The invention relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): (I), wherein L 1 , A, X 1 , X 2 , R 1 , R 2 , and R 3 are described herein. [structure]

Description

150 parts

›CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a 35 U.S.C § 371 application of International Application No. PCT/US2017/048281, filed on Aug. 23, 2017, which claims priority to U.S. Provisional Application No. 62/532,983, filed Jul. 14, 2017 and U.S. Provisional Application No. 62/378,625, filed Aug. 23, 2016. The contents of each of these applications are incorporated by reference herein.

›DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: ARDE_024_02WO_SeqList.txt, date recorded: Aug. 23, 2017, file size: 4 kilobyte).

›FIELD OF INVENTION

The present invention is directed to modulators of a nuclear hormone receptor, farnesoid X receptor (FXR), useful in the treatment of diseases or disorders associated with FXR proteins. Specifically, the invention is related to compounds and compositions which modulate FXR, methods of treating diseases or disorders associated with FXR, and methods of synthesis of these compounds.

›BACKGROUND OF THE INVENTION

FXR is a ligand-activated transcription factor. Upon binding of a ligand. FXR either binds to DNA at the FXR response elements (FXREs) as a monomer, or forms a heterodimer with retinoid X receptor (RXR) and then binds to FXREs, regulating the transcription of a variety of target genes. To date, more than 40 FXR target genes have been identified that are involved in a wide range of physiological functions including bile acid homeostasis (i.e., BACS, BAAT, BSEP, FGF15/19, etc.), cholesterol and lipoprotein metabolism (i.e., Apolipoprotein C-I, II, IV, Apolipoprotein E, MDR3, Human complement C3, ApoA-1, hepatic lipase, SREPB-1c), glucose metabolism (i.e., PEPCK, GSK3, AKR1B7, GLUT4, G6Pase), and xenobiotics metabolism (i.e., GSTα3, GSTα4, GSTμ1, GSTμ3, SULT1A1, SULT1A2). In addition to the regulation of metabolic related genes, recent results have identified FXR as a regulator of cellular inflammatory and immune responses. Activation of FXR can provide anti-inflammatory effects by negative regulation of nuclear factor κB (NFκB) pathway, reducing the expression of NFκB and the many pro-inflammatory cytokines associated with this pathway (Matsubara, T, et al., “FXR signaling in the enterohepatic system,” Mol. Cell Endocrinol. 2013, 368, 17-29; Moschetta, A., “Deciphering the nuclear bile acid receptor FXR paradigm,” Nucl. Recept. Signal., 2010, 8, e005; Huang, W., et al., “FXR: a metabolic regulator and cell protector,” Cell Res., 2008, 1087-1095).

FXR plays a key role in the synthesis, transport and metabolism of bile acids (BAs) and the many physiological and pathophysiological conditions that involve BAs. In the liver, activation of FXR has been shown to lead to the increased expression of short heterodimer partner (SHP), which in turn inactivates liver receptor homolog-1 (LRH-1) and inhibits the cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the first step of biosynthesis of primary bile acids from cholesterol, thereby reduces the production of bile acids. Activation of FXR in the liver has also been shown to downregulate transporters like Na-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting peptides (OATPs) preventing the uptake of bile acids to liver. The accumulation of BAs in the liver plays a pivotal role in cholestasis-associated liver damage, pharmacological activation of FXR by synthetic ligands can provide therapeutic intervention.

FXR has also been shown to play an important role in the inflammation control of various liver and intestinal diseases (Shaik, F. B., et al., “Role of farnesoid X receptor in inflammation and resolution.” Inflamm. Res. 2015, 64, 9-20). Activation of FXR has been shown to repress the NFκB pathway, a prototypical proinflammatory signaling pathway, and inhibit the expression of key cytokines such as TNFα, IL-1β, and IL-6. In the colon of FXR knockout mice, increased expression of both proinflammatory cytokines (e.g., TNFα, IL-1β, IFNγ) and profibrotic genes (i.e., Collagen α1, TIMP-1, and αSMA) has been observed, indicative of dysregulation in intestinal immunity and tissue remodeling. Activation of FXR with FXR activators in the TNBS induced murine inflammatory bowel disease model has been shown to inhibit the above cytokines and provide protection against inflammation and fibrosis, subsequently against the development of colitis (Vavassori, P., “The bile acid receptor FXR is a modulator of intestinal innate immunity,” J. Immunol. 2009, 183, 6251-6261). Moreover, treatment with an FXR agonist in a rat model of cholestatic liver injury (bile-duct ligation) reduced NK cells and INFγ expression, leading to reduction in intestinal inflammation, reduction in bacterial translocation, and overall improvement in gut barrier function (Verbeke, L., “The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats,” Am. J. Pathol. 2015, 185, 409-419).

Activation of FXR with small molecule activators has the potential to be a treatment for a range of diseases including bile acid related disorders, metabolic syndrome, type-2-diabetes, hyperlipidemia, hypertriglyceridemia, primary biliary cirrhosis (PBC), fatty liver disease, nonalcoholic steatohepatitis (NASH), inflammatory autoimmune diseases, Crohn's disease, multiple sclerosis, atherosclerosis, hepatic and colon cancers, and other disorders. However, known FXR activators have demonstrated toxicities, treatment limiting adverse effects, and other issues. For these reasons, there remains a need for novel and potent small molecule FXR activators.

›SUMMARY OF THE INVENTION · 1 of 3

In an aspect of the invention, there is provided a compound of Formula I:

or a salt thereof,

wherein:

one of X 1 or X 2 is NR x or N + (O − )R x and the other is CHR y or C(O);

R x is

R y is H, alkyl, cycloalkyl or cycloalkylalkyl wherein said alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;

L 1 is —(CH 2 ) m (C═O)— or —(CH 2 ) p —;

L 2 is a bond or —S(O) 2 —;

A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;

B is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 5 ;

R 1 and R 2 are each independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R 9 ;

or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same carbon atom form a spirocycloalkyl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same atom form a spiroheterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 when on non-adjacent atoms, together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or when cycloalkyl or heterocycloalkyl, R 1 and R 2 when on non-adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ;

R 3 is alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, or cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, and —OH;

R 4 is COOR 6a , —(CH 2 ) n —COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , —(CH 2 ) n CONH(CH 2 ) n R 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n R 6d , —(CH 2 ) n —CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n N(CO)R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , CONR 6b (CH 2 ) n PO(OR 6g ) 2 , CONR 6b SO 2 (CH 2 ) n N + (R 6f ) 3 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e , CN, —(CH 2 )—NR 6b C(O)R 6c , —(CH 2 ) n —N(OH)—C(O)R 6c , oxo, alkyl, cycloalkyl, —(CH 2 ) n -cycloalkyl, heterocycloalkyl, —(CH 2 ) n -heterocycloalkyl, heteroaryl or —(CH 2 ) n -heteroaryl; wherein said alkyl, cycloalkyl, —(CH 2 ) n -cycloalkyl, heterocycloalkyl, —(CH 2 ) n -heterocycloalkyl, heteroaryl and —(CH 2 ) n -heteroaryl are optionally substituted with COOR 6a , —(CH 2 ) n —COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , —(CH 2 ) n CONH(CH 2 ) n R 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n R 6d , —(CH 2 ) n —CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n N(CO)R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e , CN, —(CH 2 ) n —NR 6b C(O)R 6 , or —(CH 2 ) n —N(OH)—C(O)R 6c ;

each R 5 is independently at each occurrence halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, spiroheterocycloalkyl, —O-cycloalkyl, —O-heterocycloalkyl, aryl, heterocycloalkyl, or heteroaryl wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;

R 6a is H, alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, NR 6b R 6c , SO 2 NR 6b R 6c , and —OH;

R 6b and R 6c are each independently H, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and —OH;

R 6d is alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkoxy, —O—CO-alkyl, —O—COcycloalkyl, —O—CO-alkyl-COOH, NR 6b R 6c , NR 6f CO-alkyl, NR 6f CO-alkoxy, cycloalkyl, heterocycloalkyl and —OH;

R 6e is —OH, alkyl, haloalkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and —OH;

R 6f is alkyl or haloalkyl;

R 6g is H or alkyl optionally substituted with —O—CO-alkyl;

each R 7 is independently at each occurrence OH, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN;

each R 8 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;

each R 9 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;

›SUMMARY OF THE INVENTION · 2 of 3

m is 0, 1, or 2;

n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

p is 1 or 2.

Another aspect of the invention relates to a method of treating a disease or disorder in which FXR plays a role. The method comprises administering to a patient in need of a treatment for diseases or disorders in which FXR plays a role an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of modulating FXR. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of activating FXR. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a liver disease. The method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating an intestinal disease. The method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a kidney disease. The method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating an autoimmune disorder. The method comprises administering to a patient in need of a treatment for an autoimmune disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need of a treatment for cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

›SUMMARY OF THE INVENTION · 3 of 3

The present invention further provides methods of treating a disease or disorder associated with modulation of FXR including, but not limited to, liver diseases, intestinal diseases, kidney disease, autoimmune disorders, or cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The present invention provides activators of FXR that are therapeutic agents in the treatment of diseases, such as liver diseases, intestinal diseases, kidney disease, autoimmune disorders, and cancer. Ultimately the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with the modulation of FXR.

›BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Body weight of DSS colitis model mice measured on Day 9 immediately prior to terminal necropsy. Mice were administered vehicle with and without DSS and FXR agonist compounds OCA, FXR1 and FXR2.

FIG. 2 : DAI score measured on Day 9 immediately prior to terminal necropsy. DSS significantly increased DAI score compared to no DSS control mice. FXR1 significantly attenuated the DSS-induced increase in DAI score at both 0.3 and 1 mg/kg

FIG. 3 : Pro-inflammatory cytokine measurements in the colon on Day 9. DSS administration significantly increased the content of inflammatory cytokines IL-6 ( FIG. 3 a ), IL-1β ( FIG. 3 b ), TNFα ( FIG. 3 c ), IFNγ ( FIG. 3 d ) and KC/Gro ( FIG. 3 e ) in the colon compared to no DSS control mice. FXR agonist compounds of the invention, FXR1 and FXR2, significantly reduced the levels of all of these pro-inflammatory cytokines in the colon of DSS mice at 1 mg/kg.

FIG. 4 : Histology colitis score on Day 9. Histology colitis score was significantly increased by DSS administration compared to no DSS control mice which significantly reduced by FXR1 at 1 mg/kg.

FIG. 5 : The histological presence of epithelial erosions in the colon on Day 9. DSS administration significantly increased the presence of epithelial erosions (mucosal defects) observed histologically which was significantly prevented by FXR1 at 1 mg/kg.

FIG. 6 : Urinary sucralose excretion as a marker of colonic permeability in HFCC mice. Colonic permeability was increased in HFCC fed mice, compared to NC control mice as indicated by a significant increase in urinary sucralose excretion. FXR1 dose-dependently normalized urinary sucralose excretion in HFCC fed mice, indicating restoration of colonic permeability.

›DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that are capable of modulating the activity of FXR. The invention features methods of treating, preventing or ameliorating a disease or disorder in which FXR plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of FXR dependent diseases and disorders by increasing the activity of nuclear receptor FXR. Activation or modulation of FXR provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, liver diseases, intestinal diseases, kidney diseases, autoimmune disorders, and cancer.

In a first aspect of the invention, the compounds of Formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein L 1 , A, X 1 , X 2 , R 1 , R 2 , and R 3 are as described herein.

The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

›Definitions · 1 of 35

The articles “a” and “an” are used herein to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” is used herein to mean either “and” or “or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH 2 CN, —O—(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 )haloalkoxy, (C 3 -C 7 ) cycloalkyl, aryl, heterocycloalkyl, heteroaryl, —O—(C 2 -C 6 ) alkenyl, —O—(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 ) alkyl, —C(O)(C 1 -C 6 ) alkyl, —OC(O)O(C 1 -C 6 ) alkyl, —NH 2 , —NH((C 1 -C 6 ) alkyl), —N((C 1 -C 6 ) alkyl) 2 , —NHC(O)(C 1 -C 6 ) alkyl, —C(O)NH(C 1 -C 6 ) alkyl, —S(O) 2 (C 1 -C 6 ) alkyl, —S(O) 2 NH(C 1 -C 6 ) alkyl, and S(O) 2 N((C 1 -C 6 ) alkyl) 2 . “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified group bears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, -halogen, —O—(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, —O—(C 2 -C 6 ) alkenyl, —O—(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, —OH, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 ) alkyl, —C(O)(C 1 -C 6 ) alkyl, —OC(O)O(C 1 -C 6 ) alkyl, —NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 ) alkyl) 2 , —S(O) 2 —(C 1 -C 6 ) alkyl, —S(O) 2 NH(C 1 -C 6 ) alkyl, and —S(O) 2 N((C 1 -C 6 ) alkyl) 2 . Furthermore when containing two fused rings an aryl group herein defined may be fused to an unsaturated or partially saturated ring, or fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from the group consisting of N, O, and S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from the group consisting of N, O, and S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2 -pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore when containing two fused rings the heteroaryl groups herein defined may be fused to an unsaturated or partially saturated ring containing a heteroatom selected from N, O and S; or fused with a fully saturated ring containing a heteroatom selected from N, O and S. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

›Definitions · 2 of 35

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

“Alkyl”, either alone or in combination with other groups (e.g, alkoxy, haloalkyl and the like) refers to a straight or branched chain saturated, unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms. Examples of a (C 1 -C 6 ) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. In an embodiment, “alkyl” is fully saturated.

“Alkoxy” refers to a straight or branched chain saturated or unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., —O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. In an embodiment, “alkoxy” is fully saturated.

“Alkoxyalkoxy” refers to an alkoxy group as defined herein which is substituted with an alkoxy group e.g., —O(alkyl)-O-(alkyl). Examples of alkoxyalkoxy groups include without limitation, methoxymethoxy, ethoxyethoxy, propoxymethoxy, or ethoxymethoxy.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propanyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

“Cycloalkyl” or “carbocyclyl” means monocyclic or polycyclic saturated or unsaturated (fully or partially) non-aromatic carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A C 3 -C 8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane). In an embodiment, “cycloalkyl” is fully saturated.

“Heterocyclyl” or “heterocycloalkyl” monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms. In an embodiment, heterocycloalkyl comprises one or two 4- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl. The heterocycloalkyl ring structure may be substituted by one or more substituents. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. In an embodiment, “heterocycle” or “heterocycloalkyl” is fully saturated.

The term “hydroxyalkyl” means an alkyl group as defined above, where the alkyl group is substituted with one or more —OH groups. Examples of hydroxyalkyl groups include HO—CH 2 —, HO—CH 2 —CH 2 — and CH 3 —CH(OH)—. In an embodiment, “hydroxyalkyl” is fully saturated.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. In an embodiment, “haloalkyl” is fully saturated.

The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. In an embodiment, “haloalkoxy” is fully saturated.

The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

The term “oxo” as used herein refers to an “═O” group.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom. In an embodiment, “spirocycloalkyl” or “spirocyclyl” is fully saturated.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl). In an embodiment, “spiroheterocycloalkyl” or “spiroheterocyclyl is fully saturated.

As defined herein, “GW4064” is an FXR agonist compound having the following structure.

The term “solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

›Definitions · 3 of 35

The term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The invention also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

The term “carrier”, as used herein, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

The term “disorder” is used herein to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term “administer”. “administering”, or “administration” as used herein refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

The term “prodrug,” as used herein, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

The term “autoimmune disease” includes, but is not limited to, the following autoimmune diseases: Amyotrophic Lateral Sclerosis (ALS). Autoimmune Atherosclerosis, Autoimmune Diabetes Insipidus, Autoimmune Gastritis, Autoimmune Hepatitis, Autoimmune Interstitial Cystitis, Autoimmune Uveitis, Autoimmune Vasculitis, Behcet's Disease, Celiac Disease, Chronic Fatigue Syndrome, Crohn's Disease, chronic active hepatitis, Diabetes Mellitus, Multiple Sclerosis, PBC, Primary Biliary Cirrhosis, Primary Glomerulonephritis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Scleroderma, Sjogren's Syndrome, Systemic Lupus Erythematosus, Ulcerative Colitis, and Vasculitis.

The term “kidney disease” includes, but is not limited to the following kidney diseases: fibrotic renal disease and diabetic nephrophathy.

The term “liver disease” includes, but is not limited to, the following liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, portal vein hypertension (PAH), obesity and Type 2 Diabetes.

The term “intestinal disease” includes, but is not limited to the following intestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease and bile acid diarrhea.

The term “cancer” includes, but is not limited to, the following cancers: hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, gastric cancer, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, bile duct carcinoma, renal carcinoma, breast cancer, and Barett's esophagus, and combinations thereof.

The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein or receptor. The invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating FXR.

The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein. The invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating FXR.

›Definitions · 4 of 35

In one embodiment, compounds of the invention have the structure of Formula (I):

or a salt thereof, wherein:

one of X 1 or X 2 is NR x or N + (O − )R x and the other is CHR y or C(O);

R x is

R y is H, alkyl, cycloalkyl or cycloalkylalkyl wherein said alkyl, cycloalkyl and cycloalkylalkyl are optionally substituted with halogen or alkoxy;

L 1 is —(CH 2 ) m (C═O)— or —(CH 2 ) p —;

L 2 is a bond or —S(O) 2 —;

A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;

B is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 5 ;

R 1 and R 2 are each independently H, alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R 9 ;

or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together when attached to the same carbon atom form a spirocycloalkyl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl. R 1 and R 2 together when attached to the same atom form a spiroheterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R 8 ; or R 1 and R 2 when on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 when on non-adjacent atoms, together with the atoms to which they are attached form a cycloalkyl ring optionally substituted with one or more R 8 ; or when cycloalkyl or heterocycloalkyl, R 1 and R 2 when on non-adjacent atoms, together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ; cycloalkyl ring optionally substituted with one or more R 8 ; or when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ;

R 4 is COOR 6a , —(CH 2 ) n —COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , —(CH 2 ) n CONH(CH 2 ) n R 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n R 6d , —(CH 2 ) n —CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n N(CO)R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e , CN, —(CH 2 ) n —NR 6b C(O)R 6c , —(CH 2 ) n —N(OH)—C(O)R 6c , oxo, alkyl, cycloalkyl, —(CH 2 ) n -cycloalkyl, heterocycloalkyl, —(CH 2 ) n -heterocycloalkyl, heteroaryl and —(CH 2 ) n -heteroaryl; wherein said alkyl, cycloalkyl, —(CH 2 ) n -cycloalkyl, heterocycloalkyl, —(CH 2 ) n -heterocycloalkyl, heteroaryl and —(CH 2 ) n -heteroaryl are optionally substituted with COOR 6a , —(CH 2 ) n —COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , —(CH 2 ) n CONH(CH 2 ) n R 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n R 6d , —(CH 2 ) n —CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n N(CO)R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e , CN, —(CH 2 ) n —NR 6b C(O)R 6c , —(CH 2 ) n —N(OH)—C(O)R 6c ;

each R 5 is independently at each occurrence halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;

R 6f is alkyl or haloalkyl;

R 6g is H or alkyl optionally substituted with —O—CO-alkyl;

each R 7 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or CN;

each R 8 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;

›Definitions · 5 of 35

each R 9 is independently at each occurrence alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, or —OH;

m is 0, 1, or 2;

n is 1, 2, 3, or 4; and

p is 1 or 2.

In another embodiment, compounds of the invention have the Formula (I)

wherein:

one of X 1 or X 2 is NR x and the other is CH 2 ;

R x is

L 1 is —(CH 2 ) m (C═O)— or —(CH 2 ) p —;

L 2 is a bond or —S(O) 2 —;

A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl, wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl, wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more R 7 ;

B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 ;

R 1 and R 2 are each independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl. (C 1 -C 6 ) alkoxy. (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 7 ) cycloalkyl, or CN, wherein the cycloalkyl is optionally substituted with one or more R 9 ;

or R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ; or R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R 8 ; or R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 8 ; or when A is cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 ; or when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 ;

R 3 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and —OH;

R 4 is COOR 6a , CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) n SO 2 R 6e , CN, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S;

each R 5 is independently at each occurrence halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, CN, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) haloalkoxy;

R 6a is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen. (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and —OH;

R 6b and R 6c are each independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and —OH;

R 6d is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and —OH;

›Definitions · 6 of 35

R 6e is —OH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen. (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and —OH;

each R 7 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl. (C 1 -C 6 ) haloalkoxy, halogen, or CN;

each R 8 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —OH;

each R 9 is independently at each occurrence (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or —OH;

m is 0, 1, or 2; and

p is 1 or 2.

In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia) or (Ib):