ZA200610426B - 3-Aminocyclopentanecarboxamides as modulators of chemokine receptors - Google Patents

Description

3-AMINOCY CLOPENTANECARBOXAMIDES AS MODULATORS OF

CHEMOKINE RECEPTORS

FIELD OF THE INVENTION

The present invention relates to compounds that modulate the activity of chemokine receptors such as CCR2 and CCRS. In some embodiments, the compounds modulate both

CCR2 and CCRS5. The compounds can be used, for example, to treat diseases associated with chemokine receptor expression or activity.

BACKGROUND OF THE INVENTION

The migration and transport of leukocytes from blood vessels into diseased tissues is involved in the initiation of normal disease-fighting inflammatory responses. The process, also known as leukocyte recruitment, is also related to the onset and progression of life- threatening inflammatory, as well as debilitating autoimmune diseases. The resulting pathology of these diseases derives from the attack of the body's immune system defenses on normal tissues. Accordingly, preventing and blocking leukocyte recruitment to target tissues in inflammatory, autoimmune disease and cancer would be a highly effective approach to therapeutic intervention.

The different classes of leukocyte cells that are involved in cellular immune responses include monocytes, lymphocytes, neutrophils, eosinophils and basophils. In most cases, lymphocytes are the leukocyte class that initiates, coordinates, and maintains chronic inflammatory responses, and blockage of these cells from entering inflammatory sites is desirable. Lymphocytes attract monocytes 10 the tissue sites, which, collectively with lymphocytes, are responsible for most of the actual tissue damage that occurs in inflammatory disease. Infiltration of the lymphocytes and/or monocytes is known to lead to a wide range of chronic, autoimmune diseases, and also organ transplant rejection. These diseases include, but are not limited to, rheumatoid arthritis, chronic contact dermatitis, inflammatory bowel disease, lupus, systemic lupus erythematosus, multiple sclerosis, atherosclerosis, psoriasis, sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skin pemphigoid and related diseases, (e.g., Pemphigus vulgaris, P. foliacious, P. erythematosis),

glomerulonephritides, vasculitides, hepatitis, diabetes, allograft rejection, and graft-versus- host disease.

The process by which leukocytes leave the bloodstream, accumulate at inflammatory sites, and start disease is believed to have at least three steps which have been described as (1) rolling, (2) activation/firm adhesion and (3) transendothelial migration [Springer, T. A.

Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873 (1991); Butcher, E. Cc.

Cell 67:1033-1036 (1991)]. The second step is mediated at the molecular level by chemoattractant receptors. Chemoattractant receptors on the surface of leukocytes then bind chemoattractant chemokines which are secreted by cells at the site of damage or infection.

Receptor hinding activates leukocytes, increases the adhesiveness of the adhesion molecules that mediate transendothelial migration, and promotes directed migration of the cells toward the source of the chemoattractant chemokine.

Chemotactic chemokines (leukocyte chemoattractant/activating factors) also known as chemokines, also known as intercrines and SIS chemokines, are a group of inflammatory/ immunomodulatory polypeptide factors of molecular weight 6-15 kDa that are released by a wide variety of cells such as macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endotherial cells, smooth muscle cells, and mast cells, at inflammatory sites (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). Also, chemokines have been described in Oppenheim, J. J. et al., Annu. Rev. 50 Immunol, 9:617-648 (1991); Schall and Bacon, Curr. Opin. Immunol. 6:865-873 (1994);

Baggiolini, M., et al., and Adv. Immunol. 55:97-179 (1994). Chemokines have the ability to stimulate directed cell migration, a process known as chemotaxis. Each chemokine contains four cysteine residues (C) and two internal disulfide bonds. Chemokines can be grouped into two subfamilies, based on whether the two amino terminal cysteine residues are immediately adjacent (CC family) or separated by one amino acid (CXC family). These differences correlate with the organization of the two subfamilies into separate gene clusters. Within each gene cluster, the chemokines typically show sequence similaritics between 25 to 60%. The

CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-la,

MIP-1B, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.

MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic and activating factor) or JE) is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts, and vascular endothelial cells and causes cell migration and cell adhesion of monocytes (see for example Valente, A. J, et al., Biochemistry, 1988, 27, 4162;

Matsushima, K., et al, J. Exp. Med., 1989, 169, 1485; Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, B. J., et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B.

J., et al., Blood, 1991, 78, 1112; Jiang, Y., etal, J. Immunol., 1992, 148, 2423; Vaddi, K., et al, J. Immunol, 1994, 153, 4721). memory T lymphocytes (see for example Carr, M. W., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see for example Loetscher,

P., et al, FASEB J, 1994, 8, 1055) and natural killer cells (see for example Loetscher, P., et al., J. Immunol., 1996, 156, 322; Allavena, P., et al., Eur. J. Immunol. , 1994, 24, 3233), as well as mediating histamine release by basophils (see for example Alam, R., et al., J. Clin.

Invest., 1992, 89, 723, Bischoff, S. C., et al., J. Exp. Med., 1992, 175, 1271; Kuna, P. etal,

J. Exp. Med., 1992, 175, 489). In addition, high expression of MCP-1 has been reported in diseases where accumulation of monocyte/macrophage and/or T cells is thought to be important in the initiation or progression of diseases, such as atherosclerosis (see for example

Hayes, I. M,, et al, Arterioscler. Thromb. Vasc. Biol, 1998, 18, 397; Takeya, M.. et al,

Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S., et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; Nelken, N. A., J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see for example

Koch, A. E., et al, J. Clin. Invest., 1992, 90, 772; Akahoshi, T., et al., Arthritis Rheum, 1993, 36, 762; Robinson, E., et al,, Clin. Exp. Immunol. 101, 398), nephritis (see for example Noris, M., et al, Lab. Invest., 1995, 73, 804; Wada, T., at al., Kidney Int., 1996, 49, 761; Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (see for example Saitoh,

A., et al, J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H., et al., J. Leukoc. Biol, 1998, 63, 493), pulmonary fibrosis, pulmonary sarcoidosis (see for example Sugiyama, Y., et al,

Internal Medicine, 1997, 36, 856), asthma (see for example Karina, M., et al, J. Invest.

Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; Sousa, A. R,, et al,, Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see for example McManus, C., et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see for example Gillitzer, R., et al., J. Invest. Dermatol., 1993, 101, 127), inflammatory bowel disease (see for example Grimm, M. C., et al, J. Leukoc. Biol, 1996, 59, 804;

Reinecker, H. C., et al., Gastroenterology, 1995, 106, 40), myocarditis (see for example

Seino, Y., et al., Chemokine, 1995, 7, 301), endometriosis (see for cxample Jolicoeur, C.,et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see for example Zeyneloglu, H.

B., et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see for example

Aurust, P., et al., Circulation, 1998, 97, 1136), chronic liver disease (see for example Marra,

Fetal, Am. J. Pathol. 1998, 152, 423), viral meningitis (see for example Lahrtz, F., et al.,

Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see for example Wong, M.; et al, J.

Rheumatol, 1997, 24,1179) and sepsis (see for example Salkowski, C. A.; et al., Infect.

Immun., 1998, 66, 3569). Furthermore, anti-MCP-1 antibody has been reported to show an inhibitory effect or a therapeutic effect in animal models of rheumatoid arthritis (see for example Schimmer, R. C.. et al,, J. Immunol., 1998, 160, 1466; Schrier, D. J., J. Leukoc.

Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol, 1997, 182, 106), multiple sclerosis (see for example Karpus, W. J, et al., J. Leukoc. Biol., 1997, 62, 681), nephritis (see for example

Lloyd, C. M,, et al,, J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB I., 1996, 10, 1418), asthma (see for example Gonzalo, J.-A, et al,, J. Exp. Med., 1998, 188, 157; Lukacs,

N.W.,J. Immunol., 1997, 158, 4398), atherosclerosis (see for example Guzman, L. A., et al.,

Circulation, 1993, 88 (suppl), 1-371), delayed type hypersensitivity (see for example Rand,

M. L., et al, Am. J. Pathol, 1996, 148, 855), pulmonary hypertension (see for example

Kimura, H., et al., Lab. Invest, 1998, 78, 571), and intraperitoneal adhesion (see for example

Zeyneloglu, H. B., et al, Am. J. Obstet. Gynecol., 1998, 179, 438). A peptide antagonist of

MCP-1, MCP-1(9-76), has been also reported to inhibit arthritis in the mouse model (see

Gong, J.-H., J. Exp. ,4ed. , 1997, 186, 131), as well as studies in MCP-1-deficient mice have shown that MCP-1 is essential for monocyte recruitment in vivo (see Lu, B., et al, J. Exp.

Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).

Chronic obstructive pulmonary disease (COPD) ranks among the most common 55 causes of death in Western societies. It is defined by a progressive decline in lung function, only partly reversible by bronchodilator drugs. COPD is characterized by chronic inflammation in the airways or alveoli that differs from that seen in asthma, involving increased numbers of neutrophils, macrophages, CD8+ T cells, and/or mast cells in the airway walls, alveolar compartments, and vascular smooth muscle. Cytokines associated with COPD are believed to include tumor necrosis factor (TNF)-alpha, interferon (IFN)- gamma, interleukin (IL)-1 beta, IL-6, IL-8 and MCP-1, CCR2 is known to be a receptor for

MCP-1, and recent data support a role for MCP-1 and CCR2 in airway remodeling and inflammation directly or via macrophages. Thus, antagonists of CCR2 are an attractive approach to therapeutic treatment of COPD (De Boer, W. L, Chest, 2002, 121, 2095-2188).

The literature indicates that chemokines such as MCP-1 and MIP-la attract monocytes and lymphocytes to disease sites and mediate their activation and thus are thought to be intimately involved in the initiation, progression and maintenance of diseases deeply involving monocytes and lymphocytes, such as atherosclerosis, restenosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy,

Kawasaki disease, and sepsis (see for example Rovin, B. H., et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C., et al., Curr. Opin. Nephrol. Hypertens. 1998, 7, 281; Conti, P., et al., Alleigy and Asthma Proc, 1998, 19, 121; Ransohoff, R. M,, et al., Trends Neurosci., 1998, 21, 154; MacDermott, R. P., et al., Inflammatory Bowel Diseases, 1998, 4, 54).

The chemokines bind to specific cell-surface receptors belonging to the family of G- protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm.

Sci., 15, 159-165 (1994) which are termed "chemokine receptors." On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric

G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration.

Genes encoding receptors of specific chemokines have been cloned, and it is known that these receptors are G protein-coupled seven-transmembrane receptors present on various leukocyte populations. So far, at least five CXC chemokine receptors (CXCR1-CXCRS) and eight CC chemokine receptors (CCR1-CCR10) bave been identified. For example IL-8 isa ligand for CXCR1 and CXCR2, MIP-1a is a ligand for CCR1 and CCRS, and MCP-1 is a ligand for CCR2A and CCR2B (for reference, see for example, Holmes, W.E,, et al., Science 1991, 253, 1278-1280; Murphy P. M,, et al., Science, 253, 1280-1283; Neote, K. et al, Cell, 1993, 72, 415-425; Charo, I. F., et al, Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756;

Yamagami, S., et al., Biochem, Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier,

C., et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494, Power, C. A, et al., 1. Biol. Chem., 1995, 270, 19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362- 3367; Murphy, P. M,, Annual Review of Immunology, 1994, 12, 592-633). It has been reported that lung inflammation and granuroma formation are suppressed in CCR1-deficient mice (see Gao, J.-L., et al, J. Exp. Med., 1997, 185, 1959; Gerard, C., et al., J. Clin. Invest., 1997, 100, 2022), and that recruitment of macrophages and formation of atherosclerotic lesion decreased in CCR2-deficient mice (see Boring, L., et al., Nature, 1998, 394, 894;

Kuziel, W. A, et al., Proc. Natl. Acad. Sci., USA, 1997, 94, 12053; Kurihara, T., et al., J.

Exp. Med., 1997, 186, 1757; Boring, L., et al., J. Clin. Invest., 1997, 100, 2552).

Chemokine receptors are also known as coreceptors for viral entry leading to viral infection such as, for example, HIV infection. Reverse transcription and protein processing are the classic steps of the viral life cycle which antiretroviral therapeutic agents are designed to block. Although many new drugs that are believed to block viral entry hold promise, there is currently no agent to which HIV-1 has not been able to acquire resistance. Multiple rounds of viral replication are required to generate the genetic diversity that forms the basis of resistance. Combination therapy in which replication is maximally suppressed remains 2 cornerstone of treatment with entry inhibitors, as with other agents. The targeting of multiple steps within the viral entry process is believed to have the potential for synergy (Starr-Spires et al., Clin. Lab. Med., 2002, 22(3), 681.)

HIV-1 entry into CD4(+) cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. The TAK-779 molecule is one such antagonist of CCRS that acts to prevent HIV-1 infection. TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCRS.

The binding site for TAK-779 on CCRS is located near the extracellular surface of the receptor, within a cavity formed between {ransmembrane helices 1, 2, 3, and 7 (Dragic et al,

Proc. Natl. Acad. Sci. USA, 2000, 97(10), 5639).

The chemokine receptors CXCR4 and CCRS are believed to be used as co-receptors by the T cell-tropic (X4) and macrophage-tropic (RS) HIV-1 strains, respectively, for entering their host cells. Propagation of RS strains of HIV-1 on CD4 lymphocytes and macrophages requires expression of the CCRS5 coreceptor on the cell surface. Individuals lacking CCR5 (CCRS Delta 32 homozygous genotype) are phenotypically normal and resistant to infection with HIV-1. Viral entry can be inhibited by the natural ligands for

CXCR4 (the CXC chemokine SDF-1) and CCRS (the CC chemokines RANTES, MIP-1alpha and MIP-1beta). The first non-peptidic compound that interacts with CCRS5, and not with

CXCRA4, is a quaternary ammonium derivative, called TAK-779, which also has potent but variable anti-HIV activity (De Clercq et al., Antivir. Chem. Chemother. 2001, 12 Suppl. 1, 19.

SCH-C (SCH 351125) is another small molecule inhibitor of HIV-1 entry via the

CCRS coreceptor. SCH-C, an oxime-piperidine compound, is a specific CCRS antagonist as determined in multiple receptor binding and signal transduction assays. This compound specifically inhibits HIV-1 infection mediated by CCR5 in U-87 astroglioma cells but has no effect on infection of CXCR4-expressing cells. (Strizki et al, Proc. Natl. Acad. Sci. USA, 2001, 98(22), 12718 or Tremblay et al., Antimicrobial Agents and Chemotherapy, 2002, 46(5), 1336).

AD101, chemically related to SCH-C, also inhibits the entry of human immunodeficiency virus type 1 (HIV-1) via human CCRS. It has been found that AD101 inhibits HIV-1 entry via rhesus macaque CCRS5 while SCH-C does not. Among the eight residues that differ between the human and macaque versions of the coreceptor, only one, methionine-198, accounts for the insensitivity of macaque CCRS5 to inhibition by SCH-C.

Position 198 is in CCRS transmembrane (TM) helix 5 and is not located within the previously defined binding site for AD101 and SCH-C, which involves residues in TM helices 1, 2, 3, and 7. Based on studies of amino acid substitutions in CCRS, it has been suggested that the region of CCR5 near residue 198 can influence the conformational state of this receptor. (Billick et al, 2004, J. Virol., 78(8), 4134).

The identification of compounds that modulate the activity of chemokine receptors represents a desirable drug design approach for the needed development of pharmacological agents for the treatment of diseases associated with chemokine receptor activity. The compounds of the present invention help fulfill these and other needs.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula L:

R6 v3 ET"

SCR x

RY O— 1 or pharmaceutically acceptable salts or prodrugs thereof, wherein constituent members are provided herein.

The present invention further provides compositions comprising a compound of

Formula I and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating activity of a chemokine receptor comprising contacting the chemokine receptor with a compound of Formula IL

The present invention further provides methods of treating a disease associated with expression or activity of a chemokine receptor in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula L

The present invention further provides methods of treating HIV infection in a patient

S comprising administering to said patient a therapeutically effective amount of a compound of

Formula I.

The present invention further provides a compound described herein for use in therapy.

The present invention further provides a compound described herein for the preparation of a medicament for use in therapy.

DETAILED DESCRIPTION

Compounds

The present invention provides, infer alia, compound of Formula I: 7 o Z°7Y i” R8 \ CR oe "

RS” © 1 or pharmaceutically acceptable salts or prodrugs thereof, wherein: a dashed line indicates an optional bond;

Wis:

RA R®

WOE + (Mp RM or REY;

Vis N, NU or CR’;

X is N, NO or CR?

Y is N, NO or CR’;

Z is N,NO or CR*; wherein no more than one of V, X,Y and Z is NO;

RA, RM, RBand R®! are each, independently, H, OH, halo, Cys alkyl, C15 alkenyl, Cs alkynyl, Cy haloalkyl, Cy alkoxy, Cis haloalkoxy, heterocyclyl, carbocyclyl, NR'“R'2,

NR'°CO,R!!; NRI°CONR!RY, NRYSO,NRY RZ, NR'*-SO,-R"!, CN, CONR'R2, CORY,

NO», SR', SOR'®, SO,R'%; or SO NR'R";

R! is Cy alkyl, C1. haloalkyl, C1.¢ hydroxyalkyl, ~(Cos allcyl)-0-(Cus alkyl), (Cos alkyl)-S-(Cros alkyl), (Cos alkyl)-(Cs.7 cycloalkyD-(Cos alkyD), OH, ORY, SR, COR",

CO,RY, CONR!’R?, carbocyclyl, heterocyclyl, CN, NRURIZ, NRUSO.RY, NR'’COR",

NR'9CO,R®, NR ’CONR, CR*R"'COR" or CR!°R!'OCOR";

RZ RY, R¢, R® and R® are each, independently, H, OH, halo, Ci alkyl, C,.¢ haloalkyl,

C, alkoxy, Ci. haloalkoxy, Cie thioalkoxy, NR'R2Z, NR'°COR'; NRCONR'’R",

NRUYSO,NRR'?, NR!-SOR', heterocyclyl, carbocyclyl, ~~ carbocyelyloxy, heterocyclyloxy, CN, NOz, COR", CONRIR?, COR", NO,, SRY, SOR, SOR; or SO2-

NR'OR 2,

R is H or Cy. alkyl optionally substituted by 1-3 substituents selected from halo, OH,

CO,H, CO,-(C1.6 alkyl), or Cy.3 alkoxy;

R® is C,.; alkoxy, Ci.3 haloalkoxy, Cs. cycloalkyloxy or OH;

RY isH;

R® and RY are each, independently, H, Ci alkyl, halo, Ci.3 alkoxy, Ci3 haloalkoxy,

Css cycloalkyl, Css cycloalkyloxy, OH, CO,R!®, OCOR! , wherein said Cis alkyl is optionally substituted with one or more substituents selected from F, C13 alkoxy, OH or

COR"; or R? and R” together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;

RY is H, C,.alkyl, benzyl, phenyl, or C36 cycloalkyl, wherein said Ci. alkyl, benzyl, phenyl, or Cs cycloalkyl is optionally substituted with 1-3 selected from halo, OH, Ci; alkyl, Cy.3 haloalkyl, C, 3 alkoxy, C3 haloalkoxy, CO;H, and CO2+(Ci. alkyl);

R!! is H, OH, Cis alkyl, Ci.¢ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, Css cycloalkyl or Cig cycloalkyloxy, wherein said Cis alkyl, Ci alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, Cs.s cycloalkyl or Cs. cycloalkyloxy, is optionally substituted with 1- 3 substituents selected from halo, OH, Ci.3 alkyl, Ci. alkoxy, CO.H, CO,-(C1¢ alkyl) and

CFs;

R12 is H, C1. alkyl, benzyl, phenyl, or Cs. cycloalkyl, wherein said Ci alkyl, benzyl, phenyl, or Cis cycloalkyl is optionally substituted with 1-3 selected from halo, OH, Cis alkyl, Cy.3 haloalkyl, Cy; alkoxy, Ci3 haloalkoxy, CO;H, and CO»-(C1. alkyl); and pisOorl.

The present invention further provides, inter alia, compounds of Formula II:

RS rss es

R®

R% ©

I or pharmaceutically acceptable salts or prodrugs thereof, wherein: a dashed line indicates an optional bond;

Wis:

RA R® oe Nat Os ry RAT or RE!

X is N, NO or CR?

Y is N, NO or CR’;

Z is N, NO or CR; wherein no more than one of X, Y and Z is NO;

RA, RA! RPand RP! are each, independently, H, OH, halo, C15 alkyl, Cig alkenyl, Cis alkynyl, Cs haloalkyl, Ci. alkoxy, Ci.¢ haloalkoxy, heterocyclyl, carbocyclyl, NR'°RY,

NRYCO.R! : NR°CONR!R*?, NRSO,NR'R"2, NR!-80,-R"}, CN, CONR!RY, CORY,

NO,, SR'®, SOR, SOR", or SO-NR'R";

R! is Cy alkyl, C1. haloalkyl, (Co.¢alkyl)-O-(C1s alkyl), (Cos alkyl)-S-(C1-s alkyl), (Co.galkyl)-(Ca.s cycloalkyl)(Co. alkyl), OH, ORY, SR', COR"', COR", CONR'’R", carbocyelyl, heterocyclyl, CN, NR'R™2, NRSO,R!, NR’COR', NR’COR",

NRUCONR2, CRPR!'CO,;RY or CR’R"'OCOR";

R%, R3, RY, RS and R® are each, independently, H, OH, halo, Ci.¢ alkyl, Ci.s haloalkyl, -

C16 alkoxy, Cis haloalkoxy, Ci. thioalkoxy, NRIR!2, NR'*COR!; NR'°CONR'RY,

NRMSO,NRIPR'Z, NR'-S0,-R", heterocyclyl, carbocyelyl, carbocyclyloxy, heterocyclyloxy, CN, NOz, COR', CONRR2, COR", NO, SR', SOR’, SO,R'%; or 802-

NRIR!;

R’ is H or Cy.¢alkyl optionally substituted by 1-3 substituents selected from halo, OH,

CO,H, CO2-(Ci16 alkyl), or Cy; alkoxy;

R® is Cy; alkoxy, C13 haloalkoxy, C36 cycloalkyloxy or OH;

RY is H;

R® and B®" are each, independently, H, Ci.salkyl, halo, Cy. alkoxy, Ci.3 haloalkoxy,

C5.¢ cycloalkyl, Cs. cycloalkyloxy, OH, CO,RY®, OCOR!®, wherein said C16 alkyl is optionally substituted with one or more substituents selected from F, C;.3 alkoxy, OH or

COR"; or R® and RY together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group;

RY is H, C,.4 alkyl, benzyl, phenyl, or C36 cycloalkyl, wherein said Cy. alkyl, benzyl, phenyl, or C36 cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C3 alkyl, Cy.; haloalkyl, C).3 alkoxy, C1.3 haloalkoxy, CO;H, and CO,~(C 1.6 alkyl);

R!! is H, OH, Ci alkyl, Ci¢alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, Cs cycloalkyl or Cs. cycloalkyloxy, wherein said Cy.¢ alkyl, Ci.¢ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C3 ¢ cycloalkyl or Cs cycloalkyloxy, is optionally substituted with 1- 3 substituents selected from halo, OH, Cy.3 alkyl, C13 alkoxy, CO;H, CO2-(C16 alkyl) and

CFs;

R'? is H, C4 alkyl, benzyl, phenyl, or C3.6 cycloalkyl, wherein said Ci.6 alkyl, benzyl, phenyl, or Cs.¢ cycloalkyl is optionally substituted with 1-3 selected from halo, OH, Ci.3 alkyl, C3 haloalkyl, C;.3 alkoxy, C13 haloalkoxy, CO.H, and CO2-(Ci6 alkyl); and pisOorl.

In some embodiments, W is

RA

+) (Mp rat

In some embodiments, W is

RB ey

RB!

In some embodiments, V is CR’.

In some embodiments, X is CR.

In some embodiments, Y is CR’.

In some embodiments, Z is CR.

In some embodiments, X is N.

In some embodiments, Z is N.

In some embodiments, both X and Z are N.

In some embodiments, X is CR%; Y is CR’; and Z is CR".

In some embodiments, V is CR®, X is CR; Y is CR?; and Z is CR*.

In some embodiments, no more than 2 of V, X, Y, and Z are N.

In some embodiments, at least 2 of V, X, Y, and Z are other than N or NO.

In some embodiments, none of V, X, Y, and Z are N or NO.

In some embodiments, 1 of V, X,Y, and Zis N.

In some embodiments, 2 of V, X, Y, and Z are N.

In some embodiments, R%, R*!, RBand R®! are each, independently, H, OH, halo, Ci. alkyl, C,¢ alkenyl, Cy¢alkynyl, C,.¢ haloalkyl, C; alkoxy, or Cy. haloalkoxy.

In some embodiments, R*, R*!, RBand R®! are each, independently, H, OH or C1. alkoxy.

In some embodiments, RA, RA, RBand R®! are each, independently, H or OH.

In some embodiments, R! is C,.6 alkyl, C,.s hydroxyalkyl, -(Co.¢ alkyl)-O-(C,.¢ alkyl), or heterocyclyl.

In some embodiments, R' is C, alkyl.

In some embodiments, R' is prop-2-yl.

In some embodiments, R> and R® is other than H.

In some embodiments, R3 and R®is C14 haloalkyl.

In some embodiments, RSis C4 haloalkyl.

In some embodiments, R® is CFs.

In some embodiments, R’ is H.

In some embodiments, R® is Cy.3 alkoxy or C,.; haloalkoxy.

In some embodiments, R® is Cy.3 alkoxy.

In some embodiments, R® is methoxy.

In some embodiments, R® is ethoxy.

In some embodiments, R® and R” are both H. 1n some embodiments, p is U.

In some embodiments, pis 1.

In some embodiments, compounds of the invention have Formula Ia:

RS R i RA

CRA

9 oS a pr

Y© ORS

Ia.

In some embodiments, compounds of the invention have Formula Ib, Ic or Id: rR? 0]

RE

RE N R! N RA - 9 6

R ( 3 ZR

RTO Xs I

Y© ORS

Ib

Rr?

RE

R® ( z__R8 . p -

RY” 0 Xs I

Y© URS

Ie

R7 0 oR

R N rt N

RS zZ_RS 5 cd

R™ 0 Xe I

Y RS

Id.

In some embodiments, compounds of the invention have Formula Ie or If:

R7 0 B & RS \ ~ R ro Run

R®. ANZ. RE ‘al =’ TX

YOURS

Ie

R7 0]

RE eA 3

R>- Np RS

R% 0 Xs I

YT ORS

If.

In some embodiments, compounds of the invention have Formula Ig:

CF3

O 22 re f° er w SY

RY

CS

Ig.

In some embodiments, compounds of the invention have Formula Thor Ii: re RY H os eS R! NEANVEN CFs o] RB! LJ

Th re ord

S R! 2 CF3 5 RA J J

Y

Ii.

At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.

For example, the term “Cy alkyl” is specifically intended to individually disclose methyl, ethyl, Cs alkyl, C4 alkyl, Cs alkyl, and Cg alkyl.

For compounds of the invention in which a variable appears more than once, each variable can be a ditterent moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound; the two R groups can represent different moieties selected from the

Markush group defined for R.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity,

described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturated hydrocarbon group which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propy! and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., D- pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.

As used herein, “alkylene” refers to a divalent alkyl group.

As used herein, “C, alkylene” refers to an alkylene group comprised of from 2t0 4 carbon atoms.

As used herein, “alkenyl” refers to an alkyl group having one or more double carbon- carbon bonds. Example alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like.

As used herein, “alkyny!” refers to an alkyl group having one or more triple carbon- carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like.

As used herein, “haloalkyl” refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CFs, C;Fs, CHF,, CCls, CHCl, CCls, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.

As used herein, “carbocyclyl” groups are saturated (i.e., containing no double or triple bonds) or unsaturated (i.e., containing one or more double or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groups can be mono- , poly- (e.g., 2, 3 or 4 fused rings). Example carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, 1,3-cyclopentadienyl, c¢yclohexenyl, norbornyl, norpinyl, nuicanyl, adamantyl, phenyl, and the like. Carbocyclyl groups can be aromatic (e.g., “aryl”) or non- aromatic (e.g., “cycloalkyl”). In some embodiments, carbocyclyl groups can have from about 3 to about 30 carbon atoms, about 3 to about 20, about 3 to about 10, or about 3 to about 7 ring-forming carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spiro ring systems. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e, having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like. In some embodiments, cycloalkyl groups can have from about 3 to about 10, about 3 to about 10, or about 3 to about 7 ring- forming carbon atoms. In some embodiments, the cycloalkyl group can have 0, 1, 2, 3, 4 or 5 double or triple bonds. In yet further embodiments, one or more ring-formaing carbon atoms of a cycloalkyl group can be substituted by an oxo or sulfido group.

As used herein, “heterocyclyl” or “heterocycle” refers to a saturated or unsaturated cyclic hydrocarbon wherein onc or more of the ring-forming carbon atoms of the cyclic hydrocarbon is replaced by a heteroatom such as O, S, or N. Heterocyclyl groups can be aromatic (e.g., “heteroaryl”) or non-aromatic (e.g., “heterocycloalkyl”). Heterocyclyl groups can also correspond to hydrogenated and partially hydrogenated heteroaryl groups. Heterocyclyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems. Heterocyclyl groups can be characterized as having 3-14 or 3-7 ring-forming atoms.

In some embodiments, heterocyclyl groups can contain, in addition to at least ome heteroatom, from about 1 to about 13, about 2 to about 10, or about 2 to about 7 carbon atoms and can be attached through a carbon atom or heteroatom. In further embodiments, any ring- forming carbon or heteroatom can be oxidized (e.g., have an oxo or sulfido substituent), or a nitrogen atom can be quaternized. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dibydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well as any of the groups listed below for “heteroaryl” and “heterocycloalkyl.” Further example heterocycles include pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 3,6- dihydropyridyl, 1,2,3,6-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, piperidonyl, 4- piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoliny], tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thia-diazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thiencoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-

triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzo- thiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpbolinyl, naphthyridinyl, deca-hydroquinolinyl, 2H,6H-1,5,2dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl. 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazoly! and isoxazolyl. Further examples of heterocycles include azetidin- 1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl, piperazin-1-yi, pyrrolidin-1-yl, isoquinol-2- yl, pyridin-1-yl, 3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl, 1,3,4,9-tetrahydrocarbolin-2- yl, thieno[2,3-c]pyridin-6-yl, 3.4,10,10a-tetrahydro-1H-pyrazino[1,2-ajindol-2-yl, 1,2,4,4a,5,6-hexahydro-pyrazino{1,2-a]quinolin-3-yl, pyrazino[1,2-a]quinolin-3-yl, diazepan- 1-yl, 1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl, 1,4,4a,5,6,10b-hexahydro-2H- benzo([flisoquinolin-3-yl, 3,3a,8,8a-tetrahydro-1 H-2-aza-cyclopenta[ajinden-2-yl, and 2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yL.

As used herein, “heteroaryl” groups refer to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in turther embodiments from about 3 to about 20 cabun atuws. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocycles including cyclized alkyl, alkenyl, and alkynyl groups where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Example “heterocycloalkyl” groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,

tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double or triple bonds.

As used herein, “spirocyclyl” refers to a 3-14 membered cycloalkyl or 3-14 membered heterocycloalkyl group sharing one atom with a further cycloalkyl or heterocycloalkyl group to which it is attached.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

As used herein, “alkoxy” refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, “thioalkoxy" refers to an —S-alkyl group.

As used herein, “haloalkoxy” refers to an —O-haloalkyl group. An example haloalkoxy group is OCFs.

As used herein, “carbocyclyloxy” refers to —O-carbocyclyl.

As used herein, “cycloalkyloxy” refers to —-O-cycloalkyl.

As used herein, “carbocyclylalkyl” refers to alkyl substituted by carbocyclyl.

As used herein, “aralkyl” or “arylalkyl” refers to an alkyl group substituted by an aryl group.

As used herein, “cycloalkylalkyl” refers to an alkyl group substituted by an cycloalkyl group.

As used herein, “heterocyclylalkyl” refers to an alkyl moiety substituted by a heterocarbocyclyl group. Example heterocyclylalkyl groups include “heteroarylalkyl” (alkyl substituted by heteroaryl) and “heterocycloalkylalkyl” (alkyl substituted by heterocycloalkyl). In some embodiments, heterocyclylalkyl groups have from 3 to 24 carbon atoms in addition to at least one ring-forming heteroatom.

As used herein “oxo” refers to =O.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a “chiral resolving acid” which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as B-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N- methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two, generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed.,

Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical

Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds described herein. As used herein, “prodrugs” refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but arc not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium

Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American

Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.

Claims (1)

1. What is claimed is:

   1. A compound of Formula I: X R7 (o] Z oy hs a R! wx R%" 0 I or pharmaceutically acceptable salt or prodrug thereof, wherein: a dashed line indicates an optional bond; Wis: RA i 3 IN (7 = NE p RA or RB! Vis N, NO or CR, X is N, NO or CR%; Y is N, NO or CR%; Z is N, NO or CR*; wherein no more than one of V, X, Y and Z is NO; RA, R*!, RBand R®! are each, independently, H, OH, halo, C16 alkyl, Cy. alkenyl, C16 alkynyl, Ci¢ haloalkyl, C;.s alkoxy, Cis haloalkoxy, heterocyclyl, carbocyclyl, NR'°R*?, NR'°CO,R': NR!°CONR'’RY, NR'SO,NR!°R2, NR!-S0,-R!!, CN, CONR!’R2, CORY, NO, SR, SORY, SO:RY, or SO,-NR'’R'; R! is Cy alkyl, C6 haloalkyl, C;.¢ hydroxyalkyl, (Co.¢ alkyl)-O-(Ci alkyl), ~(Cos alkyl)-S-(C.. alkyl), -(Co alkyl)-(Cs.7 cycloalkyl)-(Cos alkyl), OH, ORY, SRY, CORY, CORY, CONR'R, carbocyclyl, heterocyclyl, CN, NR'R™2, NR'*SO.R', NR'°COR", NR'CO,R!®, NR*CONR'?, CR'*R"'CO;R" or CR™R"'OCOR'?; R?, R’, R%, R® and R® are each, independently, H, OH, halo, Cys alkyl, Cy.¢ haloalkyl, C,6 alkoxy, Cis haloalkoxy, Ci thioalkoxy, NR'°R', NR'*COR"; NR'’CONRR", NRYSO,NRR!2, NR -SO,-R!, heterocyclyl, carbocyclyl, carboeyclyloxy, heterocyclyloxy, CN, NO, CORY, CONR'R'2, CO:RY, NO, SR’, SOR’, SOR"; or SO;- NRYR R’ is H or C1.¢alkyl optionally substituted by 1-3 substituents selected from halo, OH, CO,H, CO,-(C,.6 alkyl), or Cy.3 alkoxy; R® is C,.3 alkoxy, C).3 haloalkoxy, Cs.¢ cycloalkyloxy or OH;

   RY isH; R® and R® are each, independently, H, Ci. alkyl, halo, C13 alkoxy, Ci.3 baloalkoxy, Cs cycloalkyl, Cis cycloalkyloxy, OH, CORY, OCORY , wherein said Ci. alkyl is optionally substituted with one or more substituents selected from F, C,.; alkoxy, OH or COR"; or R® and R® together with the carbon atom to which they are attached form a 3-7 membered spirocyclyl group; RIC is H, C,.¢alkyl, benzyl, phenyl, or Cy.¢cycloalkyl, wherein said C;.¢ alkyl, benzyl, phenyl, or Cy. cycloalkyl is optionally substituted with 1-3 selected from halo, OH, Ci alkyl. C1.3 haloalkyl, C;.; alkoxy, C, haloalkoxy, CO2H, and CO,-(C1 alkyl); RY is H, OH, Cys alkyl, Ci alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, Css cycloalkyl or Css cycloalkyloxy, wherein said Ci alkyl, Ci alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, Css cycloalkyl or Cs. cycloalkyloxy, is optionally substituted with 1- 3 substituents selected from halo, OH, Ci. alkyl, C,.; alkoxy, CO,H, CO»-(C, alkyl) and CFs; R!2 is H, Cy.¢alkyl, benzyl, phenyl, or C3 cycloalkyl, wherein said C,. alkyl, benzyl, phenyl, or Ci cycloalkyl is optionally substituted with 1-3 selected from halo, OH, C13 alkyl, C.3 haloalkyl, Cy.; alkoxy, C,.; haloalkoxy, CO;H, and CO,-(C1.6 alkyl); and pisOorl. :

   2. The compound of claim 1 wherein W is RA WOE (5 we,

   3. The compound of claim 1 wherein W is RE OT

   RET.

   4. The compound of claim 1 wherein V is CR’.

   5. The compound of claim 1 wherein X is CR? m

   6. The compound of claim 1 wherein Y is CR.

   7. The compound of claim 1 wherein Z is CR*.

   8. The compound of claim 1 wherein X is CR% Y is CR’; and Z is CR".

   9. The compound of claim 1 wherein V is CR’, X is CR? Y is CR’; and Z is CR".

   10. The compound of claim 1 wherein RA, R?!, RBand RP! are each, independently, H, OH, halo, Cis alkyl, Cis alkenyl, Cis alkynyl, Cis haloalkyl, Cis alkoxy or Cis haloalkoxy.

   11. The compound of claim 1 wherein R*, R*!, RBand RE! are each, independently, H, OH or C, alkoxy.

   12. The compound of claim 1 wherein RA RA, RBand RB! are each, independently, H or

   OH.

   13. The compound of claim 1 wherein R! is Cy alkyl, C,. hydroxyalkyl, -(Co.¢ alkyl)-O- (C1 alkyl), or heterocyclyl.

   14. The compound of claim 1 wherein R! is Cy.6 alkyl.

   15. The compound of claim 1 wherein R!is prop-2-yl.

   16. The compound of claim 1 wherein one of RS and RS is other than H.

   17. The compound of claim 1 wherein one of R® and R® is Cy4 haloalkyl.

   18. The compound of claim 1 wherein R® is C;.4 haloalkyl.

   19. The compound of claim 1 wherein R® is CFs.

   20. The compound of claim 1 wherein R’ is H.

   21. The compound of claim 1 wherein R? is C,.; alkoxy or C;.3 haloalkoxy.

   22. The compound of claim 1 wherein R%is C5 alkoxy.

   23. The compound of claim 1 wherein R® is methoxy. 24, The compound of claim 1 wherein R® is ethoxy.

   25. The compound of claim 1 wherein R® and R®" are both H.

   26. The compound of claim 1 having Formula Ia: rR? 0 Re | RA boli a RS hoch Zz. RS rR b ( P RA Ig I Y7 RS

   Ia.

   27. The compound of claim 1 having Formula Ib, Ic or Id: 7 10] a RC 3 RS ( _Z. _R® RY 0 PL T Y7 ORS Ib rR? 0] Re \ 8 vaee ol ° R zZ.__R ‘ad R% © Pol I YY” "RS Ie

   R7 0] Re \ RE CT R® ZR 0 JX Xoy Rs

   Id.

   28. The compound of claim 1 having Formula le or If: Rr’ 0 8 RE ~~ R Re N Ri N A

   RS. ; LNG LZ RO whoo TT YRS Ie R7 @) RE ef ICI R® N RS RO Xs I YT URS

   If.

   29. The compound of claim 1 having the Formula Ig: CF3 0} je J 8 H 7” ohh 0

   Ig.

   30. The compound of claim | having the Formula Ih or Ii: 0] B R! ® SANZ CFs (o) RB? 3 J Y Ih re¥ rr R S R! LA z._CFs 0 “LS

   Y

   L.

   31. The compound of claim 1 which is selected from: N-[(1R,3S)-3-Isopropyl-3-({4-[3-(trifluoromethyl)phenyljpiperazin-1- yl}carbonyl)eyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine; 3-Ethoxy-N-{(1R,3S)-3-isopropyl-3-({4-[3 ~(trifluoromethyl)phenyl] piperazin-1- yi} carbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine; N-[(1R,35)-3-Isopropyl-3 -({4-[4-(trifluoromethyl)pyridin-2-yl] piperazin-1- yl} carbonyl)cyclopentyl] -3-methoxytetrahydro-2H-pyran-4-amine; N-[(1R,3S5)-3-Isopropyl-3-({4-[5 trifluoromethyl)pyridin-3-yl]piperazin-1- yl} carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine; N-{(1R,3S)-3-Isopropyl-3-[(4-phenyl-3 ,6-dihydropyridin-1(2H)- yl)carbonyl]cyclopentyl}-3-methoxytetrahydro-2H-pyran-4-amine; 1-({(1S,3R)-1-Isopropyl-3-[(3 -methoxytetrahydro-2H-pyran-4- yl)amino]cyclopentyl}carbonyl)-4-phenylpiperidin-4-ol; 1-({(18,3R)-1-Isapropyl-3-[(3-methoxytetrahydro -2H-pyran-4- yl)amino]eyclopentyl} carbonyl)-4-[2-(trifluoromethyl)phenyljpiperidin-4-ol; 1-[((1S,3R)-1-Isopropyl-3-{[3-methoxytetrahydro-2H-pyran-4- yl]amino} cyclopentyl)carbonyl]-4-[3-(trifluoromethyl)phenyl]piperidin-4-ol; 1-[({1S,3R)-1-Isopropyl-3-{[3 -methoxytetrahydro-2H-pyran-4- yl)amino} cyclopentyl)carbonyl]-4-[4-(trifluoromethyl)phenyl]piperidin-4-ol N-((1R,38)-3-Isopropyl-3-{[4-[2-(trifluoromethyl)phenyl]-3 ,6-dihydropyridin-1(2H)- vl] carbonyl} cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine: : N-((1R,3S)-3-Isopropyl-3-{ [4-[3~(trifluoromethyl)phenyl]-3,6-dihydropyridin-1 (2H)- yl carbonyl}cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine; 3-Ethoxy-N-((1R,3S)-3-isopropyl-3-{{4-(3 -(trifluoromethyl)phenyl]-3,6- dihydropyridin-1(2H)-yljcarbonyl} cyclopentyl)tetrahydro-2H-pyran-4-amine; N-((1R,3S)-3-Isopropyl-3-{ [4-(trifluoromethyl)-3',6'-dihydro-2,4'-bipyridin-1'(2'H)- yl carbonyl} cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine;

   N-((1 R,3S)-3-Isopropyl-3-{[5-{trifluoromethy1)-3',6 -dihydro-3 ,4'-bipyridin-1'(2'H)- yl]jcarbonyl} cyclopentyl)-3-methoxytetrahydro-2H-pyran-4-amine; N-[(1R,35)-3 Isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1- yi} carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine; N- [(1R.3S)-3-isopropyl-3-({4-[6-(trifluoromethyl)pyridin-2-ylpiperazin-1- yl} carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine; N-[(1R,3S)-3-isopropy} -3-(4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1- ylcarbonyl)cyclopentyl]-3 -methoxytetrahydro-2H-pyran-4-amine; N-[(1R,38)-3-isopropyl-3-(4-[6-methyl-4- (trifluoromethyl)pyridin-2-yl]piperazin- 1- ylearhonyl)cyclopentyl}-3-meth oxytetrahydro-2H-pyran-4-amine; (4R)-N-[(1R,3S5)-3 -isopropyl-3-(4-[3 ~(trifluoromethyl)phenyl]piperidin- 1- ylcarbonyl)cyclopentyl]-3 -methoxytetrahydro-2H-pyran-4-amine; 2-[(1R,35)-3-[(3-methoxytetrahydro-2H-pyran-4-yl)amino]- 1-(4-[4- (trifluoromethyl)pyridin-2-yljpiperazin-1 -ylcarbonyl)cyclopentyl]propan-2-ol; 2-[(1R,35)-3-[(4R)-3-methoxytetrahydro-2H-pyran-4-ylJamino-1 -(4-[4- (trifluoromethyl)pyrimidin-2-yl]piperazin-1 -ylcarbonyl)cyclopentyl]propan-2-ol; 2-[(18,3S)-3-[(3-methoxytetrahydro-2H-pyran-4-yl)amino}-1 -(4-[6- : (trifluoromethyl)pyridin-2-yl]piperazin-1 -ylcarbonyl)cyclopentyl]propan-2-ol; N-[(18,3S)-3-ethyl-3 -(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1 - ylcarbonyl)cyclopentyl}-3 -methoxytetrahydro-2H-pyran-4-amine; (4R)-N-[(1R,3S)-3-ethyl-3 -(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1- ylcarbonyl)cyclopentyl]-3 -methoxytetrahydro-2H-pyran-4-amine; N-[(18,3S)-3-ethyl-3 -(4-[6-(trifluoromethyl)pyridin-2-yl]piperazin-1 - ylcarbonyl)cyclopentyl]-3 -methoxytetrahydro-2H-pyran-4-amine; (4R)-N-[(1R,3S5)-3-methyl-3 ~(4-[4-(triflucromethyl)pyrimidin-2-yl]piperazin-1 - ylcarbonyl)cyclopentyl] -3-methoxytetrahydro-2H-pyran-4-amine; (4R)-3-methoxy-N-[(1R,35)-3-(2-methoxyethyl)-3-(4- [4-(trifluoromethyl)pyridin-2- yl]piperazin-1 -ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine; 3-methoxy-N-[(1S,3S)-3-(2-methoxyethyl)-3-(4- [4-(trifluoromethyl)pyrimidin-2- yl]piperazin-1-ylcarbonyl)cyclopentyljtetrahydro-2H-pyran-4-amine; (4R)-N-[(1R,3S5)-3~(ethoxymethyl)-3-(4- {4-(trifluoromethyl)pyridin-2-yl]piperazin-1- ylcarbonyl)cyclopentyl}-3 -methoxytetrahydro-2H-pyran-4-amine;

   t. - PCT/US2005/022909 (4R)-N-[(1R,3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyrimidin-2- yllpiperazin-1-ylcarbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine; (4R)-3-methoxy-N-[(] R.35)-3-(methoxymethy)-3-(4-[4-(trifluoromethyl)pyridin-2- yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine: (4R)-3-methoxy-N-[(1R. 38)-3-(methoxymethyl)-3-(4-[4-(trifluoromethyl)-pyrimidin- 2-yl]piperazin-1-ylcarbonyl)cyclopentyl]tetrahydro-2H-pyran-4-amine; (4R)-3-methoxy-N-[(1R.38)-3-[(3R)-tetrahydrofuran-3-y1]-3-(4-[4-(trifluoromethyl)- pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]ietrahydro-2H-pyran-4-amine: and (4R)-5-methoxy-N-[{1R.35)-3 [(3R) etraliydiofuran-2 y1} 2 (4 (1 (trifluoromethyl)pyrimidin-2-yl]piperazin-1 -ylcarbonyl)cyclopentylitetrahydro-2H-pyran-4- amine; or pharmaceutically acceptable salt thereof.

   32. A composition comprising a compound of any one of claims 1 to 31 and a pharmaceutically acceptable carrier.

   33. A method of modulating activity of a chemokine receptor comprising contacting said chemokine receptor with a compound of any one of claims 1 to 31. 34, The method of claim 33 wherein said chemokine receptor is CCR2 or CCRS5.

   35. The method of claim 33 wherein said modulating is inhibiting.

   36. The method of claim 33 wherein said compound inhibits both CCR2 and CCR5.

   37. Use of a compound of any one of claims 1 to 31, in the manufacture of a medicament for treating a disease associated with expression or activity of a chemokine receptor in a patient.

   38. Use of claim 37 wherein said chemokine receptor is CCR2 or CCRS.

   39. Use of claim 37 wherein said disease is an inflammatory disease.

   40. Use of claim 37 wherein said preparation is administrable with an anti-inflammatory agent. 117 AMENDED SHEET

   . y “ PCT/US2005/022909

   4]. Use of claim 40 wherein said anti-inflammatory agent is an antibody.

   42. Use of claim 37 wherein said disease is an immune disorder.

   43. Use of claim 37 wherein said disease is rheumatoid arthritis. atherosclerosis. lupus, multiple sclerosis. neuropathic pain. transplant rejection, diabetes. or obesity. 44, Use of lain 37 whetein said disease 1s canes.

   45. Use of claim 44 wherein said cancer is characterized by tumor associated macrophages.

   46. Use of claim 44 wherein said cancer is breast cancer, ovarian cancer or multiple myeloma.

   47. Use of claim 37 wherein said disease or condition 1s a viral infection.

   48. Use of claim 47 wherein said viral infection is HIV infection. 49, Use of a compound of any one of claims 1 to 31, in the manufacture of a medicament for treating HIV infection in a patient.

   50. Use of claim 49 wherein said preparation is administrable simultaneously or sequentially with at least one anti-viral agent.

   51. Use of a compound of any one of claims ! to 31, in the manufacture of a medicament for modulating activity of a chemokine receptor.

   52. Use of claim 51 wherein said chemokine receptor is CCR2 or CCRS.

   53. Use of claim 51 wherein said modulating is inhibiting.

   54. Use of claim 51 wherein said compound inhibits both CCR2 and CCRS. 118 AMENDED SHEET

   . pe 2 PCT/US2005/022909

   55. A compound according to any one of claims 1 to 31, substantially as herein described with reference to and as illustrated in the examples.

   56. A composition according to claim 32, substantially as herein described with reference to and as illustrated in the examples.

   57. A method according to any one of claims 33 to 36, substantially as herein described with reference w and as Husuated in te examples.

   58. Use according to any one of claims 37 to 54, substantially as herein described with reference to and as illustrated in the examples. 119 AMENDED SHEET