43; H, 6.99; N, 18.29. Found: C, 67.42; H, 7.03; N, 18.16.
EXAMPLE 192




COMPOUND 192: N-(3-{4-[(3-Cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.88-1.23 (m, 2H), 0.98 (d, 3H, J=6.0 Hz), 1.47-1.58 (m, 1H), 1.67-1.80 (m, 3H), 2.04-2.15 (m, 1H), 2.31 (s, 6H), 2.42-2.56 (m, 1H), 2.72-2.92 (m, 3H), 3.32-3.37 (m, 2H), 3.70 (s, 2H), 3.81 (s, 3H), 3.83-3.94 (m, 1H), 6.56 (d, 1H, J=9.3 Hz), 6.89-7.02 (m, 4H), 7.36-7.54 (m, 5H), 8.37 (br s, 1H). 13C NMR (CDCl3) δ 13.38, 19.14, 29.05, 30.19, 30.98, 39.80, 43.55, 48.73, 52.04, 53.28, 58.75, 60.49, 110.73, 112.52, 118.93, 127.22, 128.35, 128.49, 129.19, 130.43, 130.62, 131.40, 134.06, 134.42, 138.61, 139.10, 141.57, 157.84, 169.83. ES-MS m/z 526 (M+H). Anal. Calcd. for C32H39N5O2.0.2CH2Cl2: C, 71.27; H, 7.32; N, 12.91. Found: C, 71.31; H, 7.20; N, 12.77.
EXAMPLE 193




COMPOUND 193: N-(3-{4-[(2-Acetyl-2,3-dihydro-1H-isoindol-5-yl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
4-Nitrophthalimide (8.0 g, 41.6 mmol) in THF (10 mL) was reduced with BH3-THF (1.0M in THF, 111 mL, 111 mmol) at reflux and treated with 6N HCl to afford 5-nitro-2,3-dihydro-1H-isoindole (1.89 g, 28%) after work-up and purification.
To the above amine (1.89 g, 11.5 mmol) in CH2Cl2 (30 mL) was added Boc2O (2.51 g, 11.5 mmol) and the mixture was stirred at room temperature for 5 minutes to afford 5-nitro-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a white solid (3.04 g, 100%).
A mixture of the above substrate (3.04 g, 11.5 mmol), 10% Pd/C (100 mg), EtOAc (20 mL), MeOH (5 mL) and CH2Cl2 (5 mL) was hydrogenated at 3 atm for 1 h. The mixture was concentrated under reduced pressure and filtered through a silica gel plug to afford 5-amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.3 g, 85%).
Using general procedure A, the above amine (2.3 g, 9.8 mmol) and 1-CBZ-4-piperidone (2.17 mg, 9.31 mmol) afforded 5-(1-benzyloxycarbonyl-piperidin-4-ylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (4.28 g, 95%).
A mixture of the above substrate (2.5 g, 5.53 mmol), 10% Pd/C (250 mg), EtOAc (10 mL) and MeOH (5 mL) was hydrogenated at 3 atm for 3 h. The mixture was concentrated under reduced pressure and filtered through Celite® to afford 5-(piperidin-4-ylamino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester as a yellow solid (1.4 g) that was used in the next reaction without purification.
Using general procedure B with the above amine (1.4 g, 4.4 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (1.91 g, 8.8 mmol) followed by general procedure H with the resulting aniline and 3-cyanobenzyl bromide (612 mg, 3.12 mmol) gave 5-((3-cyano-benzyl)-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-methyl-propyl]-piperidin-4-yl}-amino)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (1.0 g, 37% over 2 steps).
Using general procedure D with the above substrate (1.08 g, 1.57 mmol), then general procedure E with the resulting amine and 2,6-dimethylbenzoic acid (103 mg, 0.68 mmol) and then using general procedure C afforded N-(3-{4-[(3-cyano-benzyl)-(2,3-dihydro-1H-isoindol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide (230 mg, 54% over 3 steps).
To a solution of the above amine (110 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added Et3N (0.04 mL, 0.29 mmol) followed by acetic anhydride (23 μL, 0.24 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 193 as a white solid (90 mg, 87%) after work-up and purification. 1H NMR (CDCl3) δ 0.90-1.23 (m, 5H), 1.49-1.54 (m, 1H), 1.70-1.74 (m, 3H), 2.09 (s, 3H), 2.09-2.17 (m, 1H), 2.29 (s, 6H), 2.56-2.60 (m, 1H), 2.75-2.90 (m, 3H), 3.24-3.31 (m, 1H), 3.55-3.63 (m, 1H), 3.81 (s, 2H), 3.83-3.89 (m, 1H), 4.62 (s, 2H), 4.64 (s, 2H), 6.39-6.53 (m, 2H), 6.91-7.04 (m, 4H), 7.42 (m, 3H), 7.51 (s, 1H), 8.35 (br s, 1H). 13C NMR (CDCl3) δ 13.85, 19.54, 22.51, 22.56, 29.37, 30.67, 31.38, 40.13, 44.05, 48.68, 48.74, 51.74, 52.47, 52.57, 53.14, 53.97, 57.24, 57.34, 60.80, 60.85, 107.81, 108.04, 112.95, 113.94, 114.25, 119.32, 123.69, 124.08, 125.62, 126.12, 127.66, 128.76, 129.65, 130.33, 130.94, 131.28, 134.48, 138.01, 138.39, 139.00, 142.28, 148.52, 148.75, 169.81, 169.90, 170.25. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.1.1CH2Cl2: C, 66.39, H, 6.79; N, 10.43. Found: C, 66.35; H, 6.58; N, 10.52.
EXAMPLE 194




COMPOUND 194: N-(3-{4-[(3-Cyano-benzyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
To 5-nitroindoline (2.0 g, 11.81 mmol) in CH2Cl2 (20 mL) were added Boc2O (2.6 g, 11.9 mmol), Et3N (1.6 mL, 11.8 mmol) and DMAP (20 mg) and the mixture was heated at 40° C. for 48 h. The resulting substrate, 10% Pd/C (200 mg), EtOAc (30 mL) and MeOH (3 mL) was hydrogenated at 2 atm for 2 h. The mixture was concentrated under reduced pressure and filtered through a silica gel plug to afford 5-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (2.76 g, 100% over 2 steps).
Using general procedure A, the above amine (2.76 g, 11.8 mmol) and 1-CBZ-4-piperidone (2.61 g, 11.2 mmol) gave the crude material that was used in the next reaction without purification.
A mixture of the above substrate, 10% Pd/C (250 mg), EtOAc (20 mL) and MeOH (10 mL) was hydrogenated at 2 atm for 3 h. The mixture was concentrated under reduced pressure and filtered through Celite® to afford 5-(piperidin-4-ylamino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.05 g, 81% over 2 steps) following purification.
Using general procedure B with the above amine (3.05 g, 9.6 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (4.17 g, 19.2 mmol) followed by general procedure H with the resulting amine and 3-cyanobenzyl bromide (1.39 g, 7.09 mmol) gave 5-((3-cyano-benzyl)-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-methyl-propyl]-piperidin-4-yl}-amino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.24 g, 53% over 2 steps).
Using general procedure D with the above substrate (1.5 g, 2.36 mmol) and then using general procedure E with the resulting amine (490 mg, 0.97 mmol) and 2,6-dimethylbenzoic acid (161 mg, 1.07 mmol) afforded 5-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (510 mg, 68% over 2 steps).
The above amide (110 mg, 0.20 mmol) was treated with EtOAc (10 mL) saturated with HCl (g). The mixture was stirred for 1 h then concentrated under reduced pressure. Et2O (20 mL) was added and the precipitate was filtered. The solid was partitioned between 2N NaOH (10 mL) and CH2Cl2 (20 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to afford COMPOUND 194 as a white solid (300 mg, 70%). 1H NMR (CDCl3) δ 0.97-1.12 (m, 5H), 1.48-1.53 (m, 1H), 1.69-1.73 (m, 3H), 2.09-2.13 (m, 1H), 2.31 (s, 6H), 2.46-2.53 (m, 1H), 2.71-2.94 (m, 5H), 3.24-3.29 (m, 2H), 3.46 (t, 2H, J=9.0 Hz), 3.67 (s, 2H), 3.87-3.89 (m, 1H), 6.33 (d, 1H, J=6.0 Hz), 6.46 (d, 1H, J=9.0 Hz), 6.54 (s, 1H), 6.93 (m, 3H), 7.34-7.49 (m, 4H), 8.49 (br s, 1H). 13C NMR (CDCl3) δ 15.13, 20.91, 30.88, 32.24, 32.68, 41.61, 45.40, 49.31, 51.05, 53.95, 60.99, 62.31, 111.87, 113.93, 116.59, 117.99, 120.97, 129.01, 130.12, 130.63, 131.97, 132.46, 132.61, 133.32, 135.78, 140.34, 143.72, 144.65, 146.42, 171.68. ES-MS m/z 536 (M+H). Anal. Calcd. for C34H41N5O.0.6CH2Cl2: C, 70.83; H, 7.25; N, 11.94. Found: C, 70.53; H, 7.17; N, 11.89.
Scheme 10 describes the preparation of Examples 195-206, using various general procedures previously described, and reagents listed below.
















Example
R3*
R1COOH







195
CN
3,5-dichloroisonicotinic acid


196
CN
2,4-dimethyl-1-oxy-nicotinic acid


197
CN
4,6-dimethyl-pyrimidine-5-carboxylic acid


198
Cl
3,5-dichloroisonicotinic acid


199
CONMe2
4,6-dimethyl-pyrimidine-5-carboxylic acid


200
CONMe2
2,4-dimethyl-1-oxy-nicotinic acid


201
OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


202
OMe
2,4-dimethyl-1-oxy-nicotinic acid


203
O(CH2)2OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


204
O(CH2)2OMe
2,4-dimethyl-1-oxy-nicotinic acid


205
NHCOMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


206
NHCOMe
2,4-dimethyl-1-oxy-nicotinic acid









EXAMPLE 195




COMPOUND 195: 3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.04-1.18 (m, 1H), 1.21-1.35 (m, 1H), 1.54-1.64 (m, 1H), 1.73-1.87 (m, 3H), 2.18-2.27 (m, 1H), 2.55-2.64 (m, 1H), 2.80-2.98 (m, 3H), 3.33-3.44 (m, 1H), 3.69-3.88 (m, 2H), 4.09 (s, 2H), 6.57 (d, 2H, J=8.9 Hz), 6.95 (dd, 1H, J=6.6, 2.4 Hz), 7.08 (dd, 1H, J=9.2, 9.2 Hz), 7.20-7.26 (m, 1H), 7.43 (d, 2H, J=8.9 Hz), 8.29 (br s, 1H), 8.49 (s, 2H). 13C NMR (CDCl3) δ 13.29, 29.17, 30.01, 30.99, 39.30, 42.47 (d, J=5.4 Hz), 43.61, 51.37, 55.62, 59.17, 98.95, 112.30, 116.79 (d, J=22.6 Hz), 119.91, 127.04 (d, J=15.6 Hz), 127.25 (d, J=4.8 Hz), 128.55 (d, J=8.1 Hz), 128.74, 129.46 (d, J=3.8 Hz), 133.56, 142.85, 147.45, 150.86, 158.32 (d, J=246 Hz), 161.51. ESI-MS m/z 588 (MH)+, 590 (MH+2)+, 592 (MH+4)+. Anal. Calcd. for C29H29Cl3FN5O.0.2CH2Cl2: C, 58.77; H, 4.89; N, 11.56; Cl, 19.89. Found: C, 57.62; H, 4.97; N, 11.46; Cl, 19.63.
EXAMPLE 196




COMPOUND 196: N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.03 (m, 3H), 1.25-1.64 (m, 3H), 1.79-1.84 (m, 3H), 2.22-2.26 (m, 1H), 2.31 (s, 3H), 2.37 (s, 3H), 2.53-2.60 (m, 1H), 2.76-2.90 (m, 3H), 3.45 (br s, 1H), 3.63-3.76 (m, 2H), 4.30 (s, 2H), 6.59 (d, 2H, J=7.9 Hz), 6.91-7.08 (m, 3H), 7.21 (br s, 1H), 7.43 (d, 2H, J=8.4 Hz), 8.02 (d, 2H, J=9.0 Hz). 13C NMR (CDCl3) δ 13.94, 15.40, 18.90, 29.74, 30.09, 32.94, 38.86, 43.37, 44.91, 51.47, 56.39, 58.50, 99.54, 112.85, 117.22 (d, J=23 Hz), 120.50, 125.30, 127.94, 129.02 (d, J=8 Hz), 130.06, 134.15, 134.85, 137.22, 138.33, 145.95, 151.56, 158.87 (d, J=246 Hz), 165.89. ES-MS m/z 564 (M+H). Anal. Calcd. for C31H35N5O2ClF.0.9CH4O.0.3CH2Cl2: C, 62.54; H, 6.39; N, 11.32; Cl, 9.17; F, 3.07. Found: C, 62.67; H, 6.23; N, 10.98; Cl, 9.35; F, 2.75.
EXAMPLE 197




COMPOUND 197: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=5.7 Hz), 1.10-1.36 (m, 2H), 1.60-1.68 (m, 1H), 1.70-1.84 (m, 3H), 2.23 (t, 1H, J=11.7 Hz), 2.50 (s, 6H), 2.59 (t, 1H, J=11.1 Hz), 2.78-2.92 (m, 3H), 3.40 (br s, 1H), 3.70-3.80 (m, 2H), 4.16 (s, 2H), 6.57 (d, 2H, J=8.1 Hz), 6.94-6.97 (m, 1H), 7.03-7.10 (m, 1H), 7.18-7.24 (m, 1H), 7.42 (d, 2H, J=7.9 Hz), 7.70 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.43, 21.99, 29.27, 30.22, 31.58, 39.43, 42.60, 43.79, 51.71, 55.91, 59.42, 99.36, 112.53, 116.97 (d, J=23 Hz), 120.04, 127.39, 128.72 (d, J=8 Hz), 129.62, 133.75, 150.95, 157.73, 158.51 (d, J=246 Hz), 162.99, 166.52. ES-MS m/z 549 (M+H). Anal. Calcd. for C30H34N6OClF.0.3H2O: C, 64.98; H, 6.29; N, 15.16; Cl, 6.39; F, 3.43. Found: C, 65.14; H, 6.35; N, 14.96; Cl, 6.41; F, 3.25.
EXAMPLE 198




COMPOUND 198: 3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-chloro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.98-1.24 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.54-1.59 (m, 1H), 1.73-1.83 (m, 3H), 2.18 (t, 1H, J=11.4 Hz), 2.57 (t, 1H, J=11.7 Hz), 2.79-2.91 (m, 3H), 3.32-3.39 (m, 1H), 3.55-3.63 (m, 1H), 3.87-3.92 (m, 1H), 3.92 (s, 2H), 6.50 (d, 2H, J=8.7 Hz), 7.01-7.12 (m, 4H), 7.18-7.19 (m, 1H), 8.48 (s, 2H), 8.60 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 29.22, 30.29, 30.68, 40.00, 42.72, 43.57, 51.99, 56.24, 60.12, 114.56, 116.67 (d, J=23 Hz), 122.54, 127.95, 128.33 (d, J=9 Hz), 128.85, 129.15, 129.52, 143.02, 146.67, 147.67, 156.96, 158.59 (d, J=245 Hz), 161.57. ES-MS m/z 597 (M+H). Anal. Calcd. for C28H29N4Cl4OF.0.2C3H7NO: C, 56.04; H, 5.00; N, 9.60; Cl, 23.13; F, 3.10. Found: C, 55.65; H, 4.98; N, 9.61; Cl, 23.11; F, 2.80.
EXAMPLE 199




COMPOUND 199: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.0 Hz), 1.03-1.33 (m, 2H), 1.52-1.64 (m, 1H), 1.69-1.87 (m, 3H), 2.15-2.27 (m, 1H), 2.50 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.92 (m, 3H), 3.03 (s, 6H), 3.31-3.43 (m, 1H), 3.65-3.83 (m, 2H), 4.08 (s, 2H), 6.54 (d, 2H, J=7.8 Hz), 6.99-7.07 (m, 2H), 7.14-7.21 (m, 1H), 7.24-7.34 (m, 2H), 8.02 (br s, 1H), 8.88 (s, 1H). 13C NMR (CDCl3) δ 13.88, 22.35, 29.65, 30.66, 31.90, 39.79, 43.11, 44.38, 52.12, 56.30, 59.78, 112.44, 117.08 (d, J=23 Hz), 124.83, 128.25, 128.66, 129.74, 131.05, 149.64, 158.00, 158.95 (d, J=245 Hz), 163.35, 166.93, 172.09. ES-MS m/z 595 (M+H). Anal. Calcd. for C32H40ClFN6O2.0.4CH2Cl2.0.3H2O: C, 61.15; H, 6.63; N, 13.04; Cl, 10.40; F, 2.88. Found: C, 61.33; H, 6.58; N, 13.24; Cl, 10.06; F, 2.99.
EXAMPLE 200




COMPOUND 200: N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.0 Hz), 1.19-1.45 (m, 2H), 1.54-1.67 (m, 1H), 1.73-1.89 (m, 3H), 2.17-2.30 (m, 1H), 2.30 (s, 3H), 2.35 (s, 3H), 2.51-2.63 (m, 1H), 2.74-2.91 (m, 3H), 3.04 (s, 6H), 3.35-3.48 (m, 1H), 3.62-3.80 (m, 2H), 4.23 (s, 2H), 6.56 (d, 2H, J=8.1 Hz), 6.90 (d, 1H, J=6.0 Hz), 6.98-7.10 (m, 2H), 7.14-7.22 (m, 1H), 7.30 (d, 2H, J=8.1 Hz), 7.99 (d, 1H, J=6.6 Hz), 8.36 (br s, 1H). 13C NMR (CDCl3) δ 13.88, 15.50, 18.83, 29.73, 30.59, 32.24, 36.87, 39.58, 43.27, 44.53, 52.01, 56.30, 59.39, 112.40, 116.96 (d, J=23 Hz), 125.07 (d, J=18 Hz), 128.45, 128.65, 128.76, 129.01, 129.77, 133.78, 137.00, 138.64, 146.08, 149.67, 165.90, 172.16. ES-MS m/z 610 (M+H). Anal. Calcd. for C33H41ClFN5O3.0.3CH2Cl2.1.1H2O: C, 61.02; H, 6.74; N, 10.68; Cl, 8.65; F, 2.90. Found: C, 61.20; H, 6.86; N, 11.08; Cl, 8.31; F, 2.50.
EXAMPLE 201




COMPOUND 201: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.95-1.20 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.55-1.60 (m, 1H), 1.77-1.81 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.73-2.84 (m, 3H), 3.34-3.39 (m, 2H), 3.73 (s, 3H), 3.81-3.89 (m, 1H), 3.89 (s, 2H), 6.62 (d, 2H, J=8.4 Hz), 6.74 (d, 2H, J=8.4 Hz), 6.95-7.01 (m, 1H), 7.12-7.19 (m, 2H), 8.35 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.77, 22.32, 29.76, 30.83, 31.41, 40.24, 43.71, 44.16, 52.35, 55.97, 58.62, 60.37, 114.97, 116.81 (d, J=23 Hz), 118.01, 128.37 (d, J=8 Hz), 129.14 (d, J=4 Hz), 129.43, 129.63, 131.05, 142.72, 153.33, 158.05, 159.21 (d, J=245 Hz), 163.29, 166.87. ES-MS m/z 554 (M+H). Anal. Calcd. for C30H37N5ClO2F.0.3H2O: C, 64.40; H, 6.77; N, 12.52; Cl, 6.34; F, 3.40. Found: C, 64.45; H, 6.64; N, 12.40; Cl, 6.44; F, 3.61.
EXAMPLE 202




COMPOUND 202: N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.3 Hz), 1.09-1.29 (m, 2H), 1.57-1.62 (m, 1H), 1.80-1.83 (m, 3H), 2.16 (t, 1H, J=12.0 Hz), 2.30 (s, 3H), 2.41 (s, 3H), 2.52 (t, 1H, J=11.4 Hz), 2.74-2.83 (m, 3H), 3.71-3.42 (m, 1H), 3.73 (s, 3H), 3.73-3.79 (m, 1H), 4.03 (s, 2H), 6.63 (d, 2H, J=8.4 Hz), 6.75 (d, 2H, J=8.4 Hz), 6.90 (d, 1H, J=6.3 Hz), 6.94-7.00 (m, 1H), 7.12 (m, 1H), 7.21-7.22 (m, 1H), 8.01 (d, 1H, J=6.3 Hz), 8.45 (br s, 1H). 13C NMR (CDCl3) δ 13.94, 15.35, 18.86, 30.00, 30.59, 32.72, 39.17, 44.34, 45.02, 51.68, 56.02, 58.34, 58.69, 115.04, 116.69 (d, J=23 Hz), 125.24, 128.29 (d, J=8 Hz), 129.14 (d, J=4 Hz), 129.74, 129.96 (d, J=15 Hz), 134.75, 137.31, 138.25, 143.05, 145.94, 153.05, 159.12 (d, J=245 Hz), 165.82. ES-MS m/z 569 (M+H). Anal. Calcd. for C31H38N4ClO3F.0.4H2O.0.05CH2Cl2: C, 64.23; H, 6.75; N, 9.65; Cl, 6.72; F, 3.27. Found: C, 64.21; H, 6.72; N, 9.79; Cl, 6.72; F, 3.20.
EXAMPLE 203




COMPOUND 203: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
Yellow foam. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=5.7 Hz), 1.55-1.81 (m, 8H), 2.15 (t, 1H, J=10.2 Hz), 2.51 (s, 6H), 2.74-2.77 (m, 1H), 2.86 (d, 2H, J=9.3 Hz), 3.35-3.38 (m, 1H), 3.42 (s, 3H), 3.70 (s, 2H), 3.81-3.83 (m, 1H), 3.90 (s, 2H), 4.03 (s, 2H), 6.59 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.7 Hz), 6.98 (t, 1H, J=9.0 Hz), 7.12-7.15 (m, 2H), 8.34 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.75, 22.34, 29.70, 30.79, 31.41, 40.22, 43.64, 44.15, 52.39, 58.43, 59.57, 60.40, 68.11, 71.56, 115.93, 116.67, 116.98, 117.72, 128.34, 138.45, 129.09, 129.63, 142.94, 146.72, 153.21, 158.08, 163.32. ES-MS m/z 599 [M+H]+. Anal. Calcd. for C32H41N5O3FCl.0.4H2O: C, 63.49; H, 63.53; N, 11.57; Cl, 5.86; F, 3.14. Found: C, 63.53; H, 6.90; N, 11.19; Cl, 5.74; F, 2.99.
EXAMPLE 204




COMPOUND 204: N-[3-(4-{(5-Chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide
Pale yellow foam. 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.0 Hz), 1.12-1.28 (m, 2H), 1.57-1.60 (m, 1H), 1.79-1.83 (m, 3H), 2.16 (t, 1H, J=11.7 Hz), 2.30 (s, 3H), 2.38 (s, 3H), 2.51 (t, 1H, J=11.4 Hz), 2.73-2.87 (m, 3H), 3.38-3.43 (m, 5H), 3.70-3.73 (m, 3H), 4.02-4.05 (m, 4H), 6.61 (d, 2H, J=8.1 Hz), 6.78 (d, 2H, J=8.1 Hz), 6.89 (d, 1H, J=6.3 Hz), 6.97 (t, 1H, J=9.0 Hz), 7.12 (br s, 1H), 7.20-7.21 (m, 1H), 7.99 (d, 1H, J=6.0 Hz), 8.49 (s, 1H). 13C NMR (CDCl3) δ 13.45, 15.11, 18.42, 29.53, 30.36, 31.52, 39.46, 43.70, 44.10, 51.72, 53.44, 57.98, 59.18, 67.77, 71.18, 115.60, 116.18, 116.49, 117.18, 124.77, 127.99, 128.05, 128.80, 128.85, 129.20, 129.42, 133.22, 136.60, 138.29, 142.67, 145.69, 151.99, 15.52. ES-MS m/z 614 [M+H]+. Anal. Calcd. for C33H42N4O4FCl.0.1CH2Cl2.0.5H2O: C, 63.04; H, 6.90; N, 8.88; Cl, 6.75. Found: C, 63.08; H, 6.96; N, 8.76; Cl, 6.62.
EXAMPLE 205




COMPOUND 205: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.93-1.27 (m, 2H), 1.02 (d, 3H, J=6.3 Hz), 1.52-1.62 (m, 1H), 1.70-1.85 (m, 3H), 2.12 (s, 3H), 2.13-2.23 (m, 1H), 2.50 (s, 6H), 2.51-2.61 (m, 1H), 2.72-2.91 (m, 3H), 3.29-3.41 (m, 1H), 3.51-3.62 (m, 1H), 3.75-3.86 (m, 1H), 3.96 (s, 2H), 6.56 (d, 2H, J=8.4 Hz), 6.96-7.05 (m, 2H), 7.07-7.18 (m, 2H), 7.21-7.29 (m, 2H), 8.18 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.43, 21.93, 24.19, 29.26, 30.31, 31.22, 39.65, 42.77, 43.87, 51.90, 56.86, 59.68, 114.43, 116.54 (d, J=23 Hz), 122.04, 127.89, 128.07, 128.20, 128.77, 128.97, 129.40, 130.64, 145.20, 157.62, 158.67 (d, J=245 Hz), 162.95, 166.51, 168.26. ES-MS m/z 581 (M+H). Anal. Calcd. for C31H38N6ClO2F.0.6CH2Cl2: C, 60.05; H, 6.25; N, 13.30; Cl, 12.34; F, 3.01. Found: C, 59.75; H, 6.28; N, 13.21; Cl, 12.16; F, 2.89.
EXAMPLE 206




COMPOUND 206: N-(3-{4-[(4-Acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.0 Hz), 1.04-1.35 (m, 2H), 1.53-1.64 (m, 1H), 1.70-1.87 (m, 3H), 2.13 (s, 3H), 2.13-2.23 (m, 1H), 2.29 (s, 3H), 2.40 (s, 3H), 2.47-2.60 (m, 1H), 2.71-2.91 (m, 3H), 3.29-3.42 (m, 1H), 3.44-3.57 (m, 1H), 3.69-3.81 (m, 1H), 4.11 (s, 2H), 6.58 (d, 2H, J=7.5 Hz), 6.88-7.04 (m, 2H), 7.11-7.20 (m, 2H), 7.21-7.32 (m, 3H), 8.02 (d, 1H, J=6.3 Hz), 8.28 (br s, 1H). 13C NMR (CDCl3) δ 13.53, 15.03, 18.46, 24.17, 29.47, 30.15, 32.13, 38.94, 43.52, 44.47, 51.45, 56.91, 58.58, 114.64, 116.43 (d, J=23 Hz), 122.04, 124.87, 128.07 (d, J=8 Hz), 128.42, 128.99, 129.25, 129.45, 134.26, 136.79, 137.98, 145.24, 145.60, 158.64 (d, J=245 Hz), 165.45, 168.39. ES-MS m/z 596 (M+H). Anal. Calcd. for C32H39N5ClO3F.0.4CH2Cl2.0.2H2O: C, 61.41; H, 6.39; N, 11.05; Cl, 10.07; F, 3.00. Found: C, 61.47; H, 6.25; N, 10.94; Cl, 9.72; F, 2.86.
EXAMPLE 207




COMPOUND 207: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4-(4-methoxycarbonyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 85) (442 mg, 1.32 mmol) and 5-chloro-2-fluorobenzyl bromide (385 mg, 1.72 mmol) gave impure product as an oily, white foam (358 mg).
Using general procedure C with the impure carbamate, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (206 mg, 0.95 mmol) followed by general procedure D gave 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-benzoic acid methyl ester as a white foam (138 mg, 23% over 4 steps).
Using general procedure E with the primary amine (69 mg, 0.15 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (32 mg, 0.21 mmol) followed by general procedure K gave 4-[(5-chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a beige solid (41.6 mg, 47% over 2 steps).
Using general procedure E, the carboxylic acid (41.6 mg, 0.073 mmol) and NH4Cl (10 mg, 0.19 mmol) gave COMPOUND 207 as an off-white solid (30.8 mg, 74%). 1H NMR (CDCl3) δ 1.05 (d, 3H, J=6.6 Hz), 1.06-1.20 (m, 1H), 1.23-1.37 (m, 1H), 1.55-1.89 (m, 4H), 2.20-2.31 (m, 1H), 2.51 (s, 6H), 2.56-2.67 (m, 1H), 2.76-2.95 (m, 3H), 3.34-3.46 (m, 1H), 3.71-3.84 (m, 2H), 4.14 (s, 2H), 5.68 (br s, 2H), 6.58 (d, 2H, J=8.6 Hz), 6.99-7.09 (m, 2H), 7.16-7.23 (m, 1H), 7.64 (d, 2H, J=8.6 Hz), 7.90 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.41, 21.91, 29.21, 30.16, 31.49, 39.32, 42.63 (d, J=4.4 Hz), 43.88, 51.65, 55.83, 59.32, 111.99, 116.74 (d, J=22.9 Hz), 121.45, 127.64 (d, J=4.7 Hz), 127.87 (d, J=15.8 Hz), 128.41 (d, J=8.3 Hz), 129.18, 129.46 (d, J=3.2 Hz), 130.54, 150.87, 157.57, 158.49 (d, J=246 Hz), 162.94, 166.51, 168.99. ESI-MS m/z 567 (MH)+, 569 (MH+2)+. Anal. Calcd. for C30H36ClFN6O2.0.8CH2Cl2: C, 58.25; H, 5.97; N, 13.23; Cl, 14.52. Found: C, 58.12; H, 5.87; N, 12.87; Cl, 14.35.
EXAMPLE 208




COMPOUND 208: N-(3-{4-[(4-Carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2-chloro-6-methyl-benzamide
Using general procedure E with 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 207) (69 mg, 0.15 mmol) and 4,6-dimethylpyrimidine-3-carboxylic acid (32 mg, 0.21 mmol) followed by general procedure K gave 4-((5-chloro-2-fluoro-benzyl)-{1-[3-(2-chloro-6-methyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a beige solid (45.9 mg, 51% over 2 steps).
Using general procedure E, the crude carboxylic acid (45.9 mg, 0.078 mmol) and NH4Cl (13 mg, 0.24 mmol) gave COMPOUND 208 as an off-white solid (27.0 mg, 59%). 1H NMR (CDCl3) δ 0.96-1.10 (m, 1H), 1.02 (d, 3H, J=6.6 Hz), 1.14-1.28 (m, 1H), 1.50-1.60 (m, 1H), 1.71-1.86 (m, 3H), 2.16-2.26 (m, 1H), 2.36 (s, 3H), 2.54-2.65 (m, 1H), 2.79-3.00 (m, 3H), 3.26-3.38 (m, 1H), 3.67-3.78 (m, 1H), 3.82-3.93 (m, 1H), 3.97 (s, 2H), 5.64 (br s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.96-7.01 (m, 1H), 7.03-7.14 (m, 4H), 7.18-7.24 (m, 1H), 7.63 (d, 2H, J=8.4 Hz), 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.40, 19.27, 29.05, 30.21, 30.78, 39.86, 42.43 (d, J=4.3 Hz), 43.53, 51.94, 55.96, 60.29, 111.98, 116.62 (d, J=22.9 Hz), 121.44, 126.51, 127.76 (d, J=4.6 Hz), 128.00 (d, J=15.7 Hz), 128.37 (d, J=8.2 Hz), 128.43, 129.17, 129.59 (d, J=1.2 Hz), 130.41, 136.84, 137.37, 150.79, 158.47 (d, J=245 Hz), 166.89, 168.93. ESI-MS m/z 585 (MH)+, 587 (MH+2)+. Anal. Calcd. for C31H35Cl2FN4O2.0.6CH2Cl2: C, 59.63; H, 5.73; N, 8.80; Cl, 17.82. Found: C, 59.44; H, 5.57; N, 8.64; Cl, 17.69.
EXAMPLE 209




COMPOUND 209: 4,6-Dimethyl-pyrimidine-5-carboyxlic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide
Using general procedure H, 4-(4-dibenzylsulfamoyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 168) (2.19 g, 4.09 mmol) and 2-fluoro-5-chlorobenzyl bromide (1.37 g, 6.13 mmol) afforded the product as a yellow foam (1.70 g, 61%).
Using general procedure C with the above amine, then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione and then using general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-N,N-dibenzyl-benzenesulfonamide as a pale yellow foam (0.66 g, 40% over 3 steps).
Using general procedure E, the amine (320 mg, 0.49 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (97 mg, 0.64 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dibenzylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide as a pale yellow oil (137 mg, 36%).
A solution of the above amine (137 mg, 0.18 mmol) in H2SO4 (conc) (1.5 mL) was stirred for 2 h. Then the mixture was poured into ice (50 mL), basified with Na2CO3 (s) to pH-9, and extracted with CH2Cl2 (8×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford COMPOUND 209 as a pale yellow foam (41 mg, 37%) after purification. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.0 Hz), 1.17-1.21 (m, 1H), 1.25-1.32 (m, 1H), 1.59 (br s, 1H), 1.75-1.80 (m, 3H), 2.25 (t, 1H, J=12.0 Hz), 2.51 (s, 6H), 2.61 (t, 1H, J=11.1 Hz), 2.79-2.92 (m, 3H), 3.41 (br s, 1H), 3.76 (br s, 2H), 4.16 (s, 2H), 4.67 (s, 2H), 6.61 (d, 2H, J=8.4 Hz), 6.96 (d, 1H, J=5.7 Hz), 7.07 (t, 1H, J=9.0 Hz), 7.20 (br s, 1H), 7.70 (d, 2H, J=8.4 Hz), 7.79 (br s, 1H), 8.89 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.83, 22.36, 29.64, 30.63, 31.93, 39.85, 43.04, 44.17, 52.12, 56.47, 59.86, 112.55, 117.19, 117.49, 117.60, 127.84, 128.93, 129.01, 129.10, 151.65, 158.11, 166.90. ES-MS m/z 625 [M+Na]+. Anal. Calcd. for C29H36N6O3SFCl: C, 51.22; H, 5.78; N, 11.99; S, 4.57; F, 2.71; Cl, 14.16. Found: C, 51.15; H, 5.52; N, 11.98; S, 4.41; F, 2.50; Cl, 14.19.
EXAMPLE 210




COMPOUND 210: 2-Chloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-N,N-dibenzyl-benzenesulfonamide (see EXAMPLE 209) (339 mg, 0.52 mmol) and 2-chloro-6-methylbenzoic acid (116 mg, 0.68 mmol) afforded 2-chloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dibenzylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide as a yellow oil (387 mg, 100%).
A solution of the above amine (387 mg, 0.52 mmol) in H2SO4 (conc) (1.5 mL) was stirred for 1 h. Then the mixture was poured into ice (50 mL), basified with Na2CO3 (s) to pH-9, and extracted with CH2Cl2 (6×30 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford COMPOUND 210 as a pale yellow foam (70 mg, 24%) after purification. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=5.7 Hz), 1.19-1.23 (m, 1H), 1.51-1.56 (m, 1H), 1.73-1.77 (m, 3H), 2.20 (t, 1H, J=11.4 Hz), 2.34 (s, 3H), 2.58 (t, 1H, J=11.1 Hz), 2.80-2.94 (m, 4H), 3.31 (t, 1H, J=10.8 Hz), 3.71 (t, 1H, J=10.8 Hz), 3.82-3.86 (m, 1H), 3.97 (s, 2H), 4.89 (br s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.93 (d, 1H, J=4.5 Hz), 7.04-7.09 (m, 4H), 7.20 (br s, 1H), 7.67 (d, 2H, J=8.1 Hz), 8.36 (br s, 1H). 13C NMR (CDCl3) & 13.83, 19.70, 29.44, 30.57, 31.24, 40.24, 42.88, 43.93, 53.85, 58.09, 60.64, 112.67, 117.05, 117.35, 125.87, 126.92, 127.79, 127.94, 127.99, 128.80, 128.86, 128.94, 129.05, 129.62, 130.03, 130.83, 131.19, 137.32, 137.77, 151.51, 157.27, 160.52, 167.30. ES-MS m/z 622 [M+H]+. Anal. Calcd. for C30H35N4O3SFCl.1.0CH2Cl2.0.3H2O: C, 52.30; H, 5.32; N, 7.87; S, 4.50; F, 2.67; Cl, 19.92. Found: C, 52.43; H, 5.14; N, 7.99; S, 4.43; F, 2.65; Cl, 19.75.
EXAMPLE 211




COMPOUND 211: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 173) (350 mg, 0.97 mmol) and 5-chloro-2-fluorobenzyl bromide (324 mg, 1.5 mmol) afforded 4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a beige solid (316 mg, 65%).
A solution of the above carbamate (315 mg, 0.62 mmol) in 6N HCl (6 mL) was heated at 40° C. for 2 hours. The mixture was cooled to 0° C., basified with 10N NaOH and extracted with CH2Cl2 (3×15 mL). The organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white solid (233 mg).
Using general procedure B, the above amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (350 mg, 1.6 mmol) gave a pale yellow solid (181 mg).
To a solution of the imide (180 mg) from above in EtOH (2 mL) was added butylamine (0.63 mL, 6.4 mmol) and the solution was heated to reflux overnight to afford 1-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-phenyl}-ethanone as a pale brown solid (82 mg, 31% over 3 steps) after work-up and purification.
Using general procedure E, the above amine (40 mg, 0.093 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (21 mg, 0.14 mmol) afforded COMPOUND 211 as a white solid (38 mg, 73%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.0 Hz), 1.11-1.35 (m, 2H), 1.60-1.63 (m, 1H), 1.76-1.84 (m, 3H), 2.25 (t, 1H, J=11.4 Hz), 2.48 (s, 3H), 2.51 (s, 6H), 2.61 (t, 1H, J=11.7 Hz), 2.78-2.92 (m, 3H), 3.39-3.48 (m, 1H), 3.77-3.81 (m, 2H), 4.16 (s, 2H), 6.58 (d, 2H, J=8.4 Hz), 6.98-7.10 (m, 2H), 7.19-7.26 (m, 1H), 7.79-7.82 (m, 3H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.86, 20.52, 22.33, 26.39, 29.73, 30.65, 32.00, 39.71, 43.02 (d, J=4 Hz), 44.30, 52.02, 56.27, 59.64, 112.05, 117.21 (d, J=23 Hz), 127.04, 127.99 (d, J=3 Hz), 128.20, 128.90 (d, J=8 Hz), 129.94, 131.05, 152.15, 158.01, 158.89 (d, J=246 Hz), 163.34, 166.93. ES-MS m/z 566 (M+H). Anal. Calcd. for C31H37N5ClO2F.0.3H2O.0.1CH2Cl2: C, 64.40; H, 6.57; N, 12.07; Cl, 7.33; F, 3.28. Found: C, 64.13; H, 6.55; N, 12.07; Cl, 7.60; F, 3.10.
EXAMPLE 212




COMPOUND 212: N-(3-{4-[(4-Acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 1-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-phenyl}-ethanone (see EXAMPLE 211) (40 mg, 0.093 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (23 mg, 0.14 mmol) afforded COMPOUND 212 as a pale beige solid (37 mg, 69%). 1H NMR (CDCl3) δ 1.05 (d, 3H, J=6.0 Hz), 1.25-1.49 (m, 2H), 1.62-1.64 (m, 1H), 1.75-1.83 (m, 3H), 2.27 (t, 1H, J=12.0 Hz), 2.31 (s, 3H), 2.37 (s, 3H) 2.49 (s, 3H), 2.60 (t, 1H, J=11.1 Hz), 2.79-2.92 (m, 3H), 3.45 (br s, 1H), 3.65-3.71 (m, 1H), 3.79-3.86 (m, 1H), 4.32 (s, 2H), 6.59 (d, 2H, J=8.1 Hz), 6.91 (d, 1H, J=6.9 Hz), 7.02-7.08 (m, 2H), 7.19-7.26 (m, 1H), 7.82 (d, 2H, J=7.8 Hz), 8.01 (d, 1H, J=6.6 Hz), 8.13 (br s, 1H). 13C NMR (CDCl3) δ 14.02, 15.35, 18.89, 23.42, 29.96, 30.48, 33.12, 38.85, 43.42 (d, J=4 Hz), 45.00, 51.46, 56.46, 58.28, 111.95, 117.08 (d, J=23 Hz), 125.28, 126.96, 128.14 (d, J=4 Hz), 128.47, 128.83 (d, J=8 Hz), 129.94, 131.10, 135.00, 137.35, 138.17, 145.92, 152.39, 158.88 (d, J=245 Hz), 165.83. ES-MS m/z 581 (M+H). Anal. Calcd. for C32H38N4ClO3F.0.4CH2Cl2.0.5H2O: C, 62.35; H, 6.43; N, 8.98; Cl, 10.23; F, 3.04. Found: C, 62.06; H, 6.43; N, 8.93; Cl, 10.57; F, 2.81.
EXAMPLE 213




COMPOUND 213: 3-[(5-Chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester
Using general procedure A with methyl 3-aminobenzoate (2.16 g, 14.3 mmol) and 1-Boc-4-piperidone (2.39 g, 12.0 mmol) followed by general procedure H with the resulting amine and 5-chloro-2-fluorobenzyl bromide (65%, 1.04 g, 3.0 mmol) gave 4-[(5-chloro-2-fluoro-benzyl)-(3-methoxycarbonyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white foam (911 mg, 47% over 2 steps).
Using general procedure C with the carbamate (910 mg, 1.91 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (565 mg, 2.60 mmol) and then using general procedure D gave 3-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-benzoic acid methyl ester as a white foam (473 mg, 56% over 3 steps).
Using general procedure E, the primary amine (236 mg, 0.53 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (106 mg, 0.70 mmol) gave COMPOUND 213 as a white foam (228 mg, 74%). 1H NMR (CDCl3) δ 0.99-1.13 (m, 1H), 1.04 (d, 3H, J=6.6 Hz), 1.17-1.31 (m, 1H), 1.54-1.65 (m, 1H), 1.72-1.88 (m, 3H), 2.19-2.30 (m, 1H), 2.51 (s, 6H), 2.56-2.67 (m, 1H), 2.74-2.93 (m, 3H), 3.32-3.42 (m, 1H), 3.67-3.86 (m, 2H), 3.88 (s, 3H), 4.04 (s, 2H), 6.70 (d, 1H, J=8.4 Hz), 7.01-7.09 (m, 2H), 7.14-7.23 (m, 2H), 7.35-7.41 (m, 2H), 8.12 (br s, 1H), 8.87 (s, 1H). ESI-MS m/z 582 (MH)+, 584 (MH+2)+.
EXAMPLE 214




COMPOUND 214: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(3-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure K, 3-[(5-chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (see EXAMPLE 213) (208 mg, 0.36 mmol) gave 3-[(5-chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a pale yellow solid (240 mg).
Using general procedure E, the crude carboxylic acid (100 mg, 0.18 mmol) and methylamine hydrochloride (39 mg, 0.58 mmol) gave COMPOUND 214 as an off-white foam (86.4 mg, 84%). 1H NMR (CDCl3) δ 0.93-1.10 (m, 1H), 1.02 (d, 3H, J=6.6 Hz), 1.13-1.27 (m, 1H), 1.52-1.63 (m, 1H), 1.71-1.86 (m, 3H), 2.18-2.29 (m, 1H), 2.51 (s, 6H), 2.55-2.66 (m, 1H), 2.71-2.91 (m, 3H), 2.99 (d, 3H, J=3.9 Hz), 3.29-3.41 (m, 1H), 3.68-3.86 (m, 2H), 4.04 (s, 2H), 6.19 (br s, 1H), 6.60 (d, 1H, J=8.1 Hz), 6.95 (d, 1H, J=7.5 Hz), 6.99-7.08 (m, 2H), 7.12-7.20 (m, 2H), 7.25 (d, 1H, J=7.8 Hz), 8.21 (br s, 1H), 8.88 (s, 1H). 13C NMR (CDCl3) δ 13.44, 21.81, 26.68, 29.19, 30.24, 31.09, 39.48, 42.54 (d, J=4.8 Hz), 43.74, 51.51, 56.06, 59.50, 112.44, 115.03, 116.40, 116.55 (d, J=23.5 Hz), 127.86 (d, J=4.0 Hz), 128.18 (d, J=8.0 Hz), 128.31 (d, J=16.0 Hz), 129.33, 129.41, 130.55, 135.54, 148.28, 157.47, 158.53 (d, J=246 Hz), 162.84, 166.36, 168.61. ESI-MS t/z 581 (MH)+, 583 (MH+2)+. Anal. Calcd. for C31H38ClFN6O2.0.7CH2Cl2: C, 59.74; H, 6.22; N, 13.21; Cl, 12.81. Found: C, 59.66; H, 6.22; N, 13.34; Cl, 12.78.
EXAMPLE 215




COMPOUND 215: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 188) (502 mg, 1.50 mmol) and 5-chloro-2-fluoro-benzyl bromide (80%, 630 mg, 2.26 mmol) gave 4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (676 mg, 94%).
Using general procedure C with the carbamate (676 mg, 1.42 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (425 mg, 1.96 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine as a white foam (277 mg, 44% over 3 steps).
Using general procedure E, the primary amine (86 mg, 0.19 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (40 mg, 0.26 mmol) gave COMPOUND 215 as a white foam (91.8 mg, 82%). 1H NMR (CDCl3) δ 0.90-1.05 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.08-1.21 (m, 1H), 1.52-1.64 (m, 1H), 1.70-1.85 (m, 3H), 2.10-2.21 (m, 1H), 2.44-2.58 (m, 1H), 2.50 (s, 6H), 2.70-2.90 (m, 3H), 3.29-3.48 (m, 2H), 3.77-3.87 (m, 1H), 3.89 (s, 2H), 4.14-4.24 (m, 4H), 6.14 (dd, 1H, J=9.2, 2.3 Hz), 6.18 (s, 1H), 6.67 (d, 1H, J=8.7 Hz), 7.00 (t, 1H, J=8.9 Hz), 7.11-7.18 (m, 2H), 8.25 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.29, 21.81, 29.14, 30.23, 31.01, 39.63, 43.02 (d, J=3.8 Hz), 43.72, 51.83, 57.37, 59.70, 64.08, 64.58, 103.94, 108.39, 116.36 (d, J=23.3 Hz), 117.34, 127.90 (d, J=8.2 Hz), 128.32 (d, J=4.8 Hz), 129.07 (d, J=15.1 Hz), 129.22, 130.50, 136.16, 143.17, 143.70, 157.53, 158.60 (d, J=245 Hz), 162.77, 166.38. ESI-MS m/z 582 (MH)+, 584 (MH+2)+. Anal. Calcd. for C31H37ClFN5O3.0.3CH2Cl2: C, 61.87; H, 6.24; N, 11.53; Cl, 9.34. Found: C, 61.57; H, 6.16; N, 11.52; Cl, 9.07.
EXAMPLE 216




COMPOUND 216: N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E, [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (see EXAMPLE 215) (86 mg, 0.19 mmol) and 2,6-dimethyl-benzoic acid (40 mg, 0.27 mmol) gave COMPOUND 216 as a white foam (94 mg, 84%). 1H NMR (CDCl3) δ 0.83-1.14 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.57 (m, 1H), 1.66-1.81 (m, 3H), 2.06-2.17 (m, 1H), 2.30 (s, 6H), 2.46-2.57 (m, 1H), 2.69-2.90 (m, 3H), 3.22-3.33 (m, 1H), 3.36-3.47 (m, 1H), 3.75 (s, 2H), 3.81-3.93 (m, 1H), 4.12-4.23 (m, 4H), 6.07-6.17 (m, 2H), 6.66 (d, 1H, J=8.7 Hz), 6.87-7.04 (m, 4H), 7.10-7.18 (m, 2H), 8.36 (s, 1H). 13C NMR (CDCl3) δ 13.25, 18.99, 28.82, 30.02, 30.90, 39.54, 42.59 (d, J=3.8 Hz), 43.57, 52.01, 57.47, 60.23, 64.04, 64.56, 103.36, 107.81, 116.24 (d, J=23.2 Hz), 117.28, 127.13, 127.77 (d, J=8.1 Hz), 128.32 (d, J=5.5 Hz), 128.35, 129.20 (d, J=3.2 Hz), 129.35 (d, J=15.3 Hz), 133.61, 135.82, 138.27, 143.27, 143.66, 158.57 (d, J=245 Hz), 169.89. ESI-MS m/z 580 (MH)+, 582 (MH+2)+. Anal. Calcd. for C33H39ClFN3O3.0.3H2O.0.2CH2Cl2: C, 66.55; H, 6.72; N, 7.02; Cl, 7.70. Found: C, 66.44; H, 6.60; N, 7.12; Cl, 7.74.
EXAMPLE 217




COMPOUND 217: N-(3-{4-[(5-Chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo [1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-1-oxy-isonicotin-amide
Using general procedure E, 1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (see EXAMPLE 215) (86 mg, 0.19 mmol) and 3,5-dimethyl-1-oxy-isonicotinic acid (44 mg, 0.26 mmol) gave COMPOUND 217 as a white foam (85.6 mg, 75%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.12-1.38 (m, 2H), 1.54-1.65 (m, 1H), 1.74-1.88 (m, 3H), 2.13-2.24 (m, 1H), 2.30 (s, 3H), 2.35 (s, 3H), 2.47-2.58 (m, 1H), 2.71-2.90 (m, 3H), 3.34-3.54 (m, 2H), 3.64-3.76 (m, 1H), 4.08 (s, 2H), 4.14-4.24 (m, 4H), 6.13-6.22 (m, 2H), 6.69 (d, 1H, J=8.4 Hz), 6.89 (d, 1H, J=6.6 Hz), 6.98 (t, 1H, J=8.9 Hz), 7.11-7.23 (m, 2H), 7.97 (d, 1H, J=6.6 Hz), 8.51 (br s, 1H). 13C NMR (CDCl3) δ 13.50, 14.87, 18.40, 29.42, 30.03, 32.33, 38.61, 43.62 (d, J=3.9 Hz), 44.60, 51.18, 57.19, 58.11, 64.10, 64.63, 103.38, 107.87, 116.24 (d, J=23.6 Hz), 117.40, 124.76, 127.84 (d, J=8.5 Hz), 128.38 (d, J=4.5 Hz), 129.30 (d, J=2.9 Hz), 129.45 (d, J=15.5 Hz), 134.31, 135.90, 136.86, 137.73, 143.53, 143.75, 145.45, 158.54 (d, J=245 Hz), 165.33. ESI-MS m/z 597 (MH)+, 599 (MH+2)+. Anal. Calcd. for C32H38ClFN4O4.0.5CH2Cl2.0.3H2O: C, 60.52; H, 6.19; N, 8.69; Cl, 10.99. Found: C, 60.48; H, 6.10; N, 8.70; Cl, 10.90.
EXAMPLE 218




COMPOUND 218: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H with 4-(benzo[1,3]dioxol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 179) (320 mg, 1.0 mmol) and 2-fluoro-5-chlorobenzyl bromide (291 mg, 1.3 mmol) and then using general procedure C afforded benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-piperidin-4-yl-amine as a white solid (323 mg, 89% over 2 steps).
Using general procedure B with the above secondary amine (323 mg, 0.89 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (387 mg, 1.78 mmol) and then using general procedure D afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-amine as a white solid (220 mg, 57% over 2 steps).
Using general procedure E, the above amine (60 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (23 mg, 0.15 mmol) afforded COMPOUND 218 as a white solid (69 mg, 88%). 1H NMR (CDCl3) δ 0.89-1.20 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.54-1.61 (m, 1H), 1.71-1.84 (m, 3H), 2.08-2.19 (m, 1H), 2.51 (s, 6H), 2.50-2.58 (m, 1H), 2.70-2.89 (m, 3H), 3.28-3.40 (m, 2H), 3.75-3.87 (m, 1H), 3.88 (s, 2H), 5.86 (s, 2H), 6.08 (d, 1H, J=8.4 Hz), 6.29 (s, 1H), 6.61 (d, 1H, J=8.4 Hz), 6.94-7.03 (m, 1H), 7.10-7.19 (m, 2H), 8.30 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.77, 22.30, 29.77, 30.81, 31.43, 40.18, 43.91, 44.16, 52.29, 58.88, 60.27, 99.37, 101.19, 108.69, 108.92, 116.87 (d, J=23 Hz), 128.45 (d, J=8 Hz), 129.03 (d, J=4 Hz), 129.16, 129.50 (d, J=21 Hz), 131.02, 141.02, 144.33, 148.71, 158.03, 159.18 (d, J=245 Hz), 163.29, 166.86. ES-MS m/z 568 (M+H). Anal. Calcd. for C30H35N5ClO3F.0.3CH2Cl2: C, 61.31; H, 6.04; N, 11.80; Cl, 9.56; F, 3.20. Found: C, 61.34; H, 6.04; N, 11.70; Cl, 9.17; F, 3.22.
Scheme 11 describes the preparation of Examples 219-226, using various general procedures previously described, and reagents listed below.
















Example
R3*
R1COOH







219
CN
3,5-dichloroisonicotinic acid


220
Br
2,4-dimethyl-1-oxy-nicotinic acid


221
OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


222
OMe
2,4-dimethyl-1-oxy-nicotinic acid


223
O(CH2)2OMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


224
O(CH2)2OMe
2,4-dimethyl-1-oxy-nicotinic acid


225
NHCOMe
4,6-dimethyl-pyrimidine-5-carboxylic acid


226
NHCOMe
2,4-dimethyl-1-oxy-nicotinic acid









EXAMPLE 219




COMPOUND 219: 3,5-Dichloro-N-(3-{4-[(5-cyano-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-fluoro-3-methyl-benzonitrile (Khanna, Ish K., J. Med. Chem., 40, 11, 1997, 1634-1647) (0.70 g, 5.2 mmol), NBS (1.10 g, 6.2 mmol) and benzoyl peroxide (223 mg, 0.92 mmol) in CCl4 (35 mL) was stirred at reflux under nitrogen for 3 hours. To the reaction was added additional NBS (0.53 g, 2.98 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (180 mg, 0.74 mmol), and the reaction was heated at reflux for a further 1.5 hours. The reaction mixture was cooled on ice and filtered with suction through a glass frit. The filtrate was dried (Na2SO4), filtered and concentrated under reduced pressure to give a mixture of 3-(bromomethyl)-4-fluoro-benzonitrile and unreacted 1,1′-azobis(cyclohexanecarbonitrile) (660 mg) following purification.
COMPOUND 219 was isolated as a white powder. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.6 Hz), 1.05-1.18 (m, 1H), 1.21-1.34 (m, 1H), 1.53-1.64 (m, 1H), 1.73-1.86 (m, 3H), 2.18-2.29 (m, 1H), 2.56-2.66 (m, 1H), 2.79-2.99 (m, 3H), 3.33-3.45 (m, 1H), 3.71-3.87 (m, 2H), 4.13 (s, 2H), 6.55 (d, 2H, J=8.7 Hz), 7.22-7.34 (m, 2H), 7.44 (d, 2H, J=8.7 Hz), 7.58-7.65 (m, 1H), 8.15 (br s, 1H), 8.48 (s, 2H). 13C NMR (CDCl3) δ 13.38, 29.35, 30.25, 31.01, 39.65, 42.28 (d, J=4.8 Hz), 43.55, 51.62, 55.80, 59.62, 99.87, 108.86 (d, J=3.5 Hz), 112.46, 117.04 (d, J=22.3 Hz), 117.93, 119.77, 127.52 (d, J=15.5 Hz), 128.91, 132.02 (d, J=5.6 Hz), 133.40 (d, J=9.3 Hz), 133.84, 142.95, 147.62, 150.57, 161.50, 162.37 (d, J=256 Hz). ESI-MS m/z 579 (MH)+, 581 (MH+2)+. Anal. Calcd. for C30H29Cl2FN6O.0.4CH2Cl2.0.2H2O: C, 59.17; H, 4.93; N, 13.62; Cl, 16.09. Found: C, 59.11; H, 4.92; N, 13.32; Cl, 16.19.
EXAMPLE 220




COMPOUND 220: N-(3-{4-[(4-Bromo-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.0 Hz), 1.24-1.42 (m, 2H), 1.58-1.64 (m, 1H), 1.76-1.80 (m, 3H), 2.19-2.30 (m, 1H), 2.30 (s, 3H), 2.36 (s, 3H), 2.57 (t, 1H, J=12.0 Hz), 2.78-2.90 (m, 3H), 3.40-3.46 (m, 1H), 3.63-3.69 (m, 2H), 4.22 (s, 2H), 6.47 (d, 2H, J=8.2 Hz), 6.91 (d, 1H, J=6.7 Hz), 7.16-7.24 (m, 3H), 7.46 (d, 1H, J=5.9 Hz), 7.50-7.60 (m, 1H), 7.98 (d, 1H, J=6.3 Hz), 8.15 (br s, 1H). ES-MS m/z 608 (M+H).
EXAMPLE 221




COMPOUND 221: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.94-1.16 (m, 2H), 1.01 (d, 3H, J=6.3 Hz), 1.54-1.58 (m, 1H), 1.77-1.81 (m, 3H), 2.14 (t, 1H, J=12.0 Hz), 2.50 (s, 6H), 2.53 (t, 1H, J=12.6 Hz), 2.74-2.84 (m, 3H), 3.29-3.41 (m, 2H), 3.72 (s, 3H), 3.80-3.86 (m, 1H), 3.91 (s, 2H), 6.61 (d, 2H, J=8.1 Hz), 6.74 (d, 2H, J=8.1 Hz), 7.12-7.18 (m, 1H), 7.50-7.56 (m, 2H), 8.36 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.41, 21.95, 29.43, 30.48, 30.94, 39.93, 42.81, 43.72, 51.94, 55.58, 58.81, 60.08, 108.42, 114.67, 116.52 (d, J=23 Hz), 118.21, 118.40, 129.37 (d, J=15 Hz), 130.72, 132.65 (d, J=15 Hz), 133.63 (d, J=6 Hz), 141.49, 153.38, 157.61, 162.76 (d, J=255 Hz), 162.97, 166.41. ES-MS m/z 545 (M+H). Anal. Calcd. for C31H37N6O2F.0.5H2O: C, 67.25; H, 6.92; N, 15.18; F, 3.43. Found: C, 67.32; H, 6.77; N, 15.22; F, 3.47.
EXAMPLE 222




COMPOUND 222: N-(3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.0 Hz), 1.25-1.42 (m, 2H), 1.57-1.64 (m, 1H), 1.80-1.83 (m, 3H), 2.19 (t, 1H, J=11.4 Hz), 2.28 (s, 3H), 2.30 (s, 3H), 2.51 (t, 1H, J=10.2 Hz), 2.76-2.87 (m, 3H), 3.41-3.45 (m, 2H), 3.62-3.68 (m, 1H), 3.73 (s, 3H), 4.18 (s, 2H), 6.64 (d, 2H, J=8.1 Hz), 6.76 (d, 2H, J=7.8 Hz), 6.88 (d, 1H, J=6.3 Hz), 7.09-7.15 (m, 1H), 7.47-7.53 (m, 1H), 7.60 (d, 1H, J=6.3 Hz), 7.91 (d, 1H, J=6.3 Hz), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.53, 15.05, 18.47, 29.66, 30.34, 32.07, 39.01, 43.57, 44.41, 51.39, 55.62, 58.61, 108.45, 114.72, 116.41 (d, J=23 Hz), 117.88, 118.41, 124.79, 129.73 (d, J=15 Hz), 132.62 (d, J=9 Hz), 133.66 (d, J=6 Hz), 133.93, 136.82, 137.99, 142.05, 145.61, 153.23, 162.70 (d, J=255 Hz), 165.44. ES-MS m/z 560 (M+H). Anal. Calcd. for C32H38N5O3F.1.2H2O: C, 66.12; H, 7.00; N, 12.05; F, 3.27. Found: C, 66.13; H, 6.74; N, 11.95; F, 3.17.
EXAMPLE 223




COMPOUND 223: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide
Yellow foam. 1H NMR (CDCl3) δ 1.02 (d, 2H, J=3.0 Hz), 1.57-1.60 (m, 1H), 1.80 (br d, 2H, J=9.9 Hz), 2.17 (br t, 1H), 2.61 (s, 6H), 2.51-2.55 (m, 2H), 2.72-2.79 (m, 4H), 3.36 (br s, 1H), 3.42 (s, 3H), 3.69 (s, 2H), 3.79 (br s, 1H), 3.93 (s, 2H), 4.02 (s, 2H), 6.59 (d, 2H, J=8.1 Hz), 6.76 (d, 2H, J=7.8 Hz), 7.14 (t, 1H, J=8.7 Hz), 7.52 (br s, 2H), 8.32 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.76, 22.35, 29.69, 30.70, 31.42, 40.13, 43.23, 44.18, 52.29, 58.90, 59.57, 60.35, 68.09, 71.51, 108.80, 116.00, 116.76, 117.07, 118.28, 118.76, 129.62, 131.06, 132.99, 133.12, 133.94, 142.39, 152.88, 157.99, 161.45, 163.35, 164.83, 166.87. ES-MS m/z 589 [M+H]+. Anal. Calcd. for C33H41N6O3F.0.3H2O.0.2CH2Cl2: C, 65.25; H, 6.93; N, 13.75; F, 3.11. Found: C, 65.21; H, 6.93; N, 13.73; F, 2.98.
EXAMPLE 224




COMPOUND 224: N-[3-(4-{(5-Cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-1-oxy-nicotinamide
Yellow foam. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.0 Hz), 1.28-1.42 (m, 3H), 1.59-1.61 (m, 1H), 1.79-1.83 (m, 3H), 2.16-2.19 (m, 1H), 2.26 (s, 3H), 2.29 (s, 3H), 2.50 (t, 1H, J=10.8 Hz), 2.80-2.86 (m, 3H), 3.41-3.45 (m, 4H), 3.59-3.63 (m, 1H), 3.69 (s, 2H), 4.02 (d, 2H, J=3.6 Hz), 4.19 (s, 2H), 6.62 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.1 Hz), 6.87 (d, 1H, J=6.3 Hz), 7.11 (t, 1H, J=9.0 Hz), 7.49 (br s, 1H), 7.58 (d, 1H, J=6.0 Hz), 7.90 (d, 1H, J=6.3 Hz), 8.61 (br s, 1H). 13C NMR (CDCl3) δ 13.91, 15.41, 18.86, 29.99, 30.62, 32.56, 36.88, 43.97, 44.89, 51.68, 58.71, 58.85, 59.55, 68.14, 71.52, 116.06, 116.65, 116.95, 117.87, 118.78, 125.22, 130.20, 132.99, 134.99, 134.57, 137.22, 138.34, 142.69, 14597, 152.66, 161.37, 162.90, 164.75, 165.84. ES-MS nz/z 603 [M+H]+. Anal. Calcd. for C34H42N5O4F.0.4CH2Cl2: C, 64.79; H, 6.76; N, 10.98; F, 2.98. Found: C, 64.54; H, 6.85; N, 10.80; F, 2.95.
EXAMPLE 225




COMPOUND 225: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.93-1.26 (m, 2H), 1.02 (d, 3H, J=6.0 Hz), 1.52-1.61 (m, 1H), 1.72-1.85 (m, 3H), 2.12 (s, 3H), 2.13-2.25 (m, 1H), 2.50 (s, 6H), 2.51-2.62 (m, 1H), 2.73-2.92 (m, 3H), 3.30-3.42 (m, 1H), 3.51-3.64 (m, 1H), 3.75-3.87 (m, 1H), 3.99 (s, 2H), 6.55 (d, 2H, J=8.1 Hz), 7.01 (s, 1H), 7.15-7.29 (m, 3H), 7.44-7.57 (m, 2H), 8.18 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.47, 21.94, 24.22, 29.37, 30.35, 31.21, 39.64, 42.42, 43.87, 51.82, 57.27, 59.67, 108.48, 114.89, 116.66 (d, J=23 Hz), 118.29, 121.97, 129.17 (d, J=15 Hz), 129.38, 130.67, 132.84 (d, J=9 Hz), 133.05 (d, J=6 Hz), 144.71, 157.56, 162.64 (d, J=256 Hz), 162.99, 166.46, 168.27. ES-MS m/z 572 (M+H). Anal. Calcd. for C32H38N7O2F.0.4CH2Cl2: C, 64.25; H, 6.46; N, 16.19; F, 3.14. Found: C, 64.48; H, 6.57; N, 16.19; F, 3.10.
EXAMPLE 226




COMPOUND 226: N-(3-{4-[(4-Acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.0 Hz), 1.07-1.36 (m, 2H), 1.54-1.65 (m, 1H), 1.71-1.87 (m, 3H), 2.14 (s, 3H), 2.15-2.24 (m, 1H), 2.30 (s, 3H), 2.38 (s, 3H), 2.47-2.59 (m, 1H), 2.72-2.90 (m, 3H), 3.31-3.56 (m, 2H), 3.67-3.79 (m, 1H), 4.18 (s, 2H), 6.58 (d, 2H, J=8.1 Hz), 6.93 (d, 1H, =6.3 Hz), 7.11-7.20 (m, 1H), 7.22-7.28 (m, 2H), 7.36 (s, 1H), 7.49-7.57 (m, 2H), 8.01 (d, 1H, J=6.6 Hz), 8.18 (br s, 1H). 13C NMR (CDCl3) δ 13.95, 15.42, 18.86, 24.58, 29.96, 30.57, 32.67, 39.20, 43.69, 44.92, 51.71, 57.69, 58.78, 108.91, 115.53, 116.93 (d, J=23 Hz), 118.71, 122.36, 125.27, 129.76, 129.96, 133.17 (d, J=9 Hz), 133.56 (d, J=6 Hz), 134.79, 137.22, 138.30, 145.17, 145.96, 162.99 (d, J=255 Hz), 165.82, 168.77. ES-MS m/z 587 (M+H). Anal. Calcd. for C33H39N6O3F.0.9CH2Cl2: C, 61.40; H, 6.20; N, 12.67; F, 2.86. Found: C, 61.17; H, 6.11; N, 12.51; F, 2.81.
EXAMPLE 227




COMPOUND 227: (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid methyl ester
Using general procedure A, (E)-3-(4-amino-phenyl)-acrylic acid methyl ester (Ono, Shin'ichiro; et al., Chem. Pharm. Bull., 47, 12, 1999, 1694-1712) (1.00 g, 5.64 mmol) and 1-Boc-4-piperidone (1.19 g, 5.93 mmol) gave the crude amine.
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (311 mg, 1.98 mmol) gave the crude mesylate as a yellow oil. Using general procedure H, the resulting yellow oil and the above amine (550 mg, 1.53 mmol) gave 4-{(5-cyano-2-fluoro-benzyl)-[4-((E)-2-methoxycarbonyl-vinyl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (1.56 g, 56% over 2 steps).
Using general procedure C with the above carbamate (320 mg, 0.648 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (266 mg, 1.22 mmol) and then using general procedure D gave (E)-3-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenyl}-acrylic acid methyl ester as a yellow oil (106 mg, 35% over 3 steps).
Using general procedure E, the above amine (51 mg, 0.11 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (20 mg, 0.13 mmol) gave COMPOUND 227 as a yellow foam (65 mg, 98%) (91:8, trans/cis isomers). 1H NMR (CDCl3) δ 0.98-1.30 (m, 2H), 1.04 (d, 3H, J=6.6 Hz), 1.60 (m, 1H), 1.77 (m, 3H), 2.25 (m, 1H), 2.50 (s, 6H), 2.61 (m, 1H), 2.78-2.95 (m, 3H), 3.39 (m, 1H), 3.77 (m, 5H), 4.14 (s, 2H), 6.22 (d, 1H, J=15.9 Hz), 6.54 (d, 2H, J=8.7 Hz), 7.24 (m, 1H), 7.35 (d, 2H, J=8.7 Hz), 7.40 (dd, 1H, J=6.9, 2.1 Hz), 7.58 (m, 2H), 7.89 (m, 1H), 8.87 (s, 1H). ES-MS m/z 599 (M+H).
EXAMPLE 228




COMPOUND 228: 4-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid
Using general procedure H, 4-[4-(4-methoxycarbonyl-phenoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 96) (430 mg, 1.04 mmol) and 2-fluoro-5-cyanobenzyl bromide (289 mg, 1.35 mmol) afforded 4-{(5-cyano-2-fluoro-benzyl)-[4-(4-methoxycarbonyl-phenoxy)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a white solid (520 mg, 89%).
Using general procedure C with the above substrate (515 mg, 0.92 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (398 mg, 1.83 mmol) and then using general procedure D afforded 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenoxy}-benzoic acid methyl ester as a white solid (230 mg, 48% over 3 steps).
Using general procedure E with the above amine (90 mg, 0.17 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (29 mg, 0.19 mmol) and then using general procedure K with the resulting ester afforded COMPOUND 228 as a white solid (40 mg, 36% over 2 steps). 1H NMR (CDCl3) δ 1.14-1.26 (m, 3H), 1.67-2.19 (m, 4H), 2.40-2.59 (m, 1H), 2.48 (s, 6H), 2.73-2.85 (m, 1H), 3.01-3.17 (m, 3H), 3.32-3.36 (m, 2H), 3.38-3.51 (m, 1H), 3.58-3.75 (m, 2H), 4.20-4.35 (m, 2H), 6.69 (d, 2H, J=8.4 Hz), 6.82-6.92 (m, 4H), 7.10-7.18 (m, 1H), 7.49-7.61 (m, 2H), 7.71 (d, 2H, J=7.8 Hz), 8.41 (br s, 1H), 8.87 (s, 1H). 13C NMR (CDCl3) δ 12.80, 22.42, 27.60, 28.02, 32.11, 38.06, 44.46, 51.32, 53.84, 56.22, 58.67, 108.95, 116.92, 117.30, 118.65, 121.60, 127.77, 129.38 (d, J=15 Hz), 130.85, 131.82, 133.35, 144.82, 148.94, 157.73, 161.83, 163.01 (d, J=256 Hz), 163.50, 167.60, 171.81. ES-MS m/z 651 (M+H). Anal. Calcd. for C37H39N6O4F.1.1CH2Cl2: C, 61.49; H, 5.58; N, 11.29; F, 2.55. Found: C, 61.44; H, 5.70; N, 11.14; F, 2.38.
EXAMPLE 229




COMPOUND 229: 4-[4-((5-Cyano-2-fluoro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-phenoxy]-benzoic acid
Using general procedure E with 4-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenoxy}-benzoic acid methyl ester (see EXAMPLE 228) (90 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (29 mg, 0.19 mmol) followed by general procedure K with the resulting ester afforded COMPOUND 229 as a white solid (58 mg, 53% over 2 steps). 1H NMR (CDCl3) δ 1.06-1.16 (m, 3H), 1.53-1.69 (m, 1H), 1.78-2.04 (m, 3H), 2.28 (s, 6H), 2.32-2.45 (m, 1H), 2.63-2.75 (m, 1H), 2.92-3.18 (m, 3H), 3.29-3.45 (m, 2H), 3.57-3.82 (m, 3H), 4.11 (s, 2H), 6.58-6.65 (m, 2H), 6.82-7.03 (m, 7H), 7.12-7.21 (m, 1H), 7.50-7.85 (m, 2H), 7.79-8.01 (m, 3H). 13C NMR (CDCl3) δ 11.81, 18.19, 26.45, 27.05, 30.35, 36.88, 42.30, 43.32, 49.61, 55.06, 57.96, 107.47, 114.99, 115.37, 115.81, 117.29, 120.17, 125.91, 126.28, 127.40, 128.17 (d, J=15 Hz), 130.59, 131.94, 132.92, 136.93, 143.59, 147.04, 160.57, 161.58 (d, J=256 Hz), 169.66, 170.16. ES-MS m/z 649 (M+H). Anal. Calcd. for C39H41N4O4F.0.9CH2Cl2: C, 66.08; H, 5.95; N, 7.73; F, 2.62. Found: C, 66.11; H, 6.08; N, 7.64; F, 2.48.
EXAMPLE 230




COMPOUND 230: N—((R)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide
Using general procedure A with p-anisidine (738 mg, 6.00 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.11 g, 6.67 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine as an orange oil (1.43 g, 86% over 2 steps).
Using general procedure F, 3,5-dimethylisonicotinic acid (227 mg, 1.5 mmol) and the above amine (275 mg, 1.0 mmol) afforded N-{(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-3,5-dimethyl-isonicotinamide as a white solid (164 mg, 42%).
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (81 mg, 0.54 mmol) gave the crude material that was used in the next reaction without purification. Using general procedure H, the above aniline (169 mg, 0.411 mmol) and the above mesylate (142 mg) afforded COMPOUND 230 as a white solid (20 mg, 9%). 1H NMR (CDCl3) δ 0.80-1.23 (m, 5H), 1.50-1.58 (m, 1H), 1.74-1.76 (m, 3H), 2.11-2.17 (m, 1H), 2.29 (s, 6H), 2.50-2.56 (m, 1H), 2.73-2.83 (m, 3H), 3.26-3.43 (m, 2H), 3.72 (s, 3H), 3.75-3.87 (m, 3H), 6.59 (d, 2H, J=7.8 Hz), 6.74 (d, 2H, J=7.8 Hz), 7.13-7.18 (m, 1H), 7.51-7.54 (m, 2H), 8.21-8.25 (m, 3H). 13C NMR (CDCl3) δ 13.74, 16.33, 29.59, 30.71, 31.56, 39.93, 43.17, 44.08, 52.36, 55.99, 58.81, 60.54, 108.76, 115.09, 116.92 (d, J=23 Hz), 118.05, 118.84, 128.66, 130.03, 133.03 (d, J=9 Hz), 133.95, 142.32, 145.44, 149.00, 153.58, 164.87, 167.68. ES-MS m/z 545 (M+H).
EXAMPLE 231




COMPOUND 231: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine (see EXAMPLE 173) (500 mg, 2.79 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (487 mg, 2.93 mmol), then general procedure J and then using general procedure E with the resulting amine and 4,6-dimethyl-pyrimidine-5-carboxylic acid (123 mg, 0.81 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidin-1-yl}-butyl)-amide as a pale beige solid (315 mg, 29% over 3 steps).
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (61 mg, 0.39 mmol) gave the crude mesylate. Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidin-1-yl}-butyl)-amide (150 mg, 0.32 mmol) and the above mesylate (95 mg) afforded a pale yellow solid (73 mg, 38%).
The above substrate (73 mg, 0.12 mmol) in 6N HCl (2.5 mL) was heated at 40° C. for 3 hours to afford COMPOUND 231 as a white solid (41 mg, 23% over 2 steps) after basic work-up and purification. 1H NMR (CDCl3) δ 1.05 (d, 3H, J=6.9 Hz), 1.09-1.35 (m, 2H), 1.54-1.64 (m, 1H), 1.72-1.88 (m, 3H), 2.21-2.31 (m, 1H), 2.49 (s, 3H), 2.50 (s, 6H), 2.57-2.67 (m, 1H), 2.76-2.94 (m, 3H), 3.33-3.46 (m, 1H), 3.71-3.88 (m, 2H), 4.21 (s, 2H), 6.55 (d, 2H, J=9.0 Hz), 7.21-7.28 (m, 1H), 7.34-7.38 (m, 1H), 7.56-7.62 (m, 1H), 7.77-7.83 (m, 3H), 8.88 (s, 1H). 13C NMR (CDCl3) δ 13.51, 21.96, 26.06, 29.45, 30.34, 31.59, 39.35, 42.32, 42.37, 43.87, 51.59, 55.96, 59.29, 108.73 (d, J=3 Hz), 111.73, 116.94 (d, J=23 Hz), 118.06, 127.07, 127.63 (d, J=16 Hz), 130.61, 130.74, 132.29 (d, J=6 Hz), 133.24 (d, J=9 Hz), 151.35, 157.60, 162.46 (d, J=256 Hz), 163.00, 166.49, 196.31. ES-MS m/z 557 (M+H). Anal. Calcd. for C32H37N6O2F.0.4CH2Cl2: C, 65.89; H, 6.45; N, 14.23; F, 3.22. Found: C, 65.98; H, 6.49; N, 14.15; F, 3.17.
EXAMPLE 232




COMPOUND 232: N—((R)-3-{4-[(4-Acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amine (see EXAMPLE 231) (94 mg, 0.28 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (70 mg, 0.42 mmol) afforded 2,4-dimethyl-N-((R)-3-{4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidin-1-yl}-butyl)-1-oxy-nicotinamide as a white solid (98 mg, 73%).
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (71 mg, 0.45 mmol) gave the crude mesylate. Using general procedure H, 2,4-dimethyl-N-((R)-3-{4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidin-1-yl}-butyl)-1-oxy-nicotinamide (157 mg, 0.33 mmol) and the above mesylate (97 mg) afforded N—[(R)-3-(4-{(5-cyano-2-fluoro-benzyl)-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-2,4-dimethyl-nicotinamide as a brown oil (60 mg, 30%).
The above substrate (60 mg, 0.10 mmol) in 6N HCl (2 mL) was heated at 40° C. for 3 hours to afford COMPOUND 232 as a white solid (22 mg, 39%) after basic work-up and purification. 1H NMR (CDCl3) δ 1.00-1.30 (m, 2H), 1.04 (d, 3H, J=6.6 Hz), 1.52-164 (m, 1H), 1.72-1.84 (m, 3H), 2.19-2.29 (m, 1H), 2.31 (s, 3H), 2.48 (s, 3H), 2.53 (s, 3H), 2.55-2.66 (m, 1H), 2.76-2.95 (m, 3H), 3.30-3.42 (m, 1H), 3.75-3.86 (m, 2H), 4.13 (s, 2H), 6.53 (d, 2H, J=9.0 Hz), 6.92 (d, 1H, J=5.1 Hz), 7.21-7.28 (m, 1H), 7.32-7.37 (m, 1H), 7.56-7.62 (m, 1H), 7.80 (d, 2H, J=9.0 Hz), 7.91 (br s, 1H), 8.27 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.50, 18.80, 22.28, 26.06, 29.26, 30.33, 31.37, 39.48, 42.30, 43.73, 51.73, 56.01, 59.78, 108.83, 111.75, 116.89 (d, J=23 Hz), 118.05, 122.44, 127.10, 128.18 (d, J=16 Hz), 130.73, 132.37 (d, J=6 Hz), 133.21 (d, J=9 Hz), 133.62, 143.74, 148.90, 151.28, 154.20, 162.43 (d, J=256 Hz), 168.21, 196.27. ES-MS m/z 556 (M+H). Anal. Calcd. for C33H38N5O2F.0.3CH2Cl2: C, 68.82; H, 6.69; N, 12.05; F, 3.27. Found: C, 68.54; H, 6.67; N, 11.71; F, 3.25.
EXAMPLE 233




COMPOUND 233: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(5-cyano-2-fluoro-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-(tert-butyl-dimethyl-silanyloxy)-phenylamine (Swenton, John S.; et al., J. Org. Chem., 54, 1, 1989, 51-58) (1.28 g, 5.73 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.05 g, 6.32 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine as a yellow oil (1.81 g, 84% over 2 steps).
To a solution of the above amine (1.81 g, 4.79 mmol) in THF cooled to 0° C. was added a solution of Boc2O (1.15 g, 5.27 mmol) in THF (20 mL). The solution was warmed to room temperature and stirred for 14 hours then concentrated to give ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester as a yellow oil (2.26 g, 99%) after purification.
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (883 mg, 5.84 mmol) gave the crude mesylate as a yellow oil. Using general procedure H, the resulting yellow oil and the above amine (1.86 g, 3.89 mmol) gave ((R)-3-{4-[[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester as a yellow foam (1.56 g, 66%).
Using general procedure C with the carbamate from above (1.56 g, 2.55 mmol) then using general procedure E with the resulting amine (500 mg, 0.979 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (179 mg, 1.18 mmol) gave 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide as a yellow foam (553 mg, 88% over 2 steps).
To a solution of the above substrate (553 mg, 0.857 mmol) in THF (8 mL) cooled to 0° C. was added TBAF (1.0M in THF, 0.90 mL, 0.90 mmol) and the solution was stirred at 0° C. for 15 minutes. TBAF (1.0M in THF, 0.20 mL, 0.20 mmol) was added and the solution stirred at 0° C. for 5 minutes. Aqueous work-up and purification gave COMPOUND 233 as a yellow foam (393 mg, 86%). 1H NMR (CDCl3) δ 0.88-1.16 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.53-1.81 (m, 5H), 2.13 (m, 1H), 2.50 (s, 6H), 2.53 (m, 1H), 2.67-2.87 (m, 3H), 3.22-3.37 (m, 2H), 3.88 (m, 1H), 3.92 (s, 2H), 5.72 (br s, 1H), 6.57 (d, 2H, J=9.0 Hz), 6.66 (d, 2H, J=9.0 Hz), 7.13 (m, 1H), 7.50 (m, 1H), 7.56 (m, 2H), 8.37 (m, 1H), 8.86 (s, 1H). ES-MS m/z 531 (M+H).
EXAMPLE 234




COMPOUND 234: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
COMPOUND 225 (78 mg, 0.14 mmol), MeOH (1.5 mL) and 6N HCl (0.5 mL) were stirred at room temperature for 18 hours to afford a white solid after basic work-up and purification.
To the aniline (43 mg, 0.08 mmol) in AcOH (0.25 mL) and H2O (0.5 mL) was added NaOCN (11 mg, 0.16 mmol) in H2O (0.5 mL) and the mixture was stirred at room temperature overnight to afford COMPOUND 234 as a white solid (24 mg, 31% over 2 steps) after work-up and purification. 1H NMR (CDCl3) δ 0.94-1.26 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.53-1.64 (m, 1H), 1.72-1.86 (m, 3H), 2.15-2.26 (m, 1H), 2.50 (s, 6H), 2.52-2.63 (m, 1H), 2.74-2.93 (m, 3H), 3.30-3.42 (m, 1H), 3.54-3.66 (m, 1H), 3.75-3.86 (m, 1H), 4.04 (s, 2H), 4.61 (s, 2H), 6.26 (s, 1H), 6.55 (d, 2H, J=9.0 Hz), 7.08 (d, 2H, J=8.7 Hz), 7.17-7.24 (m, 1H), 7.43-7.48 (m, 1H), 7.53-7.59 (m, 1H), 8.10 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.45, 21.94, 29.35, 30.34, 31.26, 39.60, 42.65, 43.87, 51.78, 57.13, 59.62, 108.54, 115.23, 116.74 (d, J=23 Hz), 118.32, 124.92, 128.90, 128.10, 130.66, 132.86, 132.98, 145.33, 157.56, 157.71, 162.63 (d, J=256 Hz), 163.01, 166.48. ES-MS m/z 573 (M+H). Anal. Calcd. for C31H37FN8O2.0.4CH2Cl2.0.1H2O: C, 61.98; H, 6.29; N, 18.42. Found: C, 62.25; H, 6.42; N, 18.28.
EXAMPLE 235




COMPOUND 235: {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester
A mixture of COMPOUND 233 (100 mg, 0.188 mmol), t-butyl bromoacetate (37 mg, 0.19 mmol) and K2CO3 (39 mg, 0.28 mmol) in DMF (1.9 mL) were heated at 80° C. for 18 h to give COMPOUND 235 as a yellow foam (88 mg, 72%) following work-up and purification. 1H NMR (CDCl3) δ 0.92-1.03 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.08-1.20 (m, 1H), 1.46 (s, 9H), 1.52-1.63 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.54 (m, 1H), 2.68-2.95 (m, 3H), 3.31-3.46 (m, 2H), 3.82 (m, 1H), 3.92 (s, 2H), 4.41 (s, 2H), 6.58 (m, 2H), 6.73 (m, 2H), 7.16 (m, 1H), 7.51 (m, 2H), 8.30 (m, 1H), 8.83 (s, 1H). ES-MS m/z 645 (M+H).
EXAMPLE 236




COMPOUND 236: {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid
Using general procedure E, 3-({[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amino}-methyl)-4-fluoro-benzonitrile (see EXAMPLE 233) (400 mg, 0.783 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (157 mg, 0.939 mmol) gave N—((R)-3-{4-[[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide as a yellow foam (240 mg, 46%).
To a solution of the above substrate (240 mg, 0.364 mmol) in THF (4 mL) cooled to 0° C. was added TBAF (1.0M in THF, 0.40 mL, 0.40 mmol) and the solution was stirred at 0° C. for 20 minutes. Aqueous work-up and purification gave a yellow foam (181 mg).
A mixture of the above alcohol (181 mg), methyl bromoacetate (56 mg, 0.37 mmol) and K2CO3 (92 mg, 0.67 mmol) in DMF (3.3 mL) were heated at 80° C. for 13 h to give {4-[(5-cyano-2-fluoro-benzyl)-(1-{(R)-3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester as a yellow foam (70 mg, 31% over 2 steps) following work-up and purification.
Using general procedure K, the above substrate (44 mg, 0.071 mmol) gave COMPOUND 236 as a colourless solid (20 mg, 47%). 1H NMR (CD3OD) δ 1.43 (d, 3H, J=6.3 Hz), 1.61 (m, 3H), 2.19 (m, 3H), 2.35 (s, 3H), 2.47 (s, 3H), 3.28 (m, 2H), 3.55 (m, 5H), 4.44 (s, 2H), 4.52 (s, 2H), 6.84 (d, 2H, J=9.0 Hz), 6.93 (d, 2H, J=8.7 Hz), 7.25 (m, 1H), 7.33 (d, 1H, J=6.6 Hz), 7.61-7.69 (m, 2H), 8.28 (d, 1H, J=6.6 Hz). 1H NMR (CDCl3+CD3OD) δ 12.86, 15.36, 18.89, 26.41, 29.97, 31.49, 36.47, 46.60, 59.99, 66.29, 108.44, 116.09, 116.90, 117.21, 119.05, 125.55, 133.67, 136.28, 136.93, 138.99, 142.31, 166.87. ES-MS m/z 604 (M+H).
EXAMPLE 237




COMPOUND 237: {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester
A mixture of COMPOUND 233 (91 mg, 0.17 mmol), methyl bromoacetate (29 mg, 0.19 mmol) and K2CO3 (47 mg, 0.34 mmol) in DMF (1.7 mL) were heated at 80° C. for 25 h to give COMPOUND 237 as a yellow foam (90 mg, 87%) after work-up and purification. 1H NMR (CDCl3) δ 0.93-1.25 (m, 2H), 1.01 (d, 3H, J=6.9 Hz), 1.58 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.68-2.88 (m, 3H), 3.31-3.53 (m, 2H), 3.78 (s, 3H), 3.82 (m, 1H), 3.93 (s, 2H), 4.54 (s, 2H), 6.57 (m, 2H), 6.76 (m, 2H), 7.17 (m, 1H), 7.52 (m, 2H), 8.28 (m, 1H), 8.83 (s, 1H). ES-MS m/z 603 (M+H).
EXAMPLE 238




COMPOUND 238: {4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid
Using general procedure K, COMPOUND 237 (83 mg, 0.14 mmol) gave COMPOUND 238 as a yellow foam (73 mg, 90%). 1H NMR (CD3OD) δ 1.41 (d, 3H, J=6.6 Hz), 1.83-2.05 (m, 5H), 2.23 (m, 1H), 2.48 (s, 6H), 3.10-3.24 (m, 2H), 3.35-3.59 (m, 5H), 3.75 (m, 1H), 4.30 (s, 2H), 4.33 (s, 2H), 6.82 (m, 4H), 7.24 (m, 1H), 7.62 (m, 2H), 8.88 (s, 1H). 1H NMR (CDCl3+CD3OD) δ 11.91, 22.05, 24.72, 26.46, 29.71, 31.55, 39.07, 36.18, 44.66, 58.40, 66.77, 108.44, 115.26, 116.67, 116.97, 118.23, 130.24, 113.04, 141.15, 157.31, 163.18, 167.48, 167.57, 174.77. ES-MS m/z 589 (M+H). Anal. Calcd. for C32H37N6FO4.2.5CH4O: C, 61.96; H, 7.08; N, 12.57; F, 2.84. Found: C, 62.21; H, 6.84; N, 12.23; F, 2.58.
EXAMPLE 239




COMPOUND 239: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
COMPOUND 237 (74 mg, 0.12 mmol) was dissolved in MeOH (15 mL) and NH3(g) was passed through the solution for 10 minutes. The mixture was stirred at room temperature for 1 h then concentrated to give COMPOUND 239 as a yellow foam (72 mg, 100%). 1H NMR (CDCl3) δ 0.92-1.25 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.59 (m, 1H), 1.71-1.82 (m, 3H), 2.17 (m, 1H), 2.50 (s, 6H), 2.55 (m, 1H), 2.75-2.90 (m, 3H), 3.31-3.46 (m, 2H), 3.83 (m, 1H), 3.97 (s, 2H), 4.41 (s, 2H), 5.60 (br s, 1H), 6.60 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.17 (m, 1H), 7.52 (m, 2H), 8.23 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.42, 21.92, 29.40, 30.42, 31.08, 39.81, 42.94, 43.79, 51.92, 58.25, 59.94, 67.83, 108.52, 115.69, 116.49, 116.80, 117.52, 118.34, 129.01, 129.21, 130.68, 132.73, 132.86, 133.32, 133.39, 142.87, 150.71, 157.58, 161.04, 162.97, 164.43, 166.40, 171.31. ES-MS m/z 588 (M+H). Anal. Calcd. for C32H38N7FO3.1.2CH4O: C, 63.69; H, 6.89; N, 15.66; F, 3.03. Found: C, 63.77; H, 6.68; N, 15.53; F, 2.87.
EXAMPLE 240




COMPOUND 240: (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid
Using general procedure K, COMPOUND 227 (54 mg, 0.090 mmol) gave COMPOUND 240 as a yellow foam (52 mg, 98%) (78:18, trans/cis isomers). 1H NMR (CD3OD) δ 1.48 (d, 3H, J=6.6 Hz), 1.95 (m, 1H), 2.16 (m, 5H), 2.50 (s, 6H), 3.35-3.62 (m, 7H), 4.44 (m, 1H), 4.65 (s, 2H), 6.26 (d, 1H, J=15.6 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.35 (m, 1H), 7.48 (m, 3H), 7.57 (d, 1H, J=15.9 Hz), 7.70 (m, 1H), 8.90 (s, 1H). 13C NMR (CDCl3+CD3OD) δ 12.83, 22.23, 26.13, 26.35, 30.02, 31.83, 36.37, 43.25, 46.20, 51.07, 53.35, 53.82, 60.07, 108.81, 113.63, 114.56, 117.27, 117.57, 118.50, 125.02, 128.59, 128.79, 129.78, 130.48, 132.47, 133.07, 133.62, 145.46, 149.57, 157.54, 161.26, 163.62, 168.02, 170.09. ES-MS m/z 585 (M+H). Anal. Calcd. for C33H37N6FO3.0.4C6H14.1.5CH2Cl2: C, 59.37; H, 6.16; N, 11.26; F, 2.54. Found: C, 59.47; H, 6.52; N, 11.48; F, 2.35.
EXAMPLE 241




COMPOUND 241: (E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(2,4-dimethyl-1-oxy-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid
Using general procedure E with (E)-3-{4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-cyano-2-fluoro-benzyl)-amino]-phenyl}-acrylic acid methyl ester (see EXAMPLE 227) (55 mg, 0.12 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (24 mg, 0.14 mmol) followed by general procedure K with the resulting ester gave COMPOUND 241 as a yellow foam (56 mg, 90% over 2 steps) (86:11, trans/cis isomers). 1H NMR (CD3OD) δ 1.48 (d, 3H, J=6.3 Hz), 1.95 (m, 1H), 2.23 (m, 5H), 2.36 (s, 3H), 2.48 (s, 3H), 3.35-3.62 (m, 7H), 4.45 (m, 1H), 4.66 (s, 2H), 6.26 (d, 1H, J=15.9 Hz), 6.85 (d, 2H, J=8.7 Hz), 7.32 (m, 2H), 7.54 (m, 3H), 7.57 (d, 1H, J=15.9 Hz), 7.71 (m, 1H), 8.28 (d, 1H, J=6.6 Hz). 1H NMR (CDCl3+CD3OD) δ 12.05, 14.24, 17.70, 25.05, 28.70, 29.80, 35.18, 41.91, 45.90, 51.84, 52.51, 58.89, 107.40, 112.31, 113.17, 117.16, 123.60, 124.39, 127.37, 129.14, 131.20, 132.28, 135.05, 136.79, 137.84, 144.19, 145.37, 148.31, 165.47, 168.87. ES-MS m/z 600 (M+H). Anal. Calcd. for C34H38N5FO4.5.0CH4O.4.2H2O.2.7CH2Cl2: C, 47.03; H, 6.80; N, 6.58; F, 1.78. Found: C, 47.15; H, 6.74; N, 6.77; F, 1.39.
EXAMPLE 242




COMPOUND 242: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4-(benzo[1,3]dioxol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 179) (320 mg, 1.0 mmol) and 2-fluoro-5-cyanobenzyl bromide (278 mg, 1.3 mmol) afforded a white syrup (449 mg).
Using general procedure C with the above substrate (449 mg), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (343 mg, 1.58 mmol) and then using general procedure D afforded 3-({[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amino}-methyl)-4-fluoro-benzonitrile as a white solid (162 mg, 38% over 4 steps).
Using general procedure E, the above primary amine (40 mg, 0.09 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (15.8 mg, 0.10 mmol) afforded COMPOUND 242 as a white solid (46 mg, 87%). 1H NMR (CDCl3) δ 0.89-1.23 (m, 2H), 1.01 (d, J=6.3 Hz), 1.51-1.61 (m, 1H), 1.69-1.85 (m, 3H), 2.09-2.20 (m, 1H), 2.51 (s, 6H), 2.50-2.59 (m, 1H), 2.70-2.91 (m, 3H), 3.28-3.41 (m, 2H), 2.76-3.88 (m, 1H), 3.91 (s, 2H), 5.87 (s, 2H), 6.07 (d, 1H, J=8.4 Hz), 6.29 (s, 1H), 6.61 (d, 1H, J=8.7 Hz), 7.11-7.20 (m, 1H), 7.48-7.56 (m, 2H), 8.30 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.80, 22.30, 29.84, 30.82, 31.44, 40.13, 43.45, 44.16, 52.19, 59.36, 60.21, 99.74, 101.30, 108.73, 109.40, 116.95 (d, J=23 Hz), 118.75, 129.54 (d, J=15 Hz), 131.06, 133.10 (d, J=9 Hz), 133.87 (d, J=6 Hz), 141.46, 143.82, 148.82, 157.94, 163.11 (d, J=256 Hz), 163.32, 166.80. ES-MS m/z 559 (M+H). Anal. Calcd. for C31H35N6O3F.0.1CH2Cl2: C, 65.86; H, 6.26; N, 14.82; F, 3.35. Found: C, 65.57; H, 6.30; N, 14.45; F, 3.32.
EXAMPLE 243




COMPOUND 243: N-(3-{4-[Benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 3-({[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amino}-methyl)-4-fluoro-benzonitrile (see EXAMPLE 242) (40 mg, 0.09 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (17.4 mg, 0.10 mmol) afforded COMPOUND 243 as a white solid (40 mg, 74%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.0 Hz), 1.11-1.39 (m, 2H), 1.53-1.66 (m, 1H), 1.74-1.87 (m, 3H), 2.12-2.23 (m, 1H), 2.31 (s, 3H), 2.37 (s, 3H), 2.46-2.57 (m, 1H), 3.72-3.90 (m, 3H), 3.33-3.46 (m, 2H), 3.63-3.76 (m, 1H), 4.11 (s, 2H), 5.87 (s, 2H), 6.09 (d, 1H, J=8.7 Hz), 6.31 (s, 1H), 6.62 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, J=6.0 Hz), 7.09-7.18 (m, 1H), 7.48-7.59 (m, 2H), 7.98 (d, 1H, J=6.3 Hz), 8.38 (br s, 1H). 13C NMR (CDCl3) δ 13.95, 15.38, 18.87, 30.07, 30.65, 32.78, 39.11, 44.10, 44.97, 51.59, 58.60, 59.09, 99.20, 101.26, 108.74, 108.83, 116.84 (d, J=23 Hz), 118.78, 125.23, 129.92 (d, J=15 Hz), 133.07 (d, J=9 Hz), 133.88 (d, J=6 Hz), 134.79, 137.31, 138.22, 141.15, 144.18, 145.95, 148.86, 163.05 (d, J=255 Hz), 165.80. ES-MS m/z 574 (M+H). Anal. Calcd. for C32H36N5O4F.0.8CH2Cl2: C, 61.40; H, 5.91; N, 10.92; F, 2.96. Found: C, 61.67; H, 6.04; N, 10.72; F, 2.70.
EXAMPLE 244




COMPOUND 244: N-(3-{4-[(5-Cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (302 mg, 2.0 mmol) gave the crude mesylate. Using general procedure H, 4-(1H-indol-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 177) (486 mg, 1.54 mmol) and the above mesylate (448 mg) afforded 4-[(5-cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (401 mg, 58%).
Using general procedure C with the above carbamate (400 mg, 0.891 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (386 mg, 1.78 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(1H-indol-5-yl)-amino]-methyl}-4-fluoro-benzonitrile as a white solid (92 mg, 26% over 3 steps).
Using general procedure E, the above amine (45 mg, 0.11 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (22 mg, 0.13 mmol) afforded COMPOUND 244 as a white solid (20 mg, 32%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=5.4 Hz), 1.20-1.30 (m, 2H), 1.58-1.64 (m, 1H), 1.84-1.89 (m, 3H), 2.18-2.24 (m, 1H), 2.27 (s, 3H), 2.36 (s, 3H), 2.47-2.55 (m, 1H), 2.75-2.85 (m, 3H), 3.28-3.35 (m, 2H), 3.67-3.74 (m, 1H), 4.20 (s, 2H), 6.39 (s, 1H), 6.74 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=6.6 Hz), 7.04-7.22 (m, 4H), 7.42-7.46 (m, 1H), 7.68-7.72 (m, 1H), 7.95 (d, 1H, J=6.6 Hz), 8.38 (br s, 1H), 8.57 (br s, 1H). 13C NMR (CDCl3) δ 12.38, 14.09, 17.42, 28.63, 29.29, 30.43, 38.23, 43.28, 43.71, 50.54, 58.23, 59.23, 101.12, 107.24, 110.02, 110.48, 114.03 (d, J=14 Hz), 115.28 (d, J=23 Hz), 115.84, 117.49, 123.73, 123.92, 127.35, 131.35, 131.48, 132.63, 133.20, 135.56, 137.17, 140.48, 144.64, 161.89 (d, J=255 Hz), 164.53. ES-MS m/z 569 (M+H). Anal. Calcd. for C33H37N6O2F.0.5CH2Cl2.1.2CH4O: C, 64.16; H, 6.64; N, 12.94; F, 2.92. Found: C, 64.27; H, 6.39; N, 12.74; F, 2.43.
EXAMPLE 245




COMPOUND 245: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure E, 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(1H-indol-5-yl)-amino]-methyl}-4-fluoro-benzonitrile (see EXAMPLE 244) (45 mg, 0.11 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (20 mg, 0.13 mmol) afforded COMPOUND 245 as a white solid (35 mg, 60%). 1H NMR (CDCl3) δ 0.88-1.25 (m, 5H), 1.54-1.64 (m, 1H), 1.76-1.92 (m, 3H), 2.13-2.20 (m, 1H), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.69-2.84 (m, 3H), 3.31-3.37 (m, 2H), 3.82-3.85 (m, 1H), 3.98 (s, 2H), 6.39 (s, 1H), 6.72 (d, 1H, J=8.6 Hz), 7.00 (s, 1H), 7.08-7.14 (m, 2H), 7.21 (d, 1H, J=8.6 Hz), 7.43-7.45 (m, 1H), 7.65 (d, 1H, J=6.4 Hz), 8.02 (s, 1H), 8.50 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.74, 22.36, 29.89, 30.88, 31.26, 40.33, 43.81, 44.17, 52.34, 60.54, 60.81, 102.63, 108.63, 110.70, 111.94, 116.61, 116.72, 116.92, 118.91, 125.26, 128.77, 131.10, 132.79, 134.50, 157.98, 163.38. ES-MS m/z 554 (M+H). Anal. Calcd. for C32H36N7OF.0.2CH2Cl2: C, 67.77; H, 6.43; N, 17.18; F, 3.33. Found: C, 68.16; H, 6.64; N, 16.86; F, 3.05.
EXAMPLE 246




COMPOUND 246: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with N-(5-amino-pyridin-2-yl)-acetamide (Bae, Jong Woo; et al., Tetrahedron Lett., 41, 2, 2000, 175-178) (1.00 g, 6.62 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.16 g, 6.95 mmol) and then using general procedure J afforded N-{5-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-pyridin-2-yl}-acetamide as a white solid (1.05 g, 52% over 2 steps).
Using general procedure E, the above primary amine (400 mg, 1.31 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (219 mg, 1.44 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-acetylamino-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide as a white solid (523 mg, 91%).
Using general procedure G, 4-fluoro-3-hydroxymethyl-benzonitrile (300 mg, 1.91 mmol) gave the crude mesylate. Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-acetylamino-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide (500 mg, 1.14 mmol) and the above mesylate (340 mg) afforded COMPOUND 246 as a white solid (150 mg, 23%). 1H NMR (CDCl3) δ 0.98-1.30 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.53-1.62 (m, 1H), 1.71-1.86 (m, 3H), 2.15 (s, 3H), 2.16-2.25 (m, 1H), 2.51 (s, 6H), 2.52-2.63 (m, 1H), 2.75-2.94 (m, 3H), 3.31-3.43 (m, 1H), 3.48-3.59 (m, 1H), 3.74-3.86 (m, 1H), 4.02 (s, 2H), 6.99 (dd, 1H, J=9.3, 3.0 Hz), 7.17-7.24 (m, 1H), 7.44-7.48 (m, 1H), 7.53-7.59 (m, 1H), 7.63 (d, 1H, J=2.7 Hz), 7.76 (s, 1H), 7.96-8.05 (m, 2H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.49, 21.95, 24.39, 29.36, 30.22, 31.39, 39.51, 42.21, 43.82, 51.65, 57.56, 59.50, 108.75 (d, J=3 Hz), 114.74, 116.89 (d, J=23 Hz), 118.07, 124.58, 128.25 (d, J=15 Hz), 130.67, 132.73 (d, J=6 Hz), 133.16 (d, J=9 Hz), 134.31, 140.17, 143.87, 157.57, 162.34 (d, J=256 Hz), 163.01, 166.44, 168.26. ES-MS m/z 573 (M+H). Anal. Calcd. for C31H37FN8O2.0.4CH2Cl2.0.5H2O: C, 61.26; H, 6.35; N, 18.20; F, 3.09. Found: C, 61.65; H, 6.46; N, 18.19; F, 3.03.
EXAMPLE 247




COMPOUND 247: 3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 32) (604 mg, 1.61 mmol) in CH2Cl2 (8 mL) was added SiO2 (2 g) followed by PCC (1.04 g, 4.82 mmol), and the mixture was stirred at room temperature for 3 h to give 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as colourless crystals (601 mg, 100%) after purification.
A mixture of 2-bromobenzyl bromide (805 mg, 3.22 mmol), Mg turnings (180 mg, 7.40 mmol), and iodine (cat.) in Et2O (16 mL) was heated to reflux until the reaction was initiated (indicated by decolourization) then stirred at room temperature for 2 h. The mixture was added to a solution of the ketone from above (601 mg, 1.61 mmol) in Et2O (1 mL) then stirred for 19 h. Aqueous work-up and purification gave a colourless oil (791 mg).
A mixture of the alcohol from above (791 mg), (S)-BINAP (135 mg, 0.217 mmol), Pd(OAc)2 (48 mg, 0.21 mmol), and K2CO3 (602 mg, 4.36 mmol) in degassed toluene (7 mL) was heated to 110° C. for 40 h. The mixture was allowed to cool to room temperature, filtered and concentrated to give 4-[2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a colourless foam (375 mg, 50%) after purification.
Using general procedure C with the carbamate from above (375 mg, 0.809 mmol), then general procedure I with the resulting amine and then using general procedure J gave a 1:1 diastereomeric mixture of 3-{4-[2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (138 mg, 81% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (51 mg, 0.27 mmol) and the amine from above (77 mg, 0.18 mmol) in THF (2 mL) gave a 1:1 diastereomeric mixture of COMPOUND 247 (71 mg, 66%). 1H NMR (CDCl3) δ 0.57-1.32 (m, 12H), 1.47-2.00 (m, 10H), 2.24-2.41 (m, 2H), 2.68-2.88 (m, 6H), 3.13-3.39 (m, 6H), 3.87 (m, 2H), 6.84 (m, 4H), 7.11 (m, 8H), 7.29 (m, 4H), 8.58 (s, 2H), 8.60 (s, 2H), 8.88 (d, 1H, J=5.7 Hz), 9.01 (br s, 1H). 13C NMR (CDCl3) δ 13.00, 13.32, 26.32, 26.78, 26.92, 27.57, 29.89, 30.55, 39.57, 40.10, 40.19, 40.31, 43.94, 44.12, 46.98, 52.51, 60.31, 60.67, 91.88, 92.04, 109.22, 120.60, 124.63, 125.46, 126.66, 126.80, 128.26, 129.01, 143.16, 143.72, 143.92, 147.67, 148.08, 158.78, 161.49, 161.72. ES-MS m/z 608 (M+H). Anal. Calcd. for C30H30N3Cl2F3O3: C, 59.22; H, 4.97; N, 6.91; Cl, 11.65; F, 9.37. Found: C, 59.37; H, 5.03; N, 6.84; Cl, 11.58; F, 9.33.
Scheme 12 describes the preparation of Examples 248-255, using various general procedures previously described, and reagents listed below.
















Example
R3*
BrCH2DBr







248
CF3
2-bromobenzyl bromide


249
SO2Me
2-bromobenzyl bromide


250
SO2NHMe
2-bromobenzyl bromide


251
CF3
1-bromo-2-bromomethyl-3-fluoro-benzene




(Dewar, M. J. S.; Grisdale, P. J., J. Org.




Chem., 28, 1963, 1759-1762)


252
OCF3
1-bromo-2-bromomethyl-3-fluoro-benzene


253
SO2Me
1-bromo-2-bromomethyl-3-fluoro-benzene


254
SO2NHMe
1-bromo-2-bromomethyl-3-fluoro-benzene


255
CF3
2-bromo-1-bromomethyl-4-fluoro-benzene




(Musso, David L.; et al., J. Med. Chem., 46, 3,




2003, 409-416) (800 mg, 2.99 mmol)









EXAMPLE 248




COMPOUND 248: 3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-2,3-dihydrobenzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.59-0.73 (m, 1H), 0.94 (t, 3H, J=7.5 Hz), 0.91-0.96 (m, 1H), 1.04-1.24 (m, 2H), 1.47-2.02 (m, 4H), 2.24-2.42 (m, 1H), 2.66-2.89 (m, 3H), 3.16-3.38 (m, 3H), 3.75-3.97 (m, 1H), 6.80-6.90 (m, 2H), 7.07 (t, 1H, J=6 Hz), 7.17 (t, 1H, J=7.5 Hz), 7.38 (t, 2H, J=10.5 Hz), 7.57 (t, 2H, J=6.0 Hz), 8.59 (d, 2H, J=6.0 Hz), 8.83-8.97 (br s, 1H). 13C NMR (CDCl3) δ 13.34, 13.70, 26.63, 27.17, 27.23, 30.31, 31.02, 40.21, 40.51, 40.64, 44.33, 44.54, 47.23, 52.78, 52.56, 60.60, 61.02, 92.33, 92.48, 109.65, 109.70, 121.10, 122.66, 125.01, 125.57, 125.68, 125.99, 126.12, 126.26, 128.71, 129.39, 129.87, 143.52, 148.05, 149.60, 146.78, 159.03, 159.14, 161.87, 162.14. ES-MS m/z 592.8 (M+H). Anal. Calcd. for C30H30N3Cl2O2F3: C, 60.82; H, 5.10; N, 7.09; Cl, 11.97; F, 9.62. Found: C, 60.94; H, 5.23; N, 7.09; Cl, 12.08; F, 9.50.
EXAMPLE 249




COMPOUND 249: 3,5-Dichloro-N-(3-{4-[2-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.60-0.90 (m, 2H), 0.91-0.96 (m, 3H) 1.01-1.21 (m, 1H), 1.43-1.80 (m, 5H), 1.82-2.02 (m, 1H), 2.20-2.44 (m, 1H), 2.64-2.91 (m, 3H), 3.03 (s, 3H), 3.15-3.44 (m, 2H), 3.73-3.40 (m, 1H), 6.80-6.92 (m, 2H), 7.03-7.11 (m, 1H), 7.12-7.20 (m, 1H), 7.46, 7.49 (d, 2H, J=8.4 Hz), 7.88, 7.89 (d, 2H, J=8.4 Hz), 8.57, 8.60 (s, 2H), 8.79, 8.92 (br s, 1H). 13C NMR (CDCl3) δ 13.01, 13.34, 14.20, 21.07, 26.22, 26.79, 27.55, 29.92, 30.64, 39.89, 40.10, 40.30, 43.88, 44.11, 44.46, 46.79, 52.30, 52.41, 53.45, 60.16, 60.40, 60.61, 91.93, 92.06, 109.36, 109.41, 120.88, 124.63, 125.08, 126.31, 126.43, 127.37, 128.43, 129.02, 139.22, 143.16, 147.67, 151.69, 151.86, 158.52, 158.62, 161.44, 161.73. ES-MS m/z 626 (M+Na). Anal. Calcd. for C30H33N3Cl2O4S.0.8CH2Cl2.0.2H2O: C, 54.88; H, 5.23; N, 6.23; Cl, 18.93; S, 4.76. Found: C, 55.08; H, 5.28; N, 6.46; Cl, 18.69; S, 4.77.
EXAMPLE 250




COMPOUND 250: 3,5-Dichloro-N-(3-{4-[2-(4-methylsulfamoyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[hydroxy-(4-methylsulfamoyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 33) (530 mg, 1.38 mmol) in CH2Cl2 (10 ml) were added PCC (900 mg, 4.1 mmol) followed by SiO2 (1.5 g). The resultant mixture was stirred at room temperature overnight to give 4-(4-methylsulfamoyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (420 mg, 80%) as a colourless oil after purification.
COMPOUND 250 was isolated as a white foam. 1H NMR (CDCl3) δ 0.60-0.72 (m, 1H), 0.75-1.30 (m, 6H), 1.40-2.04 (m, 6H), 2.24-2.48 (m, 1H), 2.53-2.99 (m, 3H), 3.63 (d, 3H, J=3.0 Hz), 3.05-3.45 (m, 3H), 3.70-3.80 (m, 0.5H), 3.85-4.00 (m, 0.5H), 4.68 (q, 1H, J=6.0 Hz), 2.83-6.90 (m, 2H), 7.08-7.23 (m, 2H), 7.39-7.45 (m, 2H), 7.80 (d, 2H, J=6.0 Hz), 8.57 (s, 1H), 8.59 (s, 1H), 8.80 (s, 0.5H), 8.99 (s, 0.5H). 13C NMR (CDCl3) δ 13.0, 13.32, 26.19, 26.77, 27.51, 29.34, 29.93, 30.61, 39.87, 40.06, 40.16, 40.28, 43.94, 44.16, 46.84, 52.27, 52.36, 53.46, 60.07, 60.51, 91.96, 92.10, 92.78, 109.29, 109.34, 113.89, 120.78, 124.63, 125.24, 126.04, 126.17, 126.60, 127.11, 127.76, 128.36, 129.00, 137.61, 143.11, 147.63, 150.31, 150.49, 158.55, 158.65, 161.50, 161.78. ES-MS m/z 618.6 (M+H). Anal. Calcd. for C30H34Cl2N4O4S.0.3CH2Cl2: C, 56.59; H, 5.42; N, 8.71; Cl, 14.33; S, 4.99. Found: C, 55.65; H, 5.56; N, 8.60; Cl, 14.05; S, 4.94.
EXAMPLE 251




COMPOUND 251: 3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
Colourless foam. 1H NMR (CDCl3) δ 0.59-1.24 (m, 12H), 1.43-2.02 (m, 10H), 2.23-2.43 (m, 2H), 2.67-2.90 (m, 6H), 3.21-3.44 (m, 6H), 3.76-3.97 (m, 2H), 6.55 (m, 2H), 6.68 (m, 2H), 7.12 (m, 2H), 7.37 (m, 4H), 7.59 (d, 4H, J=7.8 Hz), 8.58 (s, 2H), 8.60 (s, 2H), 8.79 (d, 1H, J=5.7 Hz), 8.87 (br s, 1H). 13C NMR (CDCl3) δ 13.00, 13.31, 26.16, 26.76, 27.54, 30.04, 30.63, 36.84, 37.22, 40.13, 43.87, 44.11, 46.85, 52.36, 60.22, 60.61, 93.31, 93.45, 105.26, 107.62, 107.89, 111.80, 112.08, 122.20, 125.28, 125.47, 125.60, 128.98, 129.30, 129.72, 129.84, 143.10, 147.68, 148.58, 148.75, 157.38, 160.65, 160.89, 161.48, 161.72. ES-MS m/z 610 (M+H). Anal. Calcd. for C30H29N3Cl2F4O2.0.2C3H7NO.0.1CH2Cl2.0.1C6H14: C, 58.54; H, 5.02; N, 6.98; Cl, 12.15; F, 11.83. Found: C, 58.82; H, 4.86; N, 7.00; Cl, 11.79; F, 11.61.
EXAMPLE 252




COMPOUND 252: 3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethoxy-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
Colourless foam. 1H NMR (CDCl3) δ 0.58-1.29 (m, 12H), 1.37-1.97 (m, 10H), 2.24-2.43 (m, 2H), 2.68-2.89 (m, 6H), 3.13-3.39 (m, 6H), 3.74-3.97 (m, 2H), 6.55 (m, 2H), 6.66 (m, 2H), 7.08-7.18 (m, 6H), 7.27 (m, 4H), 8.58 (s, 2H), 8.60 (s, 2H), 8.81 (m, 1H), 8.88 (m, 1H). 13C NMR (CDCl3) δ 13.01, 13.31, 26.23, 26.79, 27.55, 30.08, 30.58, 36.65, 37.10, 40.16, 43.91, 44.12, 46.99, 52.41, 60.27, 60.60, 93.28, 93.44, 105.21, 107.53, 107.80, 111.96, 112.23, 120.69, 126.54, 126.68, 128.98, 129.65, 129.76, 143.12, 143.31, 147.69, 148.22, 157.43, 160.70, 160.84, 160.94, 161.50, 161.70. ES-MS m/z 626 (M+H). Anal. Calcd. for C30H29N3Cl2F4O3: C, 57.52; H, 4.67; N, 6.71; Cl, 11.32; F, 12.13. Found: C, 57.26; H, 4.56; N, 6.62; Cl, 11.65; F, 11.84.
EXAMPLE 253




COMPOUND 253: 3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
Colourless foam. 1H NMR (CDCl3) δ 0.62-1.24 (m, 12H), 1.48-2.06 (m, 10H), 2.23-2.43 (m, 2H), 2.55-2.89 (m, 6H), 3.03 (s, 6H), 3.21-4.06 (m, 8H), 6.56 (m, 2H), 6.69 (m, 2H), 7.13 (m, 2H), 7.46 (m, 4H), 7.90 (m, 4H), 8.57 (s, 2H), 8.59 (s, 2H), 8.68 (m, 1H), 8.77 (m, 1H). 13C NMR (CDCl3) δ 12.99, 13.29, 23.39, 26.12, 26.69, 26.76, 27.50, 30.19, 30.74, 33.25, 36.93, 37.28, 40.06, 43.88, 44.13, 44.45, 46.80, 52.22, 52.30, 60.00, 60.42, 67.39, 93.30, 93.44, 98.39, 105.34, 107.77, 108.04, 111.65, 111.93, 126.19, 126.31, 127.48, 128.99, 129.85, 129.96, 139.47, 143.10, 147.67, 151.00, 151.16, 157.36, 160.64, 160.75, 161.47, 161.72. ES-MS m/z 620 (M+H). Anal. Calcd. for C30H32N3Cl2FSO4.0.1CH2Cl2.0.6CH4O: C, 56.88; H, 5.38; N, 6.48; Cl, 12.03; F, 2.93; S, 4.95. Found: C, 57.00; H, 5.46; N, 6.24; Cl, 11.65; F, 2.63; S, 4.68.
EXAMPLE 254




COMPOUND 254: 3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-methylsulfamoyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
Yellow foam. 1H NMR (CDCl3) δ 0.65-2.07 (m, 22H), 2.27-2.44 (m, 2H), 2.65-2.91 (m, 12H), 3.16-3.46 (m, 6H), 3.70-3.90 (m, 2H), 4.52 (m, 2H), 6.56 (m, 2H), 6.69 (m, 2H), 7.13 (m, 2H), 7.41 (m, 4H), 7.82 (d, 4H, J=8.1 Hz), 8.58 (s, 2H), 8.60 (s, 2H), 8.74 (m, 1H), 8.81 (m, 1H). 13C NMR (CDCl3) δ 13.00, 13.29, 26.09, 26.70, 27.48, 29.39, 29.71, 30.13, 30.31, 30.65, 36.86, 37.23, 40.06, 43.91, 44.14, 46.85, 52.33, 60.14, 60.53, 93.31, 93.45, 105.31, 107.72, 107.99, 111.73, 112.01, 125.52, 125.94, 126.07, 127.26, 129.00, 129.82, 129.93, 137.93, 143.13, 147.67, 149.64, 149.83, 157.37, 160.66, 160.78, 160.88, 161.50, 161.73. ES-MS m/z 635 (M+H).
EXAMPLE 255




COMPOUND 255: 3,5-Dichloro-N-(3-{4-[6-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
Colourless foam. 1H NMR (CDCl3) δ 0.58-1.27 (m, 12H), 1.48-2.00 (m, 10H), 2.24-2.42 (m, 2H), 2.67-2.88 (m, 6H), 3.11-3.39 (m, 6H), 3.76-3.97 (m, 2H), 6.57 (m, 4H), 6.98 (m, 2H), 7.36 (m, 4H), 7.58 (d, 4H, J=7.8 Hz), 8.58 (s, 2H), 8.60 (s, 2H), 8.79 (d, 1H, J=4.8 Hz), 8.92 (br s, 1H). 13C NMR (CDCl3) δ 13.01, 13.32, 26.20, 26.70, 26.81, 27.47, 29.93, 30.61, 39.04, 39.47, 40.11, 40.26, 43.88, 44.09, 46.88, 52.32, 52.40, 60.20, 60.61, 93.75, 93.88, 97.62, 97.97, 107.17, 107.48, 120.80, 124.75, 124.89, 125.24, 125.49, 125.62, 129.03, 129.66, 143.12, 147.64, 148.89, 159.68, 161.44, 161.72, 164.84. ES-MS m/z 612 (M+H). Anal. Calcd. for C30H29N3Cl2F4O2.0.3C3H7NO.0.1CH2Cl2.0.1C6H14: C, 58.44; H, 5.07; N, 7.12; Cl, 12.01; F, 11.70. Found: C, 58.70; H, 4.87; N, 7.06; Cl, 11.64; F, 11.57.
EXAMPLE 256




COMPOUND 256: N-(3-{4-[2-(4-Methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 3-{4-[2-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 249) (26 mg, 0.060 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (11 mg, 0.067 mmol) afforded a 1:1 diastereomeric mixture of COMPOUND 256 (32 mg, 92%) as a white foam. 1H NMR (CDCl3) δ 0.80-1.15 (m, 2H), 0.93, 0.95 (d, 3H, J=6.7 Hz), 1.42-1.96 (m, 7H), 2.26 (s, 3H), 2.40 (s, 3H), 2.59-2.85 (m, 3H), 3.03 (s, 3H), 3.22-3.48 (m, 3H), 3.63-3.82 (m, 1H), 6.79-6.86 (m, 1H), 6.89-6.97 (m, 2H), 7.05-7.20 (m, 2H), 7.55, 7.58 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.4 Hz), 8.08, 8.12 (d, 1H, J=6.5 Hz), 8.34, 8.42 (br s, 1H). 13C NMR (CDCl3) δ 13.24, 13.40, 15.11, 18.43, 22.62, 26.36, 26.90, 27.51, 31.63, 31.87, 39.17, 39.86, 40.14, 44.48, 44.78, 47.01, 51.88, 53.45, 58.95, 59.15, 92.27, 92.40, 109.40, 120.81, 124.62, 124.86, 125.29, 125.36, 126.60, 126.69, 127.27, 128.37, 133.85, 136.70, 138.13, 139.16, 145.54, 151.47, 151.58, 158.54, 158.60, 165.39, 165.50. ES-MS m/z 626 (M+Na). Anal. Calcd. for C32H39N3O5S.0.1CH2Cl2.1.3H2O: C, 63.24; H, 6.91; N, 6.89; S, 5.26. Found: C, 62.92; H, 6.91; N, 7.26; S, 5.04.
EXAMPLE 257




COMPOUND 257: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butyl)-amide
Using general procedure E, 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 251) (60 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (42 mg, 0.28 mmol) afforded COMPOUND 257 as a white solid (32 mg, 41%). 1H NMR (CDCl3) δ 0.62-0.92 (m, 2H), 0.92-0.97 (m, 3H), 1.09-1.23 (m, 1H), 1.50-1.55 (m, 1H), 1.69-1.78 (m, 2H), 1.84-2.02 (m, 2H), 2.24-2.45 (m, 1H), 2.50 (s, 6H), 2.61-2.86 (m, 3H), 3.17-3.47 (m, 3H), 3.70-4.00 (m, 1H), 6.51-6.57 (m, 1H), 6.84, 6.89 (d, 1H, J=8.1 Hz), 7.10-7.17 (m, 1H), 7.36-7.43 (m, 2H), 7.58-7.62 (m, 2H), 8.44, 8.59 (m, 1H), 9.04, 9.09 (s, 1H). 13C NMR (CDCl3) δ 14.55, 14.95, 23.47, 27.69, 28.14, 28.30, 29.01, 31.91, 32.79, 38.48, 38.90, 41.46, 41.67, 45.53, 45.79, 48.46, 48.52, 53.92, 54.00, 61.60, 62.16, 94.67, 94.84, 107.08, 109.15, 109.42, 113.35, 113.62, 123.78, 126.91, 127.05, 127.16, 127.39, 131.29, 131.40, 131.48, 132.30, 150.24, 150.40, 158.92, 159.20, 162.19, 162.56, 164.50, 167.87, 168.26. ES-MS m/z 571 (M+H). Anal. Calcd. for C31H34N4O2F4.0.5H2O: C, 64.24; H, 6.09; N, 9.67. Found: C, 64.25; H, 6.00; N, 9.68.
Scheme 13 describes the preparation of Examples 258-260, using general procedures E or F, and reagents listed below.















Example
R1COOH







258
3,5-dichloroisonicotinic acid


259
4,6-dimethyl-pyrimidine-5-carboxylic acid


260
2,4-dimethyl-1-oxy-nicotinic acid









EXAMPLE 258




COMPOUND 258: 3,5-Dichloro-N-(3-{4-[1-imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
To a solution of 4-[hydroxy-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (990 mg, 2.75 mmol), acetone cyanohydrin (913 mg, 10.73 mmol) and Ph3P (2.5 g, 9.63 mmol) in THF (25 mL) was added DIAD (2.2 g, 10.94 mmol) in THF (10 mL) over 5 hours at 0° C. and the resulting mixture was stirred for another 72 hours at room temperature. Standard work-up and purification afforded 4-[cyano-(4-trifluoromethyl-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (539 mg, 53%) as a white foam.
To a solution of the above nitrile (280 mg, 0.76 mmol) in THF at −78° C. was added freshly prepared LDA (0.32M, 2.6 mL, 0.83 mmol). The resulting mixture was stirred for 30 min. at −78° C. and 2-bromobenzyl bromide (570 mg, 2.28 mmol) in THF (1 mL) was added. The reaction was stirred for 3 hours at 0° C. and quenched with saturated aqueous NH4Cl (20 mL) to give 4-[2-(2-bromo-phenyl)-1-cyano-1-(4-trifluoromethyl-phenyl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (264 mg, 65%) as a white foam after work-up and purification.
To a solution of the above bromo-adduct (262 mg, 0.48 mmol) in THF (5 mL) cooled to −78° C. was added t-BuLi (1.7M in hexane, 0.62 mL, 1.05 mmol) and the resulting mixture was stirred for 1 h at −78° C. and quenched with saturated aqueous NH4Cl (20 mL) to give 4-[1-imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (190 mg, 86%) as a white foam following work-up and purification.
Using general procedure C with the above carbamate, then general procedure I with the resulting amine followed by general procedure J gave 2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-1-imino-2-(4-trifluoromethyl-phenyl)-indan (47 mg, 53% over 3 steps) as a white foam.
Using general procedure F, 3,5-dichloroisonicotinic acid (25 mg, 0.13 mmol) and the above amine (47 mg, 0.11 mmol) afforded COMPOUND 258 (16 mg, 24%) as a mixture of two diastereomers. 1H NMR (CDCl3) δ 0.51-0.86 (m, 1H), 0.90 (d, 3H, J=6 Hz), 1.46-1.84 (m, 5H), 2.09-2.14 (m, 1H), 2.32-2.54 (m, 3H), 2.68-2.85 (m, 3H), 3.05 (t, 1H, J=15 Hz), 3.22-3.25 (m, 1H), 3.89-3.97 (m, 1H), 7.30-7.35 (m, 1H), 7.48-7.54 (m, 7H), 8.55 (d, 2H, J=12 Hz), 9.48-9.65 (m, 1H). 13C NMR (CDCl3) δ 13.24, 13.35, 27.22, 27.47, 28.02, 28.31, 29.37, 29.79, 36.33, 40.58, 40.73, 44.00, 44.12, 52.68, 52.81, 53.44, 57.54, 60.83, 61.03, 121.66, 122.24, 125.34, 125.84, 126.94, 127.64, 128.61, 129.27, 132.83, 135.48, 143.49, 146.76, 147.64, 161.29, 161.52, 184.21. ES-MS m/z 627 (M+Na).
EXAMPLE 259




COMPOUND 259: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[1-imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.62-0.82 (m, 2H), 0.96 (d, 3H, J=6.0 Hz), 1.31-1.55 (m, 3H), 1.67-1.79 (m, 1H), 1.97-2.37 (m, 2H), 2.43-2.53 (m, 2H), 2.48, 2.50 (s, 6H), 2.64-2.84 (m, 3H), 3.07-3.32 (m, 3H), 3.75-3.89 (m, 1H), 7.29-7.58 (m, 8H), 8.95, 9.03 (s, 1H), 9.16, 9.71 (br s, 1H). 13C NMR (CDCl3) δ 13.64, 13.73, 22.31, 27.56, 27.79, 28.45, 28.67, 30.27, 36.57, 40.97, 44.19, 44.57, 53.14, 53.32, 53.83, 57.95, 61.40, 122.00, 122.64, 125.60, 126.28, 127.51, 127.95, 129.36, 131.40, 133.18, 135.89, 146.75, 157.91, 157.98, 163.50, 166.55, 166.74, 184.60. ES-MS m/z 564 (M+H). Anal. Calcd. for C32H36N5OF3.0.7H2O: C, 66.70; H, 6.54; N, 12.15; F, 9.89. Found: C, 66.73; H, 6.41; N, 12.01; F, 9.83.
EXAMPLE 260




COMPOUND 260: N-(3-{4-[1-Imino-2-(4-trifluoromethyl-phenyl)-indan-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.62-0.77 (m, 2H), 0.97 (d, 3H, J=5.4 Hz), 1.35-1.60 (m, 4H), 1.69-1.76 (m, 1H), 2.04-2.14 (m, 1H), 2.25, 2.27 (s, 3H), 2.43-2.54 (m, 1H), 2.51 (s, 3H), 2.64-2.76 (m, 4H), 3.22-3.32 (m, 2H), 3.80-3.87 (m, 1H), 6.89, 6.95 (d, 1H, J=6.6 Hz), 7.31-7.36 (m, 1H), 7.49-7.62 (m, 6H), 8.14, 8.20 (d, 1H, J=6.6 Hz), 9.00 (br s, 1H), 9.92 (br s, 1H). 13C NMR (CDCl3) δ 13.72, 15.61, 18.77, 27.56, 27.88, 28.33, 28.66, 30.90, 37.62, 40.50, 44.88, 52.93, 53.82, 57.99, 60.70, 122.11, 125.15, 125.61, 126.38, 127.60, 127.92, 133.10, 133.97, 137.25, 138.53, 145.98, 146.74, 147.55, 165.69, 165.79. ES-MS m/z 579 (M+H). Anal. Calcd. for C33H37N4O2F3.0.1H2O.0.5CH2Cl2: C, 64.59; H, 6.18; N, 8.99; F, 9.15. Found: C, 64.76; H, 6.23; N, 8.98; F, 9.05.
Scheme 14 describes the preparation of Examples 261-263, using general procedures E or F, and reagents listed below.















Example
R1COOH







261
3,5-dichloroisonicotinic acid


262
2,4-dimethyl-1-oxy-nicotinic acid


263
4,6-dimethyl-pyrimidine-5-carboxylic acid









EXAMPLE 261




COMPOUND 261: N-(3-{4-[2-(4-Bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide
A mixture of (4-bromophenyl)-piperidin-4-yl-methanone (536 mg, 2.00 mmol), catechol (880 mg, 8.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux with a Dean-Stark apparatus to remove water for 68 hours. Standard work-up and purification gave 4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidine (629 mg, 87%) as a yellow foam.
Using general procedure B with the above amine (400 mg, 1.11 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (482 mg, 2.22 mmol) and then using general procedure D gave 3-{4-[2-(4-bromophenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (284 mg, 59% over 2 steps) as a colorless oil.
COMPOUND 261 was isolated as a white foam. 1H NMR (CDCl3) δ 0.75-1.07 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.43-1.61 (m, 3H), 1.72-1.98 (m, 3H), 2.36 (t, 1H, J=11.7 Hz), 2.74 (d, 1H, J=10.5 Hz), 2.81-2.86 (m, 2H), 3.30 (t, 1H, J=12 Hz) 3.86-3.93 (m, 1H), 6.78-6.84 (m, 4H), 7.23 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 8.59 (s, 2H), 9.16 and 9.18 (br s, 1H). 13C NMR(CDCl3) δ 14.6, 27.1, 21.6, 31.4, 41.6, 44.9, 46.5, 53.4, 62.0, 110.0, 119.0, 122.9, 124.3, 128.7, 130.3, 132.6, 140.2, 144.5, 148.2, 148.3, 149.0, 163.0. ES-MS m/z 606 (M+H). Anal. Calcd. for C28H28BrCl2N3O3.0.3CH2Cl2.0.3C6H14: C, 55.05; H, 5.03; N, 6.40; Br, 12.17; Cl, 14.04. Found: C, 55.32; H, 4.80; N, 6.70; Br, 12.12; Cl, 13.75.
EXAMPLE 262




COMPOUND 262: N-(3-{4-[2-(4-Bromo-phenyl)-benzo [1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.96 (d, 3H, J=6.6 Hz), 1.01-1.29 (m, 2H), 1.51-1.65 (m, 2H), 1.71-1.84 (m, 1H), 1.91-2.03 (m, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 3.32-2.37 (m, 1H), 2.69-2.80 (m, 3H), 3.21-3.38 (m, 1H), 3.66-3.70 (m, 1H), 6.74-6.86 (m, 4H), 6.90 (d, 1H, J=6.6 Hz), 7.32 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 8.02 (d, 1H, J=6.6 Hz), 8.68 (br s, 1H). 13C NMR (CDCl3) δ 13.68, 15.46, 18.83, 26.20, 26.70, 32.17, 39.58, 44.73, 45.90, 52.01, 59.53, 108.92, 108.95, 118.38, 121.91, 123.30, 125.15, 127.93, 131.60, 134.28, 137.12, 138.47, 139.21, 145.98, 147.38, 147.43, 165.85. ES-MS m/z 580 (M+H). Anal. Calcd. for C30H34N3O4Br.1.5H2O: C, 59.31; H, 6.14; N, 6.92. Found: C, 59.28; H, 5.81; N, 6.62.
EXAMPLE 263




COMPOUND 263: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.71-1.08 (m, 2H), 0.93 (d, 3H, J=6.6 Hz), 1.44-1.59 (m, 2H), 1.65-1.79 (m, 1H), 1.82-1.99 (m, 3H), 2.32-2.39 (m, 1H), 2.50 (s, 6H), 2.65-2.78 (m, 3H), 3.21-3.29 (m, 1H), 3.82-3.91 (m, 1H), 6.74-6.93 (m, 4H), 7.24 (d, 2H, J=8.4 Hz), 7.46 (d, 2H, J=8.4 Hz), 8.77-8.78 (m, 1H), 9.04 (s, 1H). 13C NMR (CDCl3) δ 13.99, 22.68, 26.36, 27.00, 31.42, 40.95, 44.39, 45.98, 52.92, 61.46, 109.39, 109.47, 118.38, 122.31, 123.72, 128.16, 128.42, 132.08, 139.60, 147.68, 147.78, 158.43, 163.67, 167.27. ES-MS m/z 565 (M+H). Anal. Calcd. for C29H33N4O3Br.0.2H2O: C, 61.20; H, 5.92; N, 9.84. Found: C, 61.21; H, 5.97; N, 9.56.
Scheme 15 describes the preparation of Examples 264-270, using general procedures E or F, and reagents listed below.















Example
R1COOH







264
3,5-dichloroisonicotinic acid


265
2,4-dimethyl-1-oxy-nicotinic acid


266
4,6-dimethyl-pyrimidine-5-carboxylic acid


267
2,6-dimethylbenzoic acid


268
2,4-dimethylnicotinic acid


269
2-chloro-6-methylbenzoic acid


270
3,5-dimethylisonicotinic acid









EXAMPLE 264




COMPOUND 264: 3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A mixture of 4-(4-trifluorobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (357 mg, 1.00 mmol), catechol (440 mg, 4.00 mmol) and p-TsOH.H2O (380 mg, 2.00 mmol) in xylene (10 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 47 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine (164 mg, 47%) as a yellow foam.
Using general procedure B with the above amine (115 mg, 0.330 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (143 mg, 0.660 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (96 mg, 69% over 2 steps) as a colorless oil.
COMPOUND 264 was isolated as a white foam. 1H NMR (CDCl3) δ 0.77-1.15 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.48-1.59 (m, 3H), 1.70-1.82 (m, 1H), 2.37 (t, 1H, J=11.7 Hz), 2.74 (d, 1H, J=11.4 Hz), 2.81-2.88 (m, 2H), 3.30 (t, 1H, J=12 Hz), 3.86-3.94 (m, 1H), 6.78-6.87 (m, 4H), 7.50 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.4 Hz), 8.60 (s, 2H), 9.12 and 9.14 (br s, 1H). 13C NMR (CDCl3) δ 13.2, 25.7, 26.3, 30.1, 40.3, 43.6, 45.1, 52.0, 60.6, 108.7, 121.7, 123.9 (q, J=270.7 Hz), 125.1 (q, J=3.4 Hz), 126.1, 129.0, 130.9 (q, J=32.3 Hz), 143.2, 143.8, 146.76, 146.83, 147.6, 161.6. ES-MS m/z 595 (M+H). Anal. Calcd. for C29H28Cl2F3N3O3: C, 58.59; H, 4.75; N, 7.07; Cl, 11.93; F, 9.59. Found: C, 58.47; H, 4.77; N, 6.91; Cl, 11.96; F, 9.46.
EXAMPLE 265




COMPOUND 265: 2,4-Dimethyl-1-oxy-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide
White solid. 1H NMR (CDCl3) δ0.96 (d, 3H, J=6.6 Hz), 0.97-1.26 (m, 2H), 1.49-1.61 (m, 3H), 1.68-1.83 (m, 1H), 1.91-2.04 (m, 2H), 2.29 (s, 3H), 2.31-2.42 (m, 1H), 2.44 (s, 3H), 2.67-2.84 (m, 3H), 2.36-3.39 (m, 1H), 3.73-3.84 (m, 1H), 6.76-6.90 (m, 4H), 6.93 (d, 1H, J=6.6 Hz), 7.54-7.63 (m, 4H), 8.13 (d, 1H, J=6.6 Hz), 8.48 (br s, 1H). 13C NMR (CDCl3) δ 13.35, 15.02, 18.45, 25.80, 26.25, 32.07, 38.96, 44.52, 45.56, 51.44, 58.80, 108.58, 117.82, 121.60, 124.79, 123.92 (q, J=272 Hz), 125.06 (q, J=3 Hz), 126.30, 130.85 (q, J=32 Hz), 134.15, 136.87, 137.95, 143.78, 145.55, 146.93, 146.97, 165.43. ES-MS m/z 570 (M+H). Anal. Calcd. for C31H34N3O4F3.1.1H2O.0.1CH2Cl2: C, 62.47; H, 6.14; N, 7.03. Found: C, 62.66; H, 6.14; N, 7.12.
EXAMPLE 266




COMPOUND 266: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 0.74-1.12 (m, 2H), 0.95 (d, 3H, J=6.9 Hz), 1.42-1.58 (m, 3H), 1.66-1.81 (m, 1H), 1.86-1.99 (m, 2H), 2.33-2.43 (m, 1H), 2.52 (s, 6H), 2.65-2.86 (m, 3H), 3.22-3.33 (m, 1H), 3.86-3.97 (m, 1H), 6.76-6.83 (m, 2H), 6.84-6.91 (m, 1H), 6.93-6.99 (m, 1H), 7.51 (d, 2H, J=8.1 Hz), 7.62 (d, 2H, J=8.4 Hz), 8.76 (br s, 1H), 9.07 (s, 1H). 13C NMR (CDCl3) δ 13.20, 21.91, 25.52, 26.16, 30.68, 40.18, 43.59, 45.16, 52.14, 60.72, 108.68, 108.76, 117.32, 121.65, 123.89 (q, J=272 Hz), 125.17 (q, J=3 Hz), 126.12, 130.84, 130.93 (q, J=32 Hz), 143.72, 146.80, 146.90, 157.67, 162.93, 166.49. ES-MS m/z 555 (M+H). Anal. Calcd. for C30H33N4O3F3.0.15CH2Cl2: C, 63.80; H, 5.91; N, 9.87. Found: C, 63.86; H, 6.01; N, 9.54.
EXAMPLE 267




COMPOUND 267: 2,6-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-benzamide
White foam. 1H NMR (CDCl3) δ 0.94 (d, 3H, J=6.6 Hz), 0.95-1.06 (m, 1H), 1.13-1.26 (m, 1H), 1.44-1.78 (m, 4H), 1.88-1.99 (m, 2H), 2.28-2.38 (m, 1H), 2.31 (s, 6H), 2.67-2.79 (m, 3H), 3.25-3.35 (m, 1H), 3.73-3.83 (m, 1H), 6.76-6.79 (m, 4H), 7.04 (d, 2H, J=7.5 Hz), 7.16-7.21 (m, 1H), 7.49-7.60 (m, 5H). ES-MS m/z 553 (M+H).
EXAMPLE 268




COMPOUND 268: 2,4-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide
White foam. 1H NMR (CDCl3) δ 0.85-0.98 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 1.05-1.18 (m, 1H), 1.46-1.58 (m, 3H), 1.67-1.81 (m, 1H), 1.88-1.99 (m, 2H), 2.31 (s, 3H), 2.36 (t, 1H, J=12.3 Hz), 2.55 (s, 3H), 2.68-2.81 (m, 3H), 3.25-3.35 (m, 1H), 3.80-3.89 (m, 1H), 6.76-6.86 (m, 4H), 7.00 (d, 1H, J=5.1 Hz), 7.51 (d, 2H, J=8.1 Hz), 7.60 (d, 2H, J=8.4 Hz), 8.09 (br s, 1H), 8.43 (d, 1H, J=5.1 Hz). ES-MS m/z 554 (M+H).
EXAMPLE 269




COMPOUND 269: 2-Chloro-6-methyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-benzamide
White foam. 1H NMR (CDCl3) δ 0.90-1.03 (m, 1H), 0.93 (d, 3H, J=6.6 Hz), 1.10-1.23 (m, 1H), 1.46-1.59 (m, 3H), 1.68-1.80 (m, 1H), 1.87-1.90 (m, 2H), 2.29-2.37 (m, 1H), 2.35 (s, 3H), 2.70-2.84 (m, 3H), 3.25-3.35 (m, 1H), 3.75-3.85 (m, 1H), 6.73-6.79 (m, 4H), 7.10-7.22 (m, 3H), 7.51 (d, 2H, J=8.1 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.97 (br s, 1H). ES-MS m/z 573 (M+H).
EXAMPLE 270




COMPOUND 270: 3,5-Dimethyl-N-(3-{4-[2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
White foam. 1H NMR (CDCl3) δ 0.94 (d, 3H, J=6.6 Hz), 0.79-0.92 (m, 1H), 1.01-1.51 (m, 1H), 1.42-1.59 (m, 2H), 1.66-1.80 (m, 2H), 1.88-1.99 (m, 1H), 2.29 (s, 6H), 2.36 (t, 1H, J=11.4 Hz), 2.67-2.81 (m, 3H), 3.23-3.30 (m, 1H), 3.80-3.90 (m, 1H), 6.75-6.89 (m, 4H), 7.51 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.4 Hz), 8.32 (br s, 1H), 8.38 (s, 2H). ES-MS m/z 554 (M+H).
EXAMPLE 271




COMPOUND 271: 3,5-Dichloro-N-(3-{4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (335 mg, 1.0 mmol), catechol (440 mg, 4.00 mmol) and p-TsOH.H2O (380 mg, 2.00 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 45 hours. Standard work-up and purification gave 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (286 mg, 87%).
Using general procedure B with the above amine (65 mg, 0.20 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (86 mg, 0.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (42 mg, 53% over 2 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (41 mg, 0.21 mmol) and the above amine (42 mg, 0.11 mmol) gave COMPOUND 271 as a white solid (57 mg, 93%). 1H NMR (CDCl3) δ 0.79-1.04 (m, 2H), 0.95 (d, 3H, J=6.3 Hz), 1.41-1.94 (m, 6H), 2.37 (t, 1H, J=12.0 Hz), 2.46 (s, 3H), 2.73-2.88 (m, 3H), 3.30 (t, 1H, J=12.0 Hz), 3.89 (m, 1H), 6.77-6.85 (m, 4H), 7.19 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=7.4 Hz), 8.59 (s, 2H), 9.24 (br s, 1H). 13C NMR (CDCl3) δ 13.58, 15.81, 26.13, 26.70, 30.41, 40.66, 44.01, 45.57, 52.50, 61.05, 108.97, 118.43, 121.79, 126.10, 126.41, 129.30, 136.70, 139.81, 143.51, 147.45, 147.54, 148.03, 162.05. ES-MS m/z 573 (M+2). Anal. Calcd. for C29H31N3Cl2O3S.0.5CH2Cl2: C, 57.61; H, 5.24; N, 6.83. Found: C, 57.43; H, 5.27; N, 6.78.
EXAMPLE 272




COMPOUND 272: 3,5-Dichloro-N-(3-{4-[2-(4-methanesulfinyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine (see EXAMPLE 271) (220 mg, 0.673 mmol), Boc2O (161 mg, 0.74 mmol) and Et3N (0.14 mL, 1.01 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 1.5 hours. Standard work-up and purification afforded 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (270 mg, 94%).
To the above thiol (270 mg, 0.632 mmol) in Et2O (5 mL) cooled to 0° C. was added hydrogen peroxide (50%, 0.22 mL, 3.16 mmol) and the mixture was stirred at 0° C. for 2.5 hours. Work-up and purification afforded 4-[2-(4-methanesulfinyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (283 mg, 100%).
Using general procedure C with the above carbamate (116 mg, 0.26 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (114 mg, 0.53 mmol) and then using general procedure D afforded 3-{4-[2-(4-methanesulfinyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (80 mg, 74% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (74 mg, 0.39 mmol) and the above amine (80 mg, 0.19 mmol) gave COMPOUND 272 as a white solid (99 mg, 86%). 1H NMR (CDCl3) δ 0.80-1.12 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.48-1.60 (m, 3H), 1.72-1.98 (m, 3H), 2.37 (t, 1H, J=11.4 Hz), 2.69 (s, 3H), 2.73-2.87 (m, 3H), 3.30 (t, 1H, J=11.4 Hz), 3.86-3.92 (m, 1H), 6.78-6.88 (m, 4H), 7.53 (d, 2H, J=8.4 Hz), 6.62 (d, 2H, J=8.4 Hz), 8.59 (s, 2H), 9.13 (br s, 1H). 13C NMR (CDCl3) δ 13.62, 26.06, 26.62, 30.51, 31.98, 40.58, 44.02, 44.19, 45.57, 52.33, 60.89, 109.09, 117.91, 122.03, 123.82, 127.11, 129.34, 143.50, 146.69, 147.20, 147.28, 148.01, 161.99. ES-MS m/z 588 (M+H). Anal. Calcd. for C29H31N3Cl2O4S.0.96CH2Cl2: C, 53.70, H, 4.95; N, 6.27; Cl, 20.74; S, 4.78. Found: C, 53.44; H, 4.89; N, 6.28; Cl, 20.56; S, 4.65.
EXAMPLE 273




COMPOUND 273: 3,5-Dichloro-N-(3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
To 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 272) (166 mg, 0.375 mmol) in MeOH (5 mL) cooled to 0° C. was added OXONE® (461 mg, 0.75 mmol) and the mixture was stirred at room temperature for 2 hours. A second aliquot of OXONE® (461 mg, 0.75 mmol) was added and the mixture stirred at room temperature for 24 hours. Standard work-up gave 4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (172 mg, 100%).
Using general procedure C with the above carbamate (170 mg, 0.37 mmol), then using general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) followed by general procedure D gave 3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (46 mg, 68% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (41 mg, 0.21 mmol) and the above amine (46 mg, 0.11 mmol) gave COMPOUND 273 as a white solid (55 mg, 85%). 1H NMR (CDCl3) δ 0.84-1.08 (m, 2H), 0.96 (d, 3H, J=6.0 Hz), 1.41-1.59 (m, 3H), 1.75-1.98 (m, 3H), 2.38 (t, 1H, J=11.1 Hz), 2.74-2.85 (m, 3H), 3.02 (s, 3H), 3.31 (t, 1H, J=12.0 Hz), 3.88 (m, 1H), 6.80-6.88 (m, 4H), 7.59 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 8.60 (s, 2H), 9.09 (br s, 1H). 13C NMR (CDCl3) δ 13.20, 25.56, 26.15, 30.10, 40.20, 43.55, 44.38, 44.98, 51.93, 60.57, 108.82, 117.13, 121.82, 126.82, 127.30, 128.97, 140.91, 143.14, 145.95, 146.62, 146.68, 147.63, 161.59. ES-MS m/z 606 (M+3). Anal. Calcd. for C29H31N3Cl2O5S.0.1CH2Cl2: C, 52.26; H, 4.82; N, 6.09; Cl, 20.57; S, 4.65. Found: C, 52.23; H, 4.79; N, 6.05; Cl, 20.85; S, 4.54.
EXAMPLE 274




COMPOUND 274: N-(3-{4-[2-(4-Methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
Using general procedure E, 3-{4-[2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 273) (139 mg, 0.32 mmol) and 2,4-dimethylnicotinic acid (53 mg, 0.35 mmol) afforded COMPOUND 274 as a white solid (59 mg, 32%). 1H NMR (CDCl3) δ 0.84-1.19 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.45-1.62 (m, 3H), 1.66-1.79 (m, 1H), 1.89-1.99 (m, 2H), 2.31 (s, 3H), 2.36 (t, 1H, J=11.7 Hz), 2.54 (s, 3H), 2.68-2.81 (m, 3H), 3.02 (s, 3H), 3.26-3.34 (m, 1H), 3.49 (s, 2H), 3.80-3.89 (m, 1H), 6.78-6.88 (m, 3H), 7.00 (d, 1H, J=4.8 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.91 (d, 2H, J=7.8 Hz), 8.05 (br s, 1H), 8.42 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.58, 19.20, 22.67, 25.88, 26.50, 31.68, 40.00, 44.24, 44.80, 45.65, 52.34, 60.55, 109.09, 117.67, 122.11, 122.92, 127.29, 127.63, 134.00, 141.22, 144.09, 146.41, 147.20, 149.23, 154.55, 168.70. ES-MS m/z 564 (M+H). Anal. Calcd. for C31H37N3O5S.1.0CH2Cl2.0.3H2O: C, 58.77; H, 6.10; N, 6.42. Found: C, 58.42; H, 5.79; N, 6.37.
EXAMPLE 275




COMPOUND 275: 3,5-Dichloro-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 247) (373 mg, 1.0 mmol), catechol (440 mg, 4.0 mmol) and p-TsOH.H2O (380 mg, 2.0 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 44 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (260 mg, 71%).
Using general procedure B with the above amine (260 mg, 0.712 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (309 mg, 1.42 mmol) and then using general procedure D gave 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (193 mg, 63% over 2 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (62 mg, 0.32 mmol) and the above amine (75 mg, 0.16 mmol) gave COMPOUND 275 as a white solid (68 mg, 64%). 1H NMR (CDCl3) δ 0.78-1.10 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.48-1.61 (m, 3H), 1.73-1.99 (m, 3H), 2.38 (t, 1H, J=11.1 Hz), 2.73-2.87 (m, 3H), 3.31 (t, 1H, J=11.1 Hz), 3.86-3.93 (m, 1H), 6.78-6.86 (m, 4H), 7.17 (d, 2H, J=8.1 Hz), 7.40 (d, 2H, J=8.4 Hz), 8.59 (s, 2H), 9.18 (br s, 1H). 13C NMR (CDCl3) δ 13.60, 26.08, 26.66, 30.41, 40.71, 43.98, 45.65, 52.43, 61.03, 109.07, 117.94, 120.76 (q, J=258 Hz), 120.85, 121.98, 127.61, 129.34, 138.84, 143.55, 147.24, 147.32, 148.02, 149.79, 162.01. ES-MS m/z 611 (M+H). Anal. Calcd. for C29H28N3Cl2O4F3.0.3CH2Cl2.0.2C6H14: C, 56.09; H, 4.85; N, 6.43; Cl, 14.11; F, 8.73. Found: C, 56.15; H, 4.60; N, 6.57; Cl, 14.06; F, 8.73.
EXAMPLE 276




COMPOUND 276: 2,4-Dimethyl-N-(3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-nicotinamide
Using general procedure E, 3-{4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 275) (135 mg, 0.31 mmol) and 2,4-dimethylnicotinic acid (51 mg, 0.34 mmol) afforded COMPOUND 276 (55 mg, 31%). 1H NMR (CDCl3) δ 0.83-1.17 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.46-1.63 (m, 3H), 1.67-1.80 (m, 1H), 1.86-1.99 (m, 2H), 2.31 (s, 3H), 2.33-2.40 (m, 1H), 2.54 (s, 3H), 2.67-2.81 (m, 3H), 3.25-3.35 (m, 1H), 3.79-3.89 (m, 1H), 6.76-6.86 (m, 4H), 6.99 (d, 1H, J=5.1 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.40-7.44 (m, 2H), 8.11 (br s, 1H), 8.42 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.57, 19.19, 22.63, 25.94, 26.56, 31.64, 40.02, 44.32, 45.92, 52.42, 60.54, 108.92, 118.07, 120.78, 121.86, 122.91, 127.68, 133.99, 138.89, 144.02, 147.35, 149.21, 149.76, 154.55, 168.73. ES-MS m/z 570 (M+H). Anal. Calcd. for C31H34N3F3O4.0.28CH2Cl2: C, 63.31; H, 5.87; N, 7.08. Found: C, 63.01; H, 5.88; N, 7.47.
EXAMPLE 277




COMPOUND 277: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
4-(4-Bromo-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (5.3 g, 13 mmol), catechol (5.73 g, 52 mmol), p-TsOH.H2O (4.95 g, 26 mmol) and xylene (65 mL) were heated at 180° C. for 24 hours using a Dean-Stark apparatus to remove water. Work-up and purification gave the desired amine.
The above secondary amine (4.92 g), Boc2O (4.48 g, 20.49 mmol), Et3N (2.85 mL, 20.49 mmol) and THF (46 mL) were stirred at room temperature for 2.5 hours. Standard work-up and purification afforded 4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (4.06 g, 68% over 2 steps).
The above bromide (2.0 g, 4.34 mmol), Zn(CN)2 (306 mg, 2.60 mmol), DPPF (240 mg, 0.43 mmol) and degassed DMF (22 mL) were flushed with N2. Pd2(dba)3 (199 mg, 0.22 mmol) was added and the mixture was flushed with N2 for an additional 5 minutes. The reaction mixture was heated at 130° C. overnight to afford 4-[2-(4-cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (1.49 g, 85%) after work-up and purification.
Using general procedure C with the above substrate (1.49 g, 3.67 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (1.09 g, 5.02 mmol) and then using general procedure D afforded 4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-benzonitrile as a colourless oil (370 mg, 37% over 3 steps).
Using general procedure E, the above amine (99 mg, 0.26 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (44 mg, 0.29 mmol) afforded COMPOUND 277 as a white foam (120 mg, 89%). 1H NMR (CDCl3) δ 0.74-1.11 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.41-1.55 (m, 3H), 1.67-1.81 (m, 1H), 1.86-1.99 (m, 2H), 2.34-2.44 (m, 1H), 2.52 (s, 6H), 2.67-2.82 (m, 3H), 3.23-3.30 (m, 1H), 3.86-3.94 (m, 1H), 6.77-6.83 (m, 2H), 6.86-6.90 (m, 1H), 6.94-6.97 (m, 1H), 7.51 (d, 2H, J=7.8 Hz), 7.65 (d, 2H, J=8.1 Hz), 8.68-8.70 (m, 1H), 9.06 (s, 1H). ES-MS m/z 512 (M+H).
EXAMPLE 278




COMPOUND 278: N-(3-{4-[2-(4-Cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-benzonitrile (see EXAMPLE 277) (96 mg, 0.25 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (47 mg, 0.28 mmol) afforded COMPOUND 278 as a white foam (126 mg, 94%). 1H NMR (CDCl3) δ 0.90-1.23 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.51-1.82 (m, 3H), 1.91-2.03 (m, 2H), 2.29 (s, 3H), 2.32-2.40 (m, 1H), 2.43 (s, 3H), 2.69-2.82 (m, 3H), 3.28-3.38 (m, 1H), 3.72-3.82 (m, 1H), 6.77-6.88 (m, 4H), 6.94 (d, 1H, J=6.6 Hz), 7.55-7.58 (m, 2H), 7.63-7.66 (m, 2H), 8.12 (d, 1H, J=6.6 Hz), 8.40 (br s, 1H). ES-MS m/z 527 (M+H).
EXAMPLE 279




COMPOUND 279: N-(3-{4-[2-(4-Cyano-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure E, 4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-benzonitrile (see EXAMPLE 277) (64 mg, 0.17 mmol) and 2,6-dimethylbenzoic acid (28 mg, 0.19 mmol) afforded COMPOUND 279 as a white foam (65 mg, 75%). 1H NMR (CDCl3) δ0.93 (d, 3H, J=6.6 Hz), 0.94-1.23 (m, 2H), 1.42-1.58 (m, 3H), 1.65-1.78 (m, 1H), 1.86-1.98 (m, 2H), 2.28-2.36 (m, 1H), 2.31 (s, 6H), 2.68-2.79 (m, 3H), 3.26-3.36 (m, 1H), 3.71-3.82 (m, 1H), 6.76-6.80 (m, 4H), 7.03 (d, 2H, J=7.8 Hz), 7.15-7.20 (m, 1H), 7.43 (br s, 1H), 7.51-7.53 (m, 2H), 7.61-7.64 (m, 2H). ES-MS m/z 510 (M+H).
EXAMPLE 280




COMPOUND 280: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-chloro-phenyl)-benzo [1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
To a solution of 4-bromochlorobenzene (1.35 g, 7.03 mmol) in THF (30 mL) cooled to −78° C. was added n-BuLi (2.5M in THF, 3.00 mL, 7.5 mmol) and the mixture was stirred at −78° C. for 30 minutes. TMEDA (1.06 mL, 7.02 mmol) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol) in THF (10 mL) were added and the mixture stirred at −78° C. for 3 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and after work-up and purification afforded 4-[(4-chloro-phenyl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (450 mg, 30%).
A mixture of the above alcohol (450 mg, 1.38 mmol), SiO2 (1.50 g) and PCC (895 mg, 4.15 mmol) in CH2Cl2 (25 mL) was stirred at room temperature for 1 hour to afford 4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (440 mg, 99%) after purification.
The above ketone (450 mg, 1.39 mmol), catechol (614 mg, 5.58 mmol), p-TsOH.H2O (529 mg, 2.78 mmol), toluene (5 mL) and xylene (15 mL) were heated at 185° C. overnight using a Dean-Stark apparatus to remove water. Work-up and purification afforded 4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pink oil (221 mg, 50%).
Using general procedure B with the above amine (221 mg, 0.70 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (305 mg, 1.40 mmol) and then using general procedure D afforded 3-{4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (185 mg, 68% over 2 steps).
Using general procedure E, the above amine (86 mg, 0.22 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (37 mg, 0.24 mmol) afforded COMPOUND 280 as a white foam (100 mg, 86%). 1H NMR (CDCl3) δ 0.71-0.85 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 0.96-1.09 (m, 1H), 1.45-1.61 (m, 3H), 1.67-1.80 (m, 1H), 1.85-1.98 (m, 2H), 2.37 (td, 1H, J=11.4, 2.1 Hz), 2.51 (s, 6H), 2.67-2.83 (m, 3H), 3.22-3.32 (m, 1H), 3.86-3.95 (m, 1H), 6.75-6.81 (m, 2H), 6.82-6.88 (m, 1H), 6.91-6.95 (m, 1H), 7.29-7.33 (m, 4H), 8.76-8.78 (m, 1H), 9.06 (s, 1H). 13C NMR (CDCl3) δ 13.58, 22.29, 25.97, 26.63, 30.99, 40.61, 43.97, 45.64, 52.59, 61.16, 108.99, 109.08, 117.95, 121.90, 127.44, 128.73, 158.06, 163.28. ES-MS m/z 521 (M+H). Anal. Calcd. for C29H33N4ClO3.0.05CH2Cl2: C, 66.42; H, 6.35; N, 10.67. Found: C, 66.32; H, 6.43; N, 10.49.
EXAMPLE 281




COMPOUND 281: N-(3-{4-[2-(4-Chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Using general procedure E, 3-{4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 280) (86 mg, 0.22 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (41 mg, 0.25 mmol) afforded COMPOUND 281 as a white foam (63 mg, 53%). 1H NMR (CDCl3) δ 0.87-1.00 (m, 1H), 0.95 (d, 3H, J=6.6 Hz), 1.06-1.19 (m, 1H), 1.50-1.81 (m, 4H), 1.89-2.02 (m, 2H), 2.28 (s, 3H), 2.37 (td, 1H, J=12.0, 1.8 Hz), 2.46 (s, 3H), 2.68-2.81 (m, 3H), 3.26-3.36 (m, 1H), 3.76-3.86 (m, 1H), 6.76-6.88 (m, 4H), 6.93 (d, 1H, J=6.6 Hz), 7.29-7.38 (m, 4H), 8.15 (d, 1H, J=6.6 Hz), 8.45 (br s, 1H). 13C NMR (CDCl3) δ 13.59, 15.58, 18.78, 26.11, 26.73, 31.53, 40.12, 44.32, 45.80, 52.40, 60.42, 108.96, 109.03, 111.56, 121.93, 125.04, 127.56, 128.69, 133.34, 138.75, 165.91. ES-MS m/z 536 (M+H). Anal. Calcd. for C30H34N3ClO4.0.2CH2Cl2: C, 65.59; H, 6.27; N, 7.60. Found: C, 65.73; H, 6.55; N, 7.45.
EXAMPLE 282




COMPOUND 282: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-acetyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
To a solution of 4-[2-(4-bromo-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 277) (742 mg, 1.61 mmol) in Et2O (20 mL) cooled to −78° C. was added BuLi (2.5M in Hexanes, 0.80 mL, 2.0 mmol) and the mixture was stirred at −10° C. for 1 hour. The mixture was cooled to −78° C., acetaldehyde (0.5 mL) was added and the mixture was warmed to room temperature and stirred for 30 minutes. Work-up and purification gave the desired substrate. To the substrate in CH2Cl2 (3 mL) were added H20 (2 drops) and TFA (1 mL) and the mixture was stirred at room temperature for 1 hour to afford 1-[4-(2-piperidin-4-yl-benzo[1,3]dioxol-2-yl)-phenyl]-ethanol as a pale yellow solid (170 mg, 32% over 2 steps) after basic work-up and purification.
Using general procedure B with the above amine (166 mg, 0.510 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (222 mg, 1.03 mmol) and then using general procedure D afforded 1-(4-{2-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-2-yl}-phenyl)-ethanol as a colourless oil (139 mg, 69% over 2 steps).
Using general procedure E, the above amine (139 mg, 0.351 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (59 mg, 0.38 mmol) afforded the desired amide, which was subsequently oxidized with MnO2 (1.05 g, 12.1 mmol) to afford COMPOUND 282 as a white solid (86 mg, 52% over 2 steps) following filtration through Celite® and purification. 1H NMR (CDCl3) δ 0.76-1.10 (m, 2H), 0.94 (d, 3H, J=6.6 Hz), 1.44-1.61 (m, 3H), 1.94 (t, 2H, J=11.7 Hz), 2.38 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.58 (s, 3H), 2.67-2.80 (m, 3H), 3.23-3.31 (m, 1H), 3.86-3.93 (m, 1H), 6.78-6.79 (m, 2H), 6.86-6.87 (m, 1H), 6.94-6.97 (m, 1H), 7.48 (d, 2H, J=8.1 Hz), 7.93 (d, 2H, J=8.1 Hz), 8.75-8.77 (m, 1H), 9.07 (s, 1H). 13C NMR (CDCl3) δ 13.39, 22.10, 25.74, 26.36, 26.90, 30.87, 40.37, 43.79, 45.30, 52.35, 60.93, 108.83, 108.92, 117.74, 121.79, 126.13, 128.37, 131.02, 137.52, 144.87, 147.07, 147.17, 157.86, 163.11, 166.69, 197.84. ES-MS m/z 529 (M+H). Anal. Calcd. for C31H36N4O4.0.15CH2Cl2: C, 69.11; H, 6.76; N, 10.35. Found: C, 69.08; H, 6.83; N, 10.32.
EXAMPLE 283




COMPOUND 283: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{2-[4-(1-methoxyimino-ethyl)-phenyl]-benzo[1,3]dioxol-2-yl}-piperidin-1-yl)-butyl]-amide
To a solution of COMPOUND 282 (47 mg, 0.089 mmol) in MeOH (4 mL) was added methoxylamine hydrochloride (19 mg, 0.22 mmol) and NaOAc (21 mg, 0.25 mmol) and the mixture was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 283 as a white solid (38 mg, 75%). 1H NMR (CDCl3) δ 0.76-0.81 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 1.01-1.06 (m, 1H), 1.45-1.75 (m, 4H), 1.88-1.96 (m, 2H), 2.19 (s, 3H), 2.37 (t, 1H, J=10.7 Hz), 2.51 (s, 6H), 2.66-2.82 (m, 3H), 3.22-3.30 (m, 1H), 3.84-3.94 (m, 1H), 3.98 (s, 3H), 6.75-6.78 (m, 2H), 6.84-6.87 (m, 1H), 6.93-6.96 (m, 1H), 7.37 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 8.82-8.83 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 12.63, 13.18, 21.54, 21.89, 25.60, 26.25, 30.62, 40.22, 43.57, 45.17, 52.24, 60.78, 61.77, 62.00, 108.53, 108.63, 117.87, 121.39, 125.35, 125.69, 125.79, 127.78, 130.82, 137.07, 140.48, 147.05, 147.16, 154.18, 157.68, 162.88, 166.51. ES-MS m/z 558 (M+H). Anal. Calcd. for C32H39N5O4.0.15CH2Cl2: C, 67.70; H, 6.94; N, 12.28. Found: C, 67.71; H, 7.06; N, 12.16.
EXAMPLE 284




COMPOUND 284: N-(3-{4-[2-(4-Methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
To a solution of 4-bromoanisole (5.00 g, 26.70 mmol) in THF (100 mL) at −78° C. was added n-BuLi (1.9M in hexanes, 14 mL, 26.7 mmol). After the solution was stirred at −78° C. for 45 minutes, TMEDA (4.03 mL, 26.7 mmol) was added followed by a solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (4.76 g, 22.3 mmol) in THF (20 mL), and the mixture was stirred at −78° C. for 1 hour. The reaction was quenched with saturated aqueous NH4Cl and after work-up and purification gave 4-[hydroxy-(4-methoxy-phenyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (3.40 g, 47%) as a white foam.
To a solution of the above alcohol (3.40 g, 10.6 mmol) in CH2Cl2 (50 mL) at room temperature was added SiO2 (13.60 g) and PCC (6.84 g, 31.70 mmol). The resulting mixture was stirred under N2 for 2 hours to afford 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (3.00 g, 88%) after purification.
A solution of the above ketone (957 mg, 3.00 mmol), catechol (660 mg, 6.00 mmol) and p-TsOH.H2O (1.14 g, 6.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 24 hours. Standard work-up and purification gave 4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (335 mg, 36%).
Using general procedure B with the above amine (335 mg, 1.02 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (837 mg, 2.56 mmol) and then using general procedure D afforded 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a colourless oil (240 mg, 62% over 2 steps).
Using general procedure E, the above amine (50 mg, 0.13 mmol) and 2,4-dimethylnicotinic acid (24 mg, 0.16 mmol) afforded COMPOUND 284 as a white solid (45 mg, 66%). 1H NMR (CDCl3) δ 0.84-0.93 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 1.02-1.15 (m, 1H), 1.46-1.61 (m, 3H), 1.66-1.79 (m, 1H), 1.86-1.98 (m, 2H), 2.31 (s, 3H), 2.35 (td, 1H, J=12.0, 2.1 Hz), 2.54 (s, 3H), 2.66-2.81 (m, 3H), 3.24-3.34 (m, 1H), 3.79 (s, 3H), 3.81-3.90 (m, 1H), 6.73-6.86 (m, 6H), 6.99 (d, 1H, J=5.1 Hz), 7.28-7.31 (m, 2H), 8.19 (br s, 1H), 8.43 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.36, 18.98, 22.42, 25.86, 26.49, 31.36, 39.87, 44.14, 45.83, 52.33, 55.44, 60.39, 108.54, 113.52, 118.64, 121.35, 122.73, 127.05, 132.05, 133.77, 143.73, 147.47, 147.56, 149.00, 154.31, 159.93, 168.55. ES-MS m/z 516 (M+H). Anal. Calcd. for C31H37N3O4.0.1CH2Cl2: C, 71.27; H, 7.15; N, 8.02. Found: C, 71.13; H, 7.25; N, 8.00.
EXAMPLE 285




COMPOUND 285: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-amide
Using general procedure E, 3-{4-[2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 284) (50 mg, 0.13 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (24 mg, 0.16 mmol) afforded COMPOUND 285 as a white solid (42 mg, 63%). 1H NMR (CDCl3) δ 0.70-0.84 (m, 1H), 0.94 (d, 3H, J=6.6 Hz), 0.95-1.08 (m, 1H), 1.45-1.63 (m, 3H), 1.66-1.80 (m, 1H), 1.86-1.98 (m, 2H), 2.38 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.66-2.84 (m, 3H), 3.22-3.31 (m, 1H), 3.79 (s, 3H), 3.87-3.97 (m, 1H), 6.74-6.79 (m, 2H), 6.83-6.88 (m, 3H), 6.91-6.94 (m, 1H), 7.29 (d, 2H, J=9.0 Hz), 8.86-8.88 (m, 1H), 9.08 (s, 1H). 13C NMR (CDCl3) δ 13.37, 22.07, 25.89, 26.55, 30.77, 40.43, 43.83, 45.63, 52.47, 55.45, 60.96, 108.65, 108.73, 113.61, 118.42, 121.44, 126.99, 131.00, 131.96, 147.38, 147.50, 157.84, 159.96, 163.05, 166.71. ES-MS m/z 517 (M+H). Anal. Calcd. for C30H36N4O4.0.1CH2Cl2: C, 68.85; H, 6.95; N, 10.67. Found: C, 69.00; H, 7.03; N, 10.76.
EXAMPLE 286




COMPOUND 286: 3,5-Dichloro-N-(3-{4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-(4-trifluorobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (179 mg, 0.50 mmol), 4-fluorocatechol (275 mg, 2.00 mmol) and p-TsOH.H2O (190 mg, 1.00 mmol) in xylene (5 mL) was heated at reflux under a Dean-Stark trap for 64.5 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (59 mg, 32%).
Using general procedure B with the above amine (59 mg, 0.16 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (70 mg, 0.32 mmol) and then using general procedure D gave 3-{4-[5-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (35 mg, 51% over 2 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (31.6 mg, 0.164 mmol) and the above amine (36 mg) gave COMPOUND 286 as a white solid (41 mg, 82%). 1H NMR (CDCl3) δ 0.84-1.08 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.48-1.98 (m, 6H), 2.37 (t, 1H, J=11.4 Hz), 2.74-2.88 (m, 3H), 3.31 (t, 1H, J=11.4 Hz), 3.89 (m, 1H), 6.48 (m, 1H), 6.57-6.66 (m, 1H), 6.69-6.81 (m, 1H), 7.47 (d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.1 Hz), 8.59 (s, 2H), 9.10 (br s, 1H). 13C NMR (CDCl3) δ 13.21, 25.56, 25.66, 26.13, 26.26, 30.06, 30.93, 40.28, 43.54, 45.06, 51.95, 53.45, 60.62, 98.21 (d, J=27 Hz), 106.92 (d, J=24 Hz), 108.08 (d, J=10 Hz), 118.94, 121.69, 123.82 (d, J=272 Hz), 125.20, 125.24, 126.05, 128.41, 131.13 (q, J=33 Hz), 143.17, 143.29, 147.27, 147.61, 157.92 (d, J=239 Hz), 161.57. ES-MS m/z 612 (M+H). Anal. Calcd. for C29H27N3Cl2O3F4.0.2CH2Cl2.0.1C6H14: C, 56.10; H, 4.55; N, 6.59; Cl, 13.34; F, 11.91. Found: C, 56.22; H, 4.50; N, 6.48; Cl, 13.05; F, 11.59.
EXAMPLE 287




COMPOUND 287: 3,5-Dichloro-N-(3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-(4-trifluorobenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (357 mg, 1.00 mmol), 3-fluorocatechol (512 mg, 4.00 mmol) and p-TsOH.H2O (380 mg, 2.00 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 43 hours. Standard work-up and purification gave 4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (18 mg, 3%).
Using general procedure B with the above amine (18 mg, 0.049 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (21 mg, 0.098 mmol) and then using general procedure D afforded 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (11 mg, 52% over 2 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (12 mg, 0.063 mmol) and the above amine (11 mg, 0.025 mmol) gave COMPOUND 287 as a white solid (10 mg, 63%). 1H NMR (CDCl3) δ 0.84-1.07 (m, 2H), 0.95 (d, 3H, J=6.6 Hz), 1.44-1.79 (m, 5H), 1.94-2.04 (m, 1H), 2.33-2.43 (m, 1H), 2.69-2.85 (m, 3H), 3.31 (t, 1H, J=11.7 Hz), 3.86-3.93 (m, 1H), 6.60-6.79 (m, 3H), 7.51 (d, 2H, J=8.1 Hz), 7.62 (d, 2H, J=8.4 Hz), 8.59 (s, 2H), 8.90, 9.01 (m, 1H). 13C NMR (CDCl3) δ 13.19, 25.48, 25.82, 26.07, 26.41, 30.17, 30.36, 40.19, 40.26, 43.54, 45.09, 51.93, 52.05, 60.61, 104.90, 110.36 (d, J=16 Hz), 119.47, 121.89 (d, J=7 Hz), 125.23, 125.61, 126.08, 126.37, 128.93, 131.24 (d, J=32 Hz), 133.35, 133.53, 142.99, 143.09, 146.36 (d, J=246 Hz), 147.67, 149.44, 161.61. ES-MS m/z 612 (M+H). Anal. Calcd. for C29H27N3Cl2O3F4.0.2C6H14: C, 57.61; H, 4.77; N, 6.67. Found: C, 57.59; H, 4.73; N, 6.58.
EXAMPLE 288




COMPOUND 288: 3,5-Dichloro-N-(3-{4-[5-fluoro-2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-isonicotinamide
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (168 mg, 0.50 mmol), 4-fluorocatechol (128 mg, 2.0 mmol) and p-TsOH.H2O (190 mg, 1.0 mmol) in xylene (50 mL) was heated at reflux under a Dean-Stark trap for 41 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (58 mg, 34%).
A solution of the above thiol (29 mg, 0.084 mmol), Boc2O (20 mg, 0.092 mmol) and Et3N (18 μL, 0.13 mmol) in CH2Cl2 (0.5 mL) was stirred at room temperature for 1 hour. Work-up and purification afforded 4-[5-fluoro-2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (36 mg, 97%).
To the above thiol (36 mg, 0.082 mmol) in Et2O (1 mL) cooled to 0° C. was added hydrogen peroxide (50%, 28 μL, 0.82 mmol) and the mixture was stirred at 0° C. for 2 hours. Work-up and purification afforded a white solid (35 mg, 90%).
To the above sulfoxide (35 mg, 0.076 mmol) in MeOH (1 mL) cooled to 0° C. was added OXONE® (186 mg, 0.303 mmol) and the mixture was stirred at room temperature for 21 hours. Work-up and purification gave 4-[5-fluoro-2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (36 mg, 100%).
Using general procedure C with the above carbamate (36 mg, 0.075 mmol), and then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (32 mg, 0.15 mmol) and then using general procedure D gave 3-{4-[5-fluoro-2-(4-methanesulfonyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (24 mg, 85% over 3 steps).
Using general procedure F, 3,5-dichloroisonicotinic acid (27 mg, 0.14 mmol) and the above amine (18 mg, 0.047 mmol) gave COMPOUND 288 as a white solid (25 mg, 100%). 1H NMR (CDCl3) δ 0.85-1.05 (m, 2H), 0.96 (d, 3H, J=6.3 Hz), 1.44-1.62 (m, 3H), 1.76-1.96 (m, 3H), 2.37 (m, 1H), 2.75-2.85 (m, 3H), 3.03 (s, 3H), 3.32 (t, 1H, J=11.7 Hz), 3.87 (m, 1H), 6.46-6.52 (m, 1H), 6.58-6.66 (m, 1H), 6.71-6.79 (m, 1H), 7.56 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.1 Hz), 8.58 (s, 2H), 9.04 (br s, 1H). 13C NMR (CDCl3) δ 13.60, 25.98, 26.45, 40.62, 43.91, 44.76, 45.35, 52.26, 60.95, 98.69 (d, J=28 Hz), 107.48 (d, J=24 Hz), 108.61 (d, J=7 Hz), 119.08, 127.14, 127.77, 129.40, 141.53, 143.35, 143.55, 145.87, 147.64, 148.00, 158.36 (d, J=239 Hz), 161.95. ES-MS m/z 623 (M+2). Anal. Calcd. for C29H30N3Cl2O5FS.0.8CH2Cl2: C, 51.84; H, 4.61; N, 6.09. Found: C, 51.79; H, 4.61; N, 5.98.
EXAMPLE 289




COMPOUND 289: N-(3-{4-[5-Fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
A solution of 4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 284) (638 mg, 2.00 mmol), 4-fluorocatechol (512 mg, 4.00 mmol) and p-TsOH.H2O (760 mg, 4.00 mmol) in xylene (20 mL) was heated at reflux using a Dean-Stark apparatus to remove water for 52 hours. Standard work-up and purification gave 4-[5-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pale yellow oil (220 mg, 33%).
Using general procedure I the above amine (220 mg, 0.669 mmol) afforded the nitrile, which was subsequently reduced with BH3-THF (1.0M in THF, 1.72 mL, 1.72 mmol) in THF (4 mL) at reflux and treated with ethylenediamine (1.5 mL) to give 3-{4-[5-fluoro-2-(4-methoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidin-1-yl}-butylamine as a white solid (169 mg, 74%) following work-up and purification.
Using general procedure E, the above amine (50 mg, 0.15 mmol) and 2,4-dimethylnicotinic acid (27 mg, 0.18 mmol) afforded COMPOUND 289 as a pale yellow solid (51 mg, 62%). 1H NMR (CDCl3) δ 0.88-1.17 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.46-1.62 (m, 2H), 1.73-1.77 (m, 1H), 1.88-2.01 (m, 2H), 2.31 (s, 3H), 2.32-2.41 (m, 2H), 2.54 (s, 3H), 2.69-2.82 (m, 3H), 3.29-3.33 (m, 1H), 3.73 (s, 3H), 3.79-3.88 (m, 1H), 6.39-6.46 (m, 1H), 6.54, 6.58 (dd, 1H, J=8.4, 2.7 Hz), 6.64-6.73 (m, 1H), 6.84-6.87 (m, 2H), 6.98 (d, 1H, J=5.1 Hz), 7.26-7.30 (m, 2H), 8.13 (br s, 1H), 8.41, 8.42 (d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.32, 19.00, 22.42, 25.64, 25.71, 26.26, 26.35, 31.39, 31.45, 39.72, 44.17, 45.69, 52.20, 55.47, 60.30, 97.84, 98.23, 106.46 (d, 1H, J=24 Hz), 107.78 (d, 1H, J=10 Hz), 113.62, 120.19, 122.72, 127.01, 131.53, 133.77, 143.86, 148.16, 148.97, 154.33, 157.93 (d, J=238 Hz), 160.10, 168.58. ES-MS m/z 534 (M+H). Anal. Calcd. for C31H36N3O4F.0.45CH2Cl2: C, 66.06; H, 6.50; N, 7.35. Found: C, 66.04; H, 6.53; N, 7.26.
EXAMPLE 290




COMPOUND 290: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 4-methoxyphenylamine (246 mg, 2.00 mmol) and 1-Boc-4-piperidone (418 mg, 2.10 mmol) gave 4-(4-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow oil (612 mg, 100%).
Using general procedure C with the above aniline (706 mg, 2.30 mmol), then general procedure I with the resulting amine and then using general procedure J afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine as a white solid (538 mg, 85% over 3 steps).
Using general procedure E, the above amine (538 mg, 1.94 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (325 mg, 2.13 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (638 mg, 80%).
Using general procedure H, the above amine (88 mg, 0.20 mmol) and 3-(bromomethyl)thiophene (80 mg) afforded COMPOUND 290 as a brown solid (56 mg, 54%). 1H NMR (CDCl3) δ 0.88-1.14 (m, 2H), 1.00 (d, 3H, J=6.9 Hz), 1.51-1.56 (m, 1H), 1.73-1.78 (m, 3H), 2.08-2.16 (m, 1H), 2.45-2.57 (m, 1H), 2.52 (s, 6H), 2.72-2.87 (m, 3H), 3.25-3.41 (m, 2H), 3.73 (s, 3H), 3.77 (s, 2H), 3.84-3.94 (m, 1H), 6.61-6.64 (m, 2H), 6.72-6.75 (m, 2H), 6.99-7.00 (m, 2H), 7.24-7.26 (m, 1H), 8.85-8.87 (m, 2H). 13C NMR (CDCl3) δ 13.76, 22.31, 29.64, 30.94, 40.67, 43.96, 46.54, 52.56, 56.06, 57.61, 60.96, 114.92, 117.08, 121.18, 125.91, 127.21, 131.26, 142.22, 143.46, 152.69, 158.01, 163.39, 166.76. ES-MS m/z 508 (M+H). Anal. Calcd. for C28H37N5O2S.0.73H2O: C, 64.57; H, 7.44; N, 13.45; S, 6.16. Found: C, 64.61; H, 7.21; N, 13.32; S, 5.87.
EXAMPLE 291




COMPOUND 291: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-(trifluoromethoxy)-aniline (0.21 mL, 1.55 mmol) and (R)-3-(4-oxo-piperidin-1-yl]-butyronitrile (310 mg, 1.87 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine as a white solid (277 mg, 55% over 2 steps).
Using general procedure E, the above amine (121 mg, 0.34 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (57 mg, 0.37 mmol) afforded 3,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-trifluoromethoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a pale yellow foam (123 mg, 78%).
A solution of the above amide (123 mg, 0.26 mmol) and 3-(bromomethyl)thiophene (56 mg, 0.32 mmol) in CH3CN (3 mL) was stirred overnight. Standard work-up and purification afforded COMPOUND 291 as a white foam (15 mg, 10%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=9.0 Hz), 1.77 (d, 4H, J=9.0 Hz), 2.16 (t, 1H, J=12.0 Hz), 2.52 (s, 6H), 2.59 (d, 1H, J=9.0 Hz), 2.73-2.78 (m, 1H), 2.83-2.90 (m, 2H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.55 (td, 1H, J=9.0, 3.0 Hz), 3.84 (s, 2H), 3.86-3.91 (m, 1H), 6.57 (d, 2H, J=9.0 Hz), 6.96-7.02 (m, 4H), 7.30 (dd, 1H, J=6.0, 3.0 Hz), 8.71 (d, 1H, J=3.0 Hz), 8.88 (s, 1H). ES-MS m/z 562 [M+H]+.
EXAMPLE 292




COMPOUND 292: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-chloro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-chloroaniline (230 mg, 1.80 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (263 mg, 1.58 mmol), then general procedure J and then using general procedure E with the resulting amine and 4,6-dimethyl-pyrimidine-5-carboxylic acid (100 mg, 0.66 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-chloro-phenylamino)-piperidin-1-yl]-butyl}-amide (237 mg, 35% over 3 steps).
A solution of the above aniline (119 mg, 0.29 mmol) and 3-(bromomethyl)thiophene (61 mg, 0.34 mmol) in CH3CN (5 mL) was stirred at room temperature overnight to afford COMPOUND 292 as a white solid (34 mg, 23%) following work-up and purification. 1H NMR (CDCl3) δ 0.89-1.19 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.54-1.58 (m, 1H), 1.73-1.80 (m, 3H), 2.16 (t, 1H, J=12.3 Hz), 2.52 (s, 6H), 2.56 (t, 1H, J=12.3 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.49-3.57 (m, 1H), 3.82 (s, 2H), 3.84-3.92 (m, 1H), 6.54 (d, 2H, J=8.7 Hz), 6.98-7.01 (m, 2H), 7.06-7.09 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 8.71 (br s, 1H), 8.88 (s, 1H). ES-MS m/z 512 (M+H).
EXAMPLE 293




COMPOUND 293: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amine (see EXAMPLE 231) (386 mg, 1.16 mmol) in MeOH (5 mL) and THF (5 mL) was added Boc2O (300 mg, 1.4 mmol) and the mixture was stirred at room temperature for 1.5 hours to afford a yellow foam (284 mg) following purification.
Using general procedure H, the above aniline and 3-(bromomethyl)thiophene (177 mg, 1.0 mmol) afforded [(R)-3-(4-{[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (168 mg, 54% over 2 steps).
To a solution of the above substrate (168 mg, 0.32 mmol) in MeOH (1.5 mL) was added 4N HCl (1.5 mL) and the mixture was stirred at room temperature for 3 hours. After basic work-up, general procedure C was used to afford 1-(4-{[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-thiophen-3-ylmethyl-amino}-phenyl)-ethanone as a pale yellow foam (132 mg).
Using general procedure E, the above amine (132 mg, 0.34 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (54 mg, 0.35 mmol) afforded COMPOUND 293 as a yellow oil (44 mg, 38% over 3 steps). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.3 Hz), 1.53-1.82 (m, 5H), 2.23 (t, 1H, J=12.3 Hz), 2.47 (s, 3H), 2.52 (s, 6H), 2.61 (t, 1H, J=11.4 Hz), 2.78-2.93 (m, 3H), 3.31-3.39 (m, 1H), 3.48 (s, 2H), 3.70-3.87 (m, 2H), 4.00 (s, 1H), 6.61 (d, 2H, J=9.0 Hz), 6.98-7.01 (m, 2H), 7.31 (dd, 1H, J=5.1, 3.0 Hz), 7.79 (d, 2H, J=9.0 Hz), 8.55 (br s, 1H), 8.91 (s, 1H). ES-MS m/z 520 (M+H).
EXAMPLE 294




COMPOUND 294: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(1-methoxyimino-ethyl)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide
To a solution of COMPOUND 293 in MeOH (3 mL) were added methoxylamine hydrochloride (15 mg, 0.18 mmol) followed by NaOAc (14 mg, 0.17 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 294 as a clear oil (31 mg, 82%) after work-up and purification. 1H NMR (CDCl3) δ 0.95-1.17 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.74-1.79 (m, 3H), 2.14 (s, 3H), 2.17 (t, 1H, J=11.7 Hz), 2.52 (s, 6H), 2.57 (t, 1H, J=11.4 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.59-3.68 (m, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 6.60 (d, 2H, J=9.0 Hz), 6.98-7.03 (m, 2H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 7.45 (d, 2H, J=9.0 Hz), 8.71 (br s, 1H), 8.89 (s, 1H). ES-MS m/z 549 (M+H).
EXAMPLE 295




COMPOUND 295: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethyl-phenyl)-amino-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-(trifluoromethyl)aniline (0.19 mL, 1.51 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (302 mg, 1.82 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethyl-phenyl)-amine as a pale blue solid (232 mg, 49% over 2 steps).
Using general procedure E, the above amine (104 mg, 0.33 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (55 mg, 0.36 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-trifluoromethyl-phenylamino)-piperidin-1-yl]-butyl}-amide as a pale yellow foam (114 mg, 77%).
A mixture of the above amide (79 mg, 0.18 mmol), 3-(bromomethyl)thiophene (37 mg, 0.21 mmol), and 2,2,6,6-tetramethylpiperidine (60 μL, 0.35 mmol) in CH3CN (2 mL) was stirred at 80° C. overnight. Then more 3-(bromomethyl)thiophene (37 mg, 0.21 mmol) and 2,2,6,6-tetramethylpiperidine (60 mL), 0.35 mmol) was added and after 3 h afforded COMPOUND 295 as a yellow foam (13 mg, 14%) following purification. 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.0 Hz), 1.15-1.18 (m, 1H), 1.54-1.58 (m, 2H), 1.78 (d, 3H, J=9.0 Hz), 2.19 (t, 1H, J=9.0 Hz), 2.52 (s, 6H), 2.59 (td, 1H, J=12.0, 3.0 Hz), 2.86-2.91 (m, 3H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.66 (td, 1H, J=6.0, 3.0 Hz), 3.83-3.90 (m, 1H), 3.92 (s, 2H), 6.64 (d, 2H, J=9.0 Hz), 7.01 (dd, 2H, J=6.0, 3.0 Hz), 7.31 (dd, 1H, J=6.0, 3.0 Hz), 7.37 (d, 2H, J=9.0 Hz), 8.61 (dd, 1H, J=3.0 Hz), 8.90 (s, 1H). ES-MS m/z 546 [M+H]+.
EXAMPLE 296




COMPOUND 296: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-hydroxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine (see EXAMPLE 233) (940 mg, 2.5 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (490 mg, 3.2 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-amide as a peach solid (790 mg, 62%).
Using general procedure H, the above aniline (790 mg, 1.5 mmol) and 3-(bromomethyl)thiophene (410 mg, 2.3 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide as a brown solid (117 mg, 12%).
To a solution of the above amine (115 mg, 0.19 mmol) in THF (2 mL) cooled to 0° C. was added TBAF (1.0M in THF, 0.23 mL, 0.23 mmol) and the mixture was stirred at 0° C. for 30 minutes. Aqueous work-up and purification afforded COMPOUND 296 as a pale brown solid (76 mg, 81%). 1H NMR (CDCl3) δ 0.86-1.11 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.52-1.77 (m, 4H), 2.10 (t, 1H, J=11.4 Hz), 2.47-2.52 (m, 1H), 2.51 (s, 6H), 2.71-2.85 (m, 3H), 3.26-3.33 (m, 2H), 3.78 (s, 2H), 3.85-3.91 (m, 1H), 6.55-6.66 (m, 4H), 6.98 (d, 2H, J=3.9 Hz), 7.22-7.24 (m, 1H), 8.81-8.83 (m, 1H), 8.86 (s, 1H). ES-MS m/z 494 (M+H).
EXAMPLE 297




COMPOUND 297: {4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid
A mixture of COMPOUND 296 (290 mg, 0.59 mmol), methyl bromoacetate (141 mg, 0.92 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMF (5.8 mL) was heated at 80° C. overnight to afford {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester as a brown oil (145 mg, 42%) following work-up and purification.
Using general procedure K, the above substrate (85 mg, 0.15 mmol) gave COMPOUND 297 as a white solid (95 mg). 1H NMR (CD3OD) δ 1.44 (d, 3H, J=6.6 Hz), 1.92-2.00 (m, 3H), 2.20-2.24 (m, 3H), 2.50 (s, 6H), 3.20-3.30 (m, 1H), 3.42-3.51 (m, 6H), 3.80-3.86 (m, 1H), 4.43 (s, 2H), 4.58 (s, 2H), 6.85 (d, 2H, J=8.7 Hz), 6.96-6.99 (m, 3H), 7.14 (s, 1H), 7.30 (dd, 1H, J=4.8, 3.0 Hz), 7.90 (s, 1H), 8.90 (s, 1H). ES-MS m/z 552 (M+H).
EXAMPLE 298




COMPOUND 298: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
NH3 (g) was bubbled through a solution of {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester (see EXAMPLE 297) (54 mg, 0.095 mmol) in MeOH (10 mL) for 10 minutes. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give COMPOUND 298 as a pale brown solid (52 mg, 100%). 1H NMR (CDCl3) δ 0.89-1.12 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.52-1.63 (m, 1H), 1.74-1.78 (m, 3H), 2.13 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.72-2.84 (m, 3H), 3.27-3.40 (m, 2H), 3.79 (s, 2H), 3.85-3.89 (m, 1H), 4.40 (s, 2H), 5.59 (br s, 1H), 6.59-6.76 (m, 5H), 6.99 (s, 2H), 8.78 (br s, 1H), 8.86 (s, 1H). ES-MS m/z 551 (M+H).
EXAMPLE 299




COMPOUND 299: 4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-benzoic acid methyl ester
Using general procedure A with methyl 4-aminobenzoate (507 mg, 3.35 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (669 mg, 4.03 mmol) followed by general procedure J afforded 4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-benzoic acid methyl ester as a white foam (390 mg, 38% over 2 steps).
Using general procedure E, the above amine (390 mg, 1.28 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (214 mg, 1.41 mmol) afforded 4-(1-{(R)-3-[(4,6-dimethyl-pyridimine-5-cabonyl)-amino]-1-methyl-propyl}-piperidin-4-ylamino]-benzoic acid methyl ester as a white foam (373 mg, 66%).
A solution of the above amide (373 mg, 0.85 mmol), 3-(bromomethyl)thiophene (180 mg, 1.02 mmol), and 2,2,6,6-tetramethylpiperidine (0.29 mL, 1.70 mmol) in CH3CN (5 mL) was heated at 80° C. overnight. Then more 3-(bromomethyl)thiophene (180 mg, 1.02 mmol) and 2,2,6,6-tetramethylpiperidine (0.29 mL, 1.70 mmol) was added and the mixture was heated at 80° C. overnight to afford COMPOUND 299 as a yellow oil (61 mg, 13%) following work-up and purification. 1H NMR (CDCl3) δ 0.98-1.25 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.53-1.59 (m, 1H), 1.76-1.79 (m, 3H), 2.19 (t, 1H, J=11.4 Hz), 2.53 (s, 6H), 2.59 (t, 1H, J=10.5 Hz), 2.75-2.91 (m, 3H), 3.30-3.37 (m, 1H), 3.66-3.74 (m, 1H), 3.83 (s, 3H), 3.83-3.90 (m, 1H), 8.94-3.95 (m, 2H), 6.59 (d, 2H, J=9.0 Hz), 6.99-7.02 (m, 2H), 7.30 (dd, 1H, J=4.8, 3.0 Hz), 7.82 (d, 2H, J=9.0 Hz), 8.62-8.64 (m, 1H), 8.92 (s, 1H). ES-MS m/z 536 (M+H).
EXAMPLE 300




COMPOUND 300: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure K with COMPOUND 299 (61 mg, 0.11 mmol) followed by general procedure E with the resulting acid and ammonium chloride (10 mg, 0.18 mmol) afforded COMPOUND 300 as a pale yellow foam (21 mg, 35%, over 2 steps). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.0 Hz), 1.15-1.25 (m, 1H), 1.54-1.58 (m, 2H), 1.78 (d, 3H, J=9.0 Hz), 2.20-2.23 (m, 1H), 2.53 (s, 6H), 2.60 (td, 1H, J=9.0, 3.0 Hz), 2.86-2.96 (m, 3H), 3.33 (td, 1H, J=9.0, 3.0 Hz), 3.69 (td, 1H, J=9.0, 3.0 Hz), 3.84-3.86 (m, 1H), 3.94 (s, 2H), 6.62 (d, 2H, J=9.0 Hz), 6.99-7.02 (m, 2H), 7.31 (dd, 1H, J=6.0, 3.0 Hz), 7.63 (d, 2H, J=9.0 Hz), 8.68 (d, 1H, J=3.0 Hz), 8.91 (s, 1H). ES-MS m/z 521 [M+H]+.
EXAMPLE 301




COMPOUND 301: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-bromoaniline (969 mg, 5.63 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (936 mg, 5.63 mmol) gave the nitrile, which was subsequently reduced with BH3-THF (1.0M in THF, 14.7 mL, 14.7 mmol) in THF (30 mL) at reflux and treated with 6N HCl (10 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-bromo-phenyl)-amine as a white solid (750 mg, 28% over 2 steps) following basic work-up and purification.
Using general procedure E, the above primary amine (542 mg, 1.66 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (328 mg, 2.16 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-bromo-phenylamino)-piperidin-1-yl]-butyl}-amide (237 mg, 96%).
A solution of the above aniline (95 mg, 0.21 mmol) and 3-(bromomethyl)thiophene (56 mg, 0.32 mmol) in CH3CN (10 mL) was stirred at room temperature overnight to afford COMPOUND 301 as a white solid (27 mg, 24%) following purification. 1H NMR (CDCl3) δ 0.89-1.18 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.51-1.62 (m, 1H), 1.73-1.80 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.52 (s, 6H), 2.56 (t, 1H, J=12.0 Hz), 2.73-2.86 (m, 3H), 3.28-3.36 (m, 1H), 3.49-3.58 (m, 1H), 3.83 (s, 2H), 3.83-3.92 (m, 1H), 6.49 (d, 2H, J=9.0 Hz), 6.98-7.00 (m, 2H), 7.21 (d, 2H, J=9.0 Hz), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 8.69 (br s, 1H), 8.88 (s, 1H). 13C NMR (CDCl3) δ 13.79, 22.32, 29.49, 30.76, 31.02, 40.61, 43.92, 45.61, 52.57, 56.23, 60.89, 115.15, 121.09, 126.43, 126.73, 132.21, 158.03. ES-MS m/z 556 (M+H). Anal. Calcd. for C27H34N5BrOS.0.5CH2Cl2.0.6H2O: C, 54.16; H, 5.98; N, 11.48. Found: C, 54.54; H, 5.95; N, 11.11.
EXAMPLE 302




COMPOUND 302: 4-{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-benzoic acid
Using general procedure A with 4-(4-amino-phenoxy)-benzoic acid methyl ester (see EXAMPLE 96) (300 mg, 1.2 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (225 mg, 1.4 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL). The mixture was stirred at room temperature for 20 minutes to afford 4-{4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-phenoxy}-benzoic acid methyl ester as a white solid (238 mg, 48% over 2 steps) following work-up and purification.
Using general procedure E, the above amine (238 mg, 0.6 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (110 mg, 0.7 mmol) afforded 4-[4-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-ylamino)-phenoxy]-benzoic acid methyl ester as a white solid (309 mg, 97%).
Using general procedure H with the above aniline (309 mg, 0.60 mmol) and 3-(bromomethyl)thiophene (165 mg, 0.93 mmol) followed by general procedure K with the resulting ester afforded COMPOUND 302 as a white solid (149 mg, 42% over 2 steps). 1H NMR (CD3OD) δ 1.13 (d, 3H, J=6.3 Hz), 1.58-1.80 (m, 3H), 1.86-2.01 (m, 3H), 2.41-2.49 (m, 1H), 2.49 (s, 6H), 2.59-2.70 (m, 1H), 2.83-3.03 (m, 3H), 3.37-3.59 (m, 2H), 3.64-3.77 (m, 1H), 4.35 (s, 2H), 6.76-6.88 (m, 6H), 6.99 (d, 1H, J=4.2 Hz), 7.07-7.09 (m, 1H), 7.31 (dd, 1H, J=4.8, 3.0 Hz), 7.87 (d, 2H, J=8.7 Hz), 8.86 (s, 1H). 13C NMR (CD3OD) δ 14.49, 22.23, 30.83, 31.12, 33.62, 39.34, 47.35, 47.66, 51.76, 58.36, 59.13, 117.13, 117.42, 122.20, 122.44, 127.08, 128.15, 132.58, 143.74, 147.70, 148.94, 158.60, 162.93, 165.04, 169.09, 175.54. ES-MS m/z 614 (M+H). Anal. Calcd. for C34H39N5O4S.1.4CH2Cl2: C, 58.03; H, 5.75; N, 9.56. Found: C, 58.05; H, 5.56; N, 9.73.
EXAMPLE 303




COMPOUND 303: 4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(4-carbamoyl-phenoxy)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide
Using general procedure E, COMPOUND 302 (103 mg, 0.17 mmol) and ammonium chloride (23 mg, 0.42 mmol) afforded COMPOUND 303 as a white solid (160 mg, 100%). 1H NMR (CDCl3) δ 0.87-1.21 (m, 2H), 1.01 (d, 3H, J=6.0 Hz), 1.49-1.60 (m, 1H), 1.71-1.85 (m, 3H), 2.11-2.22 (m, 1H), 2.53 (s, 6H), 2.55-2.62 (m, 1H), 2.71-2.92 (m, 3H), 3.25-3.38 (m, 1H), 3.48-3.61 (m, 1H), 3.82-3.94 (m, 1H), 3.83 (s, 2H), 5.77 (br s, 2H), 6.62 (d, 1H, J=8.1 Hz), 6.87 (d, 2H, J=8.4 Hz), 6.92 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=3.3 Hz), 7.26-7.32 (m, 1H), 7.73 (d, 2H, J=7.8 Hz), 8.81 (br s, 1H), 8.89 (s, 1H). 13C NMR (CDCl3) δ 13.80, 22.33, 29.50, 30.86, 31.03, 40.62, 43.96, 46.17, 52.59, 56.51, 60.90, 114.86, 116.77, 121.09, 121.80, 126.32, 126.87, 129.62, 131.31, 141.91, 146.46, 158.01, 162.73, 163.46, 166.72, 169.17. ES-MS m/z 613 (M+H). Anal. Calcd. for C34H40N6O3S.0.3CH2Cl2: C, 64.55; H, 6.41; N, 13.17. Found: C, 64.29; H, 6.38; N, 12.96.
EXAMPLE 304




COMPOUND 304: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-fluoro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 4-fluoroaniline (328 mg, 2.95 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (500 mg, 3.01 mmol) followed by general procedure J gave the amine, which was subsequently treated with Boc2O (680 mg, 3.12 mmol) in THF (20 mL) to afford the aniline after purification.
A solution of the above aniline (850 mg) and 3-(bromomethyl)thiophene (658 mg, 3.72 mmol) in CH3CN (30 mL) was stirred at 60° C. for several hours. Standard work-up and purification afforded ((R)-3-{4-[(4-fluoro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester as a white solid (657 mg, 48% over 3 steps).
Using general procedure C, the above substrate (657 mg, 1.43 mmol) gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-thiophen-3-ylmethyl-amine (484 mg, 94%).
Using general procedure E, the above primary amine (120 mg, 0.33 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (56 mg, 0.37 mmol) afforded COMPOUND 304 as a white solid (71 mg, 44%). 1H NMR (CDCl3) δ 0.87-1.17 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.59 (m, 1H), 1.72-1.80 (m, 3H), 2.14 (t, 1H, J=11.1 Hz), 2.52 (s, 6H), 2.54 (t, 1H, J=11.1 Hz), 2.73-2.88 (m, 3H), 3.27-3.49 (m, 2H), 3.80 (s, 2H), 3.84-3.92 (m, 1H), 6.55-6.59 (m, 2H), 6.81-6.88 (m, 2H), 6.98-7.00 (m, 2H), 7.26-7.28 (m, 1H), 8.77 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.79, 22.33, 29.47, 30.72, 31.02, 40.57, 43.93, 45.62, 52.55, 56.20, 60.85, 109.14, 115.13, 116.05, 121.08, 124.31, 126.43, 126.73, 127.32, 131.26, 132.20, 141.37, 147.95, 158.01, 163.45, 166.73. ES-MS m/z 496 (M+H). Anal. Calcd. for C27H34N5FOS.0.3CH2Cl2: C, 62.92; H, 6.69; N, 13.44. Found: C, 63.08; H, 6.69; N, 13.28.
EXAMPLE 305




COMPOUND 305: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-ethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with p-phenetidine (137 mg, 1.20 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (166 mg, 1.20 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-amine (251 mg).
Using general procedure E, the above amine (291 mg, 0.86 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (144 mg, 0.95 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (268 mg, 64% over 3 steps).
A solution of the above aniline (70 mg, 0.17 mmol) and 3-(bromomethyl)thiophene (58 mg, 0.33 mmol) in CH3CN (1.7 mL) was stirred at room temperature overnight. Standard work-up and purification afforded COMPOUND 305 as a white solid (66 mg, 77%). 1H NMR (CDCl3) δ 0.93-1.10 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.35 (t, 3H, J=6.69 Hz), 1.50-1.56 (m, 1H), 1.74-1.78 (m, 3H), 2.09-2.15 (m, 1H), 2.52 (s, 6H), 2.52-2.54 (m, 1H), 2.73-2.87 (m, 3H), 3.31-3.37 (m, 1H), 3.77 (s, 2H), 3.79-3.90 (m, 1H), 3.93 (q, 2H, J=6.6 Hz), 6.61 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 6.99-7.00 (m, 2H), 7.23-7.26 (m, 1H), 8.83-8.86 (m, 2H). 13C NMR (CDCl3) δ 13.35, 14.99, 21.92, 29.20, 30.46, 30.57, 40.21, 43.59, 46.19, 52.13, 57.11, 60.52, 63.90, 115.31, 116.65, 120.80, 125.51, 126.83, 130.86, 141.86, 143.01, 151.61, 157.61, 163.00, 166.39. ES-MS m/z 522 (M+H). Anal. Calcd. for C29H39N5O2S.0.1C6H14.0.1CH2Cl2: C, 66.20; H, 7.59; N, 13.00. Found: C, 66.40; H, 7.61; N, 12.72.
EXAMPLE 306




COMPOUND 306: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 4-(4-cyano-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 106) (1.17 g, 3.89 mmol) in THF (20 mL) cooled to −78° C. was added KHMDS (0.5M, 12.0 mL, 6.0 mmol) and the mixture was stirred at −78° C. for 20 minutes. The reaction was quenched with 3-(bromomethyl)thiophene (1.06 g, 5.99 mmol) and warmed to room temperature to afford 4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (941 mg, 61%) following work-up and purification.
Using general procedure C with the above substrate (941 mg, 2.37 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (998, 4.60 mmol) and then using general procedure D gave 4-{[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiophen-3-ylmethyl-amino}-benzonitrile (367 mg, 42% over 3 steps).
Using general procedure E, the above amine (132 mg, 0.36 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (60 mg, 0.39 mmol) afforded COMPOUND 306 as a white solid (63 mg, 35%). 1H NMR (CDCl3) δ 0.95-1.25 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.60 (m, 1H), 1.71-1.80 (m, 3H), 2.18 (t, 1H, J=12.3 Hz), 2.52 (s, 6H), 2.58 (t, 1H, J=12.0 Hz), 2.74-2.91 (m, 3H), 3.29-3.39 (m, 1H), 3.61-3.71 (m, 1H), 3.81-3.89 (m, 1H), 3.95 (s, 2H), 6.60 (d, 2H, J=9.0 Hz), 6.96-7.00 (m, 2H), 7.32 (dd, 1H, J=4.8, 3.0 Hz), 7.40 (d, 2H, J=8.7 Hz), 8.49 (br s, 1H), 8.91 (s, 1H). 13C NMR (CDCl3) δ 13.82, 22.33, 29.60, 30.70, 31.23, 40.38, 43.92, 45.42, 52.29, 55.90, 60.56, 98.70, 112.65, 120.70, 121.19, 126.42, 126.90, 131.25, 133.95, 140.01, 151.65, 158.00, 163.50, 166.71. ES-MS m/z 503 (M+H). Anal. Calcd. for C28H34N6OS.0.2CH2Cl2: C, 65.18; H, 6.67; N, 16.17. Found: C, 64.81; H, 6.71; N, 16.00.
EXAMPLE 307




COMPOUND 307: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methylsulfanyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.00 g, 6.00 mmol) and 4-(methylthio)aniline afforded (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile as a brown oil (1.55 g, 89%).
Using general procedure H, the above aniline (1.55 g, 5.37 mmol) and 3-(bromomethyl)thiophene (1.23 g, 6.96 mmol) afforded the nitrile, which was subsequently reduced with LiAlH4 (516 mg, 13.6 mmol) in Et2O (34 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methylsulfanyl-phenyl)-thiophen-3-ylmethyl-amine as a colourless oil (1.22 g, 58% over 2 steps) following a Feiser work-up and purification.
Using general procedure E, the above amine (392 mg, 1.00 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (190 mg, 1.25 mmol) afforded COMPOUND 307 as a white solid (367 mg, 70%). 1H NMR (CDCl3) δ 0.88-1.18 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.74-1.79 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.39 (s, 3H), 2.52 (s, 6H), 2.56 (t, 1H, J=11.4 Hz), 2.73-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.52-3.60 (m, 1H), 3.83 (s, 2H), 3.86-3.93 (m, 1H), 6.58 (d, 2H, J=9.0 Hz), 7.00-7.02 (m, 2H), 7.18 (d, 2H, J=9.0 Hz), 7.26-7.29 (m, 1H), 8.73 (br s, 1H), 8.81 (s, 1H). 13C NMR (CDCl3) δ 13.80, 19.32, 22.31, 29.50, 30.78, 31.05, 40.54, 43.98, 45.73, 52.55, 55.12, 60.81, 114.19, 121.04, 124.33, 126.29, 126.81, 131.57, 134.98, 141.73, 147.81, 158.00, 163.42, 166.74. ES-MS m/z 524 (M+H). Anal. Calcd. for C28H37N5OS2.0.5CH2Cl2: C, 60.46; H, 6.76; N, 12.37. Found: C, 60.61; H, 6.74; N, 12.24.
EXAMPLE 308




COMPOUND 308: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methanesulfonyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
To a solution of COMPOUND 307 (273 mg, 0.522 mmol) in MeOH (5 mL) cooled to −15° C. was added a solution of OXONE® (1.41 g, 2.30 mmol) in H2O (5 mL) and the mixture was stirred at −15° C. for 15 minutes. Standard work-up and purification afforded COMPOUND 308 as a white solid (69 mg, 23%). 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.54-1.61 (m, 1H), 1.71-1.84 (m, 3H), 2.21 (t, 1H, J=10.2 Hz), 2.53 (s, 6H), 2.60 (t, 1H, J=11.1 Hz), 2.77-2.92 (m, 3H), 2.99 (s, 3H), 3.31-3.38 (m, 1H), 3.66-3.74 (m, 1H), 3.82-3.89 (m, 1H), 3.98 (s, 2H), 6.67 (d, 2H, J=9.0 Hz), 6.98-7.01 (m, 2H), 7.32 (dd, 1H, J=5.1, 3.0 Hz), 7.66 (d, 2H, J=9.0 Hz), 8.49-8.50 (m, 1H), 8.92 (s, 1H). 13C NMR (CDCl3) δ 13.85, 22.35, 29.53, 30.67, 31.23, 40.34, 43.92, 45.40, 45.54, 52.25, 55.99, 60.54, 112.25, 121.23, 126.45, 126.93, 129.57, 130.66, 131.26, 139.96, 152.59, 157.99, 163.51, 166.72. ES-MS m/z 556 (M+H). Anal. Calcd. for C28H37N5O3S2.0.6H2O: C, 59.36; H, 6.80; N, 12.36; S, 11.32. Found: C, 59.38; H, 6.74; N, 12.07; S, 11.22.
Scheme 16 describes the preparation of Examples 309-317, using general procedure E, and reagents listed below.















Example
R1COOH







309
3,5-dimethylisonicotinic acid


310
2,6-dimethylbenzoic acid


311
2-chloro-6-methylbenzoic acid


312
3,5-dimethylisoxazole-4-carboxylic acid


313
1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid


314
2,4-dimethyl-1-oxy-nicotinic acid


315
2,6-dimethyl-4-pyridin-4-yl-benzoic acid


316
2,4-dimethylnicotinic acid


317
2,4-dimethyl-thiophene-3-carboxylic acid









EXAMPLE 309




COMPOUND 309: 3,5-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (2.0 g, 12 mmol) and 4-(trifluoromethoxy)aniline (1.34 mL, 10.0 mmol) gave (R)-3-[4-(4-trifluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a pale yellow solid (3.7 g, 94%).
Using general procedure H, the above nitrile (3.7 g, 11 mmol) and 3-(bromomethyl)thiophene (2.0 g, 11 mmol) gave the nitrile, which was subsequently reduced with LiAlH4 (780 mg, 20.5 mmol) in Et2O (35 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amine as a colourless oil (1.71 g, 80%) after a Feiser work-up and purification.
COMPOUND 309 was isolated as a white foam. 1H NMR (CDCl3) δ 0.89-1.20 (m, 5H), 1.53-1.58 (m, 1H), 1.73-1.81 (m, 3H), 2.14-2.24 (m, 1H), 2.28 (s, 6H), 2.54-2.61 (m, 1H), 2.76-2.88 (m, 3H), 3.27-3.34 (m, 1H), 3.52-3.59 (m, 1H), 3.74 (s, 2H), 3.85-3.91 (m, 1H), 6.54 (d, 2H, J=8.4 Hz), 6.96-7.00 (m, 4H), 7.29 (dd, 1H, J=4.8, 3.0 Hz), 8.28 (s, 2H), 8.72 (br s, 1H). ES-MS m/z 561 (M+H).
EXAMPLE 310




COMPOUND 310: 2,6-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide
White solid. 1H NMR (CDCl3) δ 0.96-1.20 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.50-1.56 (m, 1H), 1.70-1.80 (m, 3H), 2.14 (t, 1H, J=10.5 Hz), 2.32 (s, 6H), 2.54 (t, 1H, J=11.4 Hz), 2.74-2.90 (m, 3H), 3.24-3.32 (m, 1H), 3.48-3.56 (m, 1H), 3.75 (s, 2H), 3.86-3.94 (m, 1H), 6.55 (d, 2H, J=9.0 Hz), 6.89-7.10 (m, 7H), 7.29 (dd, 1H, J=4.8, 3.0 Hz), 8.42-8.44 (m, 1H). ES-MS m/z 560 (M+H).
EXAMPLE 311




COMPOUND 311: 2-Chloro-6-methyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide
White solid. 1H NMR (CDCl3) δ 0.99-1.27 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.49-1.57 (m, 1H), 1.72-1.84 (m, 3H), 2.14 (t, 1H, J=11.7 Hz), 2.36 (s, 3H), 2.55 (t, 1H, J=10.5 Hz), 2.79-2.96 (m, 3H), 3.17-3.35 (m, 1H), 3.50-3.58 (m, 1H), 3.78 (s, 2H), 3.87-3.94 (m, 1H), 6.56 (d, 2H, J=9.3 Hz), 6.87 (d, 1H, J=5.1 Hz), 6.91-7.14 (m, 6H), 7.29 (dd, 1H, J=4.8, 3.0 Hz), 8.63-8.65 (m, 1H). ES-MS m/z 580 (M+H).
EXAMPLE 312




COMPOUND 312: 3,5-Dimethyl-isoxazole-4-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR(CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.34-1.46 (m, 1H), 1.52-1.61 (m, 2H), 1.68-1.84 (m, 3H), 2.19 (t, 1H, J=11.7 Hz), 2.39 (s, 3H), 2.52-2.59 (m, 1H), 2.54 (s, 3H), 2.79-2.88 (m, 3H), 3.37-3.43 (m, 1H), 3.55-3.67 (m, 2H), 4.29 (s, 2H), 6.64 (d, 2H, J=9.3 Hz), 6.90 (br s, 1H), 6.98-7.03 (m, 4H), 7.29 (dd, 1H, J=4.8, 3.0 Hz). ES-MS nz/z 551 (M+H).
EXAMPLE 313




COMPOUND 313: 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
White solid. 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.6 Hz), 1.48-1.82 (m, 7H), 2.20 (t, 1H, J=10.8 Hz), 2.37 (s, 3H), 2.44 (s, 3H), 2.51 (t, 1H, J=11.7 Hz), 2.74-2.87 (m, 3H), 3.40-3.65 (m, 3H), 3.68 (s, 3H), 4.34 (s, 2H), 6.32-6.34 (m, 1H), 6.65 (d, 2H, J=9.3 Hz), 6.97-7.03 (m, 3H), 7.28 (dd, 1H, J=5.1, 3.0 Hz). ES-MS m/z 564 (M+H).
EXAMPLE 314




COMPOUND 314: 2,4-Dimethyl-1-oxy-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.97-1.28 (m, 2H), 1.02 (d, 3H, J=6.9 Hz), 1.54-1.60 (m, 1H), 1.71-1.79 (m, 3H), 2.19 (t, 1H, J=10.5 Hz), 2.28 (s, 3H), 2.54 (s, 3H), 2.61 (t, 1H, J=11.4 Hz), 2.79-2.90 (m, 3H), 3.33-3.37 (m, 1H), 3.54-3.59 (m, 1H), 3.79-3.86 (m, 1H), 4.00 (s, 2H), 6.59 (d, 2H, J=9.0 Hz), 6.81 (d, 1H, J=6.9 Hz), 6.98-7.03 (m, 4H), 7.30 (dd, 1H, J=4.8, 3.0 Hz), 7.98 (d, 1H, J=6.6 Hz), 8.59-8.60 (m, 1H). ES-MS m/z 577 (M+H).
EXAMPLE 315




COMPOUND 315: 2,6-Dimethyl-4-pyridin-4-yl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-benzamide
White solid. 1H NMR (CDCl3) δ 1.01-1.31 (m, 2H), 1.02 (d, 3H, J=6.6 Hz), 1.54-1.58 (m, 1H), 1.73-1.85 (m, 3H), 2.17 (t, 1H, J=11.1 Hz), 2.41 (s, 6H), 2.60 (t, 1H, J=12.3 Hz), 2.77-2.93 (m, 3H), 3.29-3.37 (m, 1H), 3.49-3.57 (m, 1H), 3.72 (s, 2H), 3.85-3.94 (m, 1H), 6.49 (d, 2H, J=9.3 Hz), 6.58 (d, 1H, J=4.8 Hz), 6.89 (d, 1H, J=1.5 Hz), 6.96 (d, 2H, J=8.7 Hz), 7.16 (dd, 1H, J=4.8, 3.0 Hz), 7.30 (s, 2H), 7.44-7.46 (m, 2H), 8.31-8.33 (m, 1H), 8.66 (d, 2H, J=6.0 Hz). ES-MS m/z 637 (M+H).
EXAMPLE 316




COMPOUND 316: 2,4-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide
Using general procedure G, COMPOUND 314 afforded COMPOUND 316 as a white foam. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.11-1.29 (m, 2H), 1.51-1.59 (m, 1H), 1.71-1.83 (m, 3H), 2.17 (t, 1H, J=11.1 Hz), 2.29 (s, 3H), 2.51-2.60 (m, 1H), 2.54 (s, 3H), 2.76-2.91 (m, 3H), 3.27-3.35 (m, 1H), 3.51-3.58 (m, 1H), 3.82 (s, 2H), 3.81-3.88 (m, 1H), 6.56 (d, 2H, J=9.3 Hz), 6.86 (d, 1H, J=5.1 Hz), 6.95-6.99 (m, 4H), 7.28 (dd, 1H, J=4.8, 3.0 Hz), 8.26 (d, 1H, J=5.1 Hz), 8.55 (br s, 1H). ES-MS m/z 561 (M+H).
EXAMPLE 317




COMPOUND 317: 2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 3-bromo-4-methylthiophene (500 mg, 2.82 mmol) in Et2O (10 mL) cooled to −78° C. was added t-BuLi (1.7M in Et2O, 3.7 mL, 6.36 mmol). CO2 (g) was bubbled through the solution at −78° C. for 20 minutes and while the solution was warmed to room temperature. The reaction was quenched with H2O (10 mL) to afford 4-methyl-thiophene-3-carboxylic acid as a pale grey solid (240 mg, 60%) following an acidic work-up and purification.
To a solution of the above acid (390 mg, 2.75 mmol) in THF (10 mL) cooled to −78° C. was added n-BuLi (2.5M in THF, 2.75 mL, 6.05 mmol) and the mixture was stirred −78° C. for 30 minutes. MeI (0.43 mL, 6.9 mmol) was added slowly at −78° C. and the mixture was stirred at room temperature overnight. The reaction was quenched with H2O (15 mL) to afford 2,4-dimethyl-thiophene-3-carboxylic acid as a pale grey solid (344 mg, 80%) following an acidic work-up and purification.
COMPOUND 317 was isolated as a white foam. 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.6 Hz), 1.14-1.45 (m, 2H), 1.48-1.56 (m, 1H), 1.69-1.83 (m, 3H), 2.17 (t, 1H, J=11.4 Hz), 2.21 (s, 3H), 2.47 (s, 3H), 2.56 (t, 1H, J=11.1 Hz), 2.78-2.90 (m, 3H), 3.23-3.32 (m, 1H), 3.55-3.64 (m, 1H), 3.76-3.86 (m, 1H), 4.09 (s, 2H), 6.55 (s, 1H), 6.60 (d, 2H, J=9.3 Hz), 6.94-7.01 (m, 4H), 7.28 (dd, 1H, J=4.8, 3.3 Hz), 7.64-7.95 (m, 1H). ES-MS m/z 566 (M+H).
Scheme 17 describes the preparation of Examples 318-326, using general procedure E, and reagents listed below.















Example
R1COOH







318
2,6-dimethylbenzoic acid


319
2-chloro-6-methylbenzoic acid


320
1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid


321
2,4-dimethylnicotinic acid


322
2,4-dimethyl-1-oxy-nicotinic acid


323
3,5-dichloroisonicotinic acid


324
3,5-dimethylisoxazole-4-carboxylic acid


325
3,5-dimethylisonicotinic acid


326
2,4-dimethyl-thiophene-3-carboxylic acid









EXAMPLE 318




COMPOUND 318: N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure H, (R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 230) (8.18 g, 30.1 mmol) and 3-(bromomethyl)thiophene (5.33 g, 30.1 mmol) gave the nitrile, which was subsequently reduced with LiAlH4 (3.15 g, 83.2 mmol) in Et2O (66 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-thiophen-3-ylmethyl-amine as a yellow oil (6.23 g, 80%) after a Feiser work-up and purification.
COMPOUND 318 was isolated as a yellow foam. 1H NMR (CDCl3) δ 0.91-1.20 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.55 (m, 1H), 1.68-1.82 (m, 3H), 2.10 (t, 1H, J=11.4 Hz), 2.32 (s, 6H), 2.51 (t, 1H, J=11.4 Hz), 2.72-2.88 (m, 3H), 3.23-3.43 (m, 2H), 3.70 (s, 2H), 3.71 (s, 3H), 3.85-3.94 (m, 1H), 6.58-6.62 (m, 2H), 6.71-6.74 (m, 2H), 6.89-6.94 (m, 3H), 6.96 (s, 1H), 7.05 (dd, 1H, J=8.4, 6.3 Hz), 7.24 (dd, 1H, J=5.1, 3.3 Hz), 8.49 (br s, 1H). ES-MS m/z 506 (M+H).
EXAMPLE 319




COMPOUND 319: 2-Chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide
Yellow foam. 1H NMR (CDCl3) δ 0.94-1.25 (m, 2H), 0.99 (d, 3H, J=6.3 Hz), 1.47-1.55 (m, 1H), 1.71-1.83 (m, 3H), 2.11 (t, 1H, J=11.7 Hz), 1.59 (s, 3H), 2.51 (t, 1H, J=11.7 Hz), 2.76-2.92 (m, 3H), 3.29-3.39 (m, 2H), 3.71 (s, 5H), 3.86-3.95 (m, 1H), 6.58-6.63 (m, 2H), 6.70-6.74 (m, 2H), 6.88 (dd, 1H, J=4.8, 1.5 Hz), 6.91-6.92 (m, 1H), 7.02-7.04 (m, 2H), 7.09-7.13 (m, 1H), 7.24 (dd, 1H, J=4.8, 3.0 Hz), 8.74 (br s, 1H). ES-MS m/z 526 (M+H).
EXAMPLE 320




COMPOUND 320: 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Colourless oil. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.3 Hz), 1.51-1.87 (m, 3H), 2.21 (t, 1H, J=12.0 Hz), 2.36 (s, 3H), 2.43 (s, 3H), 2.52 (t, 1H, J=11.7 Hz), 2.80-2.88 (m, 3H), 3.42-3.53 (m, 3H), 3.66 (s, 3H), 3.73 (s, 3H), 4.26 (s, 2H), 6.45 (br s, 1H), 6.69-6.78 (m, 4H), 6.96-7.00 (m, 2H), 7.22 (dd, 1H, J=4.8, 3.0 Hz). ES-MS m/z 510 (M+H).
EXAMPLE 321




COMPOUND 321: N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
Colourless oil. 1H NMR (CDCl3) δ 0.91-1.23 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.57 (m, 1H), 1.71-1.83 (m, 3H), 2.14 (t, 1H, J=12.3 Hz), 2.30 (s, 3H), 2.50-2.57 (m, 1H), 2.55 (s, 3H), 2.74-2.86 (m, 3H), 3.31-3.39 (m, 2H), 3.71 (s, 3H), 3.74 (s, 2H), 3.84-3.91 (m, 1H), 6.60-6.63 (m, 2H), 6.72-6.74 (m, 2H), 6.86 (d, 1H, J=5.1 Hz), 6.94-6.96 (m, 2H), 7.24 (dd, 1H, J=4.8, 3.0 Hz), 8.25 (d, 1H, J=5.4 Hz), 8.66 (br s, 1H). ES-MS m/z 507 (M+H).
EXAMPLE 322




COMPOUND 322: N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
Pale yellow oil. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.3 Hz), 1.12-1.37 (m, 2H), 1.53-1.62 (m, 1H), 1.78-1.84 (m, 3H), 2.17 (t, 1H, J=12.0 Hz), 2.28 (s, 3H), 2.38 (s, 3H), 2.52 (t, 1H, J=11.7 Hz), 2.75-2.88 (m, 3H), 3.35-3.41 (m, 2H), 3.71 (s, 3H), 3.71-3.76 (m, 1H), 4.00 (s, 2H), 6.64-6.68 (m, 2H), 6.71-6.76 (m, 2H), 6.80 (d, 1H, J=6.6 Hz), 6.96-7.01 (m, 2H), 2.24 (dd, 1H, J=4.8, 3.0 Hz), 7.92 (d, 1H, J=6.6 Hz), 8.82-8.85 (m, 1H). ES-MS m/z 524 (M+H).
EXAMPLE 323




COMPOUND 323: 3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-isonicotinamide
Pale yellow oil. 1H NMR (CDCl3) δ 0.92-1.23 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.47-1.55 (m, 1H), 1.72-1.83 (m, 3H), 2.12 (t, 1H, J=11.4 Hz), 2.51 (t, 1H, J=12.3 Hz), 2.76-2.92 (m, 3H), 3.27-3.42 (m, 2H), 3.71 (s, 3H), 3.76 (s, 2H), 3.81-3.88 (m, 1H), 6.60-6.64 (m, 2H), 6.70-6.74 (m, 2H), 6.93-6.96 (m, 2H), 2.25 (dd, 1H, J=4.8, 3.0 Hz), 8.46 (s, 2H), 9.14-9.16 (m, 1H). ES-MS m/z 547 (M+H).
EXAMPLE 324




COMPOUND 324: 3,5-Dimethyl-isoxazole-4-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Pale yellow oil. 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.3 Hz), 1.29-1.61 (m, 3H), 1.68-1.88 (m, 3H), 2.16 (t, 1H, J=11.1 Hz), 2.36 (s, 3H), 2.47-2.54 (m, 1H), 2.49 (s, 3H), 2.76-2.85 (m, 3H), 3.32-3.46 (m, 2H), 3.52-3.62 (m, 1H), 3.73 (s, 3H), 4.22 (s, 2H), 6.69-6.78 (m, 4H), 6.96-7.00 (m, 2H), 7.03-7.06 (m, 1H), 7.22 (dd, 1H, J=4.8, 3.0 Hz). ES-MS m/z 497 (M+H).
EXAMPLE 325




COMPOUND 325: N—((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide
Colourless oil. 1H NMR (CDCl3) δ 0.86-1.16 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.50-1.57 (m, 1H), 1.70-1.80 (m, 3H), 2.13 (t, 1H, J=11.4 Hz), 2.28 (s, 3H), 2.54 (t, 1H, J=11.4 Hz), 2.73-2.88 (m, 3H), 3.25-3.44 (m, 2H), 3.69 (s, 2H), 3.71 (s, 3H), 3.84-3.92 (m, 1H), 6.59 (d, 2H, J=9.0 Hz), 6.70-6.75 (m, 2H), 6.96-7.00 (m, 1H), 7.25 (dd, 1H, J=4.8, 3.0 Hz), 8.29 (s, 2H), 8.76 (br s, 1H). ES-MS nz/z 507 (M+H).
EXAMPLE 326




COMPOUND 326: 2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Colourless oil. 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.6 Hz), 1.10-1.42 (m, 2H), 1.48-1.55 (m, 1H), 1.70-1.81 (m, 3H), 2.13 (t, 1H, J=12.0 Hz), 2.08 (s, 3H), 2.47 (s, 3H), 2.52 (t, 1H, J=12.0 Hz), 2.75-2.88 (m, 3H), 3.23-3.32 (m, 1H), 3.39-3.49 (m, 1H), 3.72 (s, 3H), 3.76-3.85 (m, 1H), 4.03 (s, 2H), 6.55 (d, 1H, J=0.9 Hz), 6.64-6.67 (m, 2H), 6.74-6.77 (m, 2H), 6.94-6.98 (m, 2H), 7.24 (dd, 1H, J=4.8, 3.3 Hz), 7.98 (br s, 1H). ES-MS m/z 512 (M+H).
EXAMPLE 327




COMPOUND 327: 4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide
Using general procedure A, 3-aminopyridine (1.43 g, 1.01 mmol) and 1-Boc-4-piperidone (3.0 g, 1.0 mmol) afforded 4-(pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (3.15 g, 92%).
To a solution of 3-thiophenecarboxylic acid (300 mg, 2.34 mmol) in CH2Cl2 (15 mL) and DMF (catalytic) cooled to 0° C. was added oxalyl chloride (0.65 mL, 7.34 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and dried in vacuo for 10 minutes to yield a pale yellow solid. A solution of the above amine (584 mg, 2.11 mmol) in pyridine (10 mL) and DMAP (catalytic) were added and the mixture was heated to 70° C. overnight to give the crude material which was used in the next reaction without purification.
Using general procedure C, the above substrate afforded thiophene-3-carboxylic acid piperidin-4-yl-pyridin-3-yl-amide as a white solid (261 mg, 39% over 2 steps).
Using general procedure I, the above amine (261 mg, 0.91 mmol) gave the nitrile, which was subsequently reduced with BH3-THF (1M in THF, 3.4 mL, 3.4 mmol) in THF (5 mL) at reflux and treated with 6N HCl (1.7 mL) to afford [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-pyridin-3-yl-thiophen-3-ylmethyl-amine as a white solid (86 mg) following basic work-up and purification.
Using general procedure E, the above amine (86 mg) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (57 mg, 0.37 mmol) afforded COMPOUND 327 as a white solid (46 mg, 10% over 3 steps). 1H NMR (CDCl3) δ 0.96-1.34 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.51-1.59 (m, 1H), 1.71-1.79 (m, 3H), 2.16 (t, 1H, J=11.4 Hz), 2.50 (s, 6H), 2.52-2.74 (m, 1H), 2.78-2.89 (m, 3H), 3.28-3.36 (m, 1H), 3.60 (tt, 1H, J=11.7, 3.6 Hz), 3.79-3.86 (m, 1H), 3.88 (s, 2H), 6.84 (dd, 1H, J=8.4, 2.1 Hz), 6.97-7.04 (m, 3H), 7.28 (dd, 1H, J=4.8, 3.3 Hz), 7.90 (d, 1H, J=4.2 Hz), 8.04 (d, 1H, J=3.0 Hz), 8.67-8.68 (m, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.84, 22.33, 29.52, 30.68, 31.14, 40.46, 43.94, 45.24, 52.39, 55.85, 60.68, 120.04, 121.17, 123.94, 126.60, 126.65, 131.27, 135.81, 138.63, 140.82, 144.77, 157.99, 163.45, 166.73. ES-MS m/z 479 (M+H). Anal. Calcd. for C26H34N6OS.0.9H2O: C, 63.10; H, 7.29; N, 16.98. Found: C, 63.11; H, 7.08; N, 16.90.
EXAMPLE 328




COMPOUND 328: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-acetylamino-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 246) (343 mg, 0.780 mmol) and 3-(bromomethyl)thiophene (207 mg) gave COMPOUND 328 as a yellow foam (86 mg, 21%). 1H NMR (CDCl3) δ 0.94-1.22 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.55 (m, 1H), 1.75 (m, 3H), 2.10 (s, 3H), 2.19 (m, 1H), 2.51 (s, 6H), 2.55 (m, 1H), 2.73-2.89 (m, 3H), 3.32 (m, 1H), 3.48 (m, 1H), 3.84 (s, 2H), 3.87 (m, 1H), 7.49 (m, 3H), 7.27 (m, 1H), 7.65 (d, 1H, J=3.0 Hz), 7.93 (d, 1H, J=9.3 Hz), 8.06 (s, 1H), 8.63 (m, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.82, 22.33, 24.81, 29.56, 30.68, 31.10, 40.51, 53.91, 45.47, 52.40, 56.77, 60.75, 114.94, 121.30, 123.84, 126.63, 126.71, 131.23, 133.74, 140.77, 142.05, 143.02, 158.01, 163.43, 166.72, 168.47. ES-MS m/z 536 (M+H). Anal. Calcd. for C28H37N7SO2.1.1CH2Cl2: C, 55.56; H, 6.28; N, 15.58; S, 5.10. Found: C, 55.76; H, 6.30; N, 15.63; S, 5.27.
EXAMPLE 329




COMPOUND 329: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 5-amino-2-chloropyridine (254 mg, 1.98 mmol) and 1-Boc-4-piperidone (590 mg, 2.96 mmol), then general procedure H with the resulting amine and 3-(bromomethyl)thiophene (517 mg) and then using general procedure C gave (6-chloro-pyridin-3-yl)-piperidin-4-yl-thiophen-3-ylmethyl-amine as a green oil (65 mg, 10% over 3 steps).
Using general procedure B with the amine from above (65 mg, 0.21 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (115 mg, 0.529 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amine as a yellow oil (60 mg, 75% over 2 steps).
Using general procedure E, the above amine (60 mg, 0.16 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (29 mg, 0.19 mmol) gave COMPOUND 329 as a colourless foam (71 mg, 88%). 1H NMR (CDCl3) δ 0.96-1.24 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.55 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.51 (s, 6H), 2.55 (m, 1H), 2.72-2.90 (m, 3H), 3.33 (m, 1H), 3.53 (m, 1H), 3.82 (m, 1H), 3.87 (s, 2H), 6.83 (dd, 1H, J=9.0, 3.3 Hz), 6.96 (d, 2H, J=4.2 Hz), 7.02 (d, 1H, J=9.0 Hz), 7.30 (m, 1H), 7.76 (d, 1H, J=3.0 Hz), 8.53 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.47, 21.95, 29.14, 30.22, 30.83, 40.02, 43.54, 44.91, 51.93, 55.94, 60.23, 120.91, 123.07, 123.87, 126.09, 126.54, 130.85, 134.43, 138.67, 139.77, 143.54, 157.61, 163.08, 166.33. ES-MS m/z 513 (M+H). Anal. Calcd. for C26H33N6SClO.0.1CH2Cl2.0.3H2O: C, 59.49; H, 6.46; N, 15.95; S, 6.08; Cl, 8.07. Found: C, 59.55; H, 6.38; N, 15.69; S, 6.06; Cl, 8.02.
EXAMPLE 330




COMPOUND 330: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 5-amino-2-bromopyridine (Binz; v, Schickh, Chem. Ber., 68, 1935, 315-321) (308 mg, 1.78 mmol) and 1-Boc-4-piperidone (317 mg, 1.59 mmol) gave 4-(6-bromo-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (326 mg, 58%).
A solution of the secondary amine (152 mg, 0.43 mmol) in THF (3.0 mL) was cooled to −78° C. under nitrogen and KHMDS (0.5M in toluene, 1.3 mL, 0.65 mmol) was added. The resulting orange solution was stirred for 15 minutes, and then a solution of 3-(bromomethyl)thiophene (117 mg, 0.66 mmol) in THF (1.5 mL) was added. The reaction was stirred for another 1.5 hours while warming to room temperature to give 4-[(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (159 mg, 82%) following work-up and purification.
Using general procedure C with the tert-butyl carbamate (149 mg, 0.33 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (128 mg, 0.59 mmol) followed by general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amine as a colourless oil (43.4 mg, 31% over 3 steps).
Using general procedure E, the primary amine (43.4 mg, 0.10 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (22 mg, 0.14 mmol) gave COMPOUND 330 as a white foam (35.7 mg, 63%). 1H NMR (CDCl3) δ 0.95-1.27 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.52-1.64 (m, 1H), 1.71-1.84 (m, 3H), 2.12-2.24 (m, 1H), 2.52 (s, 6H), 2.53-2.63 (m, 1H), 2.73-2.95 (m, 3H), 3.29-3.41 (m, 1H), 3.49-3.60 (m, 1H), 3.79-3.91 (m, 1H), 3.88 (s, 2H), 6.76 (dd, 1H, J=8.8, 3.2 Hz), 6.97 (d, 2H, J=4.4 Hz), 7.17 (d, 1H, J=8.9 Hz), 7.31 (t, 1H, J=3.9 Hz), 7.80 (d, 1H, J=2.9 Hz), 8.49 (br s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.40, 21.91, 29.02, 30.07, 30.83, 39.86, 43.52, 44.80, 51.84, 55.74, 60.10, 120.86, 122.88, 126.01, 126.52, 127.48, 127.95, 130.77, 135.06, 139.60, 143.86, 157.55, 163.01, 166.30. ESI-MS m/z 557 (MH)+, 559 (MH+2)+. Anal. Calcd. for C26H33BrN6OS.0.3CH2Cl2: C, 54.18; H, 5.81; N, 14.41. Found: C, 54.45; H, 5.92; N, 14.20.
EXAMPLE 331




COMPOUND 331: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-ethoxy-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 6-ethoxy-pyridin-3-ylamine (Nishikawa, Yoshinori; et al., J. Med. Chem., 32, 3, 1989, 583-593) (210 mg, 1.52 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (278 mg, 1.67 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-ethoxy-pyridin-3-yl)-amine as a white solid (365 mg, 83% over 2 steps).
Using general procedure E, the above amine (147 mg, 0.50 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (92 mg, 0.60 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(6-ethoxy-pyridin-3-ylamino)-piperidin-1-yl]-butyl}-amide as a white solid (189 mg, 88%).
Using general procedure H, the above aniline (189 mg, 0.44 mmol) and 3-(bromomethyl)thiophene (126 mg, 0.71 mmol) afforded COMPOUND 331 as a white solid (40 mg, 17%). 1H NMR (CDCl3) δ 0.86-1.18 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.34 (t, 3H, J=6.9 Hz), 1.49-1.64 (m, 1H), 1.69-1.83 (m, 3H), 2.04-2.17 (m, 1H), 2.43-2.54 (m, 1H), 2.51 (s, 6H), 2.69-2.91 (m, 3H), 3.23-3.38 (m, 2H), 3.78 (s, 2H), 3.80-3.92 (m, 1H), 4.23 (q, 2H, J=6.9 Hz), 6.55 (d, 1H, J=8.7 Hz), 6.93-7.03 (m, 3H), 7.22-7.26 (m, 1H), 7.59 (d, 1H, J=2.4 Hz), 8.69 (br s, 1H), 8.83 (s, 1H). 13C NMR (CDCl3) δ 13.75, 15.17, 22.31, 29.65, 30.75, 31.07, 40.51, 43.95, 46.45, 52.31, 57.95, 60.75, 61.85, 110.95, 121.49, 126.23, 127.12, 128.73, 131.21, 134.74, 139.95, 141.25, 157.78, 157.99, 163.38, 166.75. ES-MS m/z 523 (M+H). Anal. Calcd. for C28H38N6O2S.0.1CH2Cl2: C, 63.54; H, 7.25; N, 15.82. Found: C, 63.42; H, 7.55; N, 15.56.
Scheme 18 describes the preparation of Examples 332-338, using general procedures E or F, and reagents listed below.















Example
R1COOH







332
2,6-dimethylbenzoic acid


333
2-chloro-6-methylbenzoic acid


334
2,4-dimethylnicotinic acid


335
2,4-dimethyl-1-oxy-nicotinic acid


336
3,5-dichloroisonicotinic acid


337
3,5-dimethylisonicotinic acid


338
2,4-dimethyl-thiophene-3-carboxylic acid









EXAMPLE 332




COMPOUND 332: 2,6-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]butyl}-benzamide
Yellow oil. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.6 Hz), 0.99-1.26 (m, 2H), 1.47-1.55 (m, 1H), 1.68-1.81 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.50 (s, 6H), 2.53 (t, 1H, J=11.4 Hz), 2.73-2.89 (m, 3H), 3.22-3.32 (m, 1H), 3.51-3.61 (m, 1H), 3.82 (s, 2H), 3.81-3.90 (m, 1H), 6.81-7.06 (m, 7H), 7.27 (dd, 1H, J=4.8, 3.0 Hz), 7.88 (d, 1H, J=4.2 Hz), 8.03 (d, 1H, J=2.7 Hz), 8.41-8.43 (m, 1H). ES-MS m/z 477 (M+H).
EXAMPLE 333




COMPOUND 333: 2-Chloro-6-methyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-benzamide
Yellow oil. 1H NMR (CDCl3) δ 0.98-1.31 (m, 5H), 1.48-1.55 (m, 1H), 1.71-1.82 (m, 3H), 2.14 (t, 1H, J=11.4 Hz), 2.24-2.35 (m, 1H), 2.30, 2.34 (s, 3H), 2.54 (d, 3H, J=12.3 Hz), 2.78-2.90 (m, 3H), 3.33-3.34 (m, 1H), 3.51-3.62 (m, 1H), 3.77, 3.80 (s, 2H), 3.81-3.91 (m, 1H), 6.81-7.11 (m, 7H), 7.26-7.29 (m, 1H), 7.88 (d, 1H, J=4.5 Hz), 8.04 (br s, 1H), 8.42-8.44, 8.62-8.64 (m, 1H). ES-MS m/z 497 (M+H).
EXAMPLE 334




COMPOUND 334: 2,4-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide
Yellow foam. 1H NMR (CDCl3) δ 0.96-1.25 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.48-1.57 (m, 1H), 1.69-1.80 (m, 3H), 2.15 (t, 1H, J=12.0 Hz), 2.28 (s, 3H), 2.50-2.58 (m, 1H), 2.52 (s, 3H), 2.73-2.89 (m, 3H), 3.25-3.34 (m, 1H), 3.52-3.65 (m, 1H), 3.78-3.88 (m, 1H), 3.82 (s, 2H), 6.81-6.85 (m, 2H), 6.92-6.95 (m, 2H), 7.00 (dd, 1H, J=8.4, 4.5 Hz), 7.27 (dd, 1H, J=4.8, 3.0 Hz), 7.87 (dd, 1H, J=4.5, 0.9 Hz), 8.03 (d, 1H, J=3.0 Hz), 8.23 (d, 1H, J=5.1 Hz), 8.56-8.58 (m, 1H). ES-MS m/z 478 (M+H).
EXAMPLE 335




COMPOUND 335: 2,4-Dimethyl-1-oxy-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide
Yellow foam. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.29-1.64 (m, 3H), 1.75-1.87 (m, 3H), 2.17-2.25 (m, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.53 (t, 1H, J=12.0 Hz), 2.76-2.89 (m, 3H), 3.35-3.45 (m, 1H), 3.60-3.68 (m, 2H), 4.18 (s, 2H), 6.80 (d, 1H, J=6.6 Hz), 6.86-6.90 (m, 1H), 6.94-7.04 (m, 4H), 7.25-7.27 (m, 1H), 7.85-7.89 (m, 2H), 8.07 (d, 1H, J=2.7 Hz), 8.80-8.83 (m, 1H). ES-MS m/z 494 (M+H).
EXAMPLE 336




COMPOUND 336: 3,5-Dichloro-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide
Yellow foam. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.04-1.33 (m, 2H), 1.50-1.58 (m, 1H), 1.72-1.85 (m, 3H), 2.18 (t, 1H, J=12.0 Hz), 2.56 (t, 1H, J=11.4 Hz), 2.79-2.94 (m, 3H), 3.30-3.39 (m, 1H), 3.56-3.68 (m, 1H), 3.78-3.87 (m, 1H), 3.84 (s, 2H), 6.81-6.85 (m, 1H), 6.91-6.94 (m, 2H), 7.00 (dd, 1H, J=8.4, 4.8 Hz), 7.29 (dd, 1H, J=4.8, 3.0 Hz), 7.88 (d, 1H, J=4.2 Hz), 8.03 (d, 1H, J=2.7 Hz), 8.43 (s, 2H), 8.97-8.99 (m, 1H). ES-MS m/z 518 (M+H).
EXAMPLE 337




COMPOUND 337: 3,5-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide
Yellow foam. 1H NMR (CDCl3) δ 0.93-1.24 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.50-1.58 (m, 1H), 1.70-1.83 (m, 3H), 2.17 (t, 1H, J=11.7 Hz), 2.27 (s, 6H), 2.57 (t, 1H, J=11.7 Hz), 2.75-2.91 (m, 3H), 3.26-3.35 (m, 1H), 3.55-3.65 (m, 1H), 3.77 (s, 2H), 3.81-3.91 (m, 1H), 6.81 (ddd, 1H, J=8.7, 3.0, 1.2 Hz), 6.93-7.03 (m, 3H), 7.29 (dd, 1H, J=4.8, 3.0 Hz), 7.90 (d, 1H, J=3.6 Hz), 7.90 (s, 1H), 8.27 (s, 2H), 8.64-8.65 (m, 1H). ES-MS m/z 478 (M+H).
EXAMPLE 338




COMPOUND 338: 2,4-Dimethyl-thiophene-3-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide
Colourless oil. 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.6 Hz), 1.16-1.57 (m, 2H), 1.69-1.83 (m, 3H), 2.12-2.20 (m, 1H), 2.20 (s, 3H), 2.46 (s, 3H), 2.56 (t, 1H, J=12.0 Hz), 2.78-2.90 (m, 3H), 3.23-3.33 (m, 1H), 3.59-3.68 (m, 1H), 3.75-3.84 (m, 1H), 4.11 (s, 2H), 6.88 (ddd, 1H, J=9.3, 3.0, 1.2 Hz), 6.92-6.95 (m, 2H), 7.03 (dd, 1H, J=8.4, 4.5 Hz), 7.27 (dd, 1H, J=4.8, 1.6 Hz), 7.87-7.92 (m, 2H), 8.09 (d, 1H, J=2.7 Hz). ES-MS m/z 483 (M+H).
Scheme 19 describes the preparation of Examples 339-341, using general procedure E, and reagents listed below.















Example
R1COOH







339
4,6-dimethyl-pyrimidine-5-carboxylic acid


340
2,4-dimethyl-1-oxy-nicotinic acid


341
2,6-dimethylbenzoic acid









EXAMPLE 339




COMPOUND 339: 4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide
A mixture of 5-bromopyrimidine (325 mg, 2.04 mmol), 4-amino-1-Boc-piperidine (425 mg, 2.12 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), (±)-BINAP (78 mg, 0.13 mmol) and t-BuONa (210 mg, 2.19 mmol) in freshly degassed toluene (7.0 mL) was stirred at 85° C. under argon for 2 hours. Basic work-up and purification gave 4-(pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale brown solid (415 mg, 73%).
A solution of the secondary amine (406 mg, 1.46 mmol) in THF (10 mL) was cooled to −78° C. under nitrogen and KHMDS (0.5M in toluene, 4.2 mL, 2.1 mmol) was added. The resulting orange solution was stirred for 10 minutes, and then a solution of 3-(bromomethyl)thiophene (379 mg, 2.14 mmol) in THF (5 mL) was added. The reaction was stirred for another 1.5 hours while warming to room temperature to give 4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidine-1-carboxylic acid tert-butyl ester as an orange foam (461 mg, 84%) after work-up and purification.
Using general procedure C with the tert-butyl carbamate (461 mg, 1.23 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (428 mg, 1.97 mmol) and then using general procedure D gave 2-{3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isoindole-1,3-dione as a yellow oil (214 mg, 54% over 3 steps).
COMPOUND 339 was isolated as a white foam. 1H NMR (CDCl3) δ 1.02-1.15 (m, 1H), 1.03 (d, 3H, J=6.6 Hz), 1.17-1.31 (m, 1H), 1.53-1.62 (m, 1H), 1.72-1.85 (m, 3H), 2.20 (td, 1H, J=11.7, 1.5 Hz), 2.53 (s, 6H), 2.59 (td, 1H, J=11.7, 1.8 Hz), 2.76-2.96 (m, 3H), 3.31-3.41 (m, 1H), 3.60 (tt, 1H, J=11.7, 3.9 Hz), 3.80-3.90 (m, 1H), 3.95 (s, 2H), 6.98-7.00 (m, 2H), 7.33 (dd, 1H, J=4.7, 3.5 Hz), 8.12 (s, 2H), 8.41 (br s, 1H), 8.55 (s, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.32, 21.77, 28.97, 29.90, 30.95, 39.55, 43.44, 44.17, 51.53, 55.04, 59.65, 120.84, 125.77, 126.66, 130.63, 138.93, 140.63, 141.60, 147.42, 157.41, 162.86, 166.19. ESI-MS m/z 480 (MH)+. Anal. Calcd. for C25H33N7OS.0.8CH2Cl2: C, 56.59; H, 6.37; N, 17.91. Found: C, 56.24; H, 6.45; N, 17.94.
EXAMPLE 340




COMPOUND 340: 2,4-Dimethyl-1-oxy-N-{3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide
White foam. 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.5 Hz), 1.27-1.52 (m, 2H), 1.57-1.67 (m, 1H), 1.75-1.90 (m, 3H), 2.24 (td, 1H, J=11.6, 1.5 Hz), 2.30 (s, 3H), 2.38 (s, 3H), 2.59 (td, 1H, J=11.6, 1.8 Hz), 2.78-2.97 (m, 3H), 3.36-3.47 (m, 1H), 3.59-3.78 (m, 2H), 4.19 (s, 2H), 6.82 (d, 1H, J=6.6 Hz), 6.97 (dd, 1H, J=4.8, 1.2 Hz), 7.02 (dd, 1H, J=3.0, 1.2 Hz), 7.33 (dd, 1H, J=4.8, 3.1 Hz), 7.91 (d, 1H, J=6.6 Hz), 8.14 (s, 2H), 8.54 (s, 1H), 8.55 (br s, 1H). 13C NMR (CDCl3) δ 13.42, 14.82, 18.30, 29.35, 29.83, 32.41, 38.41, 44.25, 44.41, 50.96, 55.48, 57.92, 120.83, 124.71, 125.80, 126.57, 134.44, 136.85, 137.52, 139.23, 140.67, 141.69, 145.27, 147.31, 165.19. ESI-MS t/z 495 (MH)+. Anal. Calcd. for C26H34N6O2S.CH2Cl2: C, 55.95; H, 6.26; N, 14.50. Found: C, 56.12; H, 6.36; N, 14.75.
EXAMPLE 341




COMPOUND 341: 2,6-Dimethyl-N-{3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-benzamide
White foam. 1H NMR(CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.02-1.15 (m, 1H), 1.18-1.31 (m, 1H), 1.50-1.59 (m, 1H), 1.69-1.84 (m, 3H), 2.17 (td, 1H, J=11.8, 1.6 Hz), 2.32 (s, 6H), 2.61 (td, 1H, J=11.6, 1.5 Hz), 2.76-2.97 (m, 3H), 3.25-3.35 (m, 1H), 3.56 (tt, 1H, J=11.6, 3.7 Hz), 3.81 (s, 2H), 3.84-3.94 (m, 1H), 6.88 (dd, 1H, J=5.0, 1.4 Hz), 6.92 (dd, 1H, J=3.2, 1.4 Hz), 6.94 (d, 2H, J=8.1 Hz), 7.05 (dd, 1H, J=8.4, 6.9 Hz), 7.32 (dd, 1H, J=5.0, 3.2 Hz), 8.09 (s, 2H), 8.32 (br s, 1H), 8.52 (s, 1H). 13C NMR (CDCl3) δ 13.35, 19.03, 28.72, 29.87, 30.92, 39.57, 43.39, 44.12, 51.76, 55.28, 60.26, 120.80, 125.77, 126.54, 127.20, 128.32, 133.85, 138.46, 139.24, 140.76, 141.64, 147.41, 169.76. ESI-MS m/z 478 (MH)+. Anal. Calcd. for C27H35N5OS.0.4CH2Cl2: C, 64.32; H, 7.05; N, 13.69. Found: C, 64.47; H, 7.06; N, 13.59.
EXAMPLE 342




COMPOUND 342: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 3-bromo-4-methylthiophene (500 mg, 2.82 mmol) in THF (5 mL) cooled to −78° C. was added n-BuLi (2.0M in Hexanes, 1.69 mL, 3.39 mmol). The mixture was stirred at −78° C. for 1 hour. DMF (0.26 mL, 3.39 mmol) was added and the mixture stirred at −78° C. for 30 minutes and at room temperature for 2 hours to give the aldehyde, which was subsequently reduced with NaBH4 (76 mg, 2.0 mmol) in MeOH (2 mL) to afford (4-methyl-thiophen-3-yl)-methanol as a white solid (105 mg, 29% over 2 steps) after work-up.
To a solution of the above alcohol (105 mg, 0.82 mmol) in CH2Cl2 (1 mL) was added PPh3 (215 mg, 0.82 mmol) then carbon tetrabromide (272 mg, 0.82 mmol) and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue washed with Hexanes (3×5 mL). The combined organic extracts were concentrated under reduced pressure to give 3-bromomethyl-4-methyl-thiophene as a colourless liquid (209 mg, 79%).
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine (see EXAMPLE 230) (1.59 g, 5.48 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (834 mg, 5.48 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (2.07 g, 83%).
Using general procedure H, the above amide (62 mg, 0.15 mmol) and the above bromide (97 mg, 0.30 mmol) gave COMPOUND 342 as a yellow solid (54 mg, 68%). 1H NMR (CDCl3) δ 1.06 (d, 3H, J=4.8 Hz), 1.59-1.63 (m, 2H), 1.83-2.02 (m, 4H), 2.19-2.29 (m, 1H), 2.24 (s, 3H), 2.51 (s, 6H), 2.59 (m, 1H), 2.84-2.91 (m, 3H), 3.38 (m, 1H), 3.73 (s, 3H), 3.76-3.82 (m, 1H), 3.86 (s, 2H), 6.63 (d, 2H, J=8.7 Hz), 6.74 (d, 2H, J=9.0 Hz), 6.85-6.89 (m, 2H), 8.17 (br s, 1H), 8.78 (s, 1H). 13C NMR (CDCl3) δ 13.63, 14.94, 22.43, 29.52, 31.60, 39.88, 44.52, 46.70, 52.33, 56.00, 58.06, 60.28, 114.82, 118.47, 121.82, 122.69, 130.92, 136.16, 139.89, 143.17, 153.23, 157.97, 163.28, 167.07. ES-MS m/z 522 (M+H). Anal. Calcd. for C29H39N5O2S.0.5CH2Cl2: C, 62.80; H, 7.15; N, 12.41; S, 5.68. Found: C, 63.16; H, 7.30; N, 12.12; S, 6.39.
EXAMPLE 343




COMPOUND 343: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-thiophen-3-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
A mixture of 3-bromo-4-methylthiophene (177 mg, 1.00 mmol), benzoyl peroxide (10 mg, 0.04 mmol) and CCl4 (2 mL) was heated to reflux. NBS (125 mg, 0.70 mmol) and benzoyl peroxide (10 mg, 0.04 mmol) were added and the mixture was heated to reflux for 2 hours to give 3-bromomethyl-4-methyl-thiophene as a colourless liquid (206 mg) after standard work-up and purification.
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 342) (74 mg, 0.18 mmol) and the above bromide (154 mg) gave COMPOUND 343 as a white solid (24 mg, 23%). 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6.6 Hz), 1.02-1.26 (m, 2H), 1.55-1.62 (m, 1H), 1.72-1.81 (m, 3H), 2.15 (t, 1H, J=10.2 Hz), 2.48-2.55 (m, 1H), 2.51 (s, 6H), 2.73-2.87 (m, 3H), 3.31-3.38 (m, 2H), 3.73 (s, 3H), 3.75-3.84 (m, 1H), 3.92 (s, 2H), 6.61-6.69 (m, 2H), 6.71-6.77 (m, 2H), 0.93 (d, 1H, J=3.6 Hz), 7.26 (d, 1H, J=3.6 Hz), 7.97 (br s, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.73, 22.35, 30.16, 31.00, 31.84, 40.00, 44.38, 47.35, 52.28, 56.01, 58.50, 60.05, 110.44, 114.90, 118.24, 123.31, 123.48, 130.96, 139.43, 142.94, 153.23, 158.07, 163.28, 166.96. ES-MS m/z 586 (M+H). Anal. Calcd. for C28H36N5O2SBr.0.6CH2Cl2: C, 53.88; H, 5.88; N, 10.98; S, 5.03. Found: C, 54.08; H, 5.72; N, 10.87; S, 5.30.
EXAMPLE 344




COMPOUND 344: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methoxy-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
4-Methylthiophene-3-carboxylic acid (158 mg, 1.00 mmol) was reduced with BH3-THF (1.0M in THF, 3.0 mL, 3.0 mmol) in THF (2 mL) at room temperature and treated with MeOH to give (4-methoxy-thiophen-3-yl)-methanol as an oil (144 mg, 100%) after work-up.
To a solution of phosphorous tribromide (271 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) cooled to 0° C. was added a solution of the above alcohol (144 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) and the solution was stirred at 0° C. for 5 minutes to give 3-bromomethyl-4-methoxy-thiophene as an oil (200 mg, 97%) after work-up.
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 342) (62 mg, 0.15 mmol) and the above bromide (62 mg, 0.30 mmol) gave COMPOUND 344 as a white solid (36 mg, 44%). 1H NMR (CDCl3) δ 0.98-1.28 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.54-1.62 (m, 1H), 1.69-1.80 (m, 3H), 2.14 (t, 1H, J=10.2 Hz), 2.49-2.55 (m, 1H), 2.50 (s, 6H), 2.71-2.85 (m, 3H), 3.32-3.42 (m, 2H), 3.72 (s, 3H), 3.76-3.86 (m, 1H), 3.80 (s, 2H), 3.90 (s, 3H), 6.20 (d, 1H, J=3.3 Hz), 6.61-6.69 (m, 2H), 6.71-6.78 (m, 3H), 8.14 (m, 1H), 8.85 (s, 1H). 13C NMR (CDCl3) δ 13.73, 22.30, 29.87, 30.87, 31.71, 40.01, 44.34, 44.46, 52.35, 56.06, 57.63, 57.82, 60.05, 96.59, 114.89, 117.09, 121.61, 130.96, 132.06, 143.36, 152.56, 155.98, 158.05, 163.22, 166.99. ES-MS m/z 538 (M+H). Anal. Calcd. for C29H39N5O3S.0.2CH2Cl2.0.4C4H8O2: C, 62.71; H, 7.28; N, 11.87. Found: C, 62.74; H, 6.99; N, 11.82.
EXAMPLE 345




COMPOUND 345: 4,6-Dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(benzo[1,3]dioxol-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide
Using general procedure A with 3,4-(methylenedioxy)aniline (250 mg, 1.8 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (329 mg, 2.0 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-benzo[1,3]dioxol-5-yl-amine as a white solid (281 mg, 68% over 2 steps) after work-up and purification.
Using general procedure E, the above amine (281 mg, 1.0 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (176 mg, 1.2 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(benzo[1,3]dioxol-5-ylamino)-piperidin-1-yl]-butyl}-amide as a white solid (377 mg, 92%).
Using general procedure H, the above aniline (377 mg, 0.90 mmol) and 3-(bromomethyl)thiophene (251 mg, 1.4 mmol) afforded COMPOUND 345 as a white solid (302 mg, 83%). 1H NMR (CDCl3) δ 0.81-1.14 (m, 2H), 0.98 (d, 3H, J=6.3 Hz), 1.49-1.63 (m, 1H), 1.68-1.82 (m, 3H), 2.05-2.16 (m, 1H), 2.46-2.57 (m, 1H), 2.50 (s, 6H), 2.68-2.89 (m, 3H), 3.23-3.38 (m, 2H), 3.76 (s, 2H), 3.80-3.94 (m, 1H), 5.83 (s, 2H), 6.08 (dd, 1H, J=8.7, 2.4 Hz), 6.29 (d, 1H, J=2.4 Hz), 6.60 (d, 1H, J=8.7 Hz), 6.96-7.00 (m, 2H), 7.22-7.27 (m, 1H), 8.80 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.76, 22.30, 29.67, 30.92, 30.97, 40.63, 43.96, 46.77, 52.52, 57.94, 60.91, 98.65, 101.05, 107.99, 108.63, 121.22, 126.00, 127.15, 131.24, 140.30, 141.95, 145.09, 148.63, 158.01, 163.39, 166.75. ES-MS m/z 522 (M+H). Anal. Calcd. for C28H35N5O3S.0.3C4H8O2.0.1H2O: C, 63.78; H, 6.89; N, 12.74. Found: C, 63.76; H, 6.88; N, 12.67.
EXAMPLE 346




COMPOUND 346: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A with 1,4-benzodioxan-6-amine (170 mg, 1.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (206 mg, 1.2 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL) and stirred at room temperature for 20 minutes. Work-up and purification afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine as a white solid (245 mg, 71% over 2 steps).
Using general procedure E, the above amine (110 mg, 0.4 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (66 mg, 0.4 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-piperidin-1-yl]-butyl}-amide as a white solid (160 mg, 100%).
Using general procedure H, the above aniline (160 mg, 0.36 mmol) and 3-(bromomethyl)thiophene (103 mg, 0.58 mmol) afforded COMPOUND 346 as a white solid (35 mg, 18%). 1H NMR (CDCl3) δ 0.82-1.15 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.48-1.58 (m, 1H), 1.67-1.83 (m, 3H), 2.06-2.17 (m, 1H), 2.43-2.57 (m, 1H), 2.51 (s, 6H), 2.67-2.89 (m, 3H), 3.23-3.45 (m, 2H), 3.75 (s, 2H), 3.80-3.93 (m, 1H), 4.12-4.22 (m, 4H), 6.13-6.21 (m, 2H), 6.65 (d, 1H, J=8.4 Hz), 6.96-7.01 (m, 2H), 7.22-7.26 (m, 1H), 8.81 (br s, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.75, 22.30, 29.51, 30.84, 30.95, 40.65, 43.95, 46.28, 52.60, 57.07, 60.93, 64.60, 65.11, 103.71, 108.40, 117.72, 121.05, 126.01, 127.04, 131.25, 136.04, 142.26, 144.11, 144.34, 158.01, 163.39, 166.76. ES-MS m/z 536 (M+H). Anal. Calcd. for C29H37N5O3S.0.1CH2Cl2: C, 64.23; H, 6.89; N, 12.87. Found: C, 64.13; H, 7.01; N, 12.55.
EXAMPLE 347




COMPOUND 347: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure C, 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 119) (706 mg, 2.30 mmol) afforded (4-methoxy-phenyl)-piperidin-4-yl-amine as a sticky white solid (423 mg, 89%).
Using general procedure I with the above amine (423 mg, 2.05 mmol) and then using general procedure J afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-amine as a white solid (538 mg, 95% over 2 steps).
Using general procedure E, the above amine (538 mg, 1.94 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (325 mg, 2.13 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide as a white solid (638 mg, 80%).
A mixture of 2-thiophenemethanol (0.4 mL, 4.2 mmol), carbon tetrabromide (1.4 g, 4.2 mmol) and CH2Cl2 (20 mL) was stirred at room temperature for 3 hours to give the crude material after work-up.
Using general procedure H, the above amine (84 mg, 0.20 mmol) and the above bromide (70 mg) afforded COMPOUND 347 as a pale brown solid (71 mg, 70%). 1H NMR (CDCl3) δ 0.87-0.97 (m, 1H), 1.00 (d, 3H, J=6.6 Hz), 1.06-1.18 (m, 1H), 1.52-1.54 (m, 1H), 1.70-1.83 (m, 3H), 2.11 (t, 1H, J=11.4 Hz), 2.48-2.55 (m, 1H), 2.52 (s, 6H), 2.73-2.87 (m, 3H), 3.27-3.35 (m, 2H), 3.73 (s, 3H), 3.85-3.89 (m, 1H), 3.95 (s, 2H), 6.69-6.76 (m, 4H), 6.89-6.93 (m, 2H), 7.12 (dd, 1H, J=5.1, 1.2 Hz), 8.77-8.78 (m, 1H), 8.82 (s, 1H). 13C NMR (CDCl3) δ 13.78, 22.34, 29.85, 31.03, 40.62, 44.00, 46.59, 52.42, 55.97, 58.27, 60.88, 114.77, 118.87, 124.24, 127.05, 131.21, 142.96, 145.63, 153.48, 158.03, 163.35, 166.81. ES-MS m/z 508 (M+H). Anal. Calcd. for C28H37N5O2S.0.51CH4O: C, 65.35; H, 7.51; N, 13.36; S, 6.12. Found: C, 65.64; H, 7.22; N, 12.97; S, 6.25.
EXAMPLE 348




COMPOUND 348: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(3-methyl-thiophen-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of 3-methyl-2-thiophenecarboxaldehyde (374 mg, 2.97 mmol) in MeOH (10 mL) cooled to 0° C. was added NaBH4 (230 mg, 5.97 mmol) and the mixture was stirred at 0° C. for 2 hours. Aqueous work-up gave (3-methyl-thiophen-2-yl)-methanol.
A mixture of the above alcohol (271 mg), carbon tetrabromide (702 mg, 2.12 mmol), PPh3 (555 mg, 2.12 mmol) and CH2Cl2 (10 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the crude material was used in the next reaction without purification.
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 347) (77 mg, 0.19 mmol) and the above bromide (excess) afforded COMPOUND 348 as a yellow solid (41 mg, 42%). 1H NMR (CDCl3) δ 0.89-1.20 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.52-1.56 (m, 1H), 1.71-1.85 (m, 3H), 2.08-2.15 (m, 1H), 2.21 (s, 3H), 2.48-2.53 (m, 1H), 2.51 (s, 6H), 2.73-2.86 (m, 3H), 3.20-3.36 (m, 2H), 3.73 (s, 3H), 3.83-3.89 (m, 1H), 3.90 (s, 2H), 6.66-6.79 (m, 5H), 7.01 (d, 1H, J=5.1 Hz), 8.55 (br s, 1H), 8.75 (s, 1H). 13C NMR (CDCl3) δ 13.35, 13.81, 21.93, 29.67, 30.57, 30.90, 40.03, 43.74, 45.06, 51.90, 55.51, 58.40, 60.24, 114.27, 119.73, 122.50, 129.92, 130.72, 132.21, 138.35, 142.51, 153.54, 157.54, 162.86, 166.47. ES-MS m/z 544 (M+Na). Anal. Calcd. for C29H39N5O2S.0.3C4H8O2: C, 66.17; H, 7.61; N, 12.78; S, 5.85. Found: C, 66.28; H, 7.49; N, 12.50; S, 6.54.
EXAMPLE 349




COMPOUND 349: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-thiophen-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
5-Chlorothiophene-2-carboxylic acid (436 mg, 2.6 mmol) was reduced with BH3-THF (1M in THF, 3.2 mL, 3.2 mmol) in THF (10 mL) at room temperature to give (5-chloro-thiophen-2-yl)-methanol after work-up.
A mixture of the above alcohol (179 mg), carbon tetrabromide (401 mg, 1.21 mmol), PPh3 (317 g, 1.21 mmol) and CH2Cl2 (10 mL) was stirred at room temperature for 1 hour. The mixture was diluted with Hexanes, filtered and concentrated under reduced pressure. The crude material was used in the next reaction without purification.
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 347) (75 mg, 0.18 mmol) and the above bromide (58 mg) afforded COMPOUND 349 as a yellow solid (53 mg, 54%). 1H NMR (CDCl3) δ 0.82-1.13 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.50-1.56 (m, 1H), 1.69-1.80 (m, 4H), 2.08 (t, 1H, J=10.5 Hz), 2.46-2.52 (m, 1H), 2.51 (s, 6H), 2.71-2.85 (m, 3H), 3.19-3.34 (m, 2H), 3.73 (s, 3H), 3.82-3.89 (m, 1H), 3.83 (s, 2H), 6.66 (d, 1H, J=3.9 Hz), 6.70 (d, 1H, J=3.9 Hz), 6.73-6.76 (m, 4H), 8.75-8.77 (m, 1H), 8.86 (s, 1H). 13C NMR (CDCl3) δ 13.77, 22.32, 29.76, 30.89, 31.00, 40.59, 43.94, 46.84, 52.33, 55.92, 58.81, 60.81, 114.76, 119.69, 123.33, 126.08, 128.38, 131.23, 142.53, 144.63, 153.94, 157.98, 163.39, 166.74. ES-MS m/z 542 (M+H). Anal. Calcd. for C28N36N5ClO2S.0.5H2O: C, 61.02; H, 6.77; N, 12.71; Cl, 6.43; S, 5.82. Found: 61.19; H, 6.60; N, 12.45; Cl, 7.01; S, 5.79.
EXAMPLE 350




COMPOUND 350: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[furan-2-ylmethyl-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure H, 4,6-dimethyl-pyrimidine-5-carboxylic acid {3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-amide (see EXAMPLE 347) (89 mg, 0.22 mmol) and 2-bromomethyl-1-furan (Murakarni, Teiichi; et al., Synthesis, 4, 2002, 479-482) (100 mg) afforded COMPOUND 350 as a yellow solid (48 mg, 44%). 1H NMR (CDCl3) δ 0.88-1.14 (m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.52-1.58 (m, 1H), 1.71-1.80 (m, 3H), 2.11 (t, 1H, J=10.2 Hz), 2.47-2.54 (m, 1H), 2.53 (s, 6H), 2.72-2.88 (m, 3H), 3.24-3.36 (m, 2H), 3.74 (s, 3H), 3.79 (s, 2H), 3.83-3.92 (m, 1H), 6.01 (d, 1H, J=3.3 Hz), 6.26 (dd, 1H, J=3.3, 1.8 Hz), 6.68-6.77 (m, 4H), 7.34 (s, 1H), 8.75-8.77 (m, 1H), 8.84 (s, 1H). 13C NMR (CDCl3) δ 13.37, 21.93, 29.60, 30.63, 40.18, 43.63, 44.28, 51.87, 55.61, 57.24, 60.39, 106.99, 110.20, 114.38, 118.17, 130.80, 141.34, 142.73, 152.96, 153.51, 157.67, 162.91, 166.45. ES-MS m/z 492 (M+H). Anal. Calcd. for C28H37N5O3.0.5H2O: C, 67.18; H, 7.65; N, 13.99. Found: C, 67.16; H, 7.44; N, 13.79.
EXAMPLE 351




COMPOUND 351: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl 1-butyl)-amide
Using general procedure F with 4-methylnicotinic acid hydrochloride (277 mg, 1.60 mmol) and 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 119) (350 mg, 1.14 mmol) and then using general procedure C afforded N-(4-methoxy-phenyl)-4-methyl-N-piperidin-4-yl-nicotinamide as a white solid (181 mg, 49% over 2 steps).
Using general procedure I, the above secondary amine (181 mg, 0.56 mmol) afforded the nitrile, which was subsequently reduced with BH3-THF (2.1 mL, 2.1 mmol) in THF (3.5 mL) at reflux and treated with 6N HCl to afford [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine as a white solid (71 mg, 32% over 2 steps) after basic work-up and purification.
Using general procedure E, the above amine (31 mg, 0.08 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (14 mg, 0.09 mmol) afforded COMPOUND 351 as a white solid (25 mg, 61%). 1H NMR (CDCl3) δ0.91-1.25 (m, 2H), 0.98 (d, 3H, J=6.3 Hz), 1.49-1.59 (m, 1H), 1.67-1.85 (m, 3H), 2.06-2.16 (m, 1H), 2.35 (s, 3H), 2.43-2.57 (m, 1H), 2.48 (s, 6H), 2.67-2.87 (m, 3H), 3.16-3.38 (m, 2H), 3.70 (s, 3H), 3.72-3.83 (m, 3H), 3.91 (s, 2H), 6.60 (d, 2H, J=9.0 Hz), 6.70 (d, 2H, J=9.0 Hz), 7.01 (d, 1H, J=5.1 Hz), 8.23 (s, 1H), 8.26 (d, 1H, J=5.1 Hz), 8.32 (br s, 1H), 8.77 (s, 1H). 13C NMR (CDCl3) δ 13.77, 19.18, 22.33, 30.05, 30.70, 30.91, 31.51, 33.85, 40.15, 44.28, 47.75, 52.16, 53.83, 55.92, 59.29, 60.22, 114.76, 120.49, 125.47, 131.08, 133.36, 142.59, 145.67, 148.39, 149.60, 154.14, 157.87, 163.31, 166.85. ES-MS m/z 517 (M+H). Anal. Calcd. for C30H40N6O2.0.1CH2Cl2.0.4H2O: C, 67.91; H, 7.76; N, 15.79. Found: C, 67.53; H, 7.78; N, 15.56.
EXAMPLE 352




COMPOUND 352: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 1-Boc-4-piperidone (2.42 g, 12.1 mmol) and aniline (1.0 mL, 11.0 mmol) gave 4-phenylamino-piperidine-1-carboxylic acid tert-butyl ester as a white solid (2.82 g, 93%).
Using general procedure F, 4-methylnicotinic acid hydrochloride (421 mg, 2.43 mmol) and the secondary aniline (559 mg, 2.02 mmol) gave 4-[(4-methyl-pyridine-3-carbonyl)-phenyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as an orange foam (438 mg, 55%).
Using general procedure C, the tert-butyl carbamate (438 mg, 1.11 mmol) gave the amide, which was subsequently reduced with BH3-THF (1.0M in THF, 2.5 mL, 2.5 mmol) in THF (6 mL) at reflux and then treated with 6M HCl to give (4-methyl-pyridin-3-ylmethyl)-phenyl-piperidin-4-yl-amine as a white solid (191 mg, 57% over 2 steps) after basic work-up and purification.
A solution of the amine (115 mg, 0.41 mmol), Boc2O (106 mg, 0.49 mmol) and NEt3 (0.08 mL, 0.6 mmol) in CH2Cl2 (2.5 mL) was stirred at room temperature for 1 hour. Standard work-up and purification gave 4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (142 mg, 91%).
To a 0° C. solution of the aniline (141 mg, 0.37 mmol) in CHCl3 (1.5 mL) was added dropwise a suspension of NBS (67 mg, 0.38 mmol) in CHCl3 (2.5 mL) and the resulting solution was stirred at 0° C. for 2 hours to give 4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a beige solid (163 mg, 96%) after work-up and purification.
Using general procedure C with the tert-butyl carbamate (163 mg, 0.35 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (144 mg, 0.66 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine as a white foam (85.9 mg, 57% over 3 steps).
Using general procedure E, the primary amine (85.9 mg, 0.20 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (41 mg, 0.27 mmol) gave COMPOUND 352 as a white foam (97.5 mg, 87%). 1H NMR (CDCl3) δ 1.02-1.30 (m, 2H), 1.03 (d, 3H, J=6.6 Hz), 1.53-1.63 (m, 1H), 1.71-1.90 (m, 3H), 2.17-2.25 (m, 1H), 2.39 (s, 3H), 2.51 (s, 6H), 2.53-2.61 (m, 1H), 2.72-2.91 (m, 3H), 3.32-3.43 (m, 1H), 3.59 (tt, 1H, J=11.3, 3.3 Hz), 3.73-3.84 (m, 1H), 4.03 (s, 2H), 6.43 (d, 2H, J=9.0 Hz), 7.10 (d, 1H, J=4.8 Hz), 7.21 (d, 2H, J=9.0 Hz), 7.91 (br s, 1H), 8.23 (s, 1H), 8.35 (d, 1H, J=4.8 Hz), 8.79 (s, 1H). 13C NMR (CDCl3) δ 13.38, 18.55, 21.86, 29.27, 30.11, 31.51, 39.20, 44.00, 45.23, 51.58, 56.58, 59.11, 109.56, 115.50, 125.00, 130.56, 131.82, 132.12, 144.31, 147.16, 147.66, 147.98, 157.32, 162.84, 166.37. ESI-MS m/z 565 (MH)+, 567 (MH+2)+. Anal. Calcd. for C29H37BrN6O.0.6H2O.0.3CH2Cl2: C, 58.47; H, 6.50; N, 13.96. Found: C, 58.53; H, 6.54; N, 13.88.
EXAMPLE 353




COMPOUND 353: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure A, 1-Boc-4-piperidone (665 mg, 3.34 mmol) and p-toluidine (322 mg, 3.01 mmol) gave 4-p-tolylamino-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (842 mg, 96%).
Using general procedure F, 4-methylnicotinic acid hydrochloride (601 mg, 3.46 mmol) and the secondary aniline (810 mg, 2.79 mmol) gave 4-[(4-methyl-pyridine-3-carbonyl)-p-tolyl-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale orange solid (921 mg, 81%).
Using general procedure C, the tert-butyl carbamate (921 mg, 2.25 mmol) gave the amide, which was subsequently reduced with BH3-THF (1.0M in THF, 6.0 mL, 6.0 mmol) in THF (8 mL) at reflux then treated with 6M HCl (14 mL) to give (4-methyl-pyridin-3-ylmethyl)-piperidin-4-yl-p-tolyl-amine as a colourless oil (536 mg, 82% over 2 steps) following basic work-up and purification.
Using general procedure B with the piperidine (268 mg, 0.91 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (401 mg, 1.85 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amine as a colourless oil (180 mg, 54%).
Using general procedure E, the primary amine (90 mg, 0.25 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (46 mg, 0.30 mmol) gave COMPOUND 353 as a white foam (97.5 mg, 79%). 1H NMR (CDCl3) δ 0.95-1.27 (m, 2H), 1.01 (d, 3H, J=6.6 Hz), 1.52-1.62 (m, 1H), 1.72-1.90 (m, 3H), 2.14-2.24 (m, 1H), 2.21 (s, 3H), 2.38 (s, 3H), 2.50 (s, 6H), 2.55 (td, 1H, J=11.7, 1.8 Hz), 2.70-2.89 (m, 3H), 3.30-3.40 (m, 1H), 3.52 (tt, 1H, J=11.6, 3.3 Hz), 3.75-3.85 (m, 1H), 3.98 (s, 2H), 6.51 (d, 2H, J=8.5 Hz), 6.95 (d, 2H, J=8.5 Hz), 7.06 (d, 1H, J=5.3 Hz), 8.12 (br s, 1H), 8.28 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 8.77 (s, 1H). 13C NMR (CDCl3) δ 13.36, 18.56, 20.13, 21.79, 29.29, 30.16, 31.35, 39.25, 44.05, 45.75, 51.59, 57.01, 59.20, 115.15, 124.86, 127.42, 129.57, 130.56, 132.96, 144.46, 146.01, 147.66, 148.16, 157.26, 162.77, 166.38. ESI-MS m/z 501 (MH)+. Anal. Calcd. for C30H40N6O.0.3CH2Cl2: C, 69.17; H, 7.78; N, 15.97. Found: C, 68.92; H, 7.82; N, 15.95.
EXAMPLE 354




COMPOUND 354: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
Using general procedure F, 4-methylnicotinic acid hydrochloride (363 mg, 2.09 mmol) and (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 307) (304 mg, 0.93 mmol) afforded N-[1-((R)-2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-(4-methylsulfanyl-phenyl)-nicotinamide as a brown oil (256 mg, 70%).
The above amide (276 mg, 0.70 mmol) in THF (10 mL) was reduced with BH3-THF (1.0M in THF, 4.2 mL, 4.2 mmol) at reflux and treated with 6N HCl (8 mL) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amine as a clear oil (203 mg, 70%) after basic work-up and purification.
Using general procedure E, the above amine (104 mg, 0.27 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (58 mg, 0.38 mmol) afforded COMPOUND 354 as a clear oil (100 mg, 90%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.12-1.39 (m, 2H), 1.53-1.62 (m, 1H), 1.75-1.88 (m, 3H), 2.23 (t, 1H, J=11.1 Hz), 2.36 (s, 3H), 2.37 (s, 3H), 2.48 (s, 6H), 2.75-2.88 (m, 3H), 3.32-3.42 (m, 1H), 3.57-3.77 (m, 2H), 4.06 (s, 2H), 6.51 (d, 2H, J=8.7 Hz), 7.07 (d, 1H, J=4.8 Hz), 7.12-7.16 (m, 2H), 7.99 (br s, 1H), 8.22 (s, 1H), 8.30 (d, 1H, J=4.8 Hz), 8.77 (s, 1H). ES-MS m/z 533 (M+H).
EXAMPLE 355




COMPOUND 355: 4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
To a mixture of 4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 352) (232 mg, 0.50 mmol), Zn(CN)2 (66 mg, 0.56 mmol), Pd2(dba)3 (53 mg, 0.058 mmol) and DPPF (56 mg, 0.10 mmol) was added freshly degassed DMF (2.5 mL). The reaction was flushed with argon, heated to 130° C. and stirred under argon for 16 hours giving a black foam (268 mg) after work-up.
Using general procedure C, the crude product gave 4-[(4-methyl-pyridin-3-ylmethyl)-piperidin-4-yl-amino]-benzonitrile as a brown foam (101 mg, 65%) following purification.
A solution of the above substrate (336 mg, 1.10 mmol) and NaOH (420 mg, 10.5 mmol) in 1:1 EtOH/H2O (10 mL) was stirred at reflux for 20 hours. Once cooled, the solution was neutralized with 4M HCl (3 mL) and the mixture was concentrated under reduced pressure, giving a dark brown solid. To a solution of this material in MeOH (20 mL) was added concentrated H2SO4 (1 mL) and the reaction was stirred at reflux for 3 hours to give 4-[(4-methyl-pyridin-3-ylmethyl)-piperidin-4-yl-amino]-benzoic acid methyl ester as a light brown foam (135 mg, 36%) along with 4-[(4-methyl-pyridin-3-ylmethyl)-piperidin-4-yl-amino]-benzamide as a light brown foam (98 mg, 27%) after basic work-up and purification.
Using general procedure B with the primary amide (98 mg, 0.30 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (136 mg, 0.63 mmol) and then using general procedure D gave 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-amino]-benzamide as a pale yellow foam (43.6 mg, 37% over 2 steps).
Using general procedure E, the primary amine (21.8 mg, 0.055 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (12 mg, 0.079 mmol) gave COMPOUND 355 as a beige solid (22.6 mg, 77%). 1H NMR (CDCl3) δ 1.04 (d, 3H, J=6.6 Hz), 1.08-1.37 (m, 2H), 1.54-1.83 (m, 2H), 1.84-1.93 (m, 2H), 2.26 (t, 1H, J=11.5 Hz), 2.41 (s, 3H), 2.50 (s, 6H), 2.61 (t, 1H, J=11.5 Hz), 2.74-2.92 (m, 3H), 3.34-3.45 (m, 1H), 3.71-3.83 (m, 2H), 4.17 (s, 2H), 5.63 (br s, 2H), 6.54 (d, 2H, J=8.7 Hz), 7.12 (d, 1H, J=4.8 Hz), 7.61 (d, 2H, J=8.7 Hz), 7.75 (br s, 1H), 8.19 (s, 1H), 8.37 (d, 1H, J=4.8 Hz), 8.82 (s, 1H). 13C NMR (CDCl3) δ 13.48, 18.60, 21.93, 29.39, 30.22, 31.64, 39.23, 44.10, 45.01, 51.56, 56.02, 59.12, 112.09, 121.32, 125.12, 129.16, 130.60, 131.73, 144.25, 147.38, 148.24, 150.96, 157.41, 162.96, 166.46, 169.02. ESI-MS m/z 530 (MH)+. Anal. Calcd. for C30H39N7O2.0.9CH2Cl2: C, 61.23; H, 6.78; N, 16.18. Found: C, 61.43; H, 6.77; N, 15.81.
EXAMPLE 356




COMPOUND 356: 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide
To a solution of (R)-3-[4-(4-trifluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 309) (601 mg, 1.84 mmol) and 4-methyl-3-pyridinecarboxaldehyde (Konno, Katsuhiro; et al., Heterocycles, 30, 1, 1990, 247-251) (475 mg, 3.93 mmol) in 1,2-dichloroethane (10 mL) was added NaBH(OAc)3 (754 mg, 3.56 mmol) and the reaction stirred at 60° C. overnight. Purification gave the desired nitrile, which was subsequently reduced with BH3-THF (1.0M in THF, 1.0 mL, 1.0 mmol) in THF (6 mL) at reflux and then treated with 6N HCl (2 mL) to give the desired primary amine (25 mg, 3% over 2 steps) as a clear oil after basic work-up.
Using general procedure E, the amine from above (25 mg, 0.057 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (25 mg, 0.16 mmol) gave COMPOUND 356 (22 mg, 68%) as a white solid. 1H NMR (CDCl3) δ 1.01 (d, 3H, J=6 Hz), 1.65-1.89 (m, 6H), 2.19-2.26 (m, 1H), 2.40 (s, 3H), 2.51 (s, 6H), 2.51-2.61 (m, 1H), 2.76-2.88 (m, 3H), 3.35-3.40 (m, 1H), 3.58-3.63 (m, 1H), 3.75-3.81 (m, 1H), 4.05 (s, 2H), 6.52 (d, 2H, J=9 Hz), 6.99 (d, 2H, J=9 Hz), 7.10 (d, 1H, J=4.8 Hz), 7.91 (br s, 1H), 8.25 (s, 1H), 8.37 (d, 1H, J=4.8 Hz), 8.80 (s, 1H). 13C NMR (CDCl3) δ 13.78, 19.06, 22.38, 29.60, 30.50, 31.86, 39.79, 44.40, 45.89, 52.22, 57.01, 59.88, 113.83, 114.65, 119.31, 122.66, 125.53, 131.01, 132.58, 141.00, 144.82, 147.37, 148.18, 148.64, 157.87, 163.38, 166.89. ES-MS m/z 571 (M+H). Anal. Calcd. for C30H37N6O2F3.0.1H2O.1.1CH3OH: C, 60.99; H, 6.82; N, 13.68; F, 9.28. Found: C, 61.25; H, 6.52; N, 13.31; F, 9.52.
Scheme 20 describes the preparation of Examples 357-365, using general procedures E or F, and reagents listed below.















Example
R1COOH







357a
3,5-dimethylisonicotinic acid


(racemic)


358b
2,6-dimethylbenzoic acid


359b
2,4-dimethylnicotinic acid


360b
2-amino-6-methylbenzoic acid


361b
2-chloro-6-methylbenzoic acid


362a
3,5-dichloroisonicotinic acid


363b
2,6-dimethyl-4-pyridin-4-yl-benzoic acid


(racemic)


364b
2,4-dimethyl-thiophene-3-carboxylic acid


365b
2,4-dimethyl-1-oxy-nicotinic acid





ageneral procedure F


bgeneral procedure E






EXAMPLE 357




COMPOUND 357: N-(3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.81-1.21 (m, 2H), 0.99 (d, 3H, J=6.6 Hz), 1.49-1.61 (m, 1H), 1.67-1.85 (m, 3H), 2.06-2.17 (m, 1H), 2.27 (s, 6H), 2.34 (s, 3H), 2.43-2.54 (m, 1H), 2.68-2.87 (m, 3H), 3.19-3.37 (m, 2H), 3.71 (s, 3H), 3.72-3.86 (m, 1H), 3.89 (s, 2H), 6.59 (d, 2H, J=9.0 Hz), 6.71 (d, 2H, J=9.0 Hz), 7.03 (d, 1H, J=4.8 Hz), 8.10 (br s, 1H), 8.22 (s, 2H), 8.25 (s, 1H), 8.29 (d, 1H, J=4.8 Hz). 13C NMR (CDCl3) δ 13.76, 16.32, 19.17, 30.05, 30.94, 31.66, 39.81, 44.30, 47.57, 52.18, 55.94, 58.97, 60.27, 114.79, 119.94, 125.46, 128.72, 133.52, 142.68, 145.42, 145.53, 148.35, 148.94, 149.49, 153.92, 167.68. ES-MS m/z 516 (M+H). Anal. Calcd. for C31H41N5O2.0.1CH2Cl2.0.5C4H8O2: C, 69.96; H, 8.02; N, 12.32. Found: C, 69.80; H, 8.01; N, 12.39.
EXAMPLE 358




COMPOUND 358: N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure F, 4-methylnicotinic acid hydrochloride (578 mg, 3.33 mmol) and (R)-3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyronitrile (see EXAMPLE 230) (700 mg, 2.56 mmol) afforded the amide, which was subsequently reduced with BH3-THF (1.0M in THF, 10.0 mL, 10.0 mmol) in THF (17 mL) at reflux and then treated with 6N HCl (6.7 mL, 40.1 mmol) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine as a white solid (526 mg, 53% over 2 steps) after basic work-up and purification.
COMPOUND 358 was isolated as a white solid. 1H NMR (CDCl3) δ 0.97 (d, 3H, J=6.6 Hz), 1.00-1.33 (m, 2H), 1.47-1.61 (m, 1H), 1.70-1.83 (m, 3H), 2.04-2.15 (m, 1H), 2.30 (s, 9H), 2.42-2.52 (m, 1H), 2.68-2.88 (m, 3H), 3.19-3.36 (m, 2H), 3.69 (s, 3H), 3.75-3.88 (m, 2H), 6.60 (d, 2H, J=8.4 Hz), 6.69 (d, 2H, J=8.4 Hz), 6.85-6.91 (m, 3H), 7.01 (d, 1H, J=4.8 Hz), 7.94 (br s, 1H), 8.26 (s, 1H), 8.29 (d, 1H, J=5.1 Hz). ES-MS m/z 515 (M+H).
EXAMPLE 359




COMPOUND 359: N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
White solid. 1H NMR (CDCl3) δ 0.90-1.27 (m, 2H), 0.99 (d, 3H, J=2.2 Hz), 1.49-1.84 (m, 4H), 2.06-2.17 (m, 1H), 2.30 (s, 3H), 2.35 (s, 3H), 2.42-2.57 (m, 1H), 2.54 (s, 3H), 2.68-2.89 (m, 3H), 3.17-3.38 (m, 2H), 3.71 (s, 3H), 3.77-3.91 (m, 3H), 6.61 (d, 2H, J=8.7 Hz), 6.70 (d, 2H, J=8.7 Hz), 6.83 (d, 1H, J=5.1 Hz), 7.03 (d, 1H, J=4.5 Hz), 8.09-8.17 (m, 2H), 8.26 (s, 1H), 8.30 (d, 1H, J=4.8 Hz). ES-MS m/z 516 (M+H).
EXAMPLE 360




COMPOUND 360: 2-Amino-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}1-butyl)-6-methyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.97 (d, 3H, J=4.8 Hz), 1.11-1.44 (m, 2H), 1.46-1.59 (m, 1H), 1.67-1.93 (m, 3H), 2.03-2.16 (m, 1H), 2.29 (s, 3H), 2.31 (s, 3H), 2.40-2.53 (m, 1H), 2.70-2.90 (m, 3H), 3.21-3.36 (m, 2H), 3.70 (s, 3H), 3.72-3.86 (m, 1H), 3.93 (s, 2H), 4.04 (s, 2H), 6.38-6.47 (m, 2H), 6.58-6.81 (m, 5H), 6.98-7.05 (m, 1H), 7.85 (br s, 1H), 8.25-8.33 (m, 2H). ES-MS m/z 516 (M+H).
EXAMPLE 361




COMPOUND 361: 2-Chloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide
White solid. 1H NMR (CDCl3) δ 0.84-1.18 (m, 5H), 1.49-1.61 (m, 1H), 1.72-1.89 (m, 3H), 2.04-2.17 (m, 1H), 2.30 (s, 1H), 2.35 (s, 1H), 2.42-2.56 (m, 1H), 2.73-2.95 (m, 3H), 3.19-3.39 (m, 2H), 3.70 (s, 3H), 3.77-3.91 (m, 3H), 6.61 (d, 2H, J=7.8 Hz), 6.69 (d, 0.2H, J=7.8 Hz), 6.86-7.10 (m, 4H), 8.19 (br s, 1H), 8.23-8.32 (m, 2H). ES-MS m/z 535 (M+H).
EXAMPLE 362




COMPOUND 362: 3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide
White solid. 1H NMR (CDCl3) δ 0.92-1.22 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.48-1.58 (m, 1H), 1.76-1.89 (m, 3H), 2.05-2.16 (m, 1H), 2.41 (s, 3H), 2.44-2.55 (m, 1H), 2.73-2.93 (m, 3H), 3.13-3.24 (m, 1H), 3.28-3.41 (m, 1H), 3.73 (s, 3H), 3.78-3.92 (m, 1H), 3.91 (s, 2H), 6.61 (d, 2H, J=8.7 Hz), 6.71 (d, 2H, J=8.4 Hz), 7.01-7.06 (m, 1H), 8.24-8.33 (m, 2H), 8.43 (s, 2H), 8.61 (br s, 1H). ES-MS m/z 556 (M+H).
EXAMPLE 363




COMPOUND 363: N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-4-pyridin-4-yl-benzamide
White foam. 1H NMR (CDCl3) δ 0.83-1.38 (m, 5H), 1.59-1.88 (m, 4H), 2.09-2.19 (m, 4H), 2.41 (s, 6H), 2.47-2.58 (m, 1H), 2.77-2.91 (m, 3H), 3.25-3.42 (m, 2H), 3.69 (s, 3H), 3.77-3.91 (m, 3H), 6.58-6.69 (m, 4H), 6.84-6.85 (m, 1H), 7.27 (s, 2H), 7.34 (d, 2H, J=5.1 Hz), 7.76 (br s, 1H), 8.20-8.23 (m, 2H), 8.56 (d, 2H, J=5.4 Hz). ES-MS m/z 592 (M+H).
EXAMPLE 364




COMPOUND 364: 2,4-Dimethyl-thiophene-3-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide
White foam. 1H NMR (CDCl3) δ 0.99 (d, 3H, J=6.6 Hz), 1.18-1.59 (m, 3H), 1.72-1.87 (m, 3H), 2.10-2.18 (m, 1H), 2.21 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 2.46-2.53 (m, 1H), 2.75-2.85 (m, 3H), 3.27-3.36 (m, 2H), 3.69-3.77 (m, 1H), 3.71 (s, 3H), 4.08 (s, 2H), 6.52 (s, 1H), 6.63-6.74 (m, 4H), 7.03 (d, 1H, J=5.1 Hz), 7.41 (br s, 1H), 8.30-8.32 (m, 2H). ES-MS m/z 521 (M+H).
EXAMPLE 365




COMPOUND 365: N—((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-1-oxy-nicotinamide
White solid. 1H NMR (CDCl3) δ 1.05 (d, 3H, J=6.3 Hz), 1.29-1.53 (m, 2H), 1.58-1.67 (m, 2H), 1.85-1.92 (m, 3H), 2.18-2.26 (m, 1H), 2.28 (s, 3H), 2.35 (s, 6H), 2.48-2.58 (m, 1H), 2.80-2.92 (m, 3H), 3.25-3.45 (m, 2H), 3.62-3.70 (m, 1H), 3.72 (s, 3H), 4.10 (s, 2H), 6.66-6.75 (m, 4H), 6.83 (d, 1H, J=6.6 Hz), 7.03 (d, 1H, J=4.8 Hz), 7.90 (d, 1H, J=6.6 Hz), 8.30 (s, 2H), 8.41 (br s, 1H). ES-MS m/z 532 (M+H).
EXAMPLE 366




COMPOUND 366: N-(3-{4-[(4-Carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-amino]-benzamide (see EXAMPLE 355) (21.8 mg, 0.055 mmol) and 2,4-dimethylnicotinic acid hydrochloride (15 mg, 0.080 mmol) gave COMPOUND 366 as an off-white solid (24.6 mg, 84%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.09-1.38 (m, 2H), 1.53-1.63 (m, 1H), 1.72-1.90 (m, 3H), 2.24 (t, 1H, J=11.0 Hz), 2.29 (s, 3H), 2.39 (s, 3H), 2.53 (s, 3H), 2.59 (t, 1H, J=11.0 Hz), 2.74-2.93 (m, 3H), 3.31-3.42 (m, 1H), 3.71-3.84 (m, 2H), 4.12 (s, 2H), 5.64 (br s, 2H), 6.53 (d, 2H, J=8.9 Hz), 6.84 (d, 1H, J=5.0 Hz), 7.12 (d, 1H, J=4.9 Hz), 7.61 (d, 2H, J=8.9 Hz), 7.65 (br s, 1H), 8.18 (s, 1H), 8.18 (d, 1H, J=5.0 Hz), 8.37 (d, 1H, J=4.9 Hz). 13C NMR (CDCl3) δ 13.44, 18.65, 18.72, 22.26, 29.28, 30.17, 31.72, 39.11, 44.05, 44.86, 51.61, 56.13, 59.29, 112.07, 121.24, 122.44, 125.08, 129.13, 131.84, 133.50, 143.83, 144.19, 147.41, 148.19, 148.63, 150.95, 154.03, 168.20, 169.02. ESI-MS m/z 529 (MH)+. Anal. Calcd. for C31H40N6O2.0.6CH2Cl2: C, 65.48; H, 7.16; N, 14.50. Found: C, 65.26; H, 7.46; N, 14.25.
EXAMPLE 367




COMPOUND 367: N—((R)-3{4-[(4-Carbamoylmethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide
Using general procedure A with ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (see EXAMPLE 233) (796 mg, 2.10 mmol) and 4-methyl-3-pyridinecarboxaldehyde (see EXAMPLE 356) (367 mg, 3.00 mmol) in ClCH2CH2Cl (6 mL) followed by general procedure C afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 17% over 2 steps) as a white foam.
Using general procedure E, the amine (136 mg, 0.28 mmol) and 2,4-dimethyl-nicotinic acid (69 mg, 0.37 mmol) gave N—((R)-3-{4-[[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (165 mg, 99%).
To a solution of the above substrate (165 mg, 0.27 mmol) in THF (2 mL) at 0° C. was added TBAF (1M, 0.27 mmol) and the reaction mixture was stirred for 1 h at room temperature to give N—((R)-3-{4-[(4-hydroxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimetyl-nicotinamide (100 mg, 74%) as a white foam after purification.
To the above alcohol (100 mg, 0.2 mmol), ethyl glycolate (100 μL, 1.05 mmol) and Ph3P (277 mg, 1.06 mmol) in THF (3 mL) cooled to 0° C. was added DIAD (204 μL, 1.05 mmol) and reaction mixture was stirred for 1 h at room temperature to give the desired product as a yellow foam following purification.
The intermediate above was subjected to MeOH sat. NH3 and the mixture was stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure and the crude material was purified to give COMPOUND 367 (25 mg, 22%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=4.5 Hz), 0.98-0.99 (m, 1H), 1.15-1.26 (m, 1H), 1.5-1.58 (m, 1H), 1.69-1.82 (m, 2H), 2.03 (br s, 1H), 2,15 (t, 1H, J=5.4 Hz), 2.28 (s, 3H), 2.35 (s, 3H), 2.51 (s, 1H), 2.46-2.72 (m, 1H), 2.76-2.82 (m, 3H), 3.28-3.37 (m, 2H), 3.77-3.84 (m, 1H), 3.89 (s, 2H), 4.37 (s, 2H), 6.57 (d, 2H, J=9 Hz), 5.90 (br s, 1H), 6.66 (br s, 1H), 6.74 (d, 2H, J=9 Hz), 6.82 (d, 1H, J=4.8 Hz), 7.04 (d, 1H, J=5.1 Hz), 8.04 (br s, 1H), 8.12 (d, 1H, J=6 Hz), 8.23 (s, 1H), 8.30 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.78, 19.16, 19.22, 22.65, 29.80, 30.68, 31.74, 39.97, 44.32, 46.75, 52.29, 57.61, 58.90, 60.26, 68.20, 115.81, 118.78, 122.82, 125.50, 133.22, 134.00, 143.92, 144.20, 145.37, 148.45, 149.08, 149.18, 151.00, 154.44, 168.56, 171.77. ES-MS 12/z 560.0 (M+1).
EXAMPLE 368




COMPOUND 368: Methanesulfonic acid 4-[(1-{(R)-3-[(2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-methyl-pyridin-3-ylmethyl)-amino]-phenyl ester
Using general procedure G, N—((R)-3-{4-[(4-hydroxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimetyl-nicotinamide (see EXAMPLE 368) (46 mg, 0.09 mmol) gave COMPOUND 368 (6 mg, 11%) as a white foam. 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.07-1.12 (m, 1H), 1.17-1.32 (m, 2H), 1.67-1.82 (m, 2H), 2.17-2.21 (m, 1H), 2.30 (s, 3H), 2.38 (s, 3H), 2.54 (s, 3H), 2.54-2.57 (m, 2H), 2.76-2.89 (m, 3H), 3.05 (s, 3H), 3.33-3.38 (m, 1H), 3.58-3.65 (m, 1H), 3.70-3.83 (m, 1H), 4.05 (s, 2H), 6.47 (d, 2H, J=9 Hz), 6.84 (d, 1H, J=5.1 Hz), 7.02 (d, 2H, J=9 Hz), 7.01-7.03 (m, 1H), 7.11 (d, 1H, J=6 Hz), 7.69-7.70 (m, 1H), 8.15 (d, 1H, J=5.1 Hz), 8.24 (s, 1H), 8.36 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.82, 19.15, 22.72, 29.64, 30.59, 32.00, 37.15, 39.75, 44.36, 45.61, 52.23, 57.23, 59.99, 114.59, 122.86, 123.16, 123.35, 125.56, 133.97, 140.76, 144.23, 144.72, 147.83, 148.16, 148.62, 149.10, 154.47, 168.60. ES-MS m/z 580.4 (M+1).
EXAMPLE 369




COMPOUND 369: 2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide
A solution of 4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 352) (300 mg, 0.630 mmol), Pd(OAc)2 (7.10 mg, 0.0315 mmol), potassium tert-butoxide (106 mg, 0.945 mmol), morpholine (50.0 μL, 0.573 mmol) and tri(tert-butyl)phosphine (128 mg, 0.0315 mmol) in degassed toluene (2.2 mL) was stirred at 100° C. for 16 hours under nitrogen. Standard work-up and purification gave 4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (191 mg, 74%).
Using general procedure C with the tert-butyl carbamate (191 mg, 0.422 mmol), then general procedure I with the resulting amine and then using general procedure J gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amine as a white foam (51.5 mg, 19% over 3 steps).
Using general procedure E, the primary amine (36.1 mg, 0.0824 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (18.5 mg, 0.0989 mmol) afforded COMPOUND 369 as a white foam (22.5 mg, 48%). 1H NMR (CDCl3) δ 1.00 (d, 3H, J=6.0 Hz), 1.71-1.84 (m, 9H), 2.31 (s, 3H), 2.36 (s, 3H), 2.51-2.54 (m, 4H), 2.73-2.82 (m, 3H), 3.00 (t, 4H, J=4.7 Hz), 3.35-3.38 (m, 2H), 3.82 (t, 4H, J=4.7 Hz), 3.90 (s, 2H), 6.59 (d, 2H, J=8.7 Hz), 6.75 (d, 2H, J=8.7 Hz), 6.83 (d, 1H, J=4.2 Hz), 7.05 (d, 1H, J=4.5 Hz), 8.14 (d, 1H, J=4.5 Hz), 8.27 (s, 1H), 8.31 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 13.73, 19.18, 19.26, 22.71, 29.72, 30.63, 31.75, 39.94, 44.36, 45.67, 46.63, 50.86, 52.35, 58.83, 60.29, 67.42, 114.41, 117.76, 118.46, 122.85, 125.44, 129.64, 133.56, 142.89, 144.16, 145.32, 148.34, 149.14, 149.32, 154.51. ESI-MS m/z 571 (MH)+. Anal. Calcd. for C34H46N6O2.0.4H2O.1.3CH3OH: C, 67.77; H, 8.31; N, 13.43. Found: C, 67.73; H, 8.06; N, 13.18.
EXAMPLE 370




COMPOUND 370: N-(3-{4-[(4-Methoxy-phenyl)-pyridin-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide
Using general procedure H, 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 119) (585 mg, 1.90 mmol) and 3-picolyl chloride hydrobromide (1.9 g, 9.5 mmol) afforded a white solid (575 mg).
Using general procedure C with the above substrate (575 mg), then general procedure B with 2-(3-oxo-butyl)-isoindole-1,3-dione (136 mg, 0.63 mmol) and then using general procedure D afforded [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-pyridin-(4-methoxy-phenyl)-amine as a colourless syrup (90 mg, 58% over 3 steps).
Using general procedure E, the above amine (46 mg, 0.13 mmol) and 2,6-dimethylbenzoic acid (21 mg, 0.14 mmol) afforded COMPOUND 370 as a white solid (31 mg, 49%). 1H NMR (CDCl3) δ 0.91-1.28 (m, 2H), 0.98 (d, 3H, J=5.7 Hz), 1.49-1.54 (m, 1H), 1.70-1.74 (m, 3H), 2.10 (t, 1H, J=12.0 Hz), 2.31 (s, 6H), 2.51 (t, 1H, J=11.1 Hz), 2.73-2.85 (m, 3H), 3.22-3.41 (m, 2H), 3.69 (s, 5H), 3.88-3.90 (m, 1H), 6.58 (d, 2H, J=7.8 Hz), 6.70 (d, 2H, J=8.4 Hz), 6.91-6.95 (m, 3H), 7.16-7.20 (m, 1H), 7.47 (d, 1H, J=7.5 Hz), 8.45 (s, 2H), 8.52 (br s, 1H). 13C NMR (CDCl3) δ 13.73, 19.14, 29.07, 30.37, 30.91, 39.93, 43.60, 47.01, 52.27, 55.60, 58.49, 60.69, 114.52, 117.27, 123.24, 127.27, 128.44, 134.00, 134.56, 136.00, 138.61, 142.62, 148.04, 148.92, 152.55, 169.90. ES-MS m/z 501 (M+H). Anal. Calcd. for C31H40N4O2.0.2H2O: C, 73.31; H, 8.10; N, 11.03. Found: C, 73.39; H, 8.06; N, 11.13.
EXAMPLE 371




COMPOUND 371: 2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-1-oxy-nicotinamide
Using general procedure E, [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amine (see EXAMPLE 353) (90 mg, 0.25 mmol) and 2,4-dimethyl-1-oxy-nicotinic acid (52 mg, 0.31 mmol) gave COMPOUND 371 as a white foam (55.0 mg, 43%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6.6 Hz), 1.21-1.47 (m, 2H), 1.55-1.66 (m, 1H), 1.75-1.93 (m, 3H), 2.17-2.27 (m, 1H), 2.21 (s, 3H), 2.28 (s, 3H), 2.36 (s, 6H), 2.48-2.58 (m, 1H), 2.72-2.89 (m, 3H), 3.35-3.48 (m, 1H), 3.51-3.61 (m, 1H), 3.63-3.73 (m, 1H), 4.14 (s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.79 (d, 1H, J=6.6 Hz), 6.96 (d, 2H, J=8.4 Hz), 7.06 (d, 1H, J=5.4 Hz), 7.85 (d, 1H, J=6.6 Hz), 8.19 (br s, 1H), 8.32 (s, 1H), 8.33 (d, 1H, J=5.4 Hz). 13C NMR (CDCl3) δ 13.56, 14.91, 18.39, 18.54, 20.17, 29.61, 30.06, 32.57, 38.48, 44.86, 46.10, 51.11, 56.97, 57.90, 114.83, 124.76, 124.86, 127.13, 129.64, 133.28, 134.45, 136.87, 137.60, 144.34, 145.42, 146.34, 147.81, 148.32, 165.36. ESI-MS m/z 516 (MH)+. Anal. Calcd. for C31H41N5O2.0.7CH2Cl2: C, 66.20; H, 7.43; N, 12.18. Found: C, 65.94; H, 7.39; N, 12.18.
EXAMPLE 372
Cell Fusion Assay
The assay measures the ability of a test compound to inhibit gp120 and CD4/CCR5-dependent cell-cell fusion. The assay uses two cell lines, 1) CHO-tat cell line that expresses the viral gp120 from a R5 using virus (JR-FL) and the HIV tat proteins, 2) P4-CCR5 cell line that expresses human CD4 and CCR5 on the surface and carries β-galactosidase construct under the control of the retroviral promotor LTR. Once fusion of these two cell lines occurs, the tat protein from the CHO cell line trans-activates the reporter gene O-galactosidase in the P4-CCR5 cell line. In a 96 well format, 1×104 cells of each cell line are plated per well in the presence or absence of test compound. The cells are then incubated at 37° C., 5% CO2 for 18-24 hours. The β-galactosidase activity in each well is measured by the addition of a luminescence substrate (Gal-Screen substrate, Applied Biosystems) and luminescence monitored with a Victor 2 plate reader (Wallac). The ability of test compounds to inhibit fusion is indicated by a decrease in β-galactosidase activity. Results are reported as the concentration of test compound required to inhibit 50% of the β-galactosidase activity in the test controls.
When tested in the assay described above, many compounds of the invention exhibited IC50's in the range of 0.01 nM to 100 nM.
EXAMPLE 373
Assay for Inhibition of RANTES Binding to HEK293F.CCR5 Cells
For the competition binding studies, a concentration range of antagonist was incubated for 45 minutes at room temperature in binding buffer (50 mM HEPES, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA pH 7.4) with 8 μg of HEK293F.CCR5 cell membrane and 50 pM 125I-RANTES (Perkin Elmer, 81400 GBq/mmol) in Milipore GF-B filter plates. Unbound 125I-RANTES was removed by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. Compounds were tested at a concentration range of 10000-0.6 nM. The 50% inhibitory concentration (IC50 value) was defined as the concentration of test compound required to inhibit RANTES binding by 50% relative to untested controls.
When tested in the assay described above, the compounds of the invention exhibited IC50's in the range of 1 nM to 500 nM.
EXAMPLE 374
Assay for Inhibition of HIV-1 Using PBMC and R5
Performed as described in literature (Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4. 1997—D. Schols, S. Struyf, J. Van Damme, J. A. Esté, G. Henson & E. De Clercq. J. Exp. Med. 186, 1383-1388.)
The method were as follows:
PBMC from healthy donors were isolated by density gradient centrifugation and stimulated with PHA at 1 μg/ml (Sigma Chemical Co., Bornem, Belgium) for 3 days at 37° C. The activated cells (PHA-stimulated blasts) were washed three times with PBS, and viral infections were performed. The cells were seeded in 48-well plates (5×105 cells per well in 200 uL culture medium) and pre-incubated for 15 min with compounds at different concentrations. Then 500 pg p24 viral Ag/well of CCR5-using viruses was added. The HIV-1 R5 strains BaL, SF-162, ADA, and JR-FL were all obtained through the Medical Research Council AIDS reagent project (Herts, UK).
HIV-infected or mock-infected PHA-stimulated blasts were then further cultured in the presence of 25 U/ml of IL-2 and supernatant was collected at days 8-10, and HIV-1 core antigen in the culture supernatant was analyzed by the p24 Ag ELISA kit from DuPont-Merck Pharmaceutical Co. (Wilmington, Del.).
When tested in the assay described above, many compounds of the invention exhibited IC50's in the range of 0.01 nM to 50 μM.

## Claims

1. A compound or a pharmaceutically acceptable salt thereof, having the formula:



where
n is 0 or 1;
R1 is pyridinyl or pyrimidinyl, each optionally substituted by one or more halogen, alkyl, amine or heteroaryl;
R2 is phenyl, pyridinyl, thiazolyl, furanyl, or thiophenyl, each of which is optionally linked to one or more C1-C6 alkyl, alkoxy, trifluoromethyl, carboxylalkyl, cyano, or halogen;
R3 is phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl, indolyl, indolinyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzofuranyl, 2,3-dihydroxybenzofuranyl or phthalanyl, each of which is optionally linked to one or more C1-C6 alkyl, trifluoromethyl, oxotrifluoromethyl, carboxylalkyl, cyano, halogen, sulfanyl, SO2R9, where R9 is alkyl, amine or amino alkyl, C(O)R10, where R10 is alkyl, amine, morpholine, NMe2, N(OMe)Me, NHPh, piperidine, NHMe, piperazine, NHCH2C(O)OMe or PhC(O)OH, OR11, where R11 is H, alkyl, (CH2)2OMe, CH2C(O)NH2, CH2C(O)NHNH2, CH2C(O)OCMe3, CH2C(O)OMe, CH2C(O)OH, PhC(O)OH, PhC(O)NH2, SO2Me, C(O)Me, C(O)OMe, C(O)NEt2, C(O)NMe2 or





NHR12, where R12 is H, C(O)Me, C(O)CF3, SO2Me, C(O)NH2, C(O)NMe2 or




NO2, CH2PhC(O)OH, SOMe, CH2NHC(O)Me, morpholine, CH═CHC(O)OMe, CH═CHC(O)OH,




and
R4 is hydrogen or alkyl.

2. The compound of claim 1, where R4 is hydrogen.

3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of
N-(3-{4-[(4-Bromo-phenyl)-(3-chloro-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (62);
N-(3-{4-[Benzyl-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (63);
3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (64);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (65);
3,5-Dichloro-N-(3-{4-[(4-cyano-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (66);
N-(3-{4-[Benzyl-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (67);
3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (68);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (69);
N-(3-{4-[Benzyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (70);
3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (71);
3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (72);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (73);
3,5-Dichloro-N-(3-{4-[(3-methyl-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (74);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (75);
3,5-Dichloro-N-(3-{4-[(4-methanesulfonyl-phenyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (76);
3,5-Dichloro-N-(3-{4-[(3-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (77);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (78);
N-(3-{4-Benzyl-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (79);
Methanesulfonic acid 4-[benzyl-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (80);
N-(3-{4-[Benzyl-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (81);
3,5-Dichloro-N-(3-{4-[(3-chloro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (82);
N-(3-{4-[Benzyl-(4-sulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (83);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-fluoro-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (84);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-(3-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (95);
4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl}-benzoic acid (96);
4-{4-[Benzyl-(1-{1-methyl-3-[(4-methyl-pyridine-3-carbonyl)-amino]-propyl}-piperidin-4-yl)-amino]-phenoxyl}-benzoic acid (99);
4-{4-[Benzyl-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzyl}-benzoic acid (102);
N-(3-{4-[(4-Bromo-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-3,5-dichloro-isonicotinamide (103);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-trifluoro-methyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (104);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (105);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (106);
4-[(3-Cyano-benzyl)-(1-{3-[(3,5-dichloro-pyridine-4-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (107);
3,5-Dichloro-N-(3-{4-[(4-chloro-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (108);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (111);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (114);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-hydrazinocarbonylmethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (116);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methanesulfonylamino-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (118);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (119);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (123);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfinyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (125);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-methanesulfonyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (126);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-nitro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (127);
3,5-Dichloro-N-(3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (128);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (129);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (133);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(piperazine-1-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (135);
4,6-Dimethyl-pyrimidine-5-carboxylic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (136);
Acetic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (138);
Carbonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester methyl ester (140);
{4-[(Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (144);
Dimethyl-carbamic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (146);
{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl-acetic acid methyl ester (148);
{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl-acetic acid (150);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-methylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (152);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(cyclopropanecarbonyl-amino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (154);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (157);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (159);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (161);
4-{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxyl{-benzoic acid (162);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (164);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(3-cyano-benzyl)-[4-(morpholine-4-carbonyl)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (167);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl}-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (168);
Methanesulfonic acid 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl ester (169);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (171);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (173);
{4-[(3-Cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoylamino}-acetic acid methyl ester (175);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (178);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (179);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzofuran-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (181);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzofuran-5-yl-(3-cyano-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (184);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(3,4-dimethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (186);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (188);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(3-cyano-benzyl)-(6-methoxy-pyridin-3-yl)-amino]-piperidin-1-yl}-butyl)-amide (191);
3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (195);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (197);
3,5-Dichloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-chloro-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (198);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dimethylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (199);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (201);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (203);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (205);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (207);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(4-sulfamoyl-phenyl)-amino]-piperidine-1-yl}-butyl)-amide (209);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetyl-phenyl)-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (211);
3-[(5-Chloro-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid methyl ester (2{3);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(3-methylcarbamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (214);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidin-1-yl}-butyl)-amide (215);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-chloro-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (218);
3,5-Dichloro-N-(3-{4-[(5-cyano-2-fluoro-benzyl)-(4-cyano-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (219);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (221);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [3-(4-{(5-cyano-2-fluoro-benzyl)-[4-(2-methoxy-ethoxy)-phenyl]-amino}-piperidin-1-yl)-butyl]-amide (223);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-acetylamino-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (225);
(E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl 1-acrylic acid methyl ester (227);
4-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-benzoic acid (228);
N-((R)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (230);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (231);
N-((R)-3-{4-[(4-Acetyl-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (232);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(5-cyano-2-fluoro-benzyl)-(4-hydroxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (233);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(4-ureido-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (234);
{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid tert-butyl ester (235);
{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid methyl ester (237);
{4-[(5-Cyano-2-fluoro-benzyl)-(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenoxy}-acetic acid (238); 4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (239);
(E)-3-{4-[(5-Cyano-2-fluoro-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-phenyl}-acrylic acid (240);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[benzo[1,3]dioxol-5-yl-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (242);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-cyano-2-fluoro-benzyl)-(1H-indol-5-yl)-amino]-piperidin-1-yl}-butyl)-amide (245);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-(5-cyano-2-fluoro-benzyl)-amino]-piperidin-1-yl}-butyl)-amide (246);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (290);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (291);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-chloro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (292);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-acetyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (293);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(1-methoxyimino-ethyl)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (294);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[thiophen-3-ylmethyl-(4-trifluoromethyl-phenyl)-amino-piperidin-1-yl}-butyl)-amide (295);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-hydroxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (296);
{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid (297);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-carbamoylmethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (298);
4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-benzoic acid methyl ester (299);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (300);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (301);
4-{4-[(1-{(R)-3-[(4,6-Dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-benzoic acid (302);
4,6-Dimethyl-pyrimidine-5-carboxylic acid [(R)-3-(4-{[4-(4-carbamoyl-phenoxy)-phenyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide (303);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-fluoro-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (304);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-ethoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (305);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-cyano-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (306);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methylsulfanyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (307);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methanesulfonyl-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (308);
3,5-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (309);
2,4-Dimethyl-N-((R)-3-{4-[thiophen-3-ylmethyl-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (316);
N-((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (321);
3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-isonicotinamide (323);
N-((R)-3-{4-[(4-Methoxy-phenyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (325);
4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (327);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-acetylamino-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (328);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (329);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(6-bromo-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (330);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(6-ethoxy-pyridin-3-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (331);
2,4-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide (334);
3,5-Dichloro-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (336);
3,5-Dimethyl-N-{3-[4-(pyridin-3-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-isonicotinamide (337);
4,6-Dimethyl-pyrimidine-5-carboxylic acid {3-[4-(pyrimidin-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (339);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (342);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-bromo-thiophen-3-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (343);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methoxy-phenyl)-(4-methoxy-thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (344);
4,6-Dimethyl-pyrimidine-5-carboxylic acid {(R)-3-[4-(benzo[1,3]dioxol-5-yl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-amide (345);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (346);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-thiophen-2-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (347);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(3-methyl-thiophen-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (348);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(5-chloro-thiophen-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (349);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[furan-2-ylmethyl-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (350);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (351);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (352);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-methyl-pyridin-3-ylmethyl)-p-tolyl-amino]-piperidin-1-yl}-butyl)-amide (353);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-methylsulfanyl-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (354);
4,6-Dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(4-carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (355);
4,6-Dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-trifluoromethoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-amide (356);
N-(3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-isonicotinamide (357);
N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (359);
3,5-Dichloro-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-isonicotinamide (362);
N-(3-{4-[(4-Carbamoyl-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (366);
N-((R)-3 {4-[(4-Carbamoylmethoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide (367);
Methanesulfonic acid 4-[(1-{(R)-3-[(2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-(4-methyl-pyridin-3-ylmethyl)-amino]-phenyl ester (368); and
2,4-Dimethyl-N-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (369).

5. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier.

6. The compound of claim 1, wherein R3 is indolyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, or benzofuranyl.