CARBAMATE BENZOXAXINE PROPIONIC ACIDS AND ACID DERIVATIVES FOR MODULATION OF RORGAMMA ACTIVITY AND THE TREATMENT OF DISEASE

Title:

CARBAMATE BENZOXAXINE PROPIONIC ACIDS AND ACID DERIVATIVES FOR MODULATION OF RORGAMMA ACTIVITY AND THE TREATMENT OF DISEASE

Document Type and Number:

WIPO Patent Application WO/2015/095792

Kind Code:

Abstract:

The invention provides certain benzoxazine compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R1, R2, Ra1, Ra2, Rb1, Rb2, Rc, Rd, and Cy are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds of the Formula (I) or pharmaceutically acceptable salts thereof, and methods of using the compounds of the Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for treating diseases or conditions mediated by RORgammaT.

Inventors:

AICHER THOMAS D (US)
VAN HUIS CHAD A (US)
MACLEAN JOHN K (US)
ANDRESEN BRIAN M (US)
BARR KENNETH J (US)
BIENSTOCK COREY E (US)
DANIELS MATTHEW (US)
LIU KUN (US)
LIU YUAN (US)
WHITE CATHERINE M (US)
SCIAMMETTA NUNZIO (US)
SIMOV VLADIMIR (US)

Application Number:

PCT/US2014/071663

Publication Date:

June 25, 2015

Filing Date:

December 19, 2014

Export Citation:

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Assignee:

MERCK SHARP & DOHME (US)
LYCERA CORP (US)

International Classes:

A61K31/5375

Domestic Patent References:

WO2013169704A2	2013-11-14
WO2012064744A2	2012-05-18

Foreign References:

US20090275586A1	2009-11-05
US7115750B1	2006-10-03

Attorney, Agent or Firm:

WU, Melody et al. (One CityCenter850 Tenth Street, N, Washington District of Columbia, US)

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Claims:

WHAT IS CLAIMED IS:

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is H or C₁-C₃ alkyl,

R² is H, C₁-C₃ alkyl, or halo;

R^al and R^a2 are independently H, C₁-C₃ alkyl, trifluoromethyl, or cyclopropyl;

R^bl and R^b2 are independently H, C₁-C₃ alkyl, trifluoromethyl, hydroxyl, hydroxymethyl, or cyclopropyl;

alternatively:

(a.) R^al and R^bl together with the carbon atoms to which they are attached form a C₃-

C₆ cycloalkyl ring;

(b.) R^al and R^bl together form a second bond; or

(c.) R^bl and R^b2 together with the carbon atoms to which they are attached form a C₃- C₆ cycloalkyl ring;

R^c is

(a.) H or

(b.) Ci-C₆ alkyl;

R^d is

(a.) Ci-Cg alkyl, wherein said Ci-Cg alkyl of R^d is unsubstituted or independently substituted by 1 to 6 halo, C₁-C3 alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;

(b.) C₂-Cg alkenyl, wherein said C₂-Cg alkenyl of R^d is unsubstituted or independently substituted by 1 to 6 fluoro or cyano;

(c.) a group of the formula -M-R ;

M is

(i.) a bond; or (ii.) Ci-C₆ alkylene, wherein said Ci-C₆ alkylene of M is unsubstituted or substituted by 1 to 6 fluoro;

R is a ring selected from the group consisting of

(i.) C₃-C9 mono- or bicycloalkyl;

(ii.) phenyl; and

(iii.) a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of R

contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein R is unsubstituted or independently substituted by 1 to 4 halo,

C₁-C₃ alkyl, C₁-C₃ trifluoroalkyl, cyano, C₁-C4 alkylcarbonylamino, or oxo;

(a.) phenyl;

(b.) a 5- to 7-membered, monocyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or

(c.) C₃-C6 cycloalkyl;

wherein Cy is unsubstituted or independently substituted by 1 to 4 R^k moieties selected from the group consisting of:

(i.) Ci-C₆ alkyl, wherein said Ci-C₆ alkyl is unsubstituted or independently substituted by 1 to 3 hydroxy or fluoro;

(ii.) Ci-C₆ alkoxy, wherein said Ci-C₆ alkoxy is unsubstituted or

independently substituted by 1 to 3 fluoro, hydroxy, methoxy, or phenyl; (iii.) -N(R^e)₂;

(iv.) -0(CH₂)_nlC(0)N(R^e)₂;

(v.) -0(CH₂)_n2C0₂R^f;

(vi.) hydroxyl;

(vii.) oxo;

(viii.) halo;

(ix.) C₁-C3 alkylsulfonyl;

(x.) cyano;

(xi.) oxetanyl;

(xii.) cyclopropyl; and

(xiii.) -SF₅; or alternatively, two R^k moieties, when substituted on adjacent ring atoms of Cy, form a second ring, wherein said second ring is 5- to 7-membered saturated, partially saturated, or aromatic ring system that contains 0, 1, or 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein said second ring is unsubstituted or substituted by 1 to 3 R^k moieties independently selected from (i)-(xii);

each R^e is independently H or C₁-C3 alkyl,

R^f is H or Ci-C₃ alkyl;

the subscript nl is 1, 2, or 3; and

the subscript n2 is 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R^al and R^a2 are H.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R^bl is H.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is H.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R^d is Ci-Cg alkyl, wherein said Ci-Cg alkyl of R^d is unsubstituted or independently substituted by 1 to 6 halo, C₁-C3 alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R^d is

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy is a

group of the formula ^(R¾Y or O wherein the subscript s is 0, 1, 2, or 3.

8. The compound of claim 1, having the Formula (IB)

wherein

R² is H or F;

the subscript s is 0, 1 , 2, or 3;

R^bl and R^b2 are independently H or CH₃; and

R^dl is CH₃, CHF₂, CH₂F, or CF₃;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R^k is independently:

(i.) Ci-C₆ alkyl, wherein said Ci-C₆ alkyl is unsubstituted or independently

substituted by 1 to 3 hydroxy or fluoro;

(ii.) Ci-C₆ alkoxy, wherein said Ci-C₆ alkoxy is unsubstituted or independently

substituted by 1 to 3 fluoro, hydroxy, amino, methoxy, or phenyl;

(iii.) a halo selected from fluoro or chloro;

(iv.) cyano; or

alternatively, two R^k moieties, when substituted on adjacent ring atoms of Cy, form said second ring, wherein said second ring is a 5- to 6-membered partially saturated or aromatic ring system that contains 0 or 1 N atom; wherein said second ring is unsubstituted or substituted by 1 to 2 R^k moieties independently selected from (i)- (iv).

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Cy is: ; wherein the subscript p is 1 or 2; and

s is 0, 1, or 2.

The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Cy

and R are independently F, CI, CF₃, methyl, methoxy, cyclopropyl, or cyano.

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Cy is

R k

, wherein

R^kl is Ci-C₆ alkyl or CH₂CH₂OH; and

R^k2 is Ci-C₃ alkyl or CHF₂.

13. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Cy is

R , wherein R^k2 is Ci-C₃ alkyl or CHF₂.

14. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Cy is · wherein

R^kl is Ci-C₆ alkyl or CH₂CH₂OH. 15. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R^dl is CF₃. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

The pharmaceutical composition of claim 16, further comprising an additional therapeutic agent.

18. A method of treating a disease or condition mediated by RORgammaT comprising

administering a therapeutically effective amount of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

19. The method of claim 18, further comprising administering an additional therapeutic agent to the patient.

Use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by RORgammaT.

Description:

CARBAMATE BENZOXAZINE PROPIONIC ACIDS AND ACID DERIVATIVES FOR MODULATION OF RORgamma ACTIVITY AND THE TREATMENT OF DISEASE

FIELD OF THE INVENTION [0001] The present invention relates to certain benzoxazine compounds of the Formula

(I) (also referred to herein as the "compounds of the Formula (I)" or "compounds of Formula (I)") which are antagonists of a Thymocyte/T cell specific variant of Retinoic Acid Receptor- related Orphan Receptor (ROR), RORgammaT. The present invention also provides

compositions comprising such compounds, and methods of using such compounds for treating conditions or disorders associated with inappropriate RORgammaT activity, in particular in the treatment and prevention of disease states mediated by RORgammaT. Such disease states may include immune and inflammatory disorders such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and asthma. BACKGROUND OF THE INVENTION

[0002] Upon activation by antigen-presenting cells, na ^'ive T helper cells undergo clonal expansion and will ultimately differentiate into cytokine secreting effector T cells, such as Thl and Th2 subtypes. A third and distinct effector subset has been identified, which plays a key role in providing immunity to bacteria and fungi at mucosal surfaces (Kastelein et al, Annu. Rev. Immunol. 25: 221-242, 2007). This effector T helper cell subset can be distinguished based on its ability to produce large quantities of IL-17/F, IL-21 and IL-22, and is named Thl 7 (Miossec et al, New Eng. J. Med. 361 : 888-898, 2009).

[0003] Different T helper subsets are characterized by the expression of lineage specific master transcription factors. Thl and Th2 effector cells express Tbet and GAT A3, respectively. A Thymocyte/T cell specific variant of Retinoic Acid Receptor-related Orphan Receptor (ROR),

RORgammaT, is highly expressed in Thl7 cells (He et al, Immunity 9: 797-806, 1998).

RORgammaT belongs to the nuclear hormone receptor superfamily (Hirose et al., Biochem.

Biophys. Res. Comm. 205: 1976-1983, 1994). RORgammaT is a truncated form of RORgamma, lacking the first N-terminal 21 amino acids and is, in contrast to RORgamma which is expressed in multiple tissues (heart, brain, kidney, lung, liver, and muscle), exclusively expressed in cells of the lymphoid lineage and embryonic lymphoid tissue inducers (Sun et al, Science 288: 2369-

2372, 2000; Eberl et al, Nat Immunol. 5: 64-73, 2004). [0004] Studies using heterozygous knock-in mice replacing the RORgammaT open reading frame with GFP (green fluorescent protein) revealed a constitutive expression of GFP in approximately 10% of the CD4+ T cells in the small intestinal lamina propria (LP), co- expressing the Thl7 cytokines IL-17/F and IL-22 (Ivanov et al., Cell 126: 1121-1133, 2006). In mice deficient for RORgammaT, the number of Thl7 cells was markedly decreased in the LP; and in vitro stimulation of CD4+ T cells under Thl7 polarizing conditions resulted in a drastic decrease of IL-17 expression. These results were further substantiated via forced expression of RORgammaT in naive CD4+ T cells, which resulted in an induction of IL-17/F and IL-22 (Ivanov et al, Cell 126: 1121-1133, 2006). The foregoing studies demonstrate the importance of RORgammaT in differentiation and stabilization of the Thl7 lineage. In addition, a ROR family member, RORalpha, has been demonstrated to be involved in Thl7 differentiation and stabilization (Yang et al., Immunity 28: 29-39, 2008).

[0005] Recently, RORgammaT was shown to play a crucial role in non-Thl7 lymphoid cells. In these studies, RORgammaT was critically important in innate lymphoid cells expressing Thy 1 , SCA- 1 , and IL-23R proteins. Genetic disruption of RORgamma in a mouse colitis model dependent on these innate lymphoid cells prevented colitis development

(Buonocore et al, Nature 464: 1371-1375, 2010). In addition, RORgammaT was shown to play a crucial role in other non-Thl7 cells, such as mast cells (Hueber et al, J. Immunol. 184: 3336- 3340, 2010). Finally, RORgammaT expression and secretion of Thl7-type of cytokines was reported for Lymphoid Tissue Inducer cells, NK T-cells, NK cells (Eberl et al, Nat. Immunol. 5: 64-73, 2004) and gamma-delta T-cells (Sutton et al, Immunity 31 : 331-341, 2009; Louten et al, J. Allergy Clin. Immunol. 123: 1004-1011, 2009), suggesting an important function for

RORgammaT in these subtypes of cells.

[0006] Based on the role of IL-17 producing cells (either Thl7 or non-Thl7 cells) RORgammaT has been identified as a key mediator in the pathogenesis of several diseases (Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009; Annunziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009). This was confirmed using several disease models representative of autoimmune diseases. Genetic ablation of the RORgamma gene in mice prevented the development of experimental autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE) and colitis (Ivanov et al., Cell 126: 1121-33, 2006; Buonocore et al., Nature 464: 1371-1375, 2010).

[0007] With RORgammaT being a critical mediator in Thl7-cells and non-Thl7 cells, antagonism of the transcriptional activity of RORgammaT is expected to have a beneficial effect on autoimmune diseases, such as but not limited to rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), and asthma (Annunziato et al, Nat. Rev. Rheumatol. 5: 325-331, 2009; Louten et al, J. Allergy Clin.

Immunol. 123: 1004-1011, 2009). Antagonism of RORgammaT may also be beneficial in other diseases that are characterized by increased levels of Thl7 cells and/or elevated levels of Thl7 hallmark cytokines such as IL-17, IL-22 and IL-23. Examples of such diseases are Kawasaki Disease (Jia et al., Clin. Exp. Immunol. 162: 131-137, 2010) and Hashimoto's thyroiditis (Figueroa-Vega et al, J. Clin. Endocrinol. Metab. 95: 953-62, 2010). Another example includes infectious diseases, such as but not limited to mucosal leishmaniasis (Boaventura et al, Eur. J. Immunol. 40: 2830-2836, 2010). In each of the above examples the inhibition may be enhanced by simultaneous inhibition of RORalpha.

[0008] In another aspect, compounds of Formula (I) can be used in the treatment of cancer. Those skilled in the art will recognize the term "cancer" to be a name for diseases in which the body's cells become abnormal and divide without control. The term cancer includes, but is not limited to, colorectal, lung, and pancreatic cancer.

[0009] Compounds modulating RORgammaT have been reported. Examples of agonists include T0901317 and SR1078 (Wang et al, ACS Chem. Biol. 5: 1029-1034, 2010). In addition, antagonists have been reported such as 7-oxygenated sterols (Wang et al, J. Biol. Chem. 285: 5013-5025, 2010) and the compounds described in EP 2181710 Al .

[0010] Numerous immune and inflammatory disorders continue to afflict millions of patients worldwide. Although significant advances have been made in treating these disorders, current therapies do not provide satisfactory results for all patients due to, for example, detrimental side effects or insufficient efficacy. One exemplary immune disorder in need of better therapy is psoriasis. Various therapeutics have been developed in an attempt to treat psoriasis. However, the traditional therapies for psoriasis often have toxic adverse effects. An exemplary inflammatory disorder in need of better treatment is rheumatoid arthritis. Numerous therapeutics have been developed in an attempt to treat this disorder. However, some patients develop resistance to current therapies.

[0011] Accordingly, a need exists for improved treatments for immune disorders and inflammatory disorders. The present invention addresses this need and provides other related advantages. SUMMARY OF THE INVENTION

[0012] The present invention provides compounds that alter the interaction of coregulator proteins with RORgammaT and thereby antagonize RORgammaT-mediated transcriptional activity; pharmaceutical compositions comprising such compounds and pharmaceutically acceptable excipients; and the use of such compounds or such pharmaceutical compositions for the treatment of RORgammaT-mediated diseases or conditions, in particular autoimmune diseases and inflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0013] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "fluoroalkyl," "-O-alkyl," etc.

[0014] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0015] A "patient" is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee.

[0016] The term "therapeutically effective amount" as used herein refers to an amount of the compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory, or preventative effect when administered to a patient suffering from a disease or condition mediated by

RORgammaT. In the combination therapies of the present invention, a therapeutically effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount. [0017] The term "preventing," as used herein with respect to an inflammatory disease or disorder, refers to reducing the likelihood of an autoimmune or inflammatory disease or disorder.

[0018] The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond having the specified number of carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (Ci-C ₆ alkyl) or from 1 to 3 carbon atoms (C ₁-C ₃ alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n- hexyl, isohexyl, and neohexyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched.

[0019] The term "fluoroalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a fluorine. In one embodiment, a fluoroalkyl group has from 1 to 6 carbon atoms. In another embodiment, a fluoroalkyl group has from 1 to 3 carbon atoms. In another embodiment, a fluoroalkyl group is substituted with from 1 to 3 fluorine atoms. Non- limiting examples of fluoroalkyl groups include -CH ₂F, -CHF ₂, and -CF ₃. The term "C ₁-C ₃ fluoroalkyl" refers to a fluoroalkyl group having from 1 to 3 carbon atoms.

[0020] The term "alkylene," as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non- limiting examples of alkylene groups include -CH ₂-, -CH ₂CH ₂-, -CH ₂CH ₂CH ₂-, -CH ₂CH ₂CH ₂CH ₂-, -CH(CH ₃)CH ₂CH ₂-, -CH(CH ₃)-, and -CH ₂CH(CH ₃)CH ₂-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms (Ci-C ₆ alkylene). In another embodiment, an alkylene group has from 1 to 3 carbon atoms (Ci-C ₃ alkylene). In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH ₂-. The term "Ci-C ₃ alkylene" refers to an alkylene group having from 1 to 3 carbon atoms. Unless otherwise indicated, an alkylene group is unsubstituted.

[0021] The term "alkenyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. The term "C ₂-C ₆ alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms. The term "C ₂-C ₄ alkenyl" refers to an alkenyl group having from 2 to 4 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.

[0022] The term "alkoxy," as used herein, refers to an -O-alkyl group, wherein an alkyl group is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, and tert-butoxy. An alkoxy group is bonded via its oxygen atom to the rest of the molecule.

[0023] The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to 10 carbon atoms (C ₆-Cio aryl). In another embodiment an aryl group is phenyl. Non-limiting examples of aryl groups include phenyl and naphthyl.

[0024] The term "carbocycle," as used herein, refers to a fully saturated, partially unsaturated, or an aromatic monocyclic or multicyclic ring system comprising from about 6 to 14 carbon atoms. In one embodiment, an aryl group contains from 3 to 10 carbon atoms (C ₃-C ₁₀ carbocycle). Non-limiting examples of carbocyclic groups include cycloalkyl and aryl groups, as defined herein. In specific embodiments, the carbocyclic groups are selected from

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, naphthyl, and

tetrahy dronaphthy 1.

[0025] The term "cycloalkyl," as used herein, refers to a saturated ring containing the specified number of ring carbon atoms, and no heteroatom. In a like manner the term "C3-C6 cycloalkyl" refers to a saturated ring having from 3 to 6 ring carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0026] The term "halo," as used herein, means -F, -CI, -Br or -I. In one embodiment, a halo group is -F or -CI. In another embodiment, a halo group is -F.

[0027] "Heterocyclyl" refers to a 4-, 5-, 6-, or 7-membered monocyclic ring or 8-, 9-, or

10-membered bicyclic ring, or 13- or 14-membered tricyclic ring, saturated, unsaturated or aromatic, containing 1, 2, 3, or 4 heteroatoms selected from O, N, or S, and the heterocyclyl may optionally be substituted with one to four substituents. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide, or S^S-dioxide. A heterocyclyl group can be joined to the rest of the molecule via a ring carbon or ring nitrogen atom. Representative heterocyclyls are as follows: azetidinyl, pyrrolidinyl, pyrrolyl,

tetrahydrofuran, imidazolyl, imidazolinyl, 1,3-oxazolidinyl, 1 ,2-oxazolidinyl, isoxazolyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, pyrimidinyl, pyrrolopyrazine, pyrrolopyridine, and indolyl. [0028] The term "substituted" means that one or more hydrogens on the designated atom/atoms is/are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity, and formulation into an efficacious therapeutic agent.

[0029] When any substituent or variable occurs more than one time in any constituent or in the compound of Formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0030] When an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond; for example, in the _s wherein s is an integer equal to zero, 1 or 2, the structure is T when s is zero; or it means that the indicated atom is absent; for example, -S(0)o- means -S-.

[0031] The term "in purified form," as used herein, refers to the physical state of a compound after the compound has been isolated through a synthetic process (e.g., from a reaction mixture), from a natural source, or a combination thereof. The term "in purified form" also refers to the physical state of a compound after the compound has been obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization, and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

[0032] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0033] One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves various degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non- limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H ₂0.

[0034] The compounds of Formula (I) may contain one or more stereogenic centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures, or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.

[0035] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. , chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

[0036] It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.

[0037] All stereoisomers (for example, geometric isomers, optical isomers, and the like) of the present compounds (including stereoisomers of salts and solvates of the present compounds as well as stereoisomers of salts, solvates, and esters of prodrugs of the present compounds), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.

[0038] It is also noted that the compounds of Formula (I) can be chemically modified to yield prodrugs of the compounds of the compounds of Formula (I). For example, a carboxylic acid moiety present on R ³ of the compounds of Formula (I) can be reacted to prepare esters with certain moieties. Such prodrugs of the compounds of Formula (I) can transform in vivo to yield a compound of Formula (I). The transformation may occur by various mechanisms {e.g., by metabolic or chemical processes), such as, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. 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.

[0039] The compounds of Formula (I) can form salts which are also within the scope of this invention. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)," as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety, such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0040] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates), and the like.

Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, InternationalJ. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0041] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen- containing groups may be quaternized with agents such as lower alkyl halides {e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates {e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides {e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides {e.g., benzyl and phenethyl bromides), and others.

[0042] The present invention further includes the compounds of Formula (I) in all their isolated forms. For example, the above-identified compounds are intended to encompass all forms of the compounds, such as any solvates, hydrates, stereoisomers, and tautomers thereof.

[0043] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0044] In the compounds of generic Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula (I). For example, different isotopic forms of hydrogen (H) include protium (iH) and deuterium (¾). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. In light of the present disclosure, isotopically-enriched compounds within generic Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Compounds of the Invention

[0045] The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹, R ², R ^al, R ^a2, R ^bl, R ^b2, R ^c, R ^d, and Cy are as defined below. Described below are embodiments of the compound of Formula (I). The compounds of the Formulas (IA), (IB), and (IC), shown below, are embodiments of the compound of Formula (I).

[0046] In embodiment no. 1, the invention provides a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is H or C ₁-C ₃ alkyl,

R ² is H, C ₁-C ₃ alkyl, or halo;

R ^al and R ^a2 are independently H, C ₁-C ₃ alkyl, trifluoromethyl, or cyclopropyl;

R ^bl and R ^b2 are independently H, C ₁-C ₃ alkyl, trifluoromethyl, hydroxyl, hydroxymethyl, or cyclopropyl;

alternatively:

(a.) R ^al and R ^bl together with the carbon atoms to which they are attached form a C ₃-

C ₆ cycloalkyl ring;

(b.) R ^al and R ^bl together form a second bond; or

(c.) R ^bl and R ^b2 together with the carbon atoms to which they are attached form a C ₃-

C ₆ cycloalkyl

R ^c is

H or

Ci-C ₆ alkyl;

R ^d is

Ci-Cg alkyl, wherein said Ci-Cg alkyl of R ^d is unsubstituted or independently substituted by 1 to 6 halo, C ₁-C ₃ alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;

C ₂-C ₈ alkenyl, wherein said C ₂-C ₈ alkenyl of R ^d is unsubstituted or independently substituted by 1 to 6 fluoro or cyano;

a group of the formula -M-R ;

M is

(i.) a bond; or (ii.) Ci-C ₆ alkylene, wherein said Ci-C ₆ alkylene of M is unsubstituted or substituted by 1 to 6 fluoro;

R is a ring selected from the group consisting of

(i.) C ₃-C9 mono- or bicycloalkyl;

(ii.) phenyl; and

(iii.) a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of R

contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;

wherein R is unsubstituted or independently substituted by 1 to 4 halo,

C ₁-C ₃ alkyl, C ₁-C ₃ trifluoroalkyl, cyano, C ₁-C4 alkylcarbonylamino, or oxo;

(a.) phenyl;

(b.) a 5- to 7-membered, monocyclic heterocyclyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or

(c.) C ₃-C6 cycloalkyl;

wherein Cy is unsubstituted or independently substituted by 1 to 4 R ^k moieties selected from the group consisting of:

(i.) Ci-C ₆ alkyl, wherein said Ci-C ₆ alkyl is unsubstituted or independently substituted by 1 to 3 hydroxy or fluoro;

(ii.) Ci-C ₆ alkoxy, wherein said Ci-C ₆ alkoxy is unsubstituted or

independently substituted by 1 to 3 fluoro, hydroxy, methoxy, or phenyl; (iii.) -N(R ^e) ₂;

(iv.) -0(CH ₂) _nlC(0)N(R ^e) ₂;

(v.) -0(CH ₂) _n2C0 ₂R ^f;

(vi.) hydroxyl;

(vii.) oxo;

(viii.) halo;

(ix.) C ₁-C3 alkylsulfonyl;

(x.) cyano;

(xi.) oxetanyl;

(xii.) cyclopropyl; and

(xiii.) -SF ₅; or alternatively, two R ^k moieties, when substituted on adjacent ring atoms of Cy, form a second ring, wherein said second ring is a 5- to 7-membered saturated, partially saturated, or aromatic ring system that contains 0, 1, or 2 heteroatoms independently selected from the group consisting of N, O, and S; wherein said second ring is unsubstituted or substituted by 1 to 3 R ^k moieties independently selected from (i)-(xiii);

each R ^e is independently H or C1-C3 alkyl,

R ^f is H or Ci-C ₃ alkyl;

the subscript nl is 1, 2, or 3; and

the subscript n2 is 1, 2, or 3.

[0047] In embodiment no. 2, the invention provides a compound of Formula (I), wherein

R ^al and R ^a2 are H, and the remaining variables are as set forth in embodiment no. 1.

[0048] In embodiment no. 3, the invention provides a compound of Formula (I), wherein wherein R ^bl is H, R ^al and R ^a2 are H, and the remaining variables are as set forth in embodiment no. 1.

[0049] In embodiment no. 4, the invention provides a compound of Formula (I), wherein

R ¹ is H, and the remaining variables are as set forth in embodiment no. 1.

[0050] In embodiment no. 5, the invention provides a compound of Formula (I), wherein R ^al and R ^bl together with the carbon atoms to which they are attached form a C3-C6 cycloalkyl

ring, such that the group forms a group , wherein the subscript tl is 1, 2, 3, or 4; and the remaining variables are as set forth in embodiment no. 1.

[0051] In embodiment no. 6, the invention provides a compound of Formula (I), wherein

R ^al and R ^bl form a second bond, such that the group forms a group or R ^a2 ; and the remaining variables are as set forth in embodiment no.

[0052] In embodiment no. 7, the invention provides a compound of Formula (I), wherein

R ^bl and R ^b2 together with the carbon atoms to which they are attached form a C ₃-C ₆ cycloalkyl ring, such that the group forms a group , wherein the subscript t2 is 1, 2, 3, or 4; and the remaining variables are as set forth in embodiment no. 1.

[0053] In embodiment no. 8, the invention provides a compound of Formula (I), wherein

R ¹ is methyl, and the remaining variables are as set forth in embodiment no. 1.

[0054] In embodiment no. 9, the invention provides a compound of Formula (I), wherein

R ^d is Ci-Cg alkyl, wherein said Ci-Cg alkyl of R ^d is unsubstituted or independently substituted by

1 to 6 halo, C ₁-C ₃ alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl.

[0055] In embodiment no. 10, the invention provides a compound of Formula (I),

wherein R ^d is , and the remaining variables are as set forth in embodiment no. 1.

[0056] In embodiment no. 11, the invention rovides a compound of Formula (I)

wherein Cy is a group of the formula or , wherein the subscript s is 0, 1,

2, or 3, and the remaining variables are as set forth in embodiment no. 1.

[0057] In embodiment no. 12, the invention provides a compound of Formula (I), wherein

R ¹ is H or methyl;

R ² is H or halo;

R ^al and R ^a2 are independently H or C ₁-C ₃ alkyl;

R ^bl and R ^b2 are independently H or C ₁-C ₃ alkyl;

R ^c is H;

R ^d is Ci-Cg alkyl, wherein said Ci-Cg alkyl of R ^d is unsubstituted or independently substituted by 1 to 6 halo, C ₁-C ₃ alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;

and

R ^k is as set forth in embodiment no. 1.

[0058] In embodiment no. 13, the invention provides a compound of Formula (I) as set forth in any one of embodiments nos. 1-12, wherein the compound of Formula (I) has the Formula (IA)

[0059] In embodiment no. 14, the invention provides a compound of Formula (IB),

wherein

R ² is H or F;

the subscript s is 0, 1, 2, or 3;

R ^bl and R ^b2 are independently H or CH ₃;

R ^dl is CH ₃, CHF ₂, CH ₂F, or CF ₃; and

R ^k is as set forth in embodiment no. 1.

[0060] In embodiment no. 15, the invention provides a compound of Formula (IB), wherein each R ^k is independently:

(i.) Ci-C ₆ alkyl, wherein said Ci-C ₆ alkyl is unsubstituted or independently

substituted by 1 to 3 hydroxy or fluoro;

(ii.) Ci-C ₆ alkoxy, wherein said Ci-C ₆ alkoxy is unsubstituted or independently

substituted by 1 to 3 fluoro, hydroxy, methoxy, or phenyl;

(iii). a halo selected from fluoro or chloro; or

(iv.) cyano; or

alternatively, two R ^k moieties, when substituted on adjacent ring atoms of Cy, form said second ring, wherein said second ring is a 5- to 6-membered partially saturated or aromatic ring system that contains 0 or 1 N atom; wherein said second ring is unsubstituted or substituted by 1 to 2 R ^k moieties independently selected from (i)-(iv); and

the remaining variables are as set forth as in embodiment no. 14. [0061] In embodiment no. 16, the invention provides a compound of Formula (IB), wherein Cy is: ; wherein

the subscript p is 1 or 2;

the subscript s is 0, 1, or 2;

R ^k is as set forth in embodiment no. 15; and