Substituted amide compounds useful as farnesoid X receptor modulators

Abstract

Disclosed are compounds of formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein Q is: (i) halo, cyano, hydroxy, -NR x R x , ‑C(O)OH, ‑C(O)NH2, 0 to 6 R 1a Substituted C 1‑6 Alkyl or ‑P(O)R 1c R 1c ; or (ii)-L-R 1 ; and A, X 1 、X 2 、X 3 、X 4 , Z 1 , Z 2 、R 1 、R 1a 、R 1c 、R 2 、R 3a 、R 3b 、R x , L, a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of the farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating diseases, disorders, or conditions associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using these compounds and pharmaceutical compositions. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 806,060, filed February 15, 2019, which is incorporated herein in its entirety. Technical Field

[0003] The present invention generally relates to substituted amide compounds useful as farnesoid X receptor (FXR) modulators, pharmaceutical compositions comprising such compounds, and to their use in therapy, particularly in the treatment or prevention of diseases, disorders, and conditions for which FXR modulators are indicated. Background Art

[0004] FXR or NR1H4 (nuclear receptor subfamily 1H group member 4) is a nuclear receptor that can activate the expression of specific target genes in a ligand-dependent manner. FXR is expressed in the liver, throughout the gastrointestinal tract, colon, ovaries, adrenal glands, kidneys, as well as in the gallbladder and biliary tree in the human body. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to specific response elements in target genes to regulate gene transcription (BM Forman et al., Cell 1995; 81: 687; W. Seol et al., Mol. Endocrinol. 1995; 9: 72). FXR / RXR heterodimers typically bind to an inverted repeat sequence of a common six-nucleotide sequence (AGGTCA) separated by a single nucleotide (i.e., IR-1 sequence). The relevant physiological ligand of FXR is bile acid, including chenodeoxycholic acid and its taurine conjugate (D.J. Parks et al., Science 1999; 284: 1365; M. Makishima et al., Science 1999; 284: 1362). FXR activation regulates the expression of multiple genes encoding enzymes and transporters involved in bile acid synthesis, influx and outflow into the liver and intestine, thereby leading to a net reduction in total endogenous bile acid in a negative feedback loop. FXR participates in paracrine and endocrine signaling by upregulating the expression of cytokines fibroblast growth factor 15 (rodents) or 19 (primates), which can also contribute to regulating bile acid concentrations (Holt et al., Genes Dev. 2003; 17: 1581; Inagaki et al., Cell Metab 2005; 2: 217). Therefore, FXR is considered to be the main regulator of bile acid homeostasis.

[0005] One use of FXR agonists is for treating diseases with abnormal bile acid regulation, including cholestatic diseases (e.g., primary biliary cirrhosis and primary sclerosing cholangitis), which may lead to fibrosis, sclerosis, bile duct cancer, hepatocellular carcinoma, liver failure and death. Although elevated bile acid concentrations in the liver have deleterious effects, bile acids also affect the microbial flora and integrity of the small intestine. Obstruction of bile flow in humans or rodents causes intestinal bacterial proliferation and mucosal damage, which may lead to bacterial translocation and systemic infection across the mucosal barrier (Berg, Trends Microbiol. 1995; 3: 149-154). Mice lacking FXR have increased ileal bacterial levels and damaged epithelial barriers, and the activation of intestinal FXR plays an important role in preventing bacterial overgrowth and maintaining intestinal epithelial integrity (Inagaki et al., Proc Natl Acad Sci 2006; 103: 3920-3925). Over time, FXR-deficient mice spontaneously develop hepatocellular carcinoma, and this condition can be eliminated by selectively reactivating FXR in the intestine (Degirolamo et al., Hepatology 61: 161-170). In rodent cholestasis models, activating FXR with small molecule agonist drugs or transgenic expression of FXR in the intestine can normalize bile acid concentrations, reduce cell proliferation in the hepatobiliary ducts and reduce inflammatory cell infiltration, necrotic area and liver fibrosis (Liu et al., J. Clin. Invest. 2003; 112: 1678-1687; Modica et al., Gastroenterology. 2012; 142: 355-365). Some of these beneficial effects observed in preclinical models of cholestasis have been transferred to human patients, and the FXR agonist obeticholic acid (OCA or OCALIVA) has been shown to be effective in treating hepatocellular carcinoma. TM ) has been approved for the treatment of primary biliary cirrhosis (https: / / www.fda.gov / newsevents / newsroom / pressannouncements / ucm503964.htm).

[0006] In addition to controlling bile acid homeostasis, FXR agonists also regulate the hepatic expression of hundreds of genes encoding proteins involved in cholesterol and lipid metabolism and transport, glucose homeostasis, inflammation, chemotaxis and apoptosis, as well as other pathways (Zhan et al., PLoS One 2014; 9: e105930; Ijssennagger et al., J Hepatol 2016; 64: 1158-1166). Consistent with these broad effects on gene expression, FXR agonists have also been studied in preclinical models of fibrosis, cancer, inflammatory diseases and metabolic disorders, including dyslipidemia, obesity, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (Crawley, Expert Opin. Ther. Patents 2010; 20: 1047-1057).

[0007] FXR agonists are also being studied in human clinical trials for the treatment of NAFLD (a more advanced form of fatty liver disease), non-alcoholic steatohepatitis (NASH) and related complications. NAFLD is one of the most common causes of chronic liver disease in the world today (Vernon et al., Aliment Pharmacol Ther 2011; 34: 274-285). Risk factors for developing NAFLD include obesity, type 2 diabetes (T2DM), insulin resistance, hypertension and dyslipidemia. In a 6-week clinical trial in T2DM patients with NAFLD, the FXR agonist OCA statistically significantly improved insulin sensitivity and reduced weight, showing a beneficial effect on some of these risk factors (Mudaliar et al., Gastroenterology 2013; 145: 574-582). NASH is the most serious and progressive form of NAFLD, and includes liver steatosis, inflammation and ballooning with changes in the amount of pericellular fibrosis (Sanyal et al., Hepatology 2015; 61: 1392-1405). In a 72-week clinical trial of patients with NASH, OCA statistically significantly improved liver steatosis, lobular inflammation, liver cell ballooning and fibrosis, as assessed by histological analysis of liver biopsy (Neuschwander-Tetri et al., Lancet 2015; 385: 956-965). Given that NASH is the second leading cause of hepatocellular carcinoma (HCC) and liver transplantation in the United States, these data also indicate that FXR agonists may show benefits in clinical outcomes (Wong et al., Hepatology 2014; 59: 2188-2195).

[0008] Applicants have discovered compounds that are useful for treating diseases, disorders, or conditions associated with farnesoid X receptor (FXR) activity in patients in need thereof. These compounds are provided as pharmaceuticals having desirable stability, bioavailability, therapeutic index, and toxicity values ​​that are important for their drugability. Summary of the Invention

[0009] The present invention provides compounds of formula (I) and subgenera and species thereof, including stereoisomers, tautomers, pharmaceutically acceptable salts and solvates thereof, which are useful as FXR modulators.

[0010] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0011] The compounds of formula (I) and compositions comprising the compounds of formula (I) may be used in therapy alone or in combination with one or more additional therapeutic agents.

[0012] The present invention also provides methods and intermediates for preparing the compound of formula (I) and / or its salt.

[0013] The compounds of the present invention can be used to treat a disease, disorder, or condition associated with the activity of the farnesoid X receptor (FXR) in a patient in need of such treatment by administering to the patient a therapeutically effective amount of the compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof. The disease, disorder, or condition can be associated with pathological fibrosis. The compounds of the present invention can be used alone, in combination with one or more compounds of the present invention, or in combination with one or more (e.g., one to two) other therapeutic agents.

[0014] The compounds of the present invention can be used as a single agent or in combination with other agents to treat a disease, disorder or condition selected from the group consisting of nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). The compounds of the present invention can be used as a single agent or in combination with other agents to treat idiopathic pulmonary fibrosis (IPF).

[0015] The compounds of the present invention may be used in the manufacture of a medicament for treating a disease, disorder or condition in a patient in need of such treatment.

[0016] Other features and advantages of the invention will become apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0017] The application provides a compound according to formula (I), including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable salts and solvate forms thereof. The application also provides a pharmaceutical composition containing at least one compound according to formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate and optionally at least one other therapeutic agent. In addition, the application provides a method for treating a disease or disorder (such as bile fibrosis, liver fibrosis, renal fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) and pancreatic fibrosis) regulated by FXR in the following manner: administer a therapeutically effective amount of a compound of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt or solvate (and optionally in combination with at least one other therapeutic agent) to a patient who needs this treatment.

[0018] A first aspect of the present invention provides at least one compound of formula (I):

[0019]

[0020] or a stereoisomer, tautomer, salt or solvate thereof, wherein:

[0021] X 1 It's CR 5a or N;

[0022] X 2 It's CR 5b or N;

[0023] X 3 It's CR 5c or N;

[0024] X 4 It's CR 5d or N; provided that X 1 、X 2 、X 3 and X 4 Zero, one, or two of them are N;

[0025] Z 1 and Z 2 are independently CH2 or O; provided that Z 1 and Z 2 At least one of them is CH2;

[0026] a is zero or 1;

[0027] b is zero, 1, or 2;

[0028] d is zero, 1, or 2; provided that when a, b, and d are each zero, Z1 and Z 2 Each is CH2;

[0029] Q is:

[0030] (i) Halogen, cyano, hydroxy, -NR x R x 、-C(O)OH、-C(O)NH2、0 to 6 R 1a Substituted C 1-6 Alkyl or -P(O)R 1c R 1c ;or

[0031] (ii)-LR 1 ;

[0032] L is -O-, -OCR 1d R 1d C(O)-, -C(O)--C(O)O-, -C(O)NR 1e -、-C(O)NR 1e C(O)-、-NR 1e -、-NR 1e C(O)-、-NR 1e C(O)O-、-NR 1e C(O)NR 1e -、-NR 1e S(O)2-, -S(O)2- or -S(O)2NR 1e -;

[0033] R 1 is zero to six R 1a Substituted C 1-6 an alkyl group or a cyclic group selected from a 3- to 8-membered carbocyclic group, a 6- to 10-membered aryl group, a 4- to 10-membered heterocyclic group, and a 5- to 10-membered heteroaryl group, wherein the cyclic group is surrounded by zero to three R 1b Replace; provided that when R 1 When Z is the cyclic group, 1 and Z 2 Each is CH2;

[0034] Each R 1a are independently halo, hydroxy, -NR w R w , oxo, cyano, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)OR x 、-C(O)NR w R w or -NR x C(O)R y ;

[0035] Each R 1b are independently halo, oxo, cyano, hydroxy, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NR x C(O)(C 1-6 Alkyl) or C 3-6 Cycloalkyl, wherein each of the alkyl, alkoxy and cycloalkyl groups is separated by zero to six R 1a replace;

[0036] Each R 1c Independently C 1-6 alkyl;

[0037] Each R 1d are independently hydrogen, halo, C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0038] Each R 1e are independently hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0039] R 2 yes:

[0040] (i)C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy or -NR v R v wherein each of the alkyl, alkenyl, alkynyl and alkoxy groups is replaced by zero to six R 2a replace;

[0041] (ii)C 3-8 Carbocyclic group, C 6-8 spirobicyclyl, 4 to 7 membered heterocyclyl, phenyl or 5 to 6 membered heteroaryl, wherein each of the carbocyclyl, spirobicyclyl, heterocyclyl, phenyl and heteroaryl is separated by zero to three R 2b replace; or

[0042] (iii)-CH2(C 3-6 cycloalkyl), -CH2 (4 to 6 membered heterocyclic group), -NR x (CH2) 0-2 (C 3-6 Cycloalkyl), -NR x (CH2) 0-2 (C 5-8 Bicycloalkyl), -NR x(CH2) 0-2 (C 5-8 Spirobicycloalkyl), -NR x (CH2) 0-2 (4- to 6-membered heterocyclic group), -NR x (CH2) 0-2 (5- to 6-membered heteroaryl), -NR x (CH2) 0-2 (phenyl), -O(CH2) 0-2 (C 3-6 Cycloalkyl), -O(CH2) 0-2 (C 5-8 Bicycloalkyl), -O(CH2) 0-2 (C 5-8 Spirobicycloalkyl), -O(CH2) 0-2 (4- to 6-membered heterocyclic group), -O(CH2) 0-2 (5- to 6-membered heteroaryl) or -O(CH2) 0-2 (phenyl), wherein each of the cycloalkyl, heterocyclyl, bicycloalkyl, spirobicycloalkyl, aryl, and heteroaryl is replaced by zero to three R 2b replace;

[0043] Each R 2a are independently halo, alkyl, cyano, hydroxy, oxo, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR x R x 、-C(O)(C 1-6 alkyl), -C(O)(C 3-6 Cycloalkyl), -NR x C(O)R y 、-C(O)(C 1-6 alkyl), -C(O)OR x 、-C(O)NR w R w 、-S(O)2R y 、-S(O)2(C 1-3 Fluoroalkyl), -NR x S(O)2(C 1-3 Alkyl), -NR x S(O)2(C 3-6 Cycloalkyl), -S(O)2NR z R z or -P(O)R y R y ;

[0044] Each R 2b are independently halo, cyano, hydroxy, oxo, C1-6 Alkyl, C 1-6 Alkoxy, -NR x R x 、-NR x C(O)O(C 1-3 alkyl), -C(O)(C 1-3 Alkyl) or -S(O)2(C 1-3 alkyl), wherein each of the alkyl and alkoxy groups is separated by zero to six R 2a replace;

[0045] R 3a and R 3b are independently hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-6 Cycloalkyl, or R 3a and R 3b Together with the carbon atom to which they are attached, they form C 3-6 Cycloalkyl;

[0046] A is:

[0047] (i) cyano;

[0048] (ii) phenyl or a 5- to 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl and heteroaryl groups is surrounded by zero to three R 4a replace; or

[0049]

[0050] Each R 4a are independently halo, cyano, hydroxy, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) 0-3 NH(C 1-6 alkyl), -(CH2) 0-2 N(C 1-6 alkyl)2, -(CH2) 0-3 (C 3-6 carbocyclyl) or -(CH2) 0-3 (4- to 6-membered heterocyclyl), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl groups is replaced by zero to six R 4d and each of the carbocyclic and heterocyclic groups is substituted by zero to three R 4e replace;

[0051] R 4b It is C 1-6 Alkyl, -(CH2) 0-3(C 3-6 Cycloalkyl) or -(CH2) 0-3 (4 to 6 membered heterocyclyl), wherein each of the alkyl groups is replaced by zero to six R 4d and each of the cycloalkyl and heterocyclic groups is substituted by zero to three R 4e replace;

[0052] Each R 4c are independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl;

[0053] Each R 4d are independently halo, hydroxy, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 haloalkoxy;

[0054] Each R 4e are independently halo, oxo, cyano, hydroxy, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to six R 4d replace;

[0055] R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, halo, hydroxy, cyano, 0 to 6 R 5e Substituted C 1-6 Alkyl, with zero to six R 5e Substituted C 1-6 Alkoxy, -C(O)OR x 、-C(O)NR w R w 、-S(O)2R y 、-S(O)2NR z R z or zero to three R 5f substituted phenyl;

[0056] R 5e Each of which is independently halo, hydroxy, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 haloalkoxy;

[0057] Each R 5f are independently halo, oxo, cyano, hydroxy, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to six R 5e replace;

[0058] Each R v are independently hydrogen, C 1-6 alkyl, or alternatively, two R v Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered bicyclic or spirocyclic ring moiety containing zero to two additional heteroatoms independently selected from N, O, and S, wherein each ring may be substituted by zero to six R 2a replace;

[0059] Each R w are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R w Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O, and S;

[0060] Each R x are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0061] R y It is C 1-6 Alkyl or C 3-6 cycloalkyl; and

[0062] Each R z are independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R z Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to two additional heteroatoms independently selected from N, O, and S.

[0063] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein:

[0064] Q is:

[0065] (i) F, Cl, Br, cyano, hydroxyl, -NR x R x 、-C(O)OH、-C(O)NH2、0 to 6 R 1dSubstituted C 1-4 Alkyl or -P(O)R 1c R 1c ;or

[0066] (ii)-LR 1 ;

[0067] L is -O-, -OCR 1a R 1a C(O)-, -C(O)--C(O)O-, -C(O)NR 1b -、-NR 1b -、-NR 1b C(O)-、-NR 1b C(O)NR 1b -、-NR 1b S(O)2-, -S(O)2- or -S(O)2NR 1b -;

[0068] R 1 is zero to six R 1a Substituted C 1-6 Alkyl or selected from C 3-6 Cyclic groups of cycloalkyl, phenyl, 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the cyclic groups are surrounded by zero to three R 1b replace;

[0069] Each R 1a are independently F, Cl, hydroxyl, -NR w R w , oxo, cyano, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)OH or -C(O)O(C 1-2 alkyl);

[0070] Each R 1b are independently F, Cl, cyano, hydroxy, oxo, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -NR x C(O)(C 1-6 Alkyl) or C 3-4 Cycloalkyl, wherein each of the alkyl, alkoxy and cycloalkyl groups is separated by zero to six R 1a replace;

[0071] Each R 1c Independently C 1-4 alkyl;

[0072] R 2yes:

[0073] (i)C 1-4 Alkyl, C 1-4 Alkoxy or -NR v R v wherein each of the alkyl and alkoxy groups is represented by zero to four R 2a replace;

[0074] (ii)C 3-8 Carbocyclic group, C 6-8 Spirobicyclyl, phenyl or 4 to 7 membered heterocyclyl, wherein each of the carbocyclyl, spirobicyclyl and heterocyclyl is separated by zero to three R 2b replace; or

[0075] (iii)-CH2(C 3-5 cycloalkyl), -CH2 (4 to 6 membered heterocyclic group), -NR x (CH2) 0-2 (C 3-5 Cycloalkyl), -NR x (CH2) 0-2 (4- to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl) or -O(phenyl), wherein each of the cycloalkyl, heterocyclyl, phenyl and pyridyl groups is replaced by zero to three R 2b replace;

[0076] Each R 2a are independently F, Cl, hydroxyl, -NR x R x , oxo, cyano, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH;

[0077] Each R 2b are independently F, Cl, cyano, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, -NR x R x 、-NR x C(O)O(C 1-3 alkyl), -C(O)(C 1-2 Alkyl) or -S(O)2(C 1-2 alkyl), wherein each of the alkyl and alkoxy groups is separated by zero to four R 2a replace;

[0078] A is:

[0079] (i) cyano;

[0080] (ii) phenyl or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl and heteroaryl groups is surrounded by zero to three R 4a replace; or

[0081]

[0082] Each R 4a are independently F, Cl, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -(CH2) 0-3 NH(C 1-6 alkyl), -(CH2) 0-3 N(C 1-6 alkyl)2, -(CH2) 0-3 (C 3-6 carbocyclyl) or -(CH2) 0-3 (4- to 6-membered heterocyclic group), wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d and each of the carbocyclic and heterocyclic groups is substituted by zero to 3 R 4e replace;

[0083] R 4b It is C 1-4 Alkyl, -(CH2) 0-3 (C 3-6 Cycloalkyl) or -(CH2) 0-3 (4 to 6 membered heterocyclyl), wherein each of the alkyl groups is replaced by zero to four R 4d and each of the cycloalkyl and heterocyclic groups is substituted by zero to three R 4e replace;

[0084] Each R 4c are independently hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0085] Each R 4d are independently F, Cl, hydroxyl, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 Fluoroalkoxy;

[0086] Each R 4e are independently F, Cl, oxo, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d replace;

[0087] R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, F, Cl, hydroxyl, cyano, 0 to 4 R 5e Substituted C 1-3 Alkyl, with zero to four R 5e Substituted C 1-3 Alkoxy, -C(O)OR x 、-C(O)NR w R w 、-S(O)2R y 、-S(O)2NR z R z or zero to three R 5f substituted phenyl;

[0088] R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, F, Cl, hydroxyl, cyano, 0 to 4 R 5e Substituted C 1-3 Alkyl, with zero to four R 5e Substituted C 1-3 Alkoxy, -C(O)OR x 、-C(O)NR w R w 、-S(O)2R y 、-S(O)2NR z R z or zero to three R 5f substituted phenyl;

[0089] Each R w are independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R w Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to 2 additional heteroatoms independently selected from N, O, and S;

[0090] Each R x Independently H, C 1-4 Alkyl or C 3-6 Cycloalkyl;

[0091] R y It is C 1-4 Alkyl or C 3-6cycloalkyl; and

[0092] Each R z are independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R z Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to two additional heteroatoms independently selected from N, O, and S.

[0093] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein X 1 It's CR 5a ;X 2 It's CR 5b ;X 3 It's CR 5c ;X 4 It's CR 5d The compound of this embodiment has the structure of Formula (Ia):

[0094]

[0095] Included within this embodiment are compounds wherein R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, F, Cl, cyano, -CH3 or -CF3. Also included in this embodiment are compounds wherein R 5a 、R 5b 、R 5c and R 5d is F, Cl, cyano, -CH3 or -CF3; and R 5a 、R 5b 、R 5c and R 5d Three of them are hydrogen.

[0096] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein X 1 It's CR 5a or N; X 2 It's CR 5b or N; X 3 It's CR 5c or N; X 4 It's CR 5d or N; and X 1 、X 2 、X 3 and X 4One of them is N. The compound of this embodiment has one of the following structures: a structure of formula (Ib), a structure of formula (Ic), a structure of formula (Id), and a structure of formula (Ie):

[0097]

[0098] Included within this embodiment are compounds wherein R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, F, Cl, cyano, -CH3 or -CF3.

[0099] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein X 1 It's CR 5a or N; X 2 It's CR 5b or N; X 3 It's CR 5c or N; X 4 It's CR 5d or N; and X 1 、X 2 、X 3 and X 4 Two of them are N. The compound of this embodiment has one of the following structures: the structure of formula (If), the structure of formula (Ig), the structure of formula (Ih), the structure of formula (Ii), the structure of formula (Ij), and the structure of formula (Ik):

[0100]

[0101] Included within this embodiment are compounds wherein R 5a 、R 5b 、R 5c and R 5d Each of which is independently hydrogen, F, Cl, cyano, -CH3 or -CF3.

[0102] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein Z 1 and Z 2 Each is CH2. The compound of this embodiment has the structure of formula (I1):

[0103]

[0104] Included in this embodiment are compounds wherein each of a, b, and d is 1. Also included in this embodiment are compounds wherein each of a, b, and d is zero or 1. Additionally, included in this embodiment are compounds wherein each of a, b, and d is 1 or 2.

[0105] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein Z 1 and Z 2 One of them is CH2, and Z 1 and Z 2 The other of the two is O. The compound of this embodiment has any one of the structures of Formula (Im) and Formula (In):

[0106]

[0107] Included in this embodiment are compounds wherein each of a, b, and d is 1. Also included in this embodiment are compounds wherein each of a, b, and d is zero or 1. Additionally, included in this embodiment are compounds wherein each of a, b, and d is 1 or 2.

[0108] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein Q is: (i) F, Cl, Br, cyano, hydroxy, -NR x R x 、-C(O)OH、-C(O)NH2、zero or six R 1d Substituted C 1-4 Alkyl or -P(O)R 1c R 1c or (ii)-LR 1 Included in this embodiment are compounds wherein Q is: (i) F, Cl, Br, cyano, hydroxy, -CF3, -C(CH3)2OH, -CH2CH2C(O)OCH3, -C(O)OH, -C(O)NH2, or -P(O)(CH3)2; or (ii) -LR 1 ; L is -O-, -OCR 1a R 1a C(O)O-, -C(O)O-, -C(O)NR 1b -、-NR 1b -、-NR 1b C(O)O-、-NR 1b S(O)2-, -S(O)2- or -S(O)2NR 1b -;R 1 is zero to four R1a Substituted C 1-4 Alkyl, C 3-4 Cycloalkyl, or a cyclic group selected from phenyl, thiazolyl, pyridyl and pyrimidinyl, wherein the cyclic group is surrounded by zero to one R 1b Also included in this embodiment are compounds wherein R 1 It is -CH3, -CH2CH3, -C(CH3)3, -CHF2, cyclopropyl, thiazolyl or phenyl substituted by -CHF2, -CF3, -CH2CH3 or -OCH2CH3. Additionally, included in this embodiment are compounds wherein Q is: (i) F, Cl, Br, cyano, -CF3, -CH2CH2C(O)OCH3, -C(O)NH2, or -P(O)(CH3)2; or (ii) -C(O)OCH3, -C(O)NH(CH2CH3), -OCH3, -OCH2CH3, -OCHF2, -OCH2C(O)OCH3, -NHC(O)OC(CH3)3, -NHS(O)2CH3, -S(O)2CH3, -S(O)2NH(cyclopropyl), -S(O)2NH(CH3), -P(O)(CH3)2, -C(O)NH(thiazolyl), -NH(trifluoromethylphenyl), -NH(ethylphenyl), -NH(ethoxyphenyl), or -NH(difluoromethylphenyl).

[0109] In one embodiment, there is provided a compound of formula (I), or a stereoisomer, tautomer, salt, or solvate thereof, wherein A is cyano. Included in this embodiment are compounds wherein X 1 、X 2 、X 3 and X 4 Each of is CH. Also included in this embodiment are compounds wherein Z 1 and Z 2 Each of them is CH2.

[0110] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein A is: (i) phenyl or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of said phenyl and heteroaryl groups is separated by zero to 3 R 4a replace; or (ii) Included within this embodiment are compounds wherein each R 4a are independently F, Cl, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -(CH2) 0-3 NH(C1-6 alkyl), -(CH2) 0-3 N(C 1-6 alkyl)2, -(CH2) 0-3 (C 3-6 carbocyclyl) or -(CH2) 0-3 (4- to 6-membered heterocyclic group), wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d and each of the carbocyclic and heterocyclic groups is substituted by zero to 3 R 4e Replacement; R 4b It is C 1-4 Alkyl, -(CH2) 0-3 (C 3-6 Cycloalkyl) or -(CH2) 0-3 (4 to 6 membered heterocyclyl), wherein each of the alkyl groups is replaced by zero to four R 4d and each of the cycloalkyl and heterocyclic groups is substituted by zero to three R 4e Replace; each R 4c are independently hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl; each R 4d are independently F, Cl, hydroxyl, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 fluoroalkoxy; and each R 4e are independently F, Cl, oxo, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d replace.

[0111] In one embodiment, there is provided a compound of formula (I), or a stereoisomer, tautomer, salt, or solvate thereof, wherein A is phenyl or a 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl and heteroaryl groups is separated by zero to three R 4a Included in this embodiment are compounds wherein A is phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl, each of which is replaced by zero to three R 4aAlso included in this embodiment are compounds wherein A is oxadiazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, pyrimidinyl, or thiazolyl, each of which is substituted with zero to two substituents independently selected from the group consisting of azetidinyl, fluorobicyclo[1.1.1]pentyl, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -C(CH3)2CN, -C(CH3)2OH, -OCH3, -N(CH3)2, -CH2(cyclopropyl), cyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, difluorocyclopropyl, methylcyclopropyl, morpholinyl, methyloxetanyl and tetrahydropyranyl.

[0112] In one embodiment, there is provided a compound of formula (I), or a stereoisomer, tautomer, salt, or solvate thereof, wherein A is an isocyanate containing 1 to 4 heteroatoms independently selected from N, O, and S, separated by zero to 3 R 4a Included in this embodiment are compounds wherein A is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, or oxatriazolyl, each of which is replaced by zero to three R 4a Also included in this embodiment are compounds wherein A is pyrazolyl, oxadiazolyl, oxazolyl, or thiazolyl, each of which is substituted with zero to two substituents independently selected from the group consisting of Cl, -CH3, -C(CH3)3, -CF3, -CF2CH3, -N(CH3)2, cyclopropyl, and fluorocyclopropyl.

[0113] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein A is:

[0114] Included within this embodiment are compounds wherein A is:

[0115]

[0116] Also included within this embodiment are compounds wherein R 4b It is C 1-4 Alkyl, -(CH2) 0-3 (C 3-6 Cycloalkyl) or -(CH2) 0-3 (4 to 6 membered heterocyclyl), wherein each of the alkyl groups is replaced by zero to four R 4d and each of the cycloalkyl and heterocyclic groups is substituted by zero to three R 4e Replace; each R 4c are independently hydrogen, C 1-3 Alkyl or C3-6 Cycloalkyl; each R 4d are independently F, Cl, hydroxyl, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 fluoroalkoxy; and each R 4e are independently F, Cl, oxo, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d replace.

[0117] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 Yes (i) C 1-4 Alkyl, C 1-4 Alkoxy or -NR v R v wherein each of the alkyl and alkoxy groups is represented by zero to four R 2a Replacement; (ii) C 3-8 Carbocyclic group, C 6-8 Spirobicyclyl, phenyl or 4 to 7 membered heterocyclyl, wherein each of the carbocyclyl, spirobicyclyl and heterocyclyl is separated by zero to three R 2b Substituted; or (iii) -CH2(C 3-5 cycloalkyl), -CH2 (4 to 6 membered heterocyclic group), -NR x (CH2) 0-2 (C 3-5 Cycloalkyl), -NR x (CH2) 0-2 (4- to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(phenyl) or -S(O)2(C 3-6 cycloalkyl), wherein each of the cycloalkyl, heterocyclyl and phenyl groups is replaced by zero to three R 2b Included within this embodiment are compounds wherein R 2 It is C 1-3 Alkyl, C 1-3 Alkoxy or -NR v R v wherein each of the alkyl and alkoxy groups is represented by zero to four R 2a Replacement; (ii) C 3-8 Carbocyclic group, C 6-8Spirobicyclyl, phenyl or 4 to 7 membered heterocyclyl, wherein each of the carbocyclyl, spirobicyclyl and heterocyclyl is separated by zero to three R 2b Substituted; or (iii) -CH2(C 3-5 cycloalkyl), -CH2 (4 to 6 membered heterocyclic group), -NR x (CH2) 0-2 (C 3-5 Cycloalkyl), -NR x (CH2) 0-2 (4- to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(phenyl) or -S(O)2(C 3-6 cycloalkyl), wherein each of the cycloalkyl, heterocyclyl and phenyl groups is replaced by zero to three R 2b replace.

[0118] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 Yes (i) C 1-4 Alkyl, C 1-4 Alkoxy or -NR v R v wherein each of the alkyl and alkoxy groups is represented by zero to four R 2a Replace; or (ii) C 3-8 Carbocyclic group, C 6-8 Spirobicyclyl, phenyl or 4 to 5 membered heterocyclyl, wherein each of the carbocyclyl, spirobicyclyl and heterocyclyl is separated by zero to three R 2b replace.

[0119] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 It is C 3-5 Carbon ring, C 6-8 Spirobicyclic, -NR x (CH2) 0-2 (C 3-6 cycloalkyl) or a 4- to 5-membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O, and S, wherein each of the cycloalkyl, carbocyclic, and heterocyclyl groups is independently substituted by zero to three R 2b Furthermore, included in this embodiment are compounds wherein R 2 It is -NH(methyl-hydroxycyclopropyl) or a cyclic group selected from cyclopropyl, cyclobutyl, cyclohexyl, tetrahydropyranyl, bicyclo[1.1.1]pentyl and dioxotetrahydrothiopyranyl, each cyclic group being substituted with zero to two substituents independently selected from F, -OH, -CH3 and -CF3.

[0120] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 yes:

[0121]

[0122] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 yes:

[0123]

[0124] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 2 yes:

[0125]

[0126] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein:

[0127] Q is:

[0128] (i) F, Cl, Br, cyano, hydroxyl, -NR x R x 、-C(O)OH、-C(O)NH2、0 to 6 R 1d Substituted C 1-4 Alkyl or -P(O)R 1c R 1c ;or

[0129] (ii)-LR 1 ;

[0130] L is -O-, -OCR 1a R 1a C(O)-, -C(O)--C(O)O-, -C(O)NR 1b -、-NR 1b -、-NR 1b C(O)-、-NR 1b C(O)NR 1b -、-NR 1b S(O)2-, -S(O)2- or -S(O)2NR 1b -;

[0131] R 1 is zero to six R 1a Substituted C 1-6 Alkyl or selected from C3-6 Cyclic groups of cycloalkyl, phenyl, 4- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein the cyclic groups are surrounded by zero to three R 1b replace;

[0132] R 2 Yes (i) C 1-4 Alkyl, C 1-4 Alkoxy or -NR v R v wherein each of the alkyl and alkoxy groups is represented by zero to four R 2a Replacement; (ii) C 3-5 A carbocyclic group or a 4- to 5-membered heterocyclic group having 1 or 2 heteroatoms independently selected from N, O, and S, wherein each of the cycloalkyl, carbocyclic, and heterocyclic groups is independently substituted by zero to three R 2b substituted; or (iii) -NR x (CH2) 0-2 (C 3-5 Cycloalkyl) or -NR x (CH2) 0-2 (phenyl); and

[0133] A is a substituted alkyl group containing 1 to 3 heteroatoms independently selected from N, O and S and substituted with zero to 3 R 4a Substituted 5-membered heteroaryl.

[0134] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein:

[0135] Q is:

[0136] (i) F, Cl, Br, cyano, -CF3, -CH2CH2C(O)OCH3, -C(O)NH2 or -P(O)(CH3)2; or

[0137] (ii)-LR 1 ;

[0138] L is -O-, -OCR 1a R 1a C(O)O-, -C(O)O-, -C(O)NR 1b -、-NR 1b -、-NR 1b C(O)O-、-NR 1b S(O)2-, -S(O)2- or -S(O)2NR 1b -;

[0139] R 1is -CH3, -CH2CH3, -C(CH3)3, -CHF2, cyclopropyl, thiazolyl, or phenyl substituted with -CHF2, -CF3, -CH2CH3, or -OCH2CH3;

[0140] R 2 is -NH(methyl-hydroxycyclopropyl) or a cyclic group selected from cyclopropyl, cyclobutyl and bicyclo[1.1.1]pentyl, each cyclic group being substituted with zero to two substituents independently selected from F, -OH, -CH3 and -CF3;

[0141] A is a substituted alkyl group containing 1 to 3 heteroatoms independently selected from N, O and S and substituted with zero to 3 R 4a Substituted 5-membered heteroaryl.

[0142] Included within this embodiment are compounds wherein A is pyrazolyl or oxadiazolyl, each of which is replaced by zero to three R 4a Also included in this embodiment are compounds wherein Q is: (i) -CF, -CHCHC(O)OCH, -C(O)NH, or -P(O)(CH); or (ii) -C(O)OCH, -C(O)NH(CHCH), -OCH, -OCHCH, -OCHF, -OCHC(O)OCH, -NHC(O)OC(CH), -NHS(O)CH, -S(O)CH, -S(O)NH(cyclopropyl), -S(O)NH(CH), -P(O)(CH), -C(O)NH(thiazolyl), -NH(trifluoromethylphenyl), -NH(ethylphenyl), -NH(ethoxyphenyl), or -NH(difluoromethylphenyl).

[0143] In one embodiment, there is provided a compound of formula (I), or a stereoisomer, tautomer, salt, or solvate thereof, wherein A is pyrazolyl, oxadiazolyl, phenyl, pyridinyl, or indazolyl, each of which is replaced by zero to three R 4aand Q is: (i) -CF3, -CH2CH2C(O)OCH3, -C(O)NH2, or -P(O)(CH3)2; or (ii) -C(O)OCH3, -C(O)NH(CH2CH3), -OCH3, -OCH2CH3, -OCHF2, -OCH2C(O)OCH3, -NHC(O)OC(CH3)3, -NHS(O)2CH3, -S(O)2CH3, -S(O)2NH(cyclopropyl), -S(O)2NH(CH3), -P(O)(CH3)2, -C(O)NH(thiazolyl), -NH(trifluoromethylphenyl), -NH(ethylphenyl), -NH(ethoxyphenyl), or -NH(difluoromethylphenyl). Included in this embodiment are compounds wherein A is pyrazolyl or oxadiazolyl, each of which is replaced by zero to three R 4a replace;

[0144] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein Z 1 and Z 2 each of which is CH2; a is 1; b is 1; d is 1; and A is pyrazolyl, oxadiazolyl, phenyl, pyridinyl, or indazolyl, each of which is replaced by zero to three R 4a replace.

[0145] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein R 3a and R 3b are independently hydrogen, C 1-3 Alkyl, C 1-3 Fluoroalkyl or C 3-6 Cycloalkyl; or R 3a and R 3b Together with the carbon atom to which they are attached, they form C 3-6 Included within this embodiment are compounds wherein R 3a and R 3b are independently hydrogen, C 1-2 Alkyl, -CH2F, -CHF2, -CF3 or C 3-4 Cycloalkyl; or R 3a and R 3b Together with the carbon atom to which they are attached, they form C 3-4 Also included in this embodiment are compounds wherein R 3a and R 3b are independently hydrogen, -CH3 or cyclopropyl; or R 3a and R 3b Together with the carbon atom to which they are attached, they form a cyclopropyl group. Additionally, included in this embodiment are compounds wherein R3a and R 3b One of them is hydrogen or -CH3, and R 3a and R 3b The other one is hydrogen.

[0146] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein:

[0147] X 1 is CH; X 2 is CH; X 3 is CH; X 4 It's CR 5d or N;

[0148] a is 1;

[0149] b is 1;

[0150] d is 1;

[0151] Q is:

[0152] (i) F, Cl, Br, cyano, hydroxy, -CF3, -C(CH3)2OH, -CH2CH2C(O)OCH3, -C(O)OH, -C(O)NH2 or -P(O)(CH3)2; or

[0153] (ii)-LR 1 ;

[0154] L is -O-, -OCR 1a R 1a C(O)O-, -C(O)O-, -C(O)NR 1b -、-NR 1b -、-NR 1b C(O)O-、-NR 1b S(O)2-, -S(O)2- or -S(O)2NR 1b -;

[0155] R 1 is -CH3, -CH2CH3, -C(CH3)3, -CHF2, cyclopropyl, thiazolyl, or phenyl substituted with -CHF2, -CF3, -CH2CH3, or -OCH2CH3;

[0156] A is pyrazolyl, oxadiazolyl, phenyl, pyridinyl or indazolyl, each of which is substituted by zero to three R 4a replace.

[0157] Each R 4aare independently Cl, -CH3, -C(CH3)3, -CF3, -CF2CH3, -N(CH3)2, cyclopropyl or fluorocyclopropyl;

[0158] R 5d It is hydrogen, F or Cl.

[0159] Included within this embodiment are compounds wherein A is pyrazolyl or oxadiazolyl, each of which is replaced by zero to three R 4a replace.

[0160] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein A is:

[0161]

[0162] Each R 4a are independently F, Cl, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, -(CH2) 0-3 NH(C 1-6 alkyl), -(CH2) 0-3 N(C 1-6 alkyl)2, -(CH2) 0-3 (C 3-6 carbocyclyl) or -(CH2) 0-3 (4- to 6-membered heterocyclic group), wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d and each of the carbocyclic and heterocyclic groups is substituted by zero to 3 R 4e Replacement; R 4b It is C 1-4 Alkyl, -(CH2) 0-3 (C 3-6 Cycloalkyl) or -(CH2) 0-3 (4 to 6 membered heterocyclyl), wherein each of the alkyl groups is replaced by zero to four R 4d and each of the cycloalkyl and heterocyclic groups is substituted by zero to three R 4e Replace; each R 4c are independently hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl; each R 4d are independently F, Cl, hydroxyl, -NR x R x , oxo, cyano, C 1-3 Alkoxy or C 1-3 fluoroalkoxy; and each R 4e are independently F, Cl, oxo, cyano, hydroxyl, -NH2, C 1-4 Alkyl, C1-4 Alkoxy, -NH(C 1-6 alkyl) or -N(C 1-6 alkyl) 2, wherein each of the alkyl and alkoxy groups is replaced by zero to four R 4d replace.

[0163] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein each R w are independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R w Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to two additional heteroatoms independently selected from N, O, and S. Included within this embodiment are compounds wherein each R w are independently hydrogen, C 1-4 Alkyl or C 3-6 Also included in this embodiment are compounds wherein both R W Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0164] In one embodiment, there is provided a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof, wherein each R z are independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl; or alternatively, two R z Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety containing zero to two additional heteroatoms independently selected from N, O, and S. Included within this embodiment are compounds wherein each R z are independently hydrogen, C 1-4 Alkyl or C 3-6 Also included in this embodiment are compounds wherein both R W Together with the nitrogen atom to which they are attached, they form a 4- to 7-membered ring moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

[0165] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, salt or solvate thereof is provided, wherein the compound is N-(3-chlorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (1); N-(3-chlorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (2); N-(3-chlorophenyl)-N-(( 4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluorocyclohexane-1-carboxamide (3); N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (4); N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide Amide (5); N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluorocyclohexane-1-carboxamide (6); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide (7); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-fluorophenyl)- 3-Hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (8); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-fluorophenyl)cyclohexane-1-carboxamide (9); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3,4-difluorophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (10); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3,4-difluorophenyl)-4,4-difluorocyclohexane-1-carboxamide (11); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (12); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (13); N-((4-(5-(1 1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (14); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)cyclobutane-1-carboxamide (15); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-(trifluoromethyl)phenyl) )phenyl)cyclohexane-1-carboxamide (16); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(2-methoxypyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxamide (17); N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (18); (1S,3S)-N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5 -(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (19); N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluorocyclohexane-1-carboxamide (20); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(N-methylsulfamoyl)phenyl)bicyclo[1.1.1] pentane-1-carboxamide (21); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-(N-methylsulfamoyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (22); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-(N-methylsulfamoyl)phenyl)cyclohexane-1-carboxamide (23); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-(N-methylsulfamoyl)phenyl)cyclohexane-1-carboxamide (24); 1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-4,4-difluorocyclohexane-1-carboxamide (24); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (25); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide ( 26); methyl 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)benzoate (27); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(ethylcarbamoyl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (28); N-(3-carbamoylphenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)- )methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (29); 1-(3-bromophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (30); N-(3-bromophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-2,2-difluorocyclopropane-1-carboxamide (31); (3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (32); N-(3-bromophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (33); N-(3-bromophenyl)-3-fluoro-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (34); N-(3-bromophenyl)-3-fluoro-N-((4-(5-( (1S,3S)-N-(3-bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (36); N-(3-bromo-4-chlorophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (37); N-((4-( (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (38); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (39); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3-hydroxy-3-methyl Cyclobutane-1-carboxamide (40); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3,3-difluorocyclobutane-1-carboxamide (41); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-4,4-difluorocyclohexane-1-carboxamide (42); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-fluorobicyclo[1.1.1] pentane-1-carboxamide (43); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (44); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (45); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)- N-(3-(Dimethylphosphoryl)phenyl)tetrahydro-2H-pyran-4-carboxamide (46); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (47); N-(3-bromophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (48); N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2. 2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (49); (1S,3S)-N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide (50); (1S,3S)-N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (51); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2 .2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (52); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3,3-difluorocyclobutane-1-carboxamide (53); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (54); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (55); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (56); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-methoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (57); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (56); oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-methoxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (58); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,3-difluoro-N-(3-methoxyphenyl)cyclobutane-1-carboxamide (59); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (60); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (61); 1-yl)-N-(3-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (62); (1S,3S)-N-(3-cyano-5-fluorophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (63); (1S,3S)-N-(3-cyano-5-fluorophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (64); 3); N-(3-cyano-5-fluorophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (64); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluoro-N-(3-(methylsulfonamido)phenyl)cyclobutane-1-carboxamide (65); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonamido)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (66); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonamido)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (67); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (68); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4 ,4-difluoro-N-(3-(methylsulfonyl)phenyl)cyclohexane-1-carboxamide (69); N-(3-cyanophenyl)-N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)ethyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (70); N-(3-bromophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)cyclopropanesulfonamide (71); N-(3-cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo [1.1.1]pentane-1-carboxamide (72); N-(3-cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluorocyclohexane-1-carboxamide (73); (1S,3S)-N-(3-cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide (74); (1S,3S)-N-(3-cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide )methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (75); (1S,3S)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (76); N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-(methylsulfonyl)phenyl)cyclohexane-1-carboxamide (77); N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenoxy)acetic acid methyl ester (79); 2-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenoxy)acetic acid methyl ester (80); 2-(3-(N-((1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl)tetrahydro-2H-pyran-4- 1-yl) methyl)-N-(3-((4-ethoxyphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (83); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-dimethyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-ethoxyphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (84); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-dimethyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-dimethyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-dimethyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)- 1-Fluorobicyclo[1.1.1]pentane-1-carboxamide (84); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-ethoxyphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (85); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-ethylphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (86); N-((4-(5-(tert-butyl)-1,2 ,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-((4-(trifluoromethyl)phenyl)amino)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (87); methyl 3-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenyl)propanoate (88); methyl 3-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenyl)propanoate (89); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (90); (1S,3S)-N-(3-((4-(1-cyanocyclopropyl)phenyl)amino)phenyl)-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (91); (1S,3S)-N-(3-((4-((2-cyanopropyl-2-yl)oxy)phenyl)amino)phenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2] 1-Octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (92); (1S,3S)-N-(3-((4-(1-cyanocyclopropyl)phenyl)amino)phenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (93); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(5-cyanopyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (94); 1-(3-cyanophenyl)-1- ((4-(5-(2-fluoroprop-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (95); 1-(3-cyanophenyl)-1-((4-(5-(2-fluoroprop-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (96); 1-(3-cyanophenyl)-1-((4-(5-(2-fluoroprop-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-(3-hydroxy-2,2- dimethylpropyl)urea (97); 1-(3-cyanophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (98); 1-(3-cyanophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea (99); 1-(3-cyanophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-hydroxy-2,2-dimethylpropyl)urea (100); 1-(3-bromo-4-fluorophenyl)-1-((4-(5-(2-fluoropropyl-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-((1R,4R)-4-hydroxycyclohexyl)urea (101); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (102); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- 1-yl)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((5-(difluoromethoxy)pyridin-2-yl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (104); N-(3-((5-cyclopropylpyrimidin-2-yl)amino)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl) 1-yl) methyl)bicyclo[1.1.1]pentane-1-carboxamide (105); N-(3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (106); N-(3-((4-(difluoromethoxy)phenyl)amino)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (107); N-(3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (108); 1-yl)methyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (108); N-(3-((5-cyclopropylpyridin-2-yl)amino)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (109); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (110); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(cyanomethoxy)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (111); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(2-hydroxy-2-methylpropoxy)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (112); 2-(3-(N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (113); N-(3-cyanophenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (114); (1S,3S)-N-(3-cyanophenyl)-3-hydroxy-3-(trifluoromethyl)-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutane-1-carboxamide (115); N-(3-cyanophenyl)-N- -((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (116); (1S,3S)-N-(3-cyanophenyl)-3-hydroxy-3-methyl-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutane-1-carboxamide (117); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-((5-(difluoromethoxy)pyrimidin-2-yl)oxy)phenyl)-3-fluorobicyclo[1. 1.1]pentane-1-carboxamide (118); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((5-(difluoromethoxy)pyridin-2-yl)oxy)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (119); 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide)benzoic acid (120); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.1-yl)methyl)-N-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(ethylcarbamoyl)-4-fluorophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (122); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (123); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (124); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-methylcyclobutane-1-carboxamide (125); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl) 1-Hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (126); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-isopropoxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (127); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(4-fluoro-3-(2-hydroxyprop-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide Amine (128); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-methoxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (129); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (130); (S)-1-(3-bromophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.N-(3-bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.1]hept-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (132); (1s,3s)-N-(3-bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.1]hept-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (133); N-(3-Bromophenyl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-(2-hydroxypropan-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (134); N-(3-cyano-5-fluorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (135); (1S,3S)-N-(3-cyano-5-fluorophenyl)-N -((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (136); N-(3-cyano-5-fluorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (137); N-(3-cyano-5-fluorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide 1-yl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (138); 3-(4-(((1S,3S)-N-(3-bromophenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole-5-carboxamide (139); or 3-(4-((N-(3-bromophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole-5-carboxamide (140).

[0166] Without departing from the spirit or essential attributes of the present invention, the present invention may be embodied in other specific forms. The present invention encompasses all combinations of aspects of the present invention and / or embodiments as described herein. It should be understood that any and all embodiments of the present invention can be combined with any one or more other embodiments to describe other embodiments. It should also be understood that each individual element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe other embodiments.

[0167] definition

[0168] After reading the following detailed description, those skilled in the art can more easily understand the features and advantages of the present invention. It should be understood that, for clear reasons, some features of the present invention described in the context of separate embodiments may also be combined to form a single embodiment. On the contrary, for reasons of simplicity, the various features of the present invention described in the context of a single embodiment may also be combined to form its sub-combination. The embodiments identified as exemplary or preferred in this article are intended to be illustrative and not restrictive.

[0169] Unless otherwise expressly stated herein, items mentioned in the singular may also include the plural form. For example, "a" and "an" may refer to one or more.

[0170] As used herein, the phrase "compound and / or salt thereof" refers to at least one compound, at least one salt of the compound, or a combination thereof. For example, a compound of formula (I) and / or salt thereof includes a compound of formula (I); two compounds of formula (I); a salt of a compound of formula (I); a compound of formula (I) and one or more salts of a compound of formula (I); and two or more salts of a compound of formula (I).

[0171] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0172] Definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0173] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification, either individually or as part of a larger group (unless they are otherwise limited in specific instances).

[0174] Throughout the specification, one skilled in the art can choose groups and substituents thereof to provide stable moieties and compounds.

[0175] According to the convention used in the art, the structural formulas herein are used

[0176]

[0177] to depict the bond that serves as the point of attachment of a moiety or substituent to the core or backbone structure.

[0178] As used herein, the terms "halo" and "halogen" refer to F, Cl, Br, and I.

[0179] The term "cyano" refers to the group -CN.

[0180] The term "hydroxy" refers to the group -OH.

[0181] The term "amino" refers to the group -NH2.

[0182] The term "oxo" refers to the group =0.

[0183] As used herein, the term "alkyl" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups containing, for example, from 1 to 12 carbon atoms, from 1 to 6 carbon atoms, and from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in a subscript after the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-4 "Alkyl" refers to straight and branched chain alkyl groups having one to four carbon atoms.

[0184] As used herein, the term "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more halogen atoms. For example, "C 1-4 "Haloalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more halogen atoms. Representative examples of haloalkyl groups include, but are not limited to, -CF3, -CCl3, -CHF2, and -CF2CCl3.

[0185] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0186] As used herein, the term "hydroxyalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more hydroxy groups. For example, "C1-4 "Hydroxyalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more hydroxy groups. Representative examples of fluoroalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, and -C(CH3)2OH.

[0187] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. For example, "C 2-6 "Alkenyl" refers to straight-chain and branched alkenyl groups having two to six carbon atoms.

[0188] The term "alkynyl" refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond. Exemplary such groups include ethynyl. For example, "C 2-6 "Alkynyl" refers to straight-chain and branched alkynyl groups having two to six carbon atoms.

[0189] As used herein, the term "alkoxy" refers to an alkyl group attached to the parent molecular moiety through an oxygen atom, such as methoxy (-OCH3). For example, "C 1-3 "Alkoxy" means an alkoxy group having one to three carbon atoms.

[0190] The terms "haloalkoxy" and "-O(haloalkyl)" refer to a haloalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C 1-4 "Haloalkoxy" is intended to include C1, C2, C3 and C4 haloalkoxy.

[0191] The terms "fluoroalkoxy" and "-O(fluoroalkyl)" refer to a fluoroalkyl group as defined above attached through an oxygen linkage (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3 and C4 fluoroalkoxy.

[0192] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in a subscript after the symbol "C," the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3-6 "Cycloalkyl" means a cycloalkyl group having three to six carbon atoms.

[0193] The terms "carbocyclo," "carbocyclic," or "carbocyclyl" are used interchangeably and refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring in which all atoms of all rings are carbon, and includes groups having one or more bridged rings, wherein a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. The term includes non-aromatic rings such as, for example, cycloalkyl and cycloalkenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, adamantyl, and tetrahydronaphthyl.

[0194] As used herein, the term "bicycloalkyl" refers to a carbocyclic group having at least one bridge. Representative examples of bicycloalkyl include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, and adamantyl.

[0195] As used herein, the term "aryl" refers to a group of atoms derived from a molecule containing one or more aromatic rings by removing one hydrogen bonded to the aromatic rings. Representative examples of aryl groups include, but are not limited to, phenyl and naphthyl. Aryl rings may be unsubstituted or may contain one or more substituents, as valence permits.

[0196] The term "heteroatom" refers to oxygen (O), sulfur (S) and nitrogen (N).

[0197] The terms "heterocycle," "heterocyclic," or "heterocyclyl" are used interchangeably and refer to a cyclic group having at least a saturated or partially saturated non-aromatic ring, wherein one or more rings have at least one heteroatom (O, S, or N), preferably 1 to 3 heteroatoms independently selected from O, S, and / or N. The rings of this heteroatom-containing group may contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. The heterocyclic group may be attached to any available nitrogen or carbon atom. The heterocyclic ring may be unsubstituted or may contain one or more substituents where valence permits.

[0198] Exemplary monocyclic heterocyclyls include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothiphenyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0199] The terms "spirobicyclyl" and "spirobicycle" are used interchangeably and refer to a bicyclic group in which the two rings are attached to a single carbon atom that is a member of each of the two rings. The terms include both spirobicycloalkyl, where the two rings are cycloalkyl rings attached to a single carbon atom that is a member of each of the two rings; and spirobicycloheteroalkyl, where one ring is a heterocyclyl ring and the other ring is a cycloalkyl ring attached to a single carbon atom that is a member of each of the two rings, or where both rings are heterocyclyl rings attached to a single carbon atom that is a member of each of the two rings. Examples of spirobicyclyl include spiro[3.3]heptenyl, spiro[3.4]octyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxa-azaspiro[3.3]heptyl, and azaspiro[3.4]octyl.

[0200] The term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups having at least one heteroatom (O, S, or N) in at least one ring, preferably 1, 2, or 3 heteroatoms independently selected from O, S, and / or N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Bicyclic heteroaryl groups must include only aromatic rings. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. The heteroaryl ring system may be unsubstituted or may contain one or more substituents.

[0201] Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0202] Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothiophenyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, and pyrrolopyridinyl.

[0203] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by migration of atoms or groups within the molecule. For example, one skilled in the art will readily understand that 1,2,3-triazole exists in two tautomeric forms as defined above:

[0204]

[0205] Thus, even when a structure depicts only one of all possible tautomers, the present disclosure is intended to encompass all possible tautomers. For example, a compound of formula (Ia) wherein R 5c is a hydroxyl group and R 5a 、R 5b and R 5d When each of the two is hydrogen, they can exist in tautomeric forms:

[0206]

[0207] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0208] The compound of formula (I) can form salts, which are also within the scope of the present invention. Unless otherwise indicated, mentioning the compounds of the present invention should be understood to include mentioning one or more salts thereof. The term "one or more salts" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, the term "one or more salts" can include zwitterions (inner salts), such as when the compound of formula (I) contains a basic moiety (such as an amine or pyridine or imidazole ring) and an acidic moiety (such as a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as acceptable metal salts and amine salts in which the cations therein do not contribute significantly to the toxicity or biological activity of the salt. However, other salts can, for example, be used in the separation or purification steps employed during preparation, and are therefore considered within the scope of the present invention. The salt of the compound of formula (I) can, for example, be formed in the following manner: reacting the compound of formula (I) with an amount (such as an equivalent amount) of acid or base in a medium (such as a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

[0209] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acids (e.g., trifluoroacetic acid)), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), hydrobromide (formed with hydrobromic acid), hydroiodide, maleate, salts (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (such as those formed with sulfuric acid), sulfonate (such as those mentioned herein), tartrate, thiocyanate, toluenesulfonate (such as tosylate), undecanoate, and the like.

[0210] Exemplary basic salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; barium salts, zinc salts and aluminum salts; salts with organic bases (e.g., organic amines) such as trialkylamines (e.g., triethylamine), procaine, dibenzylamine, N-benzyl-β-phenylethylamine, 1-diphenylhydroxymethylamine (ephenamine), N,N′-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines; and salts with amino acids (e.g., arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with reagents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc. Preferred salts include monohydrochloride, bisulfate, methanesulfonate, phosphate or nitrate.

[0211] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. Lyophilization may be employed to provide the compound of formula (I) as a solid.

[0212] It will also be understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of the present invention. The term "solvate" means a physical association of a compound of formula (I) with one or more solvent molecules (whether organic or inorganic). Such physical associations include hydrogen bonds. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution phase and separable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0213] Various forms of prodrugs are well known in the art and are described in:

[0214] a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Chapter 31, (Academic Press, 1996);

[0215] b) Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985);

[0216] c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., Chapter 5, pp. 113-191 (Harwood Academic Publishers, 1991); and

[0217] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[0218] e) Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018).

[0219] In addition, the compound of formula (I) can be isolated and purified after its preparation to obtain a composition containing an amount equal to or greater than 99% by weight of the compound of formula (I) ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein as part of the present invention.

[0220] "Stable compound" and "stable structure" are meant to indicate a compound sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.The present invention is contemplated to embody stable compounds.

[0221] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone or in combination with other active ingredients that are effective as FXR agonists, or that are effective in treating or preventing disorders associated with bile acid dysregulation, such as pathological fibrosis, cancer, inflammatory disorders, metabolic disorders, or cholestatic disorders.

[0222] The compounds of the present invention are intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent originally employed. Such compounds have a variety of potential uses, for example, as standards and reagents in determining the ability of potential pharmaceutical compounds to bind to target proteins or receptors, or for in vivo or in vitro imaging of compounds of the present invention bound to biological receptors.

[0223] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0224] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0225] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0226] In another embodiment, the present invention provides processes for preparing the compounds of the present invention.

[0227] In another embodiment, the present invention provides intermediates for preparing the compounds of the present invention.

[0228] In another embodiment, the present invention provides a pharmaceutical composition as defined above further comprising one or more additional therapeutic agents.

[0229] Practicality

[0230] In one embodiment, the present invention provides a method for treating a disease, disorder or condition associated with bile acid dysregulation in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0231] In another embodiment, the present invention provides a method for treating a disease, disorder or condition associated with the activity of the farnesoid X receptor (FXR) in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0232] In another embodiment, the present invention provides a method for treating the diseases, disorders or conditions, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention (alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent).

[0233] In another embodiment, the present invention provides a method for eliciting a farnesoid X receptor (FXR) agonist effect in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0234] In some embodiments, the disease, disorder, or condition associated with FXR dysfunction comprises pathological fibrosis, cancer, an inflammatory disorder, a metabolic disorder, or a cholestatic disorder.

[0235] In some embodiments, the disease, disorder, or condition is associated with fibrosis, including liver, gallbladder, kidney, heart, skin, eye, and pancreatic fibrosis.

[0236] In other embodiments, the disease, disorder or condition is associated with a cell proliferative disorder (such as cancer). In some embodiments, the cancer includes solid tumor growth or neoplasia. In other embodiments, the cancer includes tumor metastasis. In some embodiments, the cancer is liver cancer, gallbladder cancer, small intestine cancer, colorectal cancer, kidney cancer, prostate cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, genital cancer, genitourinary tract cancer, head cancer, laryngeal cancer, lung cancer, muscle tissue cancer, cervical cancer, oral or nasal mucosal cancer, ovarian cancer, pancreatic cancer, skin cancer, spleen cancer, stomach cancer, testicular cancer or thyroid cancer. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma or seminoma.

[0237] Examples of diseases, disorders or conditions associated with the activity of FXR that can be prevented, modulated or treated according to the present invention include, but are not limited to, transplantation, fibrotic disorders (e.g., liver fibrosis, renal fibrosis), inflammatory disorders (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and cell proliferative disorders (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0238] Fibrotic disorders, inflammatory disorders, and cell proliferative disorders suitable for prevention or treatment by the compounds of the present invention include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, hepatic hypofunction, hepatic blood flow disorders, kidney disease, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretion disorders, benign prostatic hyperplasia, neurogenic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, renal fibrosis, chronic kidney disease (CKD), diabetic nephropathy, kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, viral-induced fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumors, herniated disc, spinal stenosis, heart failure, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, foot-and-mouth disease, cancer, myeloma, fibroma , hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, chronic lymphocytic leukemia, Kaposi's sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuropathic pain, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtration surgery scarring, Crohn's disease or systemic lupus erythematosus; keloid formation caused by abnormal wound healing; fibrosis, myelofibrosis and fibroma occurring after organ transplantation. In one embodiment, the present invention provides a method for treating a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the present invention (alone or optionally in combination with another compound of the present invention and / or at least one other type of therapeutic agent).

[0239] In another embodiment, the present invention provides a compound of the present invention for use in therapy.

[0240] In another embodiment, the present invention provides a compound of the present invention for use in therapy for the treatment of a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder thereof.

[0241] In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder thereof.

[0242] In another embodiment, the present invention provides a method for treating a fibrotic, inflammatory, or cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a first therapeutic agent and a second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention.

[0243] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and one or more additional therapeutic agents, for simultaneous, separate or sequential use in therapy.

[0244] In another embodiment, the present invention provides a combined preparation of a compound of the present invention and one or more additional therapeutic agents for simultaneous, separate or sequential use in the treatment of a fibrotic, inflammatory, or cell proliferative disorder.

[0245] The compounds of the invention may be employed in combination with one or more additional therapeutic agents, such as one or more anti-fibrotic and / or anti-inflammatory therapeutic agents.

[0246] In one embodiment, the one or more additional therapeutic agents used in the combined pharmaceutical composition or combined method or combined use are selected from one or more, preferably one to three, of the following therapeutic agents: TGFβ receptor inhibitors (e.g., galunisertib), TGFβ synthesis inhibitors (e.g., pirfenidone), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase inhibitors (e.g., nintedanib), humanized anti-α V β6 integrin monoclonal antibody (e.g., 3G9), human recombinant penetratin-2, recombinant human serum amyloid beta, recombinant human antibodies to TGFβ-1, TGFβ-2, and TGFβ-3, endothelin receptor antagonists (e.g., macitentan), interferon gamma, c-Jun amino-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-reactive protein kinase (R-3), ... cyclohexanol, 3-pentylphenylacetic acid (PBI-4050), tetrasubstituted porphyrin derivatives containing manganese (III), monoclonal antibodies targeting eotaxin-2, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar9 、Met(O2) 11-substance P), Cintredekin Besudotox, human recombinant DNA-derived IgG1κ monoclonal antibodies to connective tissue growth factor and fully human IgG1κ antibodies selective for CC chemokine ligand 2 (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents used to treat obstructive airway diseases such as muscarinic antagonists (e.g., tiotropium bromide, ipratropium bromide Ammonium), adrenergic β2 agonists (e.g., albuterol, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and therapeutic agents that can be used to treat fibrotic disorders (e.g., liver fibrosis, biliary fibrosis, and renal fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis). Therapeutic agents that can be used to treat such fibrotic disorders include, but are not limited to, FXR agonists (e.g., OCA, GS-9674, and LJN452), LOXL2 inhibitors (e.g., simtuzumab), LPA1 antagonists (e.g., BMS-986020 and SAR 100842), PPAR modulators (e.g., elafibrinor, pioglitazone and saroglitazar, IVA337), SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302), ASK-1 inhibitors (e.g., GS-4997 or selonsertib), ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS- -0976), FGF21 mimetics (e.g., LY2405319 and BMS-986036), caspase inhibitors (e.g., emricasan), NOX4 inhibitors (e.g., GKT137831), MGAT2 inhibitors (e.g., BMS-963272), αV integrin inhibitors (e.g., abituzumab), and bile acid / fatty acid conjugates (e.g., aramchol).The FXR agonists of various embodiments of the present invention may also be used in combination with one or more therapeutic agents such as: CCR2 / 5 inhibitors (e.g., cenicriviroc), galectin-3 inhibitors (e.g., TD-139, GR-MD-02), leukotriene receptor antagonists (e.g., tipelukast, montelukast), SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin), GLP-1 receptor agonists (e.g., liraglutide and simeglutide), In another embodiment, the one or more additional therapeutic agents used in the combination pharmaceutical composition, combination method or combination use are selected from one or more, preferably one to three, of the following immuno-oncology agents: alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab and rituximab.

[0247] The compounds of the invention can be administered for any of the uses described herein by any suitable means: for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including application to the nasal membrane, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0248] The term "pharmaceutical composition" means a composition comprising a combination of a compound of the present invention and at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering biologically active agents to animals (particularly mammals), including adjuvants, excipients or vehicles such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the mode of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated based on many factors that are well within the scope of the knowledge of those of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to whom the composition containing the medicament is to be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may also include many different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, binder). Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are found in a variety of readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th edition (1990).

[0249] As used herein, the term "treating" or "treatment" refers to a method for obtaining a beneficial or desired result (including a clinical result) by using a compound or composition of the present invention. For the purposes of the present invention, a beneficial or desired clinical result includes, but is not limited to, one or more of the following: reducing the severity and / or frequency of one or more symptoms caused by a disease, disorder, or condition; reducing the extent of a disease, disorder, or condition or causing its regression; stabilizing a disease, disorder, or condition (e.g., preventing or delaying the worsening of a disease, disorder, or condition); delaying or slowing the progression of a disease, disorder, or condition; improving the state of a disease, disorder, or condition; reducing the dose of one or more other drugs required to treat a disease, disorder, or condition; and / or improving the quality of life.

[0250] Pharmaceutically acceptable carriers are formulated according to many factors that are well within the scope of knowledge of those of ordinary skill in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to be administered the composition containing the medicament; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may also include many different ingredients and additives in addition to the active agent, and such additional ingredients are included in the formulation for a variety of reasons well known to those of ordinary skill in the art (e.g., stabilization of the active agent, adhesive). Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are found in a variety of readily available sources, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (Volume 2), 22nd Edition (2012), Pharmaceutical Press.

[0251] The dosage regimen of the compounds of this invention will, of course, vary depending on known factors such as: the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient; the nature and extent of the symptoms; kind of concurrent treatment; frequency of treatment; route of administration, the patient's renal and hepatic function and the desired effect.

[0252] By way of general guidance, when used for the indicated effects, the daily oral dosage of each active ingredient will range from about 0.01 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from about 0.01 to about 250 mg / day. Intravenously, during a constant rate infusion, the most preferred dosage will range from about 0.01 to about 10 mg / kg / minute. The compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

[0253] The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) appropriately selected with respect to the intended form of administration (e.g., oral tablets, capsules, elixirs and syrups) and in accordance with conventional pharmaceutical practice.

[0254] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will generally be present in an amount of about 0.1%-95% by weight based on the total weight of the composition.

[0255] A typical capsule for oral administration contains at least one compound of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh screen and filled into size 1 gelatin capsules.

[0256] A typical injectable formulation is produced by aseptically placing at least one compound of the invention (250 mg) into a vial, aseptically freeze-drying, and sealing. For use, the contents of the vial are mixed with 2 mL of normal saline to produce an injectable formulation.

[0257] The present invention includes within its scope pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one compound of the present invention (alone or in combination with a pharmaceutical carrier). Optionally, the compounds of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more (preferably one to three) other therapeutic agents (e.g., ASK-1 inhibitors, CCR2 / 5 antagonists, autochemokine inhibitors, LPA1 receptor antagonists, or other pharmaceutically active materials).

[0258] When employed in combination with the compounds of the invention, the aforementioned other therapeutic agents can be used, for example, in amounts such as those indicated in the Physicians' Desk Reference, in the patents listed above, or as otherwise determined by one of ordinary skill in the art.

[0259] In some embodiments, the present invention provides a kind of active ingredient of the present invention.Particularly when provided as a single dose unit, there is the possibility of chemical interaction between the active ingredient of the combination.For this reason, when the compound of the present invention and the second therapeutic agent are combined with a single dose unit, they are formulated so that although the active ingredient is combined with a single dose unit, the physical contact between the active ingredient is minimized (that is, reduced).For example, a kind of active ingredient can be enteric coated.By carrying out enteric coating to one of the active ingredient, not only the contact between the active ingredient of the combination can be minimized, but also the release of one of these components in the gastrointestinal tract can be controlled so that one of these components is not released in the stomach, but released in the intestinal tract.Also, a kind of active ingredient can be coated with such a material, the material realizes sustained release in the whole gastrointestinal tract and is also used to minimize the physical contact between the active ingredient of the combination.In addition, the component of sustained release can be enteric coated in addition so that the release of this component only occurs in the intestinal tract. Yet another approach would involve formulating a combination product in which one component is coated with a sustained-release and / or enteric-release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropylmethylcellulose (HPMC) or other suitable materials as known in the art to further separate the active ingredients. The polymer coating serves to form an additional barrier to interaction with the other component.

[0260] These and other ways to minimize contact between the components of the combination products of the invention, whether administered in a single dosage form or in separate forms but administered at the same time and in the same manner, will be readily apparent to those skilled in the art after having access to this disclosure.

[0261] The compounds of the present invention can be administered alone or in combination with one or more (preferably one to three) additional therapeutic agents. "Administered in combination" or "combination therapy" means that the compounds of the present invention and one or more (preferably one to three) additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component can be administered at the same time or sequentially at different time points in any order. Thus, each component can be administered separately, but close enough in time to provide the desired therapeutic effect.

[0262] Combination therapy is intended to include administering these therapeutic agents in a sequential manner (i.e., wherein each therapeutic agent is administered at different times) and administering these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form of each therapeutic agent with a fixed ratio or with multiple single dosage forms of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any appropriate route, including but not limited to oral route, intravenous route, intramuscular route, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. Combination therapy can also include further administering the therapeutic agent as described above in combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiotherapy). In the case where combination therapy also includes non-drug therapy, the non-drug therapy can be performed at any appropriate time, as long as a beneficial effect is achieved from the combined action of the therapeutic agent and the non-drug therapy. For example, in appropriate circumstances, when the non-drug therapy is temporarily removed from the administration of the therapeutic agent (perhaps for days or even weeks), the beneficial effects are still achieved.

[0263] The compounds of the present invention can also be used as standard or reference compounds in tests or assays involving FXR agonists, for example, as quality standards or controls. Such compounds can be provided in commercial kits, for example, for use in pharmaceutical studies involving FXR agonist activity. For example, a compound of the present invention can be used as a reference in an assay to compare its known activity with a compound of unknown activity. This ensures that the assay is being performed correctly and provides a basis for comparison, particularly if the test compound is a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention can be used to test their effectiveness.

[0264] The present invention also encompasses articles of manufacture. As used herein, articles of manufacture are intended to include, but are not limited to, kits and packaging. The articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert indicating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert indicates that the pharmaceutical composition can be used in combination with a second therapeutic agent (as previously defined) for treating fibrosis and its sequelae. The article of manufacture may also comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located within or outside the second container. Being located within the first and second containers means that the respective containers keep the items within their boundaries.

[0265] The first container is a receiving container for holding a pharmaceutical composition. This container can be used for manufacturing, storage, transportation and / or individual / bulk sales. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (e.g., for cream formulations) or any other container used to manufacture, hold, store or distribute a pharmaceutical product.

[0266] The second container is a container for keeping the first container and optional package insert.The example of the second container includes but is not limited to box (for example, cardboard or plastic), crate, carton, bag (for example, paper or plastic bag), pouch and sack.The package insert can be physically attached to the outside of the first container via adhesive tape, glue, staple or another method of attachment, or it can be left still in the inside of the second container without any physical device attached with the first container. Alternatively, the package insert is located at the outside of the second container. When located at the outside of the second container, preferably, the package insert is physically attached via adhesive tape, glue, staple or another method of attachment. Alternatively, it can be adjacent to or contact with the outside of the second container, rather than physically attached.

[0267] The package insert is a label, tag, or marker that lists the information relevant to the pharmaceutical composition in the first container. The information listed will typically be determined by the regulatory agency (e.g., U.S. Food and Drug Administration) of the region where the pharmaceutical composition is managed and sold. Preferably, the package insert specifically lists the indications for which the pharmaceutical composition has been approved. The package insert can be made of any material that a person can read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic) on which the required information has been formed (e.g., printed or applied).

[0268] Preparation method

[0269] The compounds of the present invention can be synthesized by a variety of methods available to those skilled in the art of organic chemistry. The following describes a general synthesis scheme for preparing the compounds of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. The different methods for preparing the compounds of the present invention should be clear to those skilled in the art. Examples of the compounds of the present invention prepared by the methods described in the general schemes are given in the Examples section listed below. The preparation of homochiral embodiments can be carried out by techniques known to those skilled in the art. For example, homochiral compounds can be prepared by separating racemic products or diastereomers via chiral phase preparative HPLC. Alternatively, the example compounds can be prepared by known methods to obtain enantiomers or diastereomers enriched products.

[0270] The reactions and techniques described in this chapter are carried out in a solvent suitable for the reagents and materials used, and are applicable to the conversions performed. In addition, in the description of the synthetic methods given below, it should be understood that all proposed reaction conditions (including the duration and post-processing procedures for selecting solvent, reaction atmosphere, reaction temperature, experiment) are selected as standard conditions for the reaction, and those skilled in the art should readily recognize this. Those skilled in the art of organic synthesis will appreciate that the functional groups present on each part of the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents compatible with the reaction conditions should be readily clear to those skilled in the art, wherein alternatives are needed when there are incompatible substituents. This will sometimes require judgment to modify the order of the synthetic steps or to select a specific method scheme rather than another, in order to obtain the compounds of the present invention. It should also be recognized that another major consideration in the planning of any synthetic route in this field is to judiciously select the protecting group for the reactive functional groups present in the compounds of the present invention. An authoritative explanation describing many alternatives for the trained practitioner is Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., Wiley and Sons (2007).

[0271] Example

[0272] The following examples illustrate specific and preferred embodiments of the present invention and do not limit the scope of the present invention. Unless otherwise indicated, chemical abbreviations and symbols and scientific abbreviations and symbols have their usual and customary meanings. The following defines the other abbreviations used in the examples and other places in this application. Common intermediates can usually be used to prepare more than one example and are sequentially identified (e.g., intermediate 1, intermediate 2) and abbreviated as Int.1 or I1, Int.2 or I2. The compounds of the examples are identified by the examples and steps of preparing them (e.g., "1-A" represents Example 1 Step A), or are identified only by the examples when the compound is the title compound of the example (e.g., "1" represents the title compound of Example 1). In some cases, alternative preparations of intermediates or examples are described. Generally, chemical technicians in the field of synthesis can design alternative preparations that may be desired based on one or more considerations such as the following: shorter reaction time, cheaper starting materials, easy to operate or separate, improve yield, be suitable for catalysis, avoid toxic reagents, the availability of special instruments and reduce the number of linear steps. The purpose of describing alternative preparations is to further enable the preparation of examples of the present invention. In some cases, some of the functional groups in the outlined examples and claims may be replaced by well-known bioisosteric alternatives known in the art, such as replacement of a carboxylic acid group with a tetrazole or phosphate moiety. 1 H NMR data were processed using water suppression. The reported spectra were not corrected for water suppression. Protons adjacent to the water suppression frequency of 3.35 ppm exhibited reduced signal intensity.

[0273] abbreviation

[0274] The following abbreviations are used in the Schemes, Examples, and elsewhere herein:

[0275] EtOAc = Ethyl acetate

[0276] PE = Petroleum Ether

[0277] DMF = dimethylformamide

[0278] THF = Tetrahydrofuran

[0279] K2CO3=potassium carbonate

[0280] Na2CO3=sodium carbonate

[0281] MgSO4 = magnesium sulfate

[0282] DCM=CH2Cl2=dichloromethane

[0283] MeOH = methanol

[0284] HCl = hydrochloric acid

[0285] AcOH = acetic acid

[0286] Cs2CO3=cesium carbonate

[0287] DMSO = dimethyl sulfoxide

[0288] TEA = triethylamine

[0289] BOP = (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0290] DMAP = 4-dimethylaminopyridine

[0291] 2-DMAP = 2-dimethylaminopyridine

[0292] PCC = pyridinium chlorochromate

[0293] PDC = pyridinium dichromate

[0294] DIBAL-H = Diisobutylaluminum hydride

[0295] rotovap = rotary evaporation

[0296] min = minutes

[0297] h or hr = hours

[0298] d = day

[0299] rt = room temperature

[0300] mL = milliliters

[0301] g = grams

[0302] mg = milligrams

[0303] mmol = millimole

[0304] LRMS = Low Resolution Mass Spectrometry

[0305] NMR = Nuclear Magnetic Resonance

[0306] HPLC = High Performance Liquid Chromatography

[0307] synthesis

[0308] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below in conjunction with synthetic methods known in the field of organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated by reference in their entirety.

[0309] The reaction and technology described in this chapter and section can be used to prepare novel compounds of formula I. The reaction is carried out in a solvent suitable for reagents and materials used, and is applicable to the conversion carried out. In addition, in the description of the synthetic method described below, it should be understood that all proposed reaction conditions (including solvent, reaction atmosphere, reaction temperature, duration of experiment and post-processing procedure) are selected as standard conditions for the reaction, and those skilled in the art should easily recognize this point. Those skilled in the art of organic synthesis understand that the functional groups present on each part of the advertised molecule must be compatible with the proposed reagents and reactions. All compounds of formula I that are not included in a given category can be compatible with some reaction conditions required in some of the methods. Such restrictions on substituents compatible with reaction conditions should be easily clear to those skilled in the art, and alternative methods must be used.

[0310] Solution 1

[0311]

[0312] Scheme 1 describes the synthesis of compounds of Formula I. Intermediate 3 can be synthesized by coupling intermediate 1 and intermediate 2 under reductive amination conditions, which are known methods recognized by those skilled in the art. Imine synthesis can be carried out at room temperature or reflux temperature in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) in the presence of an acid (e.g., acetic acid), followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to obtain intermediate 3. Various transformations of intermediate 3 can be performed using many known methods recognized by those skilled in the art to obtain variations of Formula I, including but not limited to the following methods:

[0313] Amide: Intermediate 4 can be obtained from commercial sources or can be synthesized by known methods that can be readily recognized by those skilled in the art. Intermediate 4 can be activated for acylation using any number of reagents recognized by those skilled in the art (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from -30°C to reflux temperature. The activated acid intermediate can then be reacted with intermediate 3 in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc., or a combination of at least two of these) to produce a compound of Formula I.

[0314] Urea: Intermediate 3 can be treated with an isocyanate in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature in the presence of a base (e.g., Et3N, DIPEA, pyridine, etc.) to give the urea represented by Formula I. Alternatively, intermediate 3 can be activated by treatment with triphosgene in a solvent (e.g., DCM, DCE, etc.) at 0°C to room temperature in the presence of a base (e.g., Et3N, DIPEA, etc.). The activated intermediate 3 can then be treated with a substituted alkyl or aryl or heteroaryl amine in a solvent (e.g., DCM, DCE, THF, etc.) at room temperature to give the urea represented by Formula I.

[0315] Carbamates: Intermediate 3 can be treated with a chloroformate (or alcohol, activated to a carbonate) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) in the presence of a base (e.g., Et3N, DIPEA, pyridine, t-BuOK, etc.) at 0°C to room temperature to give the carbamate represented by Formula I.

[0316] Intermediate 1 (Scheme 1) can be obtained from commercial sources or can be synthesized by known methods that can be readily recognized by those skilled in the art. Intermediate 1 can be obtained in various ways as depicted in Schemes 2-10 using many known methods recognized by those skilled in the art, including but not limited to the following methods.

[0317] Option 2

[0318]

[0319] Intermediate 1 can be obtained in a variety of ways as depicted in Scheme 2. Intermediates 5, 6, and 7 can be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art. Intermediates 5, 6, and 7 can be subjected to metal-catalyzed cross-coupling reactions using many known methods recognized by those skilled in the art, including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, Vol. 2, 2nd Revised and Supplemented Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and the methods described in the references cited therein. Intermediates 5, 6 and 7 can be subjected to various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.). These coupling reactions can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, etc.) and an appropriate ligand (including but not limited to ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine, dppf, etc.) as needed. Intermediate 5 can be subjected to Ullmann and Buchwald coupling reactions with various coupling partners (such as alkyl or cycloalkyl or heterocyclic or heteroaryl amines, alkyl or cycloalkyl or heterocyclic or heteroaryl alcohols, phenols, etc.). Intermediates 6 and 7 can be subjected to Suzuki, Heck, and Chan-Lam coupling reactions with various coupling partners (such as olefins, alkenyl halides, or trifluoromethanesulfonates, etc.). Intermediate 5 can be subjected to Suzuki, Stille, and other cross couplings with coupling partners (such as alkyl, allyl, alkenyl boronic acid, borate, trifluoroborate; alkyl, allyl, alkynyl, organotin reagents, etc.). The reaction can be carried out in the presence of a base (if necessary) (including but not limited to Na2CO3, K2CO3, NaHCO3, K3PO4, NaO tBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents), the coupling reaction is carried out under heating conditions to obtain intermediate 1. Alternatively, intermediate 5 can be converted into an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is then coupled with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling manner (Sherer, B. et al. PCT International Application, 2016 / 039734, 2016) to obtain a compound represented by Formula I. Intermediate 5 can be converted into an organoboron reagent using bis(pinacolato)diboron, bis(neopentylethylene glycol)diboron, etc. in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., potassium acetate) in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature. The organoboron reagent is coupled with a suitable coupling partner (e.g., an olefin, an alkenyl halide, or a triflate, etc.) in a Suzuki coupling manner to obtain a compound represented by Formula I. Intermediate 7a can be subjected to a coupling reaction with dimethylphosphine oxide under heating conditions in the presence of a palladium catalyst (e.g., bis(dibenzylideneacetone)palladium), a ligand (e.g., XantPhos), and an inorganic base (e.g., cesium carbonate) in a solvent (e.g., dioxane, DMSO, etc.) to obtain the corresponding phosphine oxide.

[0320] Intermediate 7 or 7a is then subjected to a coupling reaction as described above to provide a nitro intermediate, which can be reduced to produce intermediate 1 using conditions recognized by those skilled in the art, including but not limited to reduction in the presence of a catalyst (such as Pd) and hydrogen at ambient pressure and temperature.

[0321] Option 3

[0322]

[0323] Intermediates 1a-d can be obtained in a variety of ways as depicted in Scheme 3. Intermediate 8 can be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art. Intermediate 8 can be subjected to various transformations to provide intermediates 9-12 using many known methods recognized by those skilled in the art, including but not limited to the following methods:

[0324] Amides: Intermediate 8 can be reacted with an activated acid intermediate in a polar aprotic solvent (eg, DCM, THF, etc.) in the presence of a base (eg, pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to give intermediate 9.

[0325] Carbamates: Intermediate 8 can be treated with chloroformate (or alcohol, activated to carbonate) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) in the presence of a base (e.g., Et3N, DIPEA, pyridine, t-BuOK, etc.) at 0°C to room temperature to provide intermediate 10.

[0326] Urea: Intermediate 8 can be treated with an isocyanate in a polar aprotic solvent (e.g., DCM, DCE, etc.) in the presence of a base (e.g., Et3N, DIPEA, pyridine, etc.) at room temperature to provide intermediate 11. Alternatively, intermediate 8 can be activated by treatment with triphosgene in a solvent (e.g., DCM, DCE, etc.) in the presence of a base (e.g., Et3N, DIPEA, etc.) at 0°C to room temperature. The activated intermediate 8 can then be treated with a substituted alkyl or aryl or heteroaryl amine in a solvent (e.g., DCM, DCE, etc.) in the presence of a base (e.g., Et3N, DIPEA, etc.) to provide intermediate 11.

[0327] Sulfonamides: Intermediate 8 can be treated with sulfonyl chloride in a polar aprotic solvent (e.g. DCM, THF, etc.) in the presence of a base (e.g. pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) at temperatures ranging from 0 °C to 90 °C to give intermediate 12.

[0328] Intermediates 9-12 can be reduced to produce intermediates 1a-d, respectively (as shown in Scheme 3) using conditions recognized by one skilled in the art, including but not limited to reduction in the presence of a catalyst (such as Pd) and hydrogen at ambient pressure and temperature.

[0329] Option 4

[0330]

[0331] Intermediate 1e can be obtained as depicted in Scheme 3. Intermediate 13 can be obtained from commercial sources or can be synthesized by known methods that can be readily recognized by those skilled in the art. Intermediate 13 can be alkylated using many known methods recognized by those skilled in the art to obtain intermediate 14, including but not limited to reaction with an alkyl or aryl or heteroaryl 2-bromoacetate in a polar aprotic solvent (e.g., acetone, etc.) in the presence of a base (e.g., K2CO3, Na2CO3, etc.) under heating conditions. Intermediate 14 can be reduced using conditions recognized by those skilled in the art to produce intermediate 1e, including but not limited to reduction in the presence of a catalyst (e.g., Pd) and hydrogen at ambient pressure and temperature.

[0332] Option 5

[0333]

[0334] Scheme 5 describes the synthesis of intermediate 1f. Intermediate 15 can be obtained from commercial sources or can be synthesized by known methods that can be easily recognized by those skilled in the art. Intermediate 16 can be prepared from intermediate 15 by using any number of reagents (but not limited to those described herein) (such as phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) that can be recognized by those skilled in the art at a temperature ranging from -30°C to reflux temperature in a polar aprotic solvent (such as DCM, THF, etc.). Then, activated acid intermediate 16 can be reacted with intermediate 18 in the presence of a base (such as pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to generate intermediate 17. Intermediate 17 can be reduced using conditions recognized by those skilled in the art to produce intermediate 1f, including but not limited to reduction in the presence of a catalyst (such as Pd) and hydrogen at ambient pressure and temperature.

[0335] Option 6

[0336]

[0337] Scheme 6 describes the synthesis of intermediate 1g. Intermediate 19 can be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art. Intermediate 19 can then be reacted with intermediate 18 in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to produce intermediate 20. Intermediate 20 can be reduced using conditions recognized by those skilled in the art, including but not limited to reduction in the presence of a catalyst (e.g., Pd) and hydrogen at ambient pressure and temperature to produce intermediate 1g.

[0338] Option 7

[0339]

[0340] Scheme 7 describes the synthesis of intermediate 1h. Intermediate 21 can be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art. Intermediate 21 can be reduced using conditions recognized by those skilled in the art, including but not limited to reduction in the presence of a catalyst (such as Pd) and hydrogen at ambient pressure and temperature to produce intermediate 1h. Intermediate 1h can also be obtained from commercial sources or can be synthesized by known methods readily recognized by those skilled in the art, including but not limited to those described herein.

[0341] Option 8

[0342]

[0343] Scheme 8 describes the synthesis of intermediate 1i. Intermediate 16 (synthesized as described in Scheme 5) can be reacted with a sulfonamide in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from 0°C to 90°C in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to produce intermediate 22. Intermediate 22 can be reduced to produce intermediate 1i using conditions recognized by those skilled in the art, including but not limited to reduction in the presence of a catalyst (e.g., Pd) and hydrogen at ambient pressure and temperature.

[0344] Option 9

[0345]

[0346] Scheme 9 describes the synthesis of intermediate 1j. Intermediate 16 (synthesized as described in Scheme 5) can be reacted with an alcohol or phenol in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from 0°C to 90°C in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to produce intermediate 23. Intermediate 23 can be reduced to produce intermediate 1j using conditions recognized by those skilled in the art, including but not limited to reduction in the presence of a catalyst (e.g., Pd) and hydrogen at ambient pressure and temperature.

[0347] Plan 10

[0348]

[0349] Scheme 10 describes the synthesis of intermediate 1k. Intermediate 24 can be obtained from commercial sources or can be synthesized by known methods that are readily recognized by those skilled in the art. Intermediate 24 can be reacted with alkyl 2-(dimethoxyphosphoryl)acetate in a polar protic solvent (e.g., water, methanol, ethanol, etc.) in the presence of a base (e.g., K2CO3, Na2CO3, etc.) to obtain intermediate 24a. Intermediate 24a can be reduced using conditions recognized by those skilled in the art, including but not limited to the conditions described, such as heating in the presence of tin(II) chloride dihydrate in a polar protic solvent (e.g., water) to obtain intermediate 1k. Intermediate 1k can be converted to a compound of Formula I by using the steps described in Scheme 1.

[0350] Intermediate 2 (Scheme 1) can be obtained in a variety of ways as depicted in Scheme 11 using many known methods recognized by those skilled in the art, including but not limited to the following methods.

[0351] Plan 11

[0352]

[0353] Scheme 11 describes the synthesis of intermediate 2. Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be subjected to heterocyclic synthesis to provide compounds of intermediate 26.

[0354] Heterocycle Formation (A). The formic acid portion of compound 25 can be converted to various heterocycles (A) using many known methods recognized by those skilled in the art, including but not limited to the following methods:

[0355] A = 1,2,4-oxadiazole. Intermediate 25 can be coupled with various amidoximes (derived from the corresponding nitrile by reaction with hydroxylamine; see Hirawat, S. et al. WO 2006 / 110483) using amide bond coupling reagents (e.g., CDI, BOP, EDC, etc.) at room temperature in polar aprotic solvents (e.g., THF, 1,4-dioxane, DMF, etc.). The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C). Alternatively, in situ cyclization can be achieved by coupling acid 25 with amidoxime at elevated temperatures (60°C to 100°C).

[0356] A = 1,2,5-oxadiazole. Intermediate 25 can be converted to 1,2,5-oxadiazole, such as J. et al. J. Med. Chem. 2012, 55, 1817-1830 and references described therein.

[0357] A = 1,3,4-oxadiazole or A = 1,3,4-thiadiazole. Intermediate 25 can be coupled with acetic hydrazide using an amide coupling reagent (e.g., CDI, BOP, EDC, etc.) in a polar aprotic solvent (e.g., THF, 1,4-dioxane, DMF, MeCN, etc.) (described in WO 2014 / 071247, Bradner, JE et al.). The acyclic hydrazide intermediate can then be cyclized to 1,3,4-oxadiazole or 1,3,4-thiadiazole using 4-toluenesulfonic acid (Stabile, P. et al., Tetrahedron Lett. 2010, 51, 4801-4805) or Laweson's reagent (Kitamura, S. et al., PCT International Application, 2008011130, 2008), respectively.

[0358] A = 3-substituted 5-alkyl-1-methyl-1H-pyrazole. Methyl ketones can be treated with basic and acidic chlorides of intermediate 25 to provide diketones, which, upon reaction with substituted or unsubstituted hydrazine salts in a polar protic solvent such as ethanol at reflux temperature, provide esters 26, where A is an alkyl-substituted or unsubstituted pyrazole. (As described in Cadilla, R. et al., WO 03 / 074495 A1).

[0359] A = isoxazole. The diketone prepared from intermediate 25 as described above can be reacted with hydroxylamine hydrochloride in a polar protic solvent such as ethanol at reflux temperature to give ester 26, where A is an alkyl-substituted isoxazole (as described in Cadilla, R. et al. WO 03 / 074495 A1).

[0360] A = 5-(3-alkyl-1-methyl-1H-pyrazole) The diketone prepared from intermediate 25 as described above can be reacted with an alkylhydrazine at reflux temperature in a polar protic solvent such as ethanol to give ester 26, where A is an alkyl-substituted pyrazole.

[0361] A = substituted heteroaryl. Intermediate 25 can be subjected to a Minisci reaction with a substituted heteroaryl compound (such as pyridine, pyrimidine, pyridazine, pyrazine, quinoline, pyrazole, etc.) in a mixture of DCM (or any other conditions that can be used to generate carbon-centered free radicals) and water as a solvent in the presence of silver nitrate and potassium or ammonium persulfate at ambient temperature to give ester 26 (as described in Ling-Bo, Qu et al. Org. Biomol. Chem., 2015, 13, 2750-2755 and Review: Duncton, MA J Med. Chem. Commun., 2011, 2, 1135-1161 and references described therein).

[0362] A = 2-benzothiazole. Method A: Intermediate 25 can be coupled with a substituted 2-aminobenzenethiol using an amide bond coupling reagent (e.g., BOP, T3P, EDC, etc.) in a polar aprotic solvent (e.g., DCE, THF, etc.) (see generally Chedekel, MR et al. Synth. Commun. 1980, 10, 167-173 for the synthesis of various 2-aminobenzenethiols). The coupling reaction can be carried out at an elevated temperature (60° C. to 80° C.) to achieve in situ formation of the cyclized 2-benzothiazole.

[0363] Method B: Alternatively, intermediate 25 can be coupled with a substituted 2-chloroaniline (commercially available) using an amide bond coupling reagent (e.g., T3P, BOP, etc.) or by activating intermediate 25 for acylation using any number of reagents (e.g., oxalyl chloride, POCl3, etc.). The resulting carboxamide can be treated with Lawesson's reagent at elevated temperature (120°C) to achieve in situ cyclization to the 2-benzothiazole.

[0364] A = 2-benzoxazole. Intermediate 25 can be coupled with substituted 2-aminophenols (commercially available) using amide bond coupling reagents (e.g., BOP, EDC, etc.) in polar aprotic solvents (e.g., DMF, THF, etc.). Cyclization can be achieved in refluxing toluene in the presence of p-toluenesulfonic acid.

[0365] A = 2-benzimidazole. Intermediate 25 can be coupled with ethyl 3,4-diaminobenzoate using an amide bond coupling reagent (e.g., TBTU, T3P, PyBOP, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.), and then cyclized to 2-benzimidazole under acidic conditions (neat AcOH) at elevated temperature (115°C).

[0366] A=2-quinazoline. Intermediate 25 can be coupled with 4-amino-3-(aminomethyl)benzoic acid dihydrochloride using an amide bond coupling reagent (e.g., HBTU, EDC, PyBOP, etc.) in a polar aprotic solvent (e.g., MeCN, THF, etc.) (Pascal, R. et al. Eur. J. Org. Chem. 2000, 22, 3755-3761). Cyclization can be achieved under acidic conditions (pure AcOH) at elevated temperatures (115°C). The resulting dihydroquinazoline intermediate can be oxidized to 2-quinazoline using an oxidant (e.g., DDQ).

[0367] A = 1-triazole. Intermediate 25 can be converted to the corresponding amine via Curtius rearrangement (as described in Shioiri, T. et al. J. Am. Chem. Soc. 1972, 94, 6203-6205). The amine can be converted to the corresponding azide after treatment with a reagent such as p-toluenesulfonyl azide, which, upon reaction with an appropriate alkyne (as described in Boren, BC et al. J. Am. Chem. Soc., 2008, 130, 8923-8930), affords the triazole.

[0368] A = substituted 1,2,4-triazole. Intermediate 25 can be converted to the corresponding hydrazide and reacted with a substituted carboxamide in the presence of trifluoromethanesulfonic anhydride and 2-fluoropyridine under heating conditions as described by Charette, AB et al. Org. Lett., 2015, 17, 1184-1187.

[0369] "A" can be other heterocycles, such as substituted and unsubstituted oxazoles, thiazoles, imidazoles, isoxazoles, triazoles, pyrazoles, and can be synthesized as described in Wlochal, J. et al. Org. Lett. 2014, 16, 4094-4097 and references cited therein. Alternatively, the acid function of intermediate 25 can be converted to a heterocycle as described in Schemes 2-9 using the methods described therein and the literature references.

[0370] Intermediate 26 can be reduced by a reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) in a chlorinated or ethereal solvent (e.g., DCM, diethyl ether, 1,4-dioxane, THF, etc.) to provide intermediate 27. Intermediate 27 can be oxidized using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC, etc.) by methods recognized by those skilled in the art to provide intermediate 2.

[0371] Plan 12

[0372]

[0373] Scheme 12 describes an alternative synthesis of compounds of Formula I using a modified sequence of steps. Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) to provide intermediate 28. Intermediate 28 can be oxidized to intermediate 29 using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art. Intermediate 1 and intermediate 29 can be reacted in the presence of an acid (e.g., acetic acid) in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room temperature or reflux temperature, followed by reduction with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 30. Intermediate 4 can be activated for acylation in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from -30°C to reflux temperature using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate can be reacted with intermediate 30 in the presence of a base to generate the corresponding amide. Subsequent base hydrolysis of the methyl ester with an alkaline hydroxide can provide intermediate 31. Intermediate 31 can be converted to various heterocycles (A) using many known methods recognized by those skilled in the art to obtain compounds of Formula I, including but not limited to those described in Scheme 11.

[0374] Alternatively, many known methods that those skilled in the art can recognize can be used to carry out reductive amination to intermediate 29 and intermediate 5a or 5b.At room temperature or reflux temperature, in suitable polar protic solvent (such as MeOH, EtOH etc.), in the presence of acid (such as acetic acid), carry out imine synthesis, afterwards with reducing agent (such as sodium cyanoborohydride, sodium triacetoxyborohydride etc.) reduction imine obtains intermediate 30a.Can be in scope at the temperature between-30 ℃ to reflux temperature, in polar aprotic solvent (such as DCM, THF etc.), use any number reagent (such as thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl or ethyl chloroformate etc.) activation intermediate 4 that those skilled in the art can recognize to carry out acylation.Can make activated acid intermediate and intermediate 30a react in the presence of alkali, to generate corresponding amides.Subsequently, intermediate 31a can be provided with alkaline hydroxide base hydrolysis methyl ester. Intermediate 31a can be converted to various heterocycles (A) to give intermediate 31b using many known methods recognized by those skilled in the art, including but not limited to those described in Scheme 11. Intermediate 31b can be subjected to metal-catalyzed cross-coupling reactions using many known methods recognized by those skilled in the art, including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Arminde Meijere, Diederich, Vol. 2, 2nd Revised and Supplemented Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and the methods described in the references cited therein. Intermediate 31b can be subjected to various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.). These coupling reactions can be carried out as needed and when necessary in the presence of a metal catalyst (e.g., CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, etc.) and an appropriate ligand (including but not limited to ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine, dppf, etc.). Intermediate 31b can be subjected to Ullmann and Buchwald coupling reactions with various coupling partners (such as alkyl or cycloalkyl or heterocyclic or heteroaryl amines, alkyl or cycloalkyl or heterocyclic or heteroaryl alcohols, phenols, etc.). Intermediate 31b can be subjected to Suzuki, Heck, Stille and other cross couplings with coupling partners (such as alkyl, allyl, alkenyl boronic acid, borate, trifluoroborate; alkyl, allyl, alkynyl, organotin reagents, etc.). The reaction can be carried out in a base (if necessary) (including but not limited to Na2CO3, K2CO3, NaHCO3, K3PO4, NaOt Bu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents), a coupling reaction is carried out under heating conditions to obtain a compound of Formula I. Alternatively, the intermediate 31b can be converted into an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is then coupled with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling manner (Sherer, B. et al. PCT International Application, 2016 / 039734, 2016) to obtain a compound represented by Formula I. Intermediate 31b can be converted into an organoboron reagent using bis(pinacolato)diboron, bis(neopentylethylene glycol)diboron, etc. in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., potassium acetate) in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature. The organoboron reagent is coupled with a suitable coupling partner (e.g., an olefin, an alkenyl halide, or a triflate) in a Suzuki coupling manner to give a compound represented by Formula I. Intermediate 31b can be subjected to a coupling reaction with dimethylphosphine oxide in the presence of a palladium catalyst (e.g., bis(dibenzylideneacetone)palladium), a ligand (e.g., XantPhos), and an inorganic base (e.g., cesium carbonate) in a solvent (e.g., dioxane, DMSO, etc.) under heating conditions to give the corresponding phosphine oxide.

[0375] Plan 13

[0376]

[0377] Scheme 13 describes the synthesis of compounds of Formula I using a modified sequence of steps.

[0378] Intermediate 30 (described in Scheme 12) can be subjected to methyl ester hydrolysis with an alkaline hydroxide base to provide intermediate 32. Intermediate 32 can be converted to various heterocycles (A) using many known methods recognized by those skilled in the art, including but not limited to those described in Scheme 11, to provide compounds of Formula 33. Intermediate 4 can be activated for acylation using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from -30°C to reflux temperature. The activated acid intermediate can be reacted with intermediate 33 in the presence of a base to produce a compound of Formula I.

[0379] Alternatively, intermediate 30a (described in Scheme 12) can be subjected to methyl ester hydrolysis with an alkaline hydroxide base to provide intermediate 32a. Intermediate 32a can be converted to various heterocycles (A) using many known methods recognized by those skilled in the art to obtain compounds of formula 33a, including but not limited to the methods described in Scheme 11. Intermediate 4 can be activated for acylation using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from -30°C to reflux temperature. The activated acid intermediate can be reacted with intermediate 33a in the presence of a base to generate intermediate 33b. Intermediate 33b can be subjected to a metal-catalyzed cross-coupling reaction using many known methods recognized by those skilled in the art, including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, Vol. 2, 2nd Revised and Supplemented Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and the methods described in the references cited therein. Intermediate 33b can be subjected to various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille, Sonogashira couplings, etc.). These coupling reactions can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, etc.) and an appropriate ligand (including but not limited to ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine, dppf, etc.) as needed and when required. Intermediate 33b can be subjected to Ullmann and Buchwald coupling reactions with various coupling partners (such as alkyl or cycloalkyl or heterocyclic or heteroaryl amines, alkyl or cycloalkyl or heterocyclic or heteroaryl alcohols, phenols, etc.). Intermediate 33b can be subjected to Suzuki, Heck, Stille and other cross couplings with coupling partners (such as alkyl, allyl, alkenyl boronic acid, borate, trifluoroborate; alkyl, allyl, alkynyl, organotin reagents, etc.). The reaction can be carried out in a base (if necessary) (including but not limited to Na2CO3, K2CO3, NaHCO3, K3PO4, NaO tBu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents), the coupling reaction is carried out under heating conditions to obtain a compound of Formula I. Alternatively, the intermediate 33b can be converted into an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is then coupled with a suitable coupling partner (e.g., alkyl, acyl, alkenyl, allyl halide, triflate, etc.) in a Stille coupling manner (Sherer, B. et al. PCT International Application, 2016 / 039734, 2016) to obtain a compound represented by Formula I. Intermediate 33b can be converted into an organoboron reagent using bis(pinacolato)diboron, bis(neopentylethylene glycol)diboron, etc. in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., potassium acetate) in a solvent (e.g., dioxane, DMSO, etc.) at reflux temperature. The organoboron reagent is coupled with a suitable coupling partner (e.g., an olefin, an alkenyl halide, or a triflate, etc.) in a Suzuki coupling manner to give a compound represented by Formula I. Intermediate 33b can be coupled with dimethylphosphine oxide in the presence of a palladium catalyst (e.g., bis(dibenzylideneacetone)palladium), a ligand (e.g., XantPhos), and an inorganic base (e.g., cesium carbonate) under heating conditions in a solvent (e.g., dioxane, DMSO, etc.) to give the corresponding phosphine oxide.

[0380] Plan 14

[0381]

[0382] Scheme 14 describes the synthesis of intermediate 40, wherein A is a 3-(5-substituted-1,2,4-oxadiazolyl) ring. Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be subjected to amide synthesis by treatment with an activating agent (such as BOP, HATU, etc.) in the presence of ammonium chloride in a solvent (such as DCM, DMF, etc.) and an organic base (such as Et3N, DIPEA, etc.) at ambient temperature to provide intermediate 34. Intermediate 34 can be converted to intermediate 35 by treatment with trifluoroacetic anhydride in pyridine or with POCl3 and a base (such as imidazole) at 0°C. Intermediate 36 can be synthesized by reaction of intermediate 35 with hydroxylamine; see Hirawat, S. et al. WO 2006 / 110483. Various substituted intermediates 37 can be coupled with intermediates 36 using amide bond coupling reagents (e.g., CDI, BOP, EDC, etc.) in polar aprotic solvents (e.g., THF, 1,4-dioxane, DMF, etc.) at room temperature. The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C). Alternatively, in situ cyclization can be achieved by coupling acid 37 with amide oxime 36 at elevated temperatures (60°C to 100°C) to give intermediates of formula 38. Reduction of intermediate 38 can be achieved in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) in a chlorinated or ethereal solvent (e.g., DCM, diethyl ether, 1,4-dioxane, THF, etc.) to give intermediate 39. Intermediate 39 can be oxidized to intermediate 40 by methods recognized by those skilled in the art using oxidative conditions such as Dess-Martin periodinane, Swern oxidative conditions, PDC or PCC, etc. Intermediate 40 can be converted to compounds of Formula I by the steps described in Scheme 1.

[0383] Plan 15

[0384]

[0385] Scheme 15 describes the synthesis of compounds of Formula I(ad). The intermediate represented by Formula 31 (synthesis described in Scheme 12) can be esterified. Intermediate 31 can be activated for acylation in a polar aprotic solvent (e.g., DCM, THF, etc.) at a temperature ranging from -30°C to reflux temperature using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate can be reacted with an alcohol in the presence of a base to produce a compound of Formula Ia. Intermediate 31 can be subjected to amide synthesis by activating the acid with an activating agent (e.g., BOP, CDI, HATU, etc.) in the presence of a base (e.g., Et3N, DIPEA, etc.) in the presence of ammonium chloride or a substituted amine (e.g., alkyl, cycloalkyl, aryl, heteroaryl, etc.) in a solvent (e.g., DCM, DMF, etc.) at ambient temperature or under heating conditions to provide an amide of Formula Ib. Intermediate 31 can be subjected to primary amide synthesis by treatment with an activating agent (e.g., BOP, CDI, HATU, etc.) in the presence of a base (e.g., Et3N, DIPEA, etc.) and ammonium chloride in a solvent (e.g., DCM, DMF, etc.) at ambient temperature. The primary amide thus obtained can be treated with i) trifluoroacetic anhydride in pyridine at 0°C or ii) POCl3 and imidazole to provide the nitrile of Formula Ic. Intermediate 31 can be activated using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging from -30°C to reflux. The activated acid intermediate can be reacted with a sulfonamide in a polar aprotic solvent (e.g., DCM, THF, etc.) in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) at a temperature ranging from 0°C to 90°C to generate the acylsulfonamide of Formula Id.

[0386] Plan 16

[0387]

[0388] Scheme 16 describes the synthesis of intermediate 2a. Intermediate 52 can be synthesized according to the method described by Singh, SB et al. (ACSMed.Chem.Lett.2014,5,609-614). Intermediate 53 can be deprotonated with n-BuLi in an ether solvent (e.g., THF, 1,4-dioxane, etc.) at a temperature varying between -78°C and 0°C, and then reacted with intermediate 52 to produce intermediate 54. Intermediate 54 can be cyclized at an elevated temperature (70°C) in the presence of an alkaline hydroxide base to form intermediate 55. Thioacetal deprotection can be achieved using any number of reagents (e.g., NCS, Hg(ClO4)2, DDQ, etc.) to provide an aldehyde, which can be oxidized to an acid using an oxidant (e.g., NaClO2, PCC or PDC, KMnO4, etc.) and then subsequently esterified by reaction with iodomethane to provide intermediate 56. Subsequent alkaline hydrolysis of intermediate 56 with an alkaline hydroxide can provide intermediate 57. Intermediate 57 can be converted to various heterocycles (A) using many known methods recognized by those skilled in the art, including but not limited to the methods described in Scheme 11, to provide compounds of intermediate 58. Intermediate 58 can be treated with an acetate (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at elevated temperature (120° C.) to provide the corresponding acetate, which is then hydrolyzed under acidic conditions (HCl) to provide intermediate 59. Intermediate 59 can be oxidized using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art to provide compounds of Formula 2a. Intermediate 2a can be converted to compounds of Formula I by using the steps described in Scheme 1.

[0389] Plan 17

[0390]

[0391] Scheme 17 describes an alternative synthesis of intermediate 2b. Intermediate 52 can be synthesized according to the method described by Singh, SB et al. (ACSMed. Chem. Lett. 2014, 5, 609-614). Halogenated heterocycle 60 (commercially available or obtained by methods known to those skilled in the art) can be treated with a base such as (n-BuLi, s-BuLi, MeLi, etc.) in an ether solvent (e.g., THF, 1,4-dioxane, etc.) at a temperature varying between -78°C and 0°C and then reacted with ketone 52 to give intermediate 61. Intermediate 61 can be cyclized in the presence of an alkaline hydroxide base at elevated temperature (70°C) to give intermediate 62. Intermediate 62 can be treated with an acetate (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at elevated temperature (120° C.) to provide the corresponding acetate, which is then hydrolyzed under acidic conditions (HCl) to provide intermediate 63. Intermediate 63 can be oxidized using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art to provide intermediate 2b. Intermediate 2b can be converted to a compound of Formula I by using the steps described in Scheme 1.

[0392] Plan 18A

[0393]

[0394] Scheme 18A describes an alternative synthesis of compounds of Formula I. Intermediate 57 (synthesis described in Scheme 16) can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) to provide intermediate 64. Intermediate 64 can be oxidized to aldehyde 65 using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art. Intermediate 1 and intermediate 65 can be subjected to reductive amination using many known methods recognized by those skilled in the art in the art in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room temperature or reflux temperature in the presence of an acid (e.g., acetic acid), followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 66. Intermediate 66 can be treated with an acetate (e.g., CsOAc, KOAc, etc.) at elevated temperature (120° C.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) to provide the corresponding acetate, which is subsequently hydrolyzed under acidic conditions (HCl) to provide intermediate 67. Intermediate 67 can be oxidized to the acid using an oxidizing agent (NaClO 2 , PCC or PDC, KMnO 4 , etc.), followed by the synthesis of various heterocycles (A) using many known methods recognized by those skilled in the art, including but not limited to those described in Scheme 11. Intermediate 4 can be activated for acylation using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging from −30° C. to reflux temperature. The activated acid intermediate can be reacted with intermediate 68 in the presence of a base to produce compounds of Formula I.

[0395] Plan 18B

[0396]

[0397] Scheme 18B describes an alternative synthesis of compounds of Formula I. Intermediates 86 and 65 (as described in Scheme 18A) can be subjected to reductive amination in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room temperature or reflux temperature in the presence of an acid (e.g., acetic acid) using many known methods known to those skilled in the art, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 66a. Intermediate 66a can be treated with an acetate (e.g., CsOAc, KOAc, etc.) in a polar aprotic solvent (e.g., DMF, NMP, etc.) at elevated temperature (120° C.) to provide the corresponding acetate, which is then hydrolyzed under acidic conditions (HCl) to provide intermediate 67a. Intermediate 67a can be oxidized to the acid using an oxidizing agent (NaClO2, PCC or PDC, KMnO4, etc.), followed by the synthesis of various heterocycles (A) using many known methods recognized by those skilled in the art to provide intermediate 68a, including but not limited to the method described in Scheme 11. Intermediate 68a can be converted to compounds of Formula I via sequential amide synthesis and coupling by the following steps described in Scheme 13.

[0398] Plan 19

[0399]

[0400] Scheme 19 describes an alternative synthesis of compounds of Formula I. Intermediate 2 can be treated with an organomagnesium reagent in an ethereal solvent (such as Et2O, THF, etc.) at temperatures varying between -78°C and 0°C to provide intermediate 70. Intermediate 70 can be oxidized to intermediate 71 under oxidative conditions using an oxidizing agent (such as Dess-Martin periodinane, PDC or PCC, etc.) by methods recognized by those skilled in the art. Intermediate 71 and intermediate 1 in a polar protic solvent (such as MeOH, EtOH, etc.) can be treated with triethylsilane and indium chloride at ambient temperature to provide intermediates of Formula 72. Intermediate 4 can be activated for acylation in a polar aprotic solvent (such as DCM, THF, etc.) at temperatures ranging from -30°C to reflux temperature using any number of reagents recognized by those skilled in the art (such as thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.). The activated acid intermediate can be reacted with intermediate 72 in the presence of a base to produce compounds of formula I.

[0401] Plan 20

[0402]

[0403] Scheme 20 describes the synthesis of compounds of Formula I (eg) (wherein "A" is an amide, sulfonamide, urea, or carbamate). Intermediate 25 can be converted to intermediate 73 via Curtius rearrangement (as described in Shioiri, T. et al. J. Am. Chem. Soc. 1972, 94, 6203-6205). Intermediate 73 can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) to provide intermediate 74. Intermediate 74 can be oxidized to aldehyde 75 using oxidizing conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art. Intermediate 1 and intermediate 75 can be subjected to reductive amination using many known methods known to those skilled in the art in the presence of an acid such as acetic acid in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room temperature or reflux temperature, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 76. Intermediate 4 can be activated for acylation using any number of reagents known to those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging from -30°C to reflux temperature. The activated acid intermediate can be reacted with intermediate 76 in the presence of a base to generate the corresponding amide. The amide intermediate can be subjected to Boc deprotection using trifluoroacetic acid in a polar aprotic solvent (e.g., DCM, THF, etc.) at room temperature to provide intermediate 77. Intermediate 77 can be subjected to various transformations to provide variations of Formula I using many known methods recognized by those skilled in the art, including but not limited to the following:

[0404] Amides: Intermediate 77 can be reacted with an activated acid intermediate in a polar aprotic solvent (eg, DCM, THF, etc.) in the presence of a base (eg, pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to generate amides of formula Ie.

[0405] Sulfonamides: Intermediate 77 can be treated with sulfonyl chloride in a polar aprotic solvent (e.g., DCM, THF, etc.) in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) at temperatures ranging from 0°C to 90°C to generate sulfonamides of formula If.

[0406] Urea: Intermediate 77 can be treated with an isocyanate in the presence of a base (e.g., Et3N, DIPEA, pyridine, etc.) in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature to provide the urea represented by Formula Ig. Alternatively, intermediate 77 can be activated by treatment with triphosgene in the presence of a base (e.g., Et3N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at 0°C to room temperature. The activated intermediate 77 can then be treated with a substituted alkyl or aryl or heteroaryl amine in the presence of a base (e.g., Et3N, DIPEA, etc.) in a solvent (e.g., DCM, DCE, etc.) at room temperature to provide the urea represented by Formula Ig.

[0407] Carbamates: Intermediates 77 can be treated with chloroformates (or alcohols, activated to carbonates) in polar aprotic solvents (e.g., DCM, DCE, THF, etc.) in the presence of a base (e.g., Et3N, DIPEA, pyridine, t-BuOK, etc.) at 0°C to room temperature to afford carbamates represented by formula Ih.

[0408] Plan 21

[0409]

[0410] Scheme 21 describes the synthesis of intermediate 82, wherein A is a 3-(5-substituted-1,2,4-oxadiazolyl) ring. Intermediate 30a (synthesized as described in Scheme 12) can be hydrolyzed with an alkaline hydroxide to provide intermediate 78. Primary amide synthesis of intermediate 78 can be performed by activating the acid with an activating agent (BOP, CDI, HATU, etc.) in the presence of a base (e.g., Et3N, DIPEA, etc.) in the presence of ammonium chloride at ambient temperature in a polar aprotic solvent (DCM, DMF, etc.) to provide intermediate 79. Intermediate 79 can be converted to intermediate 80 using various methods recognized by those skilled in the art, including but not limited to treatment with reagents (POCl3, SOCl2, TFAA, etc.) and bases (imidazole, Et3N, DIPEA, etc.). Intermediate 81 can be synthesized by reacting intermediate 80 with hydroxylamine; see Hirawat, S. et al. WO 2006 / 110483. Intermediate 37 can be obtained from commercial sources or can be synthesized by known methods that those skilled in the art can easily recognize. Intermediate 37 can be coupled to intermediate 81 using an amide bond coupling reagent (e.g., CDI, BOP, EDC, etc.) at room temperature in a polar aprotic solvent (e.g., THF, 1,4-dioxane, DMF, etc.). The acyclic intermediate can then be cyclized at an elevated temperature (60°C to 100°C). Alternatively, in situ cyclization can be achieved by coupling intermediate 37 to intermediate 81 at an elevated temperature (60°C to 100°C) to obtain oxadiazole 82. Intermediate 82 can be converted to a compound of formula I via sequential amide synthesis and coupling as described in Scheme 13.

[0411] Plan 22

[0412]

[0413] Scheme 22 describes the synthesis of compounds of Formula I (wherein "A" is phenyl). Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be brominated with bromine in dibromomethane as a solvent in the presence of mercuric oxide under heating conditions to provide intermediate 90 (as described by Owen et al. PCT International Application No. 2014113485, 2014). Intermediate 90 can be converted to intermediate 91 in benzene in the presence of AlCl3 under conditions described by Piyasena et al. PCT International Application No. 2015005901, 2015. Intermediate 91 can be brominated in CHCl3 at room temperature in the presence of silver trifluoroacetate and bromine to provide intermediate 92 (as described by Piyasena et al. PCT International Application No. 2015005901, 2015). Intermediate 92 can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) to provide intermediate 93. Intermediate 93 can be oxidized to aldehyde 94 using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidative conditions, PDC or PCC, etc.) by methods recognized by those skilled in the art. Intermediate 1 and intermediate 94 can be subjected to reductive amination using a number of known methods recognized by those skilled in the art in the presence of an acid such as acetic acid in a suitable polar protic solvent (e.g., MeOH, EtOH, etc.) at room temperature or reflux temperature, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) to provide intermediate 95. Intermediate 4 can be activated for acylation using any number of reagents recognized by those skilled in the art (e.g., thionyl chloride, phosphoryl chloride, oxalyl chloride, methyl or ethyl chloroformate, etc.) in a polar aprotic solvent (e.g., DCM, THF, etc.) at temperatures ranging from -30°C to reflux temperature. The activated acid intermediate can be reacted with intermediate 95 in the presence of a base to produce intermediate 96. If necessary, intermediate 96 can be subjected to various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Suzuki, Buchwald, Stille couplings, etc.) in the presence of a metal catalyst (e.g., CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2) and an appropriate ligand (including but not limited to ligands such as tricyclohexylphosphine, dppf, etc.). Intermediate 96 can be subjected to Ullmann and Buchwald coupling reactions with various coupling partners (e.g., alkyl, aryl, or heteroaryl amines, thiols, and alcohols). Intermediate 96 can be subjected to Suzuki and Stille coupling reactions with various coupling partners (e.g., alkenyl, aryl, or heteroaryl boronic acids, boronates, organotin reagents, etc.).The reaction mixture may be prepared in the presence of a base (whenever required) (including but not limited to Na2CO3, K2CO3, NaHCO3, K3PO4, NaO). t Bu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents), a coupling reaction is carried out under heating conditions to obtain a compound of formula I.

[0414] Plan 23

[0415]

[0416] Scheme 23 describes the synthesis of intermediate 99. Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be brominated as described in Scheme 22, followed by Friedel-Crafts arylation in the presence of an appropriately substituted arene to provide intermediate 97. Alternatively, intermediate 97 can be synthesized via a decarboxylative Negishi or Suzuki type cross-coupling reaction. Intermediate 25 can be activated to an N-hydroxyphthalimide ester or an N-hydroxybenzotriazole ester as a redox-active ester and can be treated with an organozinc or organoboronic acid or various substituted aryl Grignard reagents in the presence of a metal catalyst (e.g., Fe(acac)3, FeCl3, NiCl2 glyme, etc.) as described by Torriyama, F. et al. J. Am. Chem. Soc. 2016, 138, 11132-11135 and references cited therein to provide intermediate 97. Intermediate 97 can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, NaBH4, etc.) to provide intermediate 98. Intermediate 98 can be oxidized to aldehyde 99 by methods recognized by those skilled in the art using oxidative conditions (e.g., Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC, etc.). Intermediate 99 can be converted to compounds of Formula I (wherein "A" is phenyl) by using the procedures described in Scheme 1.

[0417] Plan 24

[0418]

[0419] Scheme 24 describes an alternative synthesis of compounds of Formula I (wherein "A" is an amide, sulfonamide, urea, or carbamate). Intermediate 67 (synthesized as described in Scheme 18A) can be oxidized using an oxidizing agent (NaClO2, PCC or PDC, KMnO4, etc.) to provide intermediate 100. Intermediate 100 can be converted to intermediate 101 via Curtius rearrangement (as described in Shioiri, T. et al. J. Am. Chem. Soc. 1972, 94, 6203-6205). Intermediate 101 can be subjected to sequential amide synthesis and boc deprotection as described in Scheme 20 to provide amine intermediate 102. Intermediate 102 can be subjected to various transformations to obtain variations of Formula I (wherein "A" is an amide, sulfonamide, urea, or carbamate) using many known methods recognized by those skilled in the art, including but not limited to those described in Scheme 20.

[0420] Plan 25

[0421]

[0422] Scheme 25 describes the synthesis of compounds of formula I (i, j, k, m) (wherein "A" is an amide, sulfonamide, urea, or carbamate). Intermediate 67a (synthesized as described in Scheme 18B) can be oxidized using an oxidizing agent (NaClO2, PCC or PDC, KMnO4, etc.) to provide intermediate 100a. Intermediate 100a can be converted to intermediate 101a via Curtius rearrangement (as described in Shioiri, T. et al. J. Am. Chem. Soc. 1972, 94, 6203-6205). Intermediate 101a can be subjected to sequential amide synthesis and boc deprotection as described in Scheme 20 to provide amine intermediate 102a.

[0423] Intermediate 102a can be subjected to various transformations to provide variations of Formula I using many known methods recognized by those skilled in the art, including but not limited to the following:

[0424] Amides: Intermediate 102a can be reacted with an activated acid intermediate in a polar aprotic solvent (eg, DCM, THF, etc.) in the presence of a base (eg, pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) to give intermediate 103.

[0425] Sulfonamides: Intermediate 102a can be treated with sulfonyl chloride in a polar aprotic solvent (e.g., DCM, THF, etc.) in the presence of a base (e.g., pyridine, DMAP, 2-(dimethylamino)pyridine, N-methylmorpholine, etc.) at temperatures ranging from 0°C to 90°C to generate intermediate 104.

[0426] Urea: Intermediate 102a can be treated with an isocyanate in a polar aprotic solvent (e.g., DCM, DCE, etc.) at room temperature in the presence of a base (e.g., Et3N, DIPEA, pyridine, etc.) to provide intermediate 105. Alternatively, intermediate 102a can be activated by treatment with triphosgene in a solvent (e.g., DCM, DCE, etc.) at 0°C to room temperature in the presence of a base (e.g., Et3N, DIPEA, etc.). The activated intermediate 102a can then be treated with a substituted alkyl or aryl or heteroaryl amine in a solvent (e.g., DCM, DCE, etc.) at room temperature to provide intermediate 105.

[0427] Carbamates: Intermediate 102a can be treated with chloroformate (or alcohol, activated to carbonate) in a polar aprotic solvent (e.g., DCM, DCE, THF, etc.) in the presence of a base (e.g., Et3N, DIPEA, pyridine, t-BuOK, etc.) at 0°C to room temperature to provide intermediate 106.

[0428] Intermediates 103-106 can be subjected to metal-catalyzed cross-coupling reactions using many known methods recognized by those skilled in the art, including but not limited to Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Diederich, Vol. 2, 2nd Revised and Supplemented Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and the methods described in the references cited therein. Intermediates 103-106 can be subjected to various metal-catalyzed reactions (including but not limited to reactions such as Ullmann, Buchwald, Suzuki, Stille couplings, etc.). These coupling reactions can be carried out in the presence of a metal catalyst (e.g., CuBr, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, etc.) and an appropriate ligand (including but not limited to ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine, dppf, etc.) as needed and when required. Ullmann and Buchwald coupling reactions of intermediates 103-106 can be carried out with various coupling partners (e.g., heterocyclic or heteroarylamines, etc.). Intermediates 103-106 can be subjected to Suzuki, Stille or other cross couplings with coupling partners (such as cycloalkyl or alkenyl or aryl or heteroaryl boronic acids, boronates, organotin reagents, etc.).t Bu, etc.) and a solvent (e.g., dioxane, THF, DME, toluene, methanol, DMF, water, etc., or a mixture of two or three of these solvents), the coupling reaction is carried out under heating conditions to obtain a compound of Formula I. Alternatively, the intermediates 103-106 can be converted into an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (e.g., toluene, THF, etc.) at reflux temperature, which is then coupled with a suitable coupling partner (e.g., cycloalkenyl, aryl or heteroaryl halide, triflate, etc.) in a Stille coupling manner (Sherer, B. et al. PCT International Application, 2016 / 039734, 2016) to obtain a compound represented by Formula I. Intermediates 103-106 can be converted into organoboron reagents using bis(pinacolato)diboron, bis(neopentylethylene glycol)diboron, etc. in the presence of a palladium catalyst (such as Pd(dppf)Cl2) and a base (such as potassium acetate) in a solvent (such as dioxane, DMSO, etc.) at reflux temperature. The organoboron reagent is coupled with a suitable coupling partner (such as a cycloalkenyl, aryl or heteroaryl halide or triflate, etc.) in a Suzuki coupling manner to give a compound represented by Formula I (i, j, k, m).

[0429] The sequence of steps involving installation of groups "Q" and "A" can be performed interchangeably in the schemes where appropriate. Oxadiazole regioisomers can be generated by using the sequences described in Schemes 11 and 14 for attachment to the oxabicyclic ring system.

[0430] Example 1

[0431] N-(3-Chlorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0432]

[0433] Step A. Preparation of Intermediate 1A. 4-Carbamoylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0434]

[0435] To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (0.5 g, 2.35 mmol) in DMF (10 mL) was added ammonium chloride (1.26 g, 23.56 mmol), TEA (1.3 mL, 9.42 mmol) and BOP (1.0 g, 2.35 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL). The combined organic extracts were washed with saline solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (0.4 g, 1.89 mmol, 80% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ6.95(br.s.,1H),6.74(br.s.,1H),3.57(s,3H),1.74-1.61(m,12H). MS(ESI)212(M+H).

[0436] Step B. Preparation of Intermediate 1B. 4-Cyanobicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0437]

[0438] The stirred solution of intermediate 1A (0.35g, 1.65mmol) in pyridine (7mL) is cooled to 0 DEG C. Trifluoroacetic anhydride (1.74g, 8.28mmol) is added dropwise, and the reaction mixture is stirred at 0 DEG C for 30min. The reaction mixture is quenched with 10% NaHCO3 aqueous solution, diluted with water (20mL) and extracted with ethyl acetate (2x20mL). The combined organic layer is washed with saline solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material is purified by flash column chromatography (24g silica gel cartridges; A=Hex, B=EtOAc; 30min gradient; 0% B to 30% B; flow rate=24mL / min). The pure fractions are combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.25g, 1.22mmol, 74% yield) as an off-white solid. 1 HNMR (400MHz, DMSO-d6) δ3.58(s,3H),1.93-1.83(m,6H),1.78-1.68(m,6H).

[0439] Step C. Preparation of Intermediate 1C. 4-Cyanobicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0440]

[0441] To a stirred solution of intermediate 1B (0.25 g, 1.29 mmol) in ethanol (5 mL) was added hydroxylamine (50% aqueous solution, 0.32 mL, 5.17 mmol). The reaction mixture was refluxed for 2 h at 80 ° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with water (10 mL). The precipitated solid was filtered and vacuum dried to obtain the title compound (0.28 g, 1.18 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.88 (s, 1H), 5.15 (s, 2H), 3.57 (s, 3H), 1.73-1.62 (m, 12H). MS (ESI) 227 (M+H).

[0442] Step D. Preparation of Intermediate 1D. Methyl 4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

[0443]

[0444] To a stirred solution of intermediate 1C (5 g, 22.10 mmol) in DMF (100 mL) was added 2,2-difluoropropionic acid (3.16 g, 28.7 mmol), TEA (12.32 mL, 88 mmol) and BOP (10.75 g, 24.31 mmol) at room temperature. The reaction mixture was stirred at 110 ° C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 24 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (4.2 g, 11.75 mmol, 53% yield) as a colorless gummy solid. MS (ESI) 301 (M+H).

[0445] Step E. Preparation of Intermediate 1E. (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0446]

[0447] To a stirred solution of intermediate 1D (4.2 g, 13.99 mmol) in THF (20 mL) was added DIBAL-H (35 mL, 35.0 mmol) dropwise at -78 ° C. The reaction mixture was stirred for 1 h at -78 ° C. The reaction mixture was allowed to warm to 0 ° C and quenched with 1.5 N HCl aqueous solution (100 mL). The aqueous solution was extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 40 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (3 g, 10.58 mmol, 76% yield) as a colorless liquid. MS (ESI) 273 (M + H).

[0448] Step F. Preparation of Intermediate 1F. 4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0449]

[0450] To a stirred solution of intermediate 1E (3 g, 11.02 mmol) in DCM (70 mL) was added Dess-Martin periodinane (5.6 g, 13.22 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 30 min. The reaction mixture was allowed to warm to room temperature, diluted with DCM (50 mL), and washed with 10% aqueous sodium bicarbonate solution (3x20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 24 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (2 g, 7.40 mmol, 67% yield) as a colorless white gummy solid. 1 H NMR (400MHz, DMSO-d6) δ9.46 (br.s., 1H), 2.16 (t, J = 19.6Hz, 3H), 1.94-1.76 (m, 12H).

[0451] Step G. Preparation of Intermediate 1G. 3-chloro-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)aniline

[0452]

[0453] To a stirred solution of intermediate 1F (50 mg, 0.18 mmol) in MeOH (1 mL) was added 3-chloroaniline (23 mg, 0.18 mmol), AcOH (0.02 mL, 0.37 mmol), followed by To the product of 4-nitro-2-nitro-1-oxo-2-nitro-2-oxo-4-nitro-2-oxo-4-nitro-2-oxo-4-nitro-2-oxo-2 ...

[0454] Step H. Example 1. Preparation of N-(3-chlorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0455] To a stirred solution of intermediate 1G (20 mg, 0.05 mmol) in DCM (1 mL) was added 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (10.22 mg, 0.08 mmol) at room temperature followed by pyridine (0.03 mL, 0.36 mmol). The reaction mixture was cooled to 0°C and POCl (0.02 mL, 0.16 mmol) was added. After stirring at 0°C for 1 h, the reaction mixture was diluted with DCM (25 mL). The organic layer was washed with 10% aqueous sodium bicarbonate solution (2 x 15 mL) followed by brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative LC / MS using the following conditions: Column: Waters XBridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water containing 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile: water containing 10 mM ammonium acetate; Gradient: 30% B for 2 minutes, 30%-75% B over 25 minutes, then 100% B for 5 minutes; Flow rate: 15 mL / min; Column temperature: 25°C. Fraction collection was signal-triggered. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.8 mg, 9.72 μmol, 19% yield). 1 H NMR (400MHz, DMSO-d6) δ7.59 (s, 1H), 7.54-7.45 (m, 2H), 7.41 (dt, J = 5.7, 2.7Hz, 1H), 3.59 (br.s., 1H) ),3.51(br.s.,1H),2.14(t,J=19.7Hz,3H),1.88(br.s.,6H),1.84-1.62(m,6H),1.53-1.32(m,6H). FXR EC 50 (nM)=11. MS(ESI)494(M+H).

[0456] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 1G and the corresponding acid where appropriate:

[0457]

[0458]

[0459] Example 4

[0460] N-(3-Cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0461]

[0462] Step A. Preparation of Intermediate 4A. 3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzonitrile

[0463]

[0464] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3-aminobenzonitrile at the appropriate places: (60 mg, 0.15 mmol, 86% yield). 1 H NMR (400MHz, DMSO-d6) δ7.24-7.18(m,1H),6.97-6.92(m,2H),6.85(dt,J=7.5,1.3Hz,1H),6.01(t, J=6.0Hz,1H),2.86(d,J=6.0Hz,2H),2.15(t,J=19.6Hz,3H),1.91-1.82(m,6H),1.61-1.53(m,6H). MS(ESI)373(M+H).

[0465] Step B. Example 4. Preparation of N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0466] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 4A where appropriate: (7 mg, 0.06 mmol, 28% yield). 1 H NMR (400MHz, DMSO-d6) δ8.05 (s, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.84-7.77 (m, 1H), 7.71-7.59 (m, 1H), 3.58(br.s.,2H),2.14(t,J=19.6Hz,3H),1.87(br.s.,6H),1.84-1.66(m,6H),1.53-1.30(m,6H). FXR EC 50 (nM)=12. MS(ESI)485(M+H).

[0467] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 4A and the corresponding acid where appropriate:

[0468]

[0469]

[0470] Example 7

[0471] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0472]

[0473] Step A. Preparation of Intermediate 7A. N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoroaniline

[0474]

[0475] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3-fluoroaniline at the appropriate places: (60 mg, 0.16 mmol, 89% yield). 1 H NMR(400MHz, DMSO-d6)δ7.05-6.98(m,1H),6.43(d,J=8.5Hz,1H),6.39-6.33(m,1H),6.25-6.18(m ,1H),5.78(s,1H),2.81(d,J=6.0Hz,2H),2.21-2.09(m,3H),1.90-1.83(m,6H),1.60-1.53(m,6H). MS(ESI)366(M+H).

[0476] Step B. Example 7. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-fluorophenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0477] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 7A where appropriate: (7 mg, 0.06 mmol, 27% yield). 1H NMR (400MHz, DMSO-d6) δ7.50(td,J=8.1,6.7Hz,1H),7.39(dt,J=10.1,2.1Hz,1H),7.34-7.19(m,2H),3.61(b r.s.,1H),3.50(br.s.,1H),2.14(t,J=19.7Hz,3H),1.89(br.s.,6H),1.84-1.56(m,6H),1.54-1.35(m,6H). FXR EC 50 (nM)=30. MS(ESI)478(M+H).

[0478] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 7A and the corresponding acid where appropriate:

[0479]

[0480]

[0481] Example 10

[0482] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3,4-difluorophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0483]

[0484] Step A. Preparation of Intermediate 10A. N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,4-difluoroaniline

[0485]

[0486] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3,4-difluoroaniline at the appropriate places: (48 mg, 0.12 mmol, 68% yield). 1 H NMR (300MHz, DMSO-d6) δ7.13-7.00(m,1H),6.62-6.50(m,1H),6.38(d,J=9.1Hz,1H),5.66(t, J=5.6Hz,1H),2.78(d,J=5.9Hz,2H),2.25-2.07(m,3H),1.95-1.80(m,6H),1.66-1.46(m,6H). MS(ESI)384(M+H).

[0487] Step B. Example 10. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3,4-difluorophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0488] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 10A where appropriate: (4.0 mg, 15% yield). 1 H NMR(400MHz,DMSO-d6)δ7.78-7.63(m,1H),7.59-7.45(m,1H),7.39-7.22(m,1H),3.59(br.s.,1H) ,3.45(br.s.,1H),2.14(t,J=19.6Hz,3H),1.91(br.s.,6H),1.86-1.58(m,6H),1.57-1.32(m,6H). FXR EC 50 (nM)=124. MS(ESI)496(M+H).

[0489] Example 11

[0490] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3,4-difluorophenyl)-4,4-difluorocyclohexane-1-carboxamide

[0491]

[0492] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 10A where appropriate: (2 mg, 7% yield). 1 H NMR(400MHz,DMSO-d6)δ7.77-7.66(m,1H),7.57-7.46(m,1H),7.39-7.29(m,1H),3.59-3.49(m,2H),2.42-2.34(m,1H), 2.14(t,J=19.7Hz,3H),2.00-1.87(m,2H),1.82-1.73(m,6H),1.73-1.64(m,2H),1.63-1.48(m,4H),1.45-1.37(m,6H). FXR EC 50 (nM)=881. MS(ESI)530(M+H).

[0493] Example 12

[0494] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0495]

[0496] Step A. Preparation of Intermediate 12A. N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-(difluoromethoxy)aniline

[0497]

[0498] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3-(difluoromethoxy)aniline at the appropriate places: (50 mg, 0.12 mmol, 65% yield). MS (ESI) 414 (M+H).

[0499] Step B. Example 12. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0500] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 12A where appropriate: (9.0 mg, 0.02 mmol, 35% yield). 1 H NMR (400MHz, DMSO-d6) δ7.57-7.50(m,1H),7.33-7.14(m,4H),3.55(d,J=16.1Hz,2 H), 2.14 (t, J = 19.7Hz, 3H), 1.87 (br.s., 6H), 1.82-1.63 (m, 6H), 1.54-1.33 (m, 6H). FXR EC 50 (nM)=73. MS(ESI)526(M+H).

[0501] Example 13

[0502] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0503]

[0504] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 12A where appropriate: (8 mg, 0.01 mmol, 28% yield). 1 H NMR (400MHz, DMSO-d6) δ7.51-7.13(m,5H),6.53(s,1H),3.62(s,2H),2.76(t,J=8.9 Hz,1H),2.35-2.26(m,2H),2.21-1.99(m,5H),1.87-1.69(m,6H),1.54-1.31(m,6H). FXR EC 50 (nM)=302. MS(ESI)580(M+H).

[0505] Example 14

[0506] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0507]

[0508] Step A. Preparation of Intermediate 14A. N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(trifluoromethyl)aniline

[0509]

[0510] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3-(trifluoromethyl)aniline at the appropriate places: (65 mg, 0.13 mmol, 69% yield). MS (ESI) 416 (M+H).

[0511] Step B. Example 14. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(trifluoromethyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0512] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 14A where appropriate: (4 mg, 7.58 μιηοΐ, 16% yield). 1H NMR (400MHz, DMSO-d6) δ7.86 (s, 1H), 7.81-7.74 (m, 2H), 7.71 (d, J = 7.8Hz, 1H), 3 .67-3.48(m,2H),2.14(t,J=19.7Hz,3H),1.90-1.72(m,12H),1.50-1.36(m,6H). FXR EC 50 (nM)=29. MS(ESI)528(M+H).

[0513] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 14A and the corresponding acid where appropriate:

[0514]

[0515]

[0516] Example 17

[0517] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(2-methoxypyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0518]

[0519] Step A. Preparation of Intermediate 17A. N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-2-methoxypyridin-4-amine

[0520]

[0521] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 2-methoxypyridin-4-amine in the appropriate places: (20 mg, 0.05 mmol, 28% yield). MS (ESI) 380.2 (M+H).

[0522] Step B. Example 17. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(2-methoxypyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxamide

[0523] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 17A where appropriate: (2 mg, 3.80 μmol, 7% yield). 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=5.6Hz,1H),7.09(dd,J=1.8,5.5Hz,1H),6.96(d,J=1.7Hz,1H),3.90( s,3H),3.56(s,2H),2.14(t,J=19.6Hz,3H),1.97(d,J=2.4Hz,6H),1.84-1.71(m,6H),1.48-1.34(m,6H). FXREC 50 (nM)=149. MS(ESI)491(M+H).

[0524] Example 18

[0525] N-(3-(N-Cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0526]

[0527] Step A. Preparation of Intermediate 18A. N-cyclopropyl-3-nitrobenzenesulfonamide

[0528]

[0529] To a stirred solution of 3-nitrobenzenesulfonyl chloride (250 mg, 1.128 mmol) and TEA (0.472 mL, 3.38 mmol) in tetrahydrofuran (5 mL) was added cyclopropylamine (0.08 mL, 1.13 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2x50 mL). The combined organic layer was washed with saline solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24 g silica gel cartridges; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 24 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (200 mg, 0.82 mmol, 73% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.56-8.49(m,2H),8.30-8.20(m,2H),7.94(t,J=7. 8Hz, 1H), 2.18 (tt, J = 6.8, 3.5Hz, 1H), 0.55-0.48 (m, 2H), 0.43-0.36 (m, 2H).

[0530] Step B. Preparation of Intermediate 18B. 3-Amino-N-cyclopropylbenzenesulfonamide

[0531]

[0532] A stirred solution of intermediate 18A (200 mg, 0.82 mmol) in methanol (5 mL) was degassed and backfilled with argon, and 10% Pd-C (44 mg, 0.04 mmol) was added to the reaction mixture. After stirring overnight under hydrogen (1 atm, balloon), the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 0.67 mmol, 81% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.72 (s, 1H), 7.24-7.16 (m, 1H), 7.01 (t, J = 2.0Hz, 1H), 6.93-6.87 (m, 1H) ,6.76(ddd,J=8.0,2.0,1.0Hz,1H),5.57(s,2H),2.08(tt,J=6.8,3.5Hz,1H),0.52-0.36(m,4H).

[0533] Step C. Preparation of Intermediate 18C. N-cyclopropyl-3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzenesulfonamide

[0534]

[0535] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and Intermediate 18B where appropriate: (90 mg, 0.18 mmol, 71% yield). 1H NMR (400MHz, DMSO-d6) δ7.73(d,J=2.5Hz,1H),7.27-7.20(m,1H),7.04(s,1H),6.90(d,J=8.0Hz,1H),6.85(dd,J=8.3,1.8Hz,1H),6.03(t,J=5.8 Hz,1H),2.86(d,J=5.5Hz,2H),2.22-2.09(m,3H),2.09-2.03(m,1H),1.9 2-1.80(m,6H),1.65-1.54(m,4H),1.49-1.42(m,2H),0.51-0.37(m,4H). MS(ESI)467(M+H).

[0536] Step D. Example 18. Preparation of N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0537] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 18C where appropriate: (8 mg, 0.014 mmol, 34% yield). 1 H NMR(400MHz, DMSO-d6)δ8.12(d,J=3.2Hz,1H),7.86-7.79(m,1H),7.78-7.66(m,3H),3.82-3.64(m,1H),3.47(br s,1H),2.14(t,J=19.7Hz,4H),1.99-1.82(m,6H),1.78(br t,J=7.8Hz,6H),1.51-1.33(m,6H),0.58-0.26(m,4H). FXR EC 50 (nM)=1563. MS(ESI)579(M+H).

[0538] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 18C and the corresponding acid where appropriate:

[0539]

[0540] Example 21

[0541] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(N-methylsulfamoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0542]

[0543] Step A. Preparation of Intermediate 21A. N-Methyl-3-nitrobenzenesulfonamide

[0544]

[0545] The title compound was prepared according to the procedure described for the synthesis of Intermediate 18A by substituting 3-nitrobenzenesulfonyl chloride and methylamine hydrochloride where appropriate: (220 mg, 0.97 mmol, 86% yield). 1 H NMR (400MHz, DMSO-d6) δ8.53-8.48(m,2H),8.23-8.19(m,1H),7.96-7.90(m,1H),7.84(br.s.,1H),2.47(s,3H).

[0546] Step B. Preparation of Intermediate 21B. 3-Amino-N-methylbenzenesulfonamide

[0547]

[0548] The title compound was prepared according to the procedure described for the synthesis of Intermediate 18B by substituting Intermediate 21A in the appropriate places: (180 mg, 0.822 mmol, 81% yield). 1 H NMR (400MHz, DMSO-d6) δ7.28-7.17(m,2H),6.96(t,J=2.0Hz,1H),6.88-6.83(m,1H),6.76(dt,J=8.0,1.3Hz,1H),5.57(s,2H),2.39(s,3H).

[0549] Step C. Preparation of Intermediate 21C. 3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)-N-methylbenzenesulfonamide

[0550]

[0551] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and Intermediate 21B where appropriate: (60 mg, 0.116 mmol, 45% yield).1 H NMR (400MHz, DMSO-d6) δ7.27-7.20(m,2H),7.00(t,J=2.0Hz,1H),6.88-6.82(m,2H),6.02(t,J=6.0Hz,1H ), 2.85 (d, J = 6.0Hz, 2H), 2.40 (d, J = 5.0Hz, 3H), 2.21-2.09 (m, 3H), 1.93-1.83 (m, 6H), 1.65-1.54 (m, 6H). MS(ESI)441(M+H).

[0552] Step D. Example 21. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(N-methylsulfamoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0553] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 21C where appropriate: (11 mg, 0.020 mmol, 59% yield). 1 H NMR(400MHz,DMSO-d6)δ7.83-7.78(m,1H),7.76-7.62(m,4H),3.77-3.59(m,1H),3.56-3.42(m,1H),2 .43(d,J=5.1Hz,3H),2.14(t,J=19.7Hz,3H),1.97-1.82(m,6H),1.81-1.69(m,6H),1.50-1.33(m,6H). FXR EC 50 (nM)=4000. MS(ESI)553(M+H).

[0554] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 21C and the corresponding acid where appropriate:

[0555]

[0556]

[0557] Example 24

[0558] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-4,4-difluorocyclohexane-1-carboxamide

[0559]

[0560] Step A. Intermediate 24A. Preparation of dimethyl (3-nitrophenyl) phosphine oxide

[0561]

[0562] To a stirred suspension of 1-iodo-3-nitrobenzene (200 mg, 0.80 mmol) in anhydrous 1,4-dioxane (2 mL) was added dimethylphosphine oxide (62 mg, 0.80 mmol), XantPhos (465 mg, 0.80 mmol) and cesium carbonate (260 mg, 0.80 mmol) at room temperature. The reaction mixture was degassed and backfilled three times with argon. Bis(dibenzylideneacetone)palladium (462 mg, 0.803 mmol) was added to the reaction mixture, and the reaction vial was sealed. The reaction mixture was heated to 90 ° C and stirred for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 24 mL / min). Pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (150 mg, 0.72 mmol, 89% yield) as a white solid. MS (ESI) 200 (M+H).

[0563] Step B. Intermediate 24B. Preparation of (3-aminophenyl)dimethylphosphine oxide

[0564]

[0565] A solution of intermediate 24A (200 mg, 1 mmol) in methanol (5 mL) was degassed and backfilled with nitrogen, and 10% Pd-C (53 mg, 0.05 mmol) was added to the reaction. After stirring overnight under hydrogen (1 atm, balloon), the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 0.84 mmol, 84% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.13(td,J=7.7,3.8Hz,1H),6.97-6.91(m,1H),6.85-6 .78(m,1H),6.69(dt,J=8.0,1.0Hz,1H),5.30(s,2H),1.54(s,3H),1.57(s,3H).

[0566] Step C. Intermediate 24C. Preparation of (3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenyl)dimethylphosphine oxide

[0567]

[0568] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and Intermediate 24B where appropriate: (85 mg, 0.19 mmol, 74% yield). 1 H NMR(400MHz, DMSO-d6)δ7.17(td,J=7.8,3.5Hz,1H),6.97-7.00(m,1H),6.86-6.73(m,2H),5.74(t, J=5.8Hz,1H),2.85(d,J=5.5Hz,2H),2.16(t,J=19.6Hz,3H),1.92-1.82(m,6H),1.64-1.54(m,12H). MS(ESI)424(M+H).

[0569] Step D. Example 24. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-4,4-difluorocyclohexane-1-carboxamide

[0570] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 24C where appropriate: (10 mg, 0.02 mmol, 36% yield). 1 H NMR(400MHz,DMSO-d6)δ7.84-7.71(m,2H),7.67-7.55(m,2H),3.61(br d,J=1.0Hz,2H),2.32-2.22(m,1H),2.21-2.07(m,3H),2.02-1.88(m,2H),1.82-1.64(m,15H),1.64-1.55(m,3H),1.45-1.36(m,6H). FXR EC 50 (nM)=4000. MS(ESI)570(M+H).

[0571] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 24C and the corresponding acid where appropriate:

[0572]

[0573]

[0574] Example 27

[0575] Methyl 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)benzoate

[0576]

[0577] Step A. Preparation of Intermediate 27A. Methyl 3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzoate

[0578]

[0579] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and methyl 3-aminobenzoate at the appropriate places: (75 mg, 0.17 mmol, 68% yield). MS (ESI) 406.3 (M+H).

[0580] Step B. Example 27. Preparation of methyl 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)benzoate

[0581] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 27A where appropriate: (75 mg, 0.14 mmol, 77% yield). 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.1Hz,1H),7.91-7.86(m,1H),7.77-7.70(m,1H) ,7.66-7.57(m,1H),3.90(s,3H),3.66-3.50(m,2H),2.14(t,J=19.7Hz,3H),1.84(br s,6H),1.80-1.66(m,6H),1.50-1.35(m,6H). FXR EC 50 (nM)=72. MS(ESI)518.3(M+H).

[0582] Example 28

[0583] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(ethylcarbamoyl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0584]

[0585] Step A. Preparation of Intermediate 28A. Methyl 3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzoate

[0586]

[0587] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and methyl 3-aminobenzoate at the appropriate places: (75 mg, 0.18 mmol, 68% yield). MS (ESI) 406 (M+H).

[0588] Step B. Preparation of Intermediate 28B. 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)benzoic acid methyl ester

[0589]

[0590] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 28A where appropriate: (75 mg, 0.143 mmol, 77% yield). 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=8.1Hz,1H),7.91-7.86(m,1H),7.77-7.70(m,1H) ,7.66-7.57(m,1H),3.90(s,3H),3.66-3.50(m,2H),2.14(t,J=19.7Hz,3H),1.84(br s,6H),1.80-1.66(m,6H),1.50-1.35(m,6H). MS(ESI)518(M+H).

[0591] Step C. Preparation of Intermediate 28C. 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)benzoic acid

[0592]

[0593] To a solution of intermediate 28B (65 mg, 0.126 mmol) in methanol (1 mL) was added a solution of sodium hydroxide (20 mg, 0.502 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (5 mL), acidified with 1.5 N HCl aqueous solution and extracted with EtOAc (2x20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (50 mg, 0.01 mmol, 79% yield) as a pale solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.3 Hz, 1H), 7.83 (s, 1H), 7.70-7.62 (m, 1H), 7.61-7.54 (m, 1H), 3.58 (s, 2H), 2.13 (t, J = 19.6 Hz, 3H), 1.83 (br s, 6H), 1.81-1.73 (m, 6H), 1.49-1.37 (m, 6H) (Exchangeable protons are hidden by the solvent peak). MS (ESI) 504 (M+H).

[0594] Step D. Example 28. Preparation of N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(ethylcarbamoyl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0595] To a stirred solution of intermediate 28C (20 mg, 0.040 mmol) in DMF (1 mL) was added ethylamine (0.06 mL, 0.12 mmol) and TEA (0.02 mL, 0.16 mmol) at room temperature, followed by the addition of BOP (17.57 mg, 0.04 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative LC / MS using the following conditions: Column: Waters XBridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water containing 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water containing 10 mM ammonium acetate; Gradient: 20% B for 0 minutes, 20% to 59% B over 20 minutes, then 100% B for 5 minutes; Flow rate: 15 mL / min; Column temperature: 25°C. Fraction collection was signal-triggered. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (11 mg, 0.02 mmol, 49% yield).1 H NMR (400MHz, DMSO-d6) δ8.58 (t, J = 5.3Hz, 1H), 7.90-7.85 (m, 1H), 7.84-7.80 (m, 1H), 7. 61-7.49(m,2H),3.68-3.50(m,2H),3.32-3.26(m,2H),2.14(t,J=19.7Hz,3H),1.84(br s, 6H), 1.81-1.75 (m, 6H), 1.49-1.40 (m, 6H), 1.15 (t, J = 7.2Hz, 3H). FXR EC 50 (nM)=210. MS(ESI)531(M+H).

[0596] Example 29

[0597] N-(3-Carbamoylphenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0598]

[0599] The title compound was prepared according to the procedure described for the synthesis of Example 28 (Step D) by substituting Intermediate 28C and ammonium chloride where appropriate: (15 mg, 0.03 mmol, 75% yield). 1 HNMR(400MHz,DMSO-d6)δ8.12(s,1H),7.93-7.87(m,1H),7.86(s,1H),7.62-7.49(m,3 H), 3.67-3.50 (m, 2H), 2.14 (t, J = 19.7Hz, 3H), 1.88-1.70 (m, 12H), 1.53-1.35 (m, 6H). FXR EC 50 (nM)=902. MS(ESI)503(M+H).

[0600] Example 30

[0601] 1-(3-Bromophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea

[0602]

[0603] Step A. Preparation of Intermediate 30A. 3-Bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)aniline

[0604]

[0605] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and 3-bromoaniline at the appropriate places: (300 mg, 0.70 mmol, 86% yield). 1 H NMR(400MHz, DMSO-d6)δ7.01-6.93(m,1H),6.78(t,J=2.0Hz,1H),6.65-6.57(m,2H),5.81-5.7 3(m,1H),2.81(d,J=6.0Hz,2H),2.16(t,J=19.6Hz,3H),1.93-1.81(m,6H),1.62-1.52(m,6H). MS(ESI)427.9(M+H).

[0606] Step B. Example 30. Preparation of 1-(3-bromophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-((1R,4R)-4-hydroxy-4-methylcyclohexyl)urea

[0607] By intermediate 30A (15mg, 0.035mmol) and TEA (0.02mL, 0.17mmol) stirred solution in DCM (3mL) is cooled to 0 DEG C.To be added into reaction mixture as triphosgene (10mg, 0.03mmol) of the solution in DCM (1mL).Allow reaction mixture to be warmed to room temperature and stir 12h.In above-mentioned reaction mixture, add trans-4-amino-1-methylcyclohexanol (5.46mg, 0.04mmol), and reaction mixture is at room temperature stirred 4h.Reaction mixture is concentrated under reduced pressure. The crude compound was purified by preparative LC / MS using the following conditions: Column: Waters XBridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water containing 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water containing 0.1% trifluoroacetic acid; Gradient: hold at 18% B for 2 minutes, 18%-62% B over 25 minutes, then hold at 100% B for 5 minutes; Flow rate: 15 mL / min; Column temperature: 25°C. Fraction collection was signal-triggered. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (6 mg, 10.84 μmol, 31% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ7.54(d,J=1.7Hz,1H),7.44-7.38(m,1H),7.37-7.27(m,2H),5.44(d,J=7.8Hz,1H),4.20(s,1H),3.5 3(s,2H),3.49-3.42(m,1H),2.14(t,J=19.7Hz,3H),1.82-1.68(m,6H),1.65-1.53(m,2H),1.45-1.23(m,12H),1.06(s,3H). FXREC 50 (nM) = 150; MS (ESI) 581 (M+H).

[0608] Example 31

[0609] N-(3-Bromophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-2,2-difluorocyclopropane-1-carboxamide (racemic)

[0610]

[0611] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 30A where appropriate: (8 mg, 0.015 mmol, 21% yield).1 H NMR (400MHz, DMSO-d6) δ7.75-7.65(m,1H),7.59(br d,J=7.1Hz,1H),7.51-7.34(m,2H),3.87(br d,J=13.9Hz,1H),3.47(br d,J=14.4Hz,1H),2.37-2.28(m,1H),2.14(t,J=19.7Hz,3H),2.00-1.89(m,1H),1.78(br t,J=7.9Hz,7H),1.49-1.30(m,6H). FXR EC 50 (nM)=261. MS(ESI)530(M+H).

[0612] Example 32

[0613] tert-Butyl (3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)phenyl)carbamate

[0614]

[0615] Step A. Intermediate 32A. Preparation of tert-butyl (3-nitrophenyl)carbamate

[0616]

[0617] To a stirred solution of 3-nitroaniline (5g, 36.2mmol) in THF (50mL) was added boc-anhydride (8.40mL, 36.2mmol) at room temperature. The reaction mixture was cooled to 0°C and DMAP (4.86g, 39.8mmol) was added in batches. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100mL), and the organic solution was washed with water (50mL) and then with a saline solution (2x50mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (80g silica gel cartridge; A=Hex, B=EtOAc; 30min gradient; 0% B to 70% B; flow rate=40mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (8g, 33.6mmol, 93% yield) as a brown solid. MS (ESI) 237 (MH).

[0618] Step B. Intermediate 32B. Preparation of tert-butyl (3-aminophenyl)carbamate

[0619]

[0620] To a stirred solution of intermediate 32A (1g, 4.20mmol) in ethanol (20mL) and water (5mL) was added ammonium chloride (3.37g, 63mmol) at room temperature, followed by zinc (4.12g, 63mmol). After stirring overnight at room temperature, the reaction mixture was filtered through a celite pad, and the filtrate was diluted with ethyl acetate (50mL). The organic solution was then washed with a saline solution (2x25mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica gel cartridges; A=Hex, B=EtOAc; 30min gradient; 0% B to 60% B; flow rate=40mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (800mg, 3.73mmol, 89% yield) as a brown solid. MS (ESI) 209 (M+H).

[0621] Step C. Intermediate 32C. Preparation of tert-butyl (3-(((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenyl)carbamate

[0622]

[0623] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 1F and Intermediate 32B where appropriate: (40 mg, 0.08 mmol, 45% yield). MS (ESI) 463 (M+H).

[0624] Step D. Example 32. Preparation of tert-butyl (3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)phenyl)carbamate

[0625] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 32C where appropriate: (15 mg, 0.027 mmol, 62% yield). 1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),7.47(br d,J=8.6Hz,1H),7.43(t,J=1.8Hz,1H),7.33(t,J=7.9Hz,1H),6.98(dd,J=1.2,7.8Hz,1H),3.59-3.42(m,2H),2.14(t,J=19.7Hz,3H),1.87(br d,J=9.8Hz,6H),1.82-1.71(m,6H),1.49(s,9H),1.47-1.36(m,6H). FXR EC 50 (nM)=62. MS(ESI)575(M+H).

[0626] Example 33

[0627] N-(3-Bromophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0628]

[0629] Step A. Preparation of Intermediate 33A. Methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate

[0630]

[0631] To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (10 g, 47.1 mmol) in THF (100 mL) was added dropwise BH .DMS (14.3 mL, 141 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was cooled to 0° C. and carefully quenched with methanol. The resulting solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The aqueous solution was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with saline solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (80 g silica gel cartridge; A=Hex, B=EtOAc; 30 min gradient; 0% B to 70% B; flow rate=40 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (7 g, 35.3 mmol, 75% yield). 1H NMR (400MHz, DMSO-d6) δ4.12 (dd, J = 28.40, Hz, 1H), 3.65 (s, 3H), 3.29 (s, 2H), 1.82-1.77 (m, 6H), 1.47-1.42 (m, 6H).

[0632] Step B. Preparation of Intermediate 33A. 4-Formylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester.

[0633]

[0634] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1F by substituting Intermediate 33A in the appropriate places. (900 mg, 4.59 mmol, 91% yield) as a gummy liquid. 1 HNMR (400MHz, DMSO-d6) δ9.43 (s, 1H), 3.59 (s, 3H), 1.78-1.57 (m, 12H). MS(ESI)197(M+H).

[0635] Step C. Preparation of Intermediate 33C. 4-(((3-bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0636]

[0637] The title compound was prepared according to the method described for the synthesis of Intermediate 1G by substituting 3-bromoaniline and Intermediate 33B at the appropriate locations. (6.4 g, 18.17 mmol, 79% yield) was obtained as a brown gummy liquid. MS (ESI) 353 (M+H).

[0638] Step D. Preparation of Intermediate 33D. Methyl 4-((N-(3-bromophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylate

[0639]

[0640] The title compound was prepared by substituting Intermediate 33C and the corresponding acid according to the method described for the synthesis of Example 1 (Step H). It was obtained as a brown, gummy liquid (2.5 g, 5.38 mmol, 54% yield). MS (ESI) 464 (M+H).

[0641] Step E. Preparation of Intermediate 33E. 4-((N-(3-bromophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

[0642]

[0643] The title compound was prepared according to the method described for the synthesis of Intermediate 28C by substituting Intermediate 33D in the appropriate place. (2.1 g, 4.66 mmol, 98% yield) as a brown gummy liquid. MS (ESI) 452 (M+H).

[0644] Step F. Preparation of Intermediate 33F. 4-((N-(3-bromophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

[0645]

[0646] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1A by substituting Intermediate 33E in the appropriate place. (1.6 g, 3.56 mmol, 97% yield). MS (ESI) 450 (M+H).

[0647] Step G. Preparation of Intermediate 33G. N-(3-bromophenyl)-N-((4-cyanobicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0648]

[0649] The title compound was prepared by substituting Intermediate 33F in the appropriate place according to the method described for the synthesis of Intermediate 1B. (850 mg, 1.97 mmol, 55% yield) was obtained as a light brown gummy liquid. MS (ESI) 431 (M+H).

[0650] Step H. Preparation of Intermediate 33H. (E)-N-(3-bromophenyl)-3-fluoro-N-((4-(N'-hydroxycarbamimidoyl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

[0651]

[0652] The title compound was prepared according to the method described for the synthesis of Intermediate 1C by substituting Intermediate 33G in the appropriate place. (820 mg, 1.766 mmol, 92% yield) as a white solid. MS (ESI) 464 (M+H).

[0653] Step I. Example 33. Preparation of N-(3-bromophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0654] The title compound was prepared according to the procedure described for the synthesis of Intermediate ID by substituting Intermediate 33H in the appropriate place (9.6 mg, 0.017 mmol, 55% yield). 1 H NMR (400MHz, DMSO-d6) δ7.74-7.68(m,1H),7.61(dt,J=7.3,1.7Hz,1H),7.49-7.36(m,2H),3.58(br. s.,1H),3.51(br.s.,1H),2.23-2.05(m,3H),1.88(br.s.,6H),1.82-1.69(m,6H),1.53-1.33(m,6H). FXR EC 50 (nM)=13. MS(ESI)538(M+H).

[0655] Example 34

[0656] N-(3-Bromophenyl)-3-fluoro-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

[0657]

[0658] The title compound was prepared according to the procedure described for the synthesis of Intermediate ID by substituting Intermediate 33H in the appropriate places: (450 mg, 0.845 mmol, 65% yield). 1 H NMR(400MHz,DMSO-d6)δ7.75-7.67(m,1H),7.61(dt,J=7.3,1.7Hz,1H),7.50-7.36(m,2H), 3.58(br.s.,1H),3.50(br.s.,1H),1.87(br.s.,6H),1.81-1.61(m,8H),1.52-1.31(m,8H). FXR EC 50 (nM)=20. MS(ESI)533(M+H).

[0659] Example 35

[0660] N-(3-Bromophenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

[0661]

[0662] The title compound was prepared according to the procedure described for the synthesis of Intermediate ID by substituting Intermediate 33H in the appropriate places: (1.2 g, 2.18 mmol, 78% yield). 1 H NMR(400MHz,DMSO-d6)δ7.71(t,J=1.8Hz,1H),7.61(dt,J=7.6,1.7Hz,1H),7.50-7.37(m,2H) ,3.59(br.s.,1H),3.52(br.s.,1H),1.88(br.s.,6H),1.84-1.67(m,6H),1.54-1.35(m,6H). FXR EC 50 (nM)=42. MS(ESI)543(M+H).

[0663] Example 36

[0664] (1S,3S)-N-(3-Bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0665]

[0666] Step A. Preparation of Intermediate 36A. 4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0667]

[0668] The title compound was prepared according to the method described for the synthesis of Intermediate 1D by substituting 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid and N'-hydroxypivalimidamide at the appropriate positions. (2.2 g, 7.52 mmol, 97% yield) as a white solid. MS (ESI) 293 (M+H). 1 H NMR (400MHz, DMSO-d6) δ3.61(s,3H),1.96-1.87(m,6H),1.87-1.79(m,6H),1.29(s,9H).

[0669] Step B. Preparation of Intermediate 36B. (4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0670]

[0671] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1E by substituting Intermediate 36A in the appropriate place. (1.5 g, 5.62 mmol, 75% yield) as a white solid. MS (ESI) 265 (M+H). 1 H NMR (400MHz, DMSO-d6) δ4.43 (t, J = 5.5 Hz, 1H), 3.09 (d, J = 5.5 Hz, 2H), 1.94-1.79 (m, 6H), 1.52-1.39 (m, 6H), 1.29 (s, 9H).

[0672] Step C. Preparation of Intermediate 36C. 4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0673]

[0674] The title compound was prepared according to the method described for the synthesis of Intermediate 1F by substituting Intermediate 36B in the appropriate place. (1.1 g, 3.44 mmol, 60% yield) as a white solid. MS (ESI) 263 (M+H). 1 H NMR (400MHz, DMSO-d6) δ9.47(s,1H),1.97-1.88(m,6H),1.76-1.65(m,6H),1.29(s,9H).

[0675] Step D. Preparation of Intermediate 36D. 3-Bromo-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)aniline

[0676]

[0677] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 36C and 3-bromoaniline at the appropriate places: (350 mg, 0.83 mmol, 72% yield). MS (ESI) 419 (M+H).

[0678] Step E. Example 36. Preparation of (1S,3S)-N-(3-bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0679] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 36D where appropriate: (46.3 mg, 0.08 mmol, 55% yield). 1 H NMR (400MHz, DMSO-d6) δ7.70 (s, 1H), 7.55 (d, J = 7.6Hz, 1H), 7.49-7.26 (m, 2H), 6.54 (s, 1H), 3.60 (br.s., 2H), 2. 79-2.68(m,1H),2.40-2.24(m,2H),2.13-1.93(m,2H),1.90-1.61(m,6H),1.56-1.31(m,6H),1.31-1.14(m,9H). FXR EC 50 (nM)=135. MS(ESI)584(M+H).

[0680] Example 37

[0681] N-(3-Bromo-4-chlorophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0682]

[0683] Step A. Preparation of Intermediate 37A. 3-Bromo-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-chloroaniline

[0684]

[0685] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 36C and 3-bromo-4-chloroaniline where appropriate: (620 mg, 1.37 mmol, 81% yield). 1H NMR(400MHz,DMSO-d6)δ7.21(d,J=8.5Hz,1H),6.94(d,J=2.5Hz,1H),6.67-6.62(m,1H),5.9 5(t,J=5.8Hz,1H),2.81(d,J=6.0Hz,2H),1.95-1.84(m,6H),1.60-1.49(m,6H),1.28(s,9H). MS(ESI)452.2(M+H).

[0686] Step B. Example 37. Preparation of N-(3-bromo-4-chlorophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0687] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 37A where appropriate: (500 mg, 0.88 mmol, 65% yield). 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=2.4Hz,1H),7.71(d,J=8.3Hz,1H),7.50(dd,J=2.4,8.6Hz,1H),3.56(br s,2H),1.91(brs,6H),1.84-1.77(m,6H),1.46-1.36(m,6H),1.27(s,9H). FXR EC 50 (nM)=1078. MS(ESI)564(M+H).

[0688] Example 38

[0689] N-((4-(3-(tert-Butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0690]

[0691] Step A. Preparation of Intermediate 38A. 3-(((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzonitrile

[0692]

[0693] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 36C and 3-aminobenzonitrile at the appropriate places: (110 mg, 0.3 mmol, 78% yield). 1 H NMR(300MHz,DMSO-d6)δ7.25-7.16(m,1H),6.98-6.90(m,2H),6.88-6.81(m,1H),6.03(t ,J=6.1Hz,1H),2.86(d,J=5.9Hz,2H),1.95-1.81(m,6H),1.61-1.49(m,6H),1.28(s,9H). MS(ESI)365.2(M+H).

[0694] Step B. Example 38. Preparation of N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-cyanophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0695] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 38A where appropriate: (9 mg, 0.018 mmol, 33% yield). 1 H NMR (400MHz, DMSO-d6) δ8.04(d,J=1.5Hz,1H),7.88(d,J=7.6Hz,1H),7.82-7.77(m,1H),7.70-7 .62(m,1H),3.65-3.49(m,2H),1.87(s,6H),1.82-1.74(m,6H),1.47-1.34(m,6H),1.27(s,9H). FXR EC 50 (nM)=142. MS(ESI)477(M+H).

[0696] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 38A and the corresponding acid where appropriate:

[0697]

[0698]

[0699] Example 43

[0700] N-((4-(3-(tert-Butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0701]

[0702] Step A. Preparation of Intermediate 43A. (3-(((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenyl)dimethylphosphine oxide

[0703]

[0704] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 36C and Intermediate 24B in the appropriate places: (100 mg, 0.23 mmol, 77% yield). MS (ESI) 416 (M+H).

[0705] Step B. Example 43. Preparation of N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(dimethylphosphoryl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0706] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 43A where appropriate: (16 mg, 0.03 mmol, 63% yield). 1 H NMR (400MHz, DMSO-d6) δ7.84-7.71(m,2H),7.66-7.55(m,2H),3.65-3.48(m,2H),1.91-1.75(m,12H),1.70(br d, J=13.4Hz, 6H), 1.50-1.35 (m, 6H), 1.31-1.20 (m, 9H). FXR EC 50 (nM)=4000. MS(ESI)528(M+H).

[0707] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 43A and the corresponding acid where appropriate:

[0708]

[0709]

[0710]

[0711] Example 48

[0712] N-(3-Bromophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0713]

[0714] Step A. Preparation of Intermediate 48A. 3-(1,1-difluoroethyl)pyridine

[0715]

[0716] To a stirred solution of 1-(pyridin-3-yl)ethan-1-one (2g, 16.51mmol) in DCM (20mL) was added DAST (17.45mL, 132mmol) at room temperature. The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to room temperature and poured dropwise into a cooled 2N NaOH aqueous solution (50mL). The resulting solution was extracted with DCM (2x100mL). The combined organic layers were washed with brine solution (100mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40g silica gel cartridge; A=Hex, B=EtOAc; 30min gradient; 0% B to 30% B; flow rate=40mL / min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (1.95g, 13.35mmol, 81% yield) as a light yellow liquid. Note: rotary evaporation was performed at 30°C under reduced pressure. 1 H NMR (400MHz, DMSO-d6) δ8.80 (d, J = 1.0 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.58-7.51 (m, 1H), 2.10-1.97 (m, 3H). MS(ESI)145.2(M+H).

[0717] Step B. Preparation of Intermediate 48B. 4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0718]

[0719] To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2.3 g, 10.84 mmol) and intermediate 48A (1.86 g, 13 mmol) in DCM (70 mL) and water (70 mL) was added ammonium persulfate (2.47 g, 10.84 mmol) at room temperature followed by silver nitrate (0.37 g, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (25 mL) and filtered through celite. The filtrate was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 60% B; flow rate = 40 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (1.6 g, 5.12 mmol, 47% yield) as a white solid. MS (ESI) 310 (M+H).

[0720] Step C. Preparation of Intermediate 48C. (4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0721]

[0722] The title compound (1.4 g, 4.98 mmol, 96% yield) was prepared as a brown gum by substituting Intermediate 48B in the appropriate places according to the procedure described for the synthesis of Intermediate IE. 1 H NMR (400MHz, DMSO-d6) δ8.70(dd,J=2.5,1.0Hz,1H),7.89(dd,J=8.0,2.5Hz,1H),7.45(d,J=7.5Hz,1H) ,4.36(t,J=5.5Hz,1H),3.10(d,J=5.5Hz,2H),2.08-1.93(m,3H),1.89-1.79(m,6H),1.52-1.42(m,6H).

[0723] Step D. Preparation of Intermediate 48D. 4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0724]

[0725] The title compound (0.9 g, 3.22 mmol, 64% yield) was prepared as a white solid by substituting Intermediate 48C in the appropriate place according to the procedure described for the synthesis of Intermediate 1F. 1H NMR (400MHz, DMSO-d6) δ9.49 (s, 1H), 8.72 (dd, J = 2.5, 1.0Hz, 1H), 7.95-7.88 (m, 1H ),7.51-7.44(m,1H),2.01(t,J=19.1Hz,3H),1.94-1.85(m,6H),1.76-1.67(m,6H).

[0726] Step E. Preparation of Intermediate 48E. 3-Bromo-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

[0727]

[0728] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 48D and 3-bromoaniline at the appropriate places: (300 mg, 0.60 mmol, 68% yield). MS (ESI) 435 (M+H).

[0729] Step F. Example 48. Preparation of N-(3-bromophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0730] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 48E where appropriate: (300 mg, 0.548 mmol, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ8.72-8.61(m,1H),7.87(dd,J=2.4,8.6Hz,1H),7.70(t,J=1.7Hz,1H),7.61(td,J=1.8,7.2Hz,1H),7.49- 7.35(m,3H),3.68-3.56(m,1H),3.55-3.43(m,1H),1.99(t,J=19.1Hz,3H),1.88(brs,6H),1.81-1.68(m,6H),1.52-1.35(m,6H). FXR EC 50 (nM)=288. MS(ESI)549(M+H).

[0731] Example 49

[0732] N-(3-Cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0733]

[0734] Step A. Preparation of Intermediate 49A. 3-(((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)benzonitrile

[0735]

[0736] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 48D and 3-aminobenzonitrile in the appropriate places: (150 mg, 0.32 mmol, 90% yield). 1 HNMR(300MHz,DMSO-d6)δ8.70(d,J=1.7Hz,1H),7.89(dd,J=8.3,2.3Hz,1H),7.46(d,J=8.6Hz,1H),7.26-7.16(m,1H),6.98-6.91 (m,2H),6.88-6.82(m,1H),6.01(t,J=5.4Hz,1H),2.86(d,J=5.9Hz,2H),2.08-1.92(m,3H),1.91-1.81(m,6H),1.62-1.52(m,6H). MS(ESI)382(M+H).

[0737] Step B. Example 49. Preparation of N-(3-cyanophenyl)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0738] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 49A where appropriate: (12.8 mg, 0.026 mmol, 40% yield). 1H NMR(400MHz, DMSO-d6)δ8.68(d,J=1.5Hz,1H),8.05(s,1H),7.91-7.84(m,2H),7.83-7.78(m,1H),7.70-7.62(m ,1H),7.40(d,J=8.6Hz,1H),3.68-3.44(m,2H),1.99(t,J=19.1Hz,3H),1.92-1.68(m,12H),1.51-1.29(m,6H). FXR EC 50 (nM)=327. MS(ESI)494(M+H).

[0739] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 49A and the corresponding acid where appropriate:

[0740]

[0741] Example 52

[0742] N-((4-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0743]

[0744] Step A. Preparation of Intermediate 52A. 4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0745]

[0746] The title compound was prepared according to the method described for the synthesis of Intermediate 1D by substituting 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid and (Z)-N'-hydroxycyclopropanecarboximidamide (commercially available) at the appropriate positions. (490 mg, 1.66 mmol, 71% yield). MS (ESI) 277 (M+H).

[0747] Step B. Preparation of Intermediate 52B. (4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0748]

[0749] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1E by substituting Intermediate 52A in the appropriate place. (500 mg, 1.08 mmol, 61% yield). MS (ESI) 249 (M+H).

[0750] Step C. Preparation of Intermediate 52C. 4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0751]

[0752] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1F by substituting Intermediate 52B in the appropriate place. (350 mg, 1.421 mmol, 71% yield). MS (ESI) 247 (M+H).

[0753] Step D. Preparation of Intermediate 52D. N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-ethoxyaniline

[0754]

[0755] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 52C and 3-ethoxyaniline at the appropriate places: (120 mg, 0.31 mmol, 76% yield). 1 H NMR(400MHz,DMSO-d6)δ6.90(t,J=8.0Hz,1H),6.18(dd,J=8.0,1.5Hz,1H),6.14 (t,J=2.0Hz,1H),6.04(dd,J=7.5,2.5Hz,1H),5.39(t,J=6.0Hz,1H),3.91(q,J=7 .0Hz,2H),2.78(d,J=6.0Hz,2H),2.06(tt,J=8.3,4.8Hz,1H),1.91-1.79(m,6H) ,1.59-1.48(m,6H),1.28(t,J=7.0Hz,3H),1.06-0.98(m,2H),0.89-0.81(m,2H). MS (ESI) 368.3 (M+H).

[0756] Step E. Example 52. Preparation of N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0757] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 52D where appropriate: (8 mg, 0.017 mmol, 30% yield). 1 H NMR (400MHz, DMSO-d6) δ7.38-7.29(m,1H),7.00-6.88(m,3H),4.13-3.99(m,2H),3.63-3.55(m,1H),3.49-3.41(m,1H),2.09-2. 01(m,1H),1.94-1.81(m,6H),1.81-1.71(m,6H),1.49-1.38(m,6H),1.34(t,J=7.0Hz,3H),1.05-0.97(m,2H),0.86-0.79(m,2H). FXR EC 50 (nM)=102. MS(ESI)480(M+H).

[0758] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 52D and the corresponding acid where appropriate:

[0759]

[0760]

[0761]

[0762] Example 57

[0763] (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-methoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0764]

[0765] Step A. Preparation of Intermediate 57A. N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-methoxyaniline

[0766]

[0767] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 52C and 3-methoxyaniline at the appropriate places: (85 mg, 0.23 mmol, 56% yield). 1HNMR (400MHz, DMSO-d6) δ6.92(t,J=8.0Hz,1H),6.20(dd,J=8.3,1.3Hz,1H),6.16(t,J=2.0Hz,1H),6.06(dd,J=8.0,2.5Hz,1H),5.44(t,J=6. 0Hz,1H),3.66(s,3H),2.78(d,J=6.0Hz,2H),2.11-2.02(m,1H),1.90- 1.81(m,6H),1.59-1.50(m,6H),1.06-1.00(m,2H),0.89-0.83(m,2H). MS(ESI)354.3(M+H).

[0768] Step B. Example 57. Preparation of (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-methoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0769] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 57A in the appropriate places: (1 mg, 1.92 μmol, 5% yield). 1 H NMR(400MHz,DMSO-d6)δ7.37-7.29(m,1H),6.98-6.86(m,3H),6.51(s,1H),3.77(s, 3H),3.63-3.53(m,2H),2.98-2.88(m,1H),2.79-2.71(m,1H),2.13-2.00(m,4H),(br dd,J=7.1,8.3Hz,6H),1.44-1.34(m,6H),1.04-0.98(m,2H),0.88-0.77(m,2H). FXR EC 50 (nM)=304. MS(ESI)520(M+H).

[0770] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 57A and the corresponding acid where appropriate:

[0771]

[0772]

[0773] Example 62

[0774] N-(3-Cyano-5-fluorophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0775]

[0776] Step A. Preparation of Intermediate 62A. 3-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)-5-fluorobenzonitrile

[0777]

[0778] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 52C and 3-amino-5-fluorobenzonitrile where appropriate: (90 mg, 0.246 mmol, 48% yield). 1 H NMR (400MHz, DMSO-d6) δ6.85(s,1H),6.80-6.71(m,1H),6.66-6.60(m,1H),6.40-6.35(m,1H),2.87(d,J=6 .0Hz,2H),2.11-2.03(m,1H),1.90-1.82(m,6H),1.57-1.50(m,6H),1.06-1.00(m,2H),0.88-0.82(m,2H). MS(ESI)367.2(M+H).

[0779] Step B. Example 62. Preparation of N-(3-cyano-5-fluorophenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0780] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 62A where appropriate: (7.1 mg). 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=1.2Hz,1H),7.95-7.84(m,2H),3.66-3.45(m,2H),2.05(tt,J=4.7,8. 3Hz,1H),1.98-1.84(m,6H),1.82-1.69(m,6H),1.48-1.30(m,6H),1.06-0.96(m,2H),0.87-0.76(m,2H). FXR EC 50(nM)=185. MS(ESI)479(M+H).

[0781] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 62A and the corresponding acid where appropriate:

[0782]

[0783] Example 65

[0784] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,3-difluoro-N-(3-(methylsulfonamido)phenyl)cyclobutane-1-carboxamide

[0785]

[0786] Step A. Intermediate 65A. Preparation of tert-butyl (3-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenyl)carbamate

[0787]

[0788] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 32B and Intermediate 52C where appropriate: (360 mg, 0.82 mmol, 68% yield). 1 HNMR(400MHz,DMSO-d6)δ8.97(s,1H),6.91-6.78(m,2H),6.54(d,J=7.5Hz,1H),6.22(dd,J=8.3,1.8Hz,1H),5.38(t,J=5.8Hz,1H), 2.75(d,J=6.0Hz,2H),2.10-2.01(m,1H),1.91-1.80(m,6H),1.59-1.49(m,6H),1.46(s,9H),1.06-0.97(m,2H),0.89-0.80(m,2H). MS(ESI)439(M+H).

[0789] Step B. Preparation of Intermediate 65B. N1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)benzene-1,3-diamine

[0790]

[0791] To a stirred solution of intermediate 65A (60 mg, 0.13 mmol) in DCM (2 mL) was added 4M HCl (0.10 mL, 0.41 mmol) in dioxane at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was alkalized with 10% sodium bicarbonate aqueous solution (2 mL). The gained aqueous solution was extracted with ethyl acetate (2x5 mL). The combined organic layer was washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (40 mg, 0.118 mmol, 86% yield). 1 H NMR (400MHz, DMSO-d6) δ6.71-6.64(m,1H),5.87-5.82(m,2H),5.80-5.74(m,1H),5.01(t,J=6.0Hz,1H),4.68(br.s.,2H ), 2.73 (d, J = 6.0Hz, 2H), 2.11-2.02 (m, 1H), 1.90-1.80 (m, 6H), 1.58-1.48 (m, 6H), 1.07-0.99 (m, 2H), 0.89-0.82 (m, 2H). MS(ESI)339(M+H).

[0792] Step C. Preparation of Intermediate 65C. N-(3-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenyl)methanesulfonamide

[0793]

[0794] To a stirred solution of intermediate 65B (60 mg, 0.17 mmol) in DCM (2 mL) was added TEA (0.08 mL, 0.53 mmol) at 0 ° C., followed by methanesulfonyl chloride (30 mg, 0.26 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL), a saline solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (100 mg, crude product) as a brown solid. MS (ESI) 417 (M+H).

[0795] Step D. Example 65. Preparation of N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluoro-N-(3-(methylsulfonamido)phenyl)cyclobutane-1-carboxamide

[0796] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 65C where appropriate: (17 mg, 0.03 mmol, 68% yield). 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.46-7.37(m,1H),7.22-7.08(m,3H),3.58(s,2H),3.03(s,3H),2.91-2.83(m,1H),2.79- 2.63(m,2H),2.45-2.35(m,2H),2.09-2.00(m,1H),1.84-1.68(m,6H),1.48-1.27(m,6H),1.07-0.97(m,2H),0.86-0.80(m,2H). FXR EC 50 (nM)=1279. MS(ESI)535(M+H).

[0797] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 65C and the corresponding acid where appropriate:

[0798]

[0799]

[0800] Example 68

[0801] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0802]

[0803] Step A. Preparation of Intermediate 68A. N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-(methylsulfonyl)aniline

[0804]

[0805] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 52C and 3-(methylsulfonyl)aniline where appropriate: (110 mg, 0.25 mmol, 63% yield). 1H NMR (400MHz, DMSO-d6) δ7.31-7.25(m,1H),7.09(t,J=2.0Hz,1H),6.97(d,J=6.0Hz,1H),6.91(dd,J=7.5,2.5Hz,1H),6.11(t,J=5.8Hz, 1H), 3.12 (s, 3H), 2.87 (d, J = 5.5Hz, 2H), 2.11-2.03 (m, 1H), 1.90-1.84 (m, 6H), 1.61-1.53 ​​(m, 6H), 1.06-1.00 (m, 2H), 0.88-0.83 (m, 2H). MS(ESI)402(M+H).

[0806] Step B. Example 68. Preparation of N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0807] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 68A where appropriate: (7 mg, 0.014 mmol, 23% yield). 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=1.7Hz,1H),7.94(d,J=8.1Hz,1H),7.84-7.78 (m,1H),7.77-7.70(m,1H),3.58(s,2H),3.31(s,3H),2.09-2.00(m,1H),1.85(br s,6H),1.80-1.70(m,6H),1.47-1.33(m,6H),1.06-0.98(m,2H),0.86-0.79(m,2H). FXR EC 50 (nM)=1488. MS(ESI)534(M+H).

[0808] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 68A and the corresponding acid where appropriate:

[0809]

[0810] Example 70

[0811] N-(3-Cyanophenyl)-N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0812]

[0813] Step A. Preparation of Intermediate 70A. 1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethan-1-ol

[0814]

[0815] To a solution of intermediate 52C (1.5 g, 6.09 mmol) in anhydrous tetrahydrofuran (15 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (3 mL, 9.13 mmol) at -78 ° C under an argon atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 ° C, quenched with saturated NH4Cl solution and extracted with EtOAc (2x50 mL). The combined organic layers were washed with saline solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography (40 g silica gel cartridges; A = Hex, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 40 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (1.25 g, 4.53 mmol, 74% yield) as an oil. 1 H NMR(400MHz,DMSO-d6)δ4.29(d,J=6.80Hz,1H),3.25-3.21(m,1H),2.10-2.00(m,1H),1.98-1 .78(m,6H),1.53-1.37(m,6H),1.04-0.99(m,2H),0.94(d,J=8.40Hz,3H),0.87-0.85(m,2H).

[0816] Step B. Preparation of Intermediate 70B. 1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethan-1-one

[0817]

[0818] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1F by substituting Intermediate 70A in the appropriate places. (1 g, 3.65 mmol, 80% yield). 1 H NMR (400MHz, DMSO-d6) δ2.09-2.05(m,4H),1.99-1.85(m,6H),1.76-1.71(m,6H),1.06-1.00(m,2H),0.87-0.84(m,2H).

[0819] Step C. Preparation of Intermediate 70C. 3-((1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)-113-ethyl)amino)benzonitrile

[0820]

[0821] To a stirred solution of intermediate 70B (198 mg, 0.762 mmol) in methanol (2 mL) was added 3-aminobenzonitrile (90 mg, 0.76 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Triethylsilane (177 mg, 1.524 mmol) and indium (III) chloride (16.85 mg, 0.076 mmol) were added to the reaction. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL). The organic solution was washed with water (10 mL) and then with a saline solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (12 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 24 mL / min). Pure fractions were combined, concentrated and dried in vacuo to give the title compound (110 mg, 0.30 mmol, 40% yield) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ7.27-7.17(m,1H),6.96-6.82(m,3H),3.25(d,J=6.6Hz,1H),2.09-20.05(d,J=9.6Hz,1H),1.92-1.71( m, 6H), 1.50 (d, J = 7.3Hz, 3H), 1.42 (br.s., 3H), 1.04 (dd, J = 8.4, 2.5Hz, 2H), 0.96 (d, J = 6.6Hz, 3H), 0.85 (dd, J = 4.8, 2.5Hz, 2H). MS(ESI)363(M+H).

[0822] Step D. Example 70. Preparation of N-(3-cyanophenyl)-N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)ethyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0823] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 70C where appropriate: (0.5 mg, 1.0 μmol, 1% yield). 1H NMR (400MHz, DMSO-d6) δ7.97-7.85 (m, 2H), 7.67 (t, J = 5.5Hz, 1H), 3.18 (br d,J=5.5Hz,1H),4.80-4.70(m,1H),2.10-2.03(m,1H),1.88-1.66(m,12H),1.58-1.40(m,6H),1.06-0.91(m,5H),0.88-0.80(m,2H). FXR EC 50 (nM)=2000. MS(ESI)475(M+H).

[0824] Example 72

[0825] N-(3-Cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0826]

[0827] Step A. Preparation of Intermediate 72A. Methyl 4-(chlorocarbonyl)bicyclo[2.2.2]octane-1-carboxylate

[0828]

[0829] By 4- (methoxycarbonyl) two rings [2.2.2] octane -1- formic acid (2g) in SOCl (15mL) in solution is heated under reflux for 2h.The process of reaction mixture is monitored by TLC (a small amount of reaction mixture is quenched with MeOH and TLC is checked). After TLC display reaction has been completed, reaction mixture is concentrated under reduced pressure.Crude material and DCM are co-distilled twice and vacuum-dried to obtain the title compound (1.8g, 7.80mmol) in off-white solid, which is used for next step without further purification.

[0830] Step B. Preparation of Intermediate 72B. 4-(3-cyclopropyl-3-oxopropanoyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0831]

[0832] 1-Cyclopropylethyl-1-one (0.38 g, 4.55 mmol) was added to a stirred solution of 1M LiHMDS in THF (9.10 mL, 9.10 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 45 min. A solution of intermediate 72A (1 g, 4.33 mmol) in tetrahydrofuran (10 mL) was added to the reaction mixture and stirred for 1 h at -78 ° C. The reaction mixture was allowed to warm to 0 ° C, quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 24 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound as an oily liquid (800 mg, 2.73 mmol, 63% yield).MS (ESI) 279 (M+H).

[0833] Step C. Preparation of Intermediates 72C1 and 72C2. Methyl 4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate and Methyl 4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate

[0834]

[0835] To a stirred solution of intermediate 72B (800 mg, 2.87 mmol) in methanol (10 mL) was added methylhydrazine sulfate (1 g, 7.19 mmol) at room temperature. The reaction mixture was heated to 80 ° C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was washed with saline solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 24 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound as a mixture of regioisomers. The regioisomers were separated by preparative HPLC to give the first eluting isomer (RT = 4.31 min, Peak 1) Intermediate 72C1 (270 mg, 0.89 mmol, 30% yield), 1H NMR (400 MHz, DMSO-d6) δ 5.65 (s, 1H), 3.71 (s, 3H), 3.57 (s, 3H), 1.69-1.81 (m, 13H), 0.88-0.91 (m, 2H), 0.52-0.57 (m, 2H); and the second eluting isomer (RT = 4.90 min, peak 2) intermediate 72C2 (320 mg, 1.054 mmol, 37% yield), 1 H NMR (400MHz, DMSO-d6) δ5.67(s,1H),3.76(s,3H),3.59(s,3H),1.75-1.83(m,12H),1.69-1.74(m,1H),0.73-0.78(m,2H),0.56-0.57(m,2H). MS(ESI)289(M+H).

[0836] Step D. Preparation of Intermediate 72D. (4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanol

[0837]

[0838] The title compound was prepared as a pale yellow oil by substituting Intermediate 72C2 in the appropriate place according to the procedure described for the synthesis of Intermediate 1E (120 mg, 0.44 mmol, 42% yield). 1 H NMR (400MHz, DMSO-d6) δ5.65(s,1H),3.75(s,3H),3.05(s,2H),1.68-1.79(m,7H),1.35-1.44(m,6H),0.72-0.78(m,2H),0.50-0.56(m,2H).

[0839] Step E. Preparation of Intermediate 72E. 4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0840]

[0841] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1F by substituting Intermediate 72D in the appropriate places (90 mg, 0.35 mmol, 76% yield) as an off-white solid. 1HNMR (400MHz, DMSO-d6) δ9.45(s,1H),5.69(s,1H),3.77(s,3H),1.68-1.79(m,7H),1.55-1.61(m,6H),0.73-0.79(m,2H),0.53-0.58(m,2H).

[0842] Step F. Preparation of Intermediate 72F. 3-(((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)amino)benzonitrile

[0843]

[0844] The title compound was prepared according to the method described for the synthesis of Intermediate 1G by substituting Intermediate 72E and 3-aminobenzonitrile in the appropriate places: (70 mg, 0.184 mmol, 79% yield). H NMR (400 MHz, DMSO-d6) δ 7.24-7.17 (m, 1H), 6.97-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.01 (t, J = 5.8 Hz, 1H), 3.76 (s, 3H), 2.83 (d, J = 6.0 Hz, 2H), 1.86-1.76 (m, 6H), 1.72 (tt, J = 8.5, 5.0 Hz, 1H), 1.59-1.49 (m, 6H), 0.80-0.72 (m, 2H), 0.58-0.52 (m, 2H). MS (ESI) 361 (M+H).

[0845] Step G. Example 72. Preparation of N-(3-cyanophenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0846] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 72F where appropriate: (12 mg, 0.025 mmol, 61% yield). 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),7.87(d,J=7.8Hz,1H),7.79(td,J=1.0,8.0Hz,1H),7.70-7.61(m,1H),5.64(s ,1H),3.73(s,5H),1.96-1.77(m,6H),1.76-1.63(m,7H),1.47-1.31(m,6H),0.80-0.72(m,2H),0.59-0.50(m,2H). FXR EC50 (nM)=993. MS(ESI)473(M+H).

[0847] The following examples were prepared according to the method described for the synthesis of Example 1 (Step H) by substituting Intermediate 72F and the corresponding acid where appropriate:

[0848]

[0849]

[0850] Example 76

[0851] (1S,3S)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0852]

[0853] Step A. Preparation of Intermediate 76A. N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(methylsulfonyl)aniline

[0854]

[0855] The title compound was prepared according to the procedure described for the synthesis of Intermediate 1G by substituting Intermediate 72E and 3-(methylsulfonyl)aniline at the appropriate places: (20 mg, crude). MS (ESI) 414 (M+H).

[0856] Step B. Example 76. Preparation of (1s,3s)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

[0857] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 76A where appropriate: (17 mg, 0.03 mmol, 59% yield). 1H NMR (400MHz, DMSO-d6) δ7.95 (s, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.83-7.77 (m, 1 H),7.75-7.68(m,1H),6.57(s,1H),5.62(s,1H),3.72(s,3H),3.68-3.59(m, 2H),3.27(s,3H),2.78-2.68(m,1H),2.38-2.26(m,2H),2.10-1.98(m,2H), 1.79-1.60(m,7H),1.45-1.29(m,6H),0.78-0.70(m,2H),0.57-0.48(m,2H). FXR EC 50 (nM)=4000. MS(ESI)580(M+H).

[0858] Example 77

[0859] N-((4-(3-Cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,4-difluoro-N-(3-(methylsulfonyl)phenyl)cyclohexane-1-carboxamide

[0860]

[0861] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 76A where appropriate: (4 mg, 7.15 μιηοΐ, 15% yield). 1 H NMR (400MHz, DMSO-d6) δ8.02-7.94(m,1H),7.92-7.86(m,1H),7.85-7.79(m,1H),7.77-7.68(m,1H),5.62(s,1H),3.72(s,3H),3.61(br s,2H),3.30(s,3H),2.58-2.53(m,5H),2.31-2.23(m,1H),2.03-1.89(m,2H),1.78-1.44(m,8H),1.36(br dd,J=7.2,8.4Hz,6H),0.79-0.68(m,2H),0.58-0.48(m,2H). FXR EC 50 (nM)=4000. MS(ESI)560(M+H).

[0862] Example 78

[0863] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

[0864]

[0865] The title compound was prepared according to the procedure described for the synthesis of Example 1 (Step H) by substituting Intermediate 76A where appropriate: (11 mg, 0.019 mmol, 40% yield). 1 H NMR (400MHz, DMSO-d6) δ8.02-7.88(m,2H),7.83-7.78(m,1H),7.75(d,J=7.6Hz,1H),5.62(s,1H),3.72(s,3H),3.63-3. 48(m,2H),3.31(s,3H),1.94-1.79(m,6H),1.77-1.63(m,7H),1.47-1.34(m,6H),0.77-0.69(m,2H),0.57-0.49(m,2H). FXR EC 50 (nM)=4000. MS(ESI)526(M+H).

[0866] Example 79

[0867] Methyl 2-(3-(N-((4-(3-chloro-4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenoxy)acetate

[0868]

[0869] Step A. Preparation of Intermediate 79A. Methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate

[0870]

[0871] To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1 g, 4.71 mmol) in CHBr (10 mL) at room temperature, add mercuric oxide (1.73 g, 8.01 mmol). The reaction mixture is heated to 80 ° C, and Br (0.36 mL, 7.07 mmol) is added dropwise to the reaction mixture and continues to stir for 3 h. The reaction mixture is cooled to room temperature and filtered through a celite pad. The filtrate is concentrated under reduced pressure to obtain the title compound (1 g, 4.05 mmol, 86% yield). This compound is used in the next step without further purification. 1H NMR (300MHz, DMSO-d6) δ3.56 (s, 3H), 2.25-2.15 (m, 6H), 1.94-1.85 (m, 6H).

[0872] Step B. Preparation of Intermediate 79B. 4-phenylbicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0873]

[0874] Benzene (12mL, 142mmol) is cooled to -10 ℃, and aluminum chloride (2.70g, 20.23mmol) is added under nitrogen atmosphere. The solution is stirred at -10 ℃ for 5min, and a solution of intermediate 79A (1g, 4.0mmol) in benzene (12mL) is added. The reaction mixture is allowed to warm to room temperature and stirred for 12h. The reaction mixture is poured into crushed ice and diluted with water (50mL). The organic layer is separated, washed with water (2x10mL), dried over MgSO4 and concentrated under reduced pressure to obtain title compound (0.82g, 2.10mmol, 52% yield). This compound is used for the next step without further purification. 1 H NMR (300 MHz, chloroform-d) δ 7.34-7.30 (m, 4H), 7.21 (dt, J=5.8, 2.6 Hz, 1H), 3.73 (s, 3H), 1.99-1.84 (m, 12H). MS (ESI) 445 (M+H).

[0875] Step C. Preparation of Intermediate 79C. 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0876]

[0877] The solution of intermediate 79B (0.8g, 3.27mmol) and silver trifluoroacetate (0.86g, 3.93mmol) is at room temperature stirred to 5min under nitrogen atmosphere.By Br (0.17mL, 3.27mmol) in CHCl (40mL) solution is added in reaction mixture and stirs 2h.Reaction mixture is filtered through diatomite pad, and filtrate is evaporated under reduced pressure.Resistates is ground and vacuum-dried with normal hexane, to obtain title compound (0.74g, 1.58mmol, 48% productive rate). 1 H NMR (300 MHz, chloroform-d) δ 7.43 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 3.69 (s, 3H), 1.99-1.78 (m, 12H). MS (ESI) 323 (M+H).

[0878] Step D. Preparation of Intermediate 79D. (4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)methanol

[0879]

[0880] A solution of intermediate 79C (0.65 g, 2.011 mmol) in DCM (5 mL) was cooled to -78 ° C, and DIBAL-H (4.0 mL, 4.02 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into crushed ice and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.59 g, 1.9 mmol, 99% yield). 1 H NMR (300MHz, DMSO-d6) δ7.44(d,J=8.7Hz,2H),7.28(d,J=8.7Hz,2H),4.35(t ,J=5.3Hz,1H),3.08(d,J=5.3Hz,2H),1.78-1.66(m,6H),1.51-1.39(m,6H).

[0881] Step E. Preparation of Intermediate 79E. (4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]octan-1-yl)methanol

[0882]

[0883] At room temperature, dimethylamine (10mL, 10.16mmol), 2-di-tert-butylphosphino-2', 4', 6'-triisopropylbiphenyl (28mg, 0.068mmol) and sodium tert-butoxide (195mg, 2.032mmol) are added to the stirred solution of intermediate 79D (200mg, 0.677mmol) in toluene (5mL).Reactant mixture is degassed and backfilled three times with argon, and by Pd (dba) (31.0mg, 0.034mmol) is added in reactant mixture, and sealed vial (pressure release vial).Reactant mixture is heated to 80 DEG C and stirred for 4h.Reactant mixture is cooled to room temperature and concentrated under reduced pressure.Residue is diluted with water (10mL) and extracted with ethyl acetate (2x10mL).The organic layer merged is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (4 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 30 mL / min). Pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (130 mg, 0.501 mmol, 74% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.11(dd,J=2.00,6.80Hz,2H),6.64(dd,J=2.00,6.80Hz,2H),4.31( t,J=5.60Hz,1H),3.07(d,J=5.60Hz,2H),2.77(s,6H),1.66-1.72(m,6H),1.40-1.43(m,6H).

[0884] Step F. Preparation of Intermediate 79F. 4-(3-chloro-4-(dimethylamino)phenyl)bicyclo[2.2.2]octane-1-carbaldehyde

[0885]

[0886] To the stirred solution of oxalyl chloride (0.053mL, 0.601mmol) in anhydrous DCM (1.5mL) at -78 ℃ under nitrogen atmosphere, add a solution of DMSO (0.10mL, 1.50mmol) in anhydrous DCM (1.5mL).Reactant mixture is stirred for 15min at -78 ℃.A solution of intermediate 79E (0.13g, 0.50mmol) in DCM (2.5mL) is added to the reaction mixture over a period of 10min.Reactant mixture is stirred for 3h at -78 ℃.TEA (0.42mL, 3.01mmol) is added to the reaction and continues to stir for 5min.Reactant mixture is allowed to warm to room temperature and stir for 1h. The reaction mixture was diluted with DCM (10 mL), washed with water (2 x 20 mL), brine solution (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.11 g, 0.28 mmol, 57% yield) as a colorless gummy liquid. MS (ESI) 292 (M+H).

[0887] Step G. Preparation of Intermediate 79G. Methyl 2-(3-nitrophenoxy)acetate

[0888]

[0889] To a stirred solution of 3-nitrophenol (2g, 14.38mmol) in acetone (40mL) was added K2CO3 (3.97g, 28.8mmol) at room temperature, followed by 2-bromoacetic acid methyl ester (3.30g, 21.57mmol). The reaction mixture was heated to 60°C and stirred for 7h. The reaction mixture was diluted with ethyl acetate (50mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure, and the crude material was purified by flash chromatography (40g silica gel cartridges; A=Hex, B=EtOAc; 30min gradient; 0% B to 20% B; flow rate=30mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (3g, 14.21mmol, 99% yield) as a white solid. MS (ESI) 229 (M+18, NH3 adduct).

[0890] Step H. Preparation of Intermediate 79H. 2-(3-aminophenoxy)acetic acid methyl ester

[0891]

[0892] The stirred solution of intermediate 79G (1 g, 4.74 mmol) in methanol (15 mL) was degassed and backfilled with argon, and 10% Pd / C (150 mg, 0.141 mmol) was added. The resulting solution was stirred overnight under a hydrogen atmosphere (balloon pressure, 1 atm). The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.8 g, 4.42 mmol, 93% yield) as a colorless colloidal liquid. MS (ESI) 189 (M+H).

[0893] Step I. Preparation of Intermediate 79I. Methyl 2-(3-(((4-(3-chloro-4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)amino)phenoxy)acetate

[0894]

[0895] The title compound was prepared by substituting Intermediate 79D and Intermediate 79H according to the method described for the synthesis of Intermediate 1G. (120 mg, 0.20 mmol, 59% yield) as a yellow liquid. MS (ESI) 457 (M+H).

[0896] Step J. Example 79. Preparation of methyl 2-(3-(N-((4-(3-chloro-4-(dimethylamino)phenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamido)phenyl)acetate

[0897] To a stirred solution of intermediate 79I (0.12 g, 0.263 mmol) in DCM (5 mL) was added TEA (0.146 mL, 1.050 mmol) at 0 ° C., followed by cyclohexanecarbonyl chloride (0.05 mL, 0.39 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with DCM (20 mL). The organic solution was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative LC / MS using the following conditions: column: Waters XBridge C18, 19x150 mm, 5 μm particles; mobile phase A: 10 mM ammonium acetate; mobile phase B: acetonitrile; gradient: 10%-45% B over 25 minutes, then maintained at 100% B for 5 minutes; flow rate: 15 mL / min. The fractions containing the desired product were combined and dried via centrifugal evaporation to obtain the title compound (23 mg, 0.04 mmol, 15% yield). 1H NMR (400MHz, DMSO-d6) δ7.34(t,J=8.0Hz,1H),7.21(d,J=2.0Hz,1H),7.19-7.11(m,1H),7.04(d,J=8.5Hz,1H),7.00-6.83(m,3H),4.86(s,2H),3.6 9(s,3H),3.54(s,2H),2.71-2.61(m,6H),1.73-1.54(m,10H),1.49(br.s .,1H),1.43-1.18(m,8H),1.09(d,J=12.5Hz,1H),0.90(d,J=13.1Hz,2H). FXR EC50 (nM)=1,044. MS (ESI) 567 (M+H).

[0898] Example 80

[0899] Methyl 2-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenoxy)acetate

[0900]

[0901] The stirring solution of embodiment 79 (30mg, 0.053mmol) in methanol (10mL) is degassed and backfilled with nitrogen, and 10% Pd / C (10mg, 0.094mmol) is added. The resulting solution is stirred overnight under a hydrogen atmosphere (balloon pressure, 1atm). The reaction mixture is filtered through a celite pad, and the filtrate is concentrated under reduced pressure. The crude material is purified by preparative LC / MS using the following conditions: (post: Waters XBridge C18, 19x150mm, 5 μm particles; Mobile phase A: 10mM ammonium acetate; Mobile phase B: acetonitrile; Gradient: 40%-80% B over 20 minutes, then kept at 100% B for 5 minutes; Flow rate: 20mL / min). The fractions containing the desired product are combined and dried via centrifugal evaporation to obtain the title compound (6mg, 0.011mmol, 21% yield) as a pale solid. 1H NMR (400MHz, DMSO-d6) δ7.34(t,J=7.9Hz,1H),7.06(d,J=9.0Hz,2H),7.00-6.80(m,3H),6.62(d,J=8.8Hz,2H),3.69(s,3H),3.53(s,2H), 2.87-2.77(m,6H),2.23(br.s.,1H),1.71-1.54(m,10H),1.49(br.s.,1H),1.43-1.19(m,8H),1.15-1.02(m,1H),0.90(d,J=11.7Hz,2H). FXR EC 50 (nM) 1,597; MS (ESI) 533 (M+H).

[0902] Example 81

[0903] Methyl 2-(3-(N-((1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamido)phenoxy)acetate

[0904]

[0905] Step A. Preparation of Intermediates 81A1 and 81A2 (5-bromo-1-methyl-1H-indazole and 5-bromo-2-methyl-2H-indazole)

[0906]

[0907] To a stirred solution of 5- bromo- 1H- indazole (2g, 10.15mmol) in DMSO (20mL) was added iodomethane (0.82mL, 13.20mmol) at room temperature, followed by potassium carbonate (7.0g, 50.8mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50mL), and the aqueous solution was extracted with EtOAc (3x50). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40g silica gel cartridges; A=Hex, B=EtOAc; 30min gradient; 0% B to 40% B; flow rate=30mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain intermediate 81A1 (1.2g, 5.40mmol, 53% yield) as a white solid and intermediate 81A2 (0.6g, 2.70mmol, 27% yield) as a pale white solid. The desired compound was confirmed by NOE studies. MS (ESI) 213 (M+H).

[0908] Step B. Preparation of Intermediate 81B.5-iodo-1-methyl-1H-indazole

[0909]

[0910] To a solution of intermediate 81A1 (1 g, 4.74 mmol) in 1,4-dioxane (5 mL) was added sodium iodide (1.42 g, 9.48 mmol), copper (I) iodide (0.05 g, 0.237 mmol) and (1r, 2r)-N,N'-dimethyl-1,2-cyclohexanediamine (0.07 g, 0.474 mmol) at room temperature under argon atmosphere. The reaction mixture was heated to 110 ° C and stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The aqueous solution was extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL / min). Pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (1 g, 3.60 mmol, 76% yield) as an off-white crystalline solid. MS (ESI) 259 (M+H).

[0911] Step C. Preparation of Intermediate 81C. (4-hydroxy-4-(1-methyl-1H-indazol-5-yl)cyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

[0912]

[0913] A stirred solution of intermediate 81B (0.3 g, 1.163 mmol) in tetrahydrofuran (5 mL) was cooled to -78 ° C, and n-BuLi (0.93 mL, 2.33 mmol) in hexane was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 ° C for 1 h. A solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (see ACSMed.Chem.Lett., 5 (5), 609-614; 2014) (0.70 g, 1.511 mmol) in 2 mL of anhydrous THF was added to the reaction. The reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL), and the aqueous solution was extracted with EtOAc (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 30 mL / min). Pure fractions were combined, concentrated under reduced pressure, and dried in vacuo to afford the title compound (0.25 g, 0.4 mmol, 34% yield) as an off-white solid. MS (ESI) 599 (M+H).

[0914] Step D. Preparation of Intermediate 81D. (1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl 4-methylbenzenesulfonate

[0915]

[0916] To a stirred solution of intermediate 81C (0.25 g, 0.418 mmol) in anhydrous 1,2-dimethoxyethane (10 mL) was added sodium hydride (0.050 g, 1.253 mmol) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ° C for 30 min and then heated under reflux for 12 h. The reaction mixture was cooled to 0 ° C, quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (2x10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (0.18 g, 0.401 mmol, 96% yield) as a white solid. MS (ESI) 427 (M + H).

[0917] Step E. Preparation of Intermediate 81E. (1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl acetate

[0918]

[0919] To a solution of intermediate 81D (2.5 g, 5.86 mmol) in DMF (30 mL) was added sodium acetate (2.88 g, 35.2 mmol) in a pressure tube. The reaction mixture was heated to 120 ° C and stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The aqueous solution was extracted with EtOAc (2x30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.6 g, 1.813 mmol, 31% yield) as an off-white solid. MS (ESI) 315 (M + H).

[0920] Step F. Preparation of Intermediate 81F. (1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methanol

[0921]

[0922] To a stirred solution of intermediate 81E (0.6 g, 1.909 mmol) in methanol (10 mL) was added a solution of potassium carbonate (1.32 g, 9.54 mmol) in water (15 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was removed under reduced pressure, and the residue was diluted with water (15 mL). The aqueous solution was extracted with EtOAc (2x20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (0.45 g, 1.57 mmol, 82% yield) as a white solid. MS (ESI) 273 (M+H).

[0923] Step G. Preparation of Intermediate 81G. 1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-carbaldehyde

[0924]

[0925] To a stirred solution of intermediate 81F (0.4 g, 1.47 mmol) in dichloromethane (2 mL) was added Dess-Martin periodinane (0.748 g, 1.76 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM (30 mL), and the organic solution was washed with water (10 mL) and 10% sodium bicarbonate aqueous solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.4 g, 1.40 mmol, 96% yield) as a semi-solid. 1 H NMR (400MHz, DMSO-d6) δ9.53 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 7.5Hz, 1H), 7.74-7.71 (m, 1H),7.57-7.53(m,1H),4.03(s,2H),4.01(s,3H),2.23-2.12(m,2H),2.01-1.85(m,6H).

[0926] Step H. Preparation of Intermediate 81H. Methyl 2-(3-(((1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]oct-4-yl)methyl)amino)phenoxy)acetate

[0927]

[0928] The title compound was prepared according to the method described for the synthesis of Intermediate 1G by substituting Intermediate 81G and Intermediate 79H in the appropriate places. (0.19 g, 0.41 mmol, 56% yield) as a pale yellow solid. MS (ESI) 436 (M+H).

[0929] Step I. Example 81. Preparation of methyl 2-(3-(N-((1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamido)phenoxy)acetate

[0930] The title compound was prepared according to the procedure described for the synthesis of Example 79 (Step J) by substituting Intermediate 81H and the corresponding acid where appropriate (8 mg, 0.013 mmol, 22% yield). 1H NMR (400MHz, DMSO-d6) δ7.94 (s, 1H), 7.65 (s, 1H), 7.50 (d, J = 8.8Hz, 1H), 7.44-7 .30(m,2H),7.10-6.98(m,2H),6.95(d,J=7.1Hz,1H),4.88(s,2H),3.99(s,3H), 3.76(d,J=8.1Hz,2H),3.70-3.64(m,6H),3.59(s,2H),3.02(t,J=11.7Hz,2H),2 .11-1.95(m,2H),1.90-1.74(m,2H),1.70-1.49(m,6H),1.44(d,J=13.2Hz,2H). FXR EC 50 (nM) 4355; MS (ESI) 548 (M+H).

[0931] Example 82

[0932] 3-(N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamido)-N-(thiazol-2-yl)benzamide

[0933]

[0934] Step A. Preparation of Intermediate 82A. 3-Nitro-N-(thiazol-2-yl)benzamide

[0935]

[0936] To a stirred solution of thiazole-2-amine (0.27g, 2.69mmol) in dichloromethane (10mL) was added TEA (1.12mL, 8.08mmol) at 0°C, followed by 3-nitrobenzoyl chloride (0.5g, 2.69mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (30mL). The organic solution was washed with water (20mL), a saline solution (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (0.35g, 1.334mmol, 49% yield) as a pale solid. MS (ESI) 250 (M+H).

[0937] Step B. Preparation of Intermediate 82B. 3-amino-N-(thiazol-2-yl)benzamide

[0938]

[0939] To a stirred solution of intermediate 82A (0.35 g, 1.40 mmol) in ethanol (10 mL) was added tin (II) chloride (1.06 g, 5.62 mmol) at room temperature. The reaction mixture was heated to 90 ° C and stirred for 12 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was dissolved in EtOAc (20 mL), and the resulting solution was washed with 10% NaHCO3 aqueous solution (10 mL) and brine solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (12 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 60% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.15 g, 0.616 mmol, 43% yield) as an off-white solid. MS (ESI) 220 (M + H).

[0940] Step C. Preparation of Intermediate 82C. 4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester

[0941]

[0942] To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2 g, 9.42 mmol) in DMF (20 mL) was added (E)-N'-hydroxyacetimidamide (1.4 g, 18.85 mmol), BOP (4.17 g, 9.42 mmol) and TEA (4 mL, 28.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and heated at 110 ° C overnight. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 30 mL / min). Pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (0.6 g, 2.27 mmol, 24% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ3.60(s,3H),2.29(s,3H),1.95-1.86(m,6H),1.86-1.78(m,6H).

[0943] Step D. Preparation of Intermediate 82D. Methyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate

[0944]

[0945] To a stirred solution of intermediate 82C (0.6 g, 2.397 mmol) in tetrahydrofuran (20 mL) was added DIBAL-H (6 mL, 5.99 mmol) at -78 ° C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 ° C, quenched with 1.5N HCl aqueous solution (30 mL) and extracted with EtOAc (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridges; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.58 g, 2.35 mmol, 98% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ4.41(br.s.,1H),3.08(s,2H),2.29(s,3H),1.90-1.80(m,6H),1.50-1.40(m,6H).

[0946] Step E. Preparation of Intermediate 82E. 4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

[0947]

[0948] To a stirred solution of intermediate 82D (0.58 g, 2.61 mmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (2.2 g, 5.22 mmol) at 0 ° C under a nitrogen atmosphere. The reaction mixture was stirred for 1 h at 0 ° C. The reaction mixture was allowed to warm to room temperature, diluted with DCM (20 mL) and filtered through celite. The filtrate was washed with 10% aqueous sodium bicarbonate solution (2x20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (24 g silica gel cartridge; A = Hex, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL / min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to obtain the title compound (0.46 g, 1.98 mmol, 76% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.46 (s, 1H), 2.30 (s, 3H), 1.96-1.84 (m, 6H), 1.73-1.66 (m, 6H).

[0949] Step C. Preparation of Intermediate 82C. 3-(((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)-N-(thiazol-2-yl)benzamide

[0950]

[0951] The title compound was prepared according to the method described for the synthesis of Intermediate 1G by substituting Intermediate 82B and Intermediate 82E in the appropriate places. (40 mg, 0.09 mmol, 39% yield) as a pale yellow solid. MS (ESI) 424 (M+H).

[0952] Step D. Example 82. Preparation of 3-(N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamido)-N-(thiazol-2-yl)benzamide

[0953] The title compound was prepared according to the procedure described for the synthesis of Example 79 (Step J) by substituting Intermediate 82C and cyclohexanecarbonyl chloride (32 mg, 0.06 mmol, 72% yield). 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.15(s,1H),8.06(d,J=7.6Hz,1H), 7.73-7.66(m,1H),7.66-7.51(m,2H),7.31(d,J=3.7Hz,1H),3.67(br.s.,2 H),2.27(s,3H),2.21(br.s.,1H),1.88-1.73(m,6H),1.61(br.s.,4H),1.4 9(br.s.,1H),1.46-1.27(m,8H),1.10(d,J=13.2Hz,1H),0.90(br.s.,2H). FXR EC 50 (nM) = 3011; MS (ESI) 534 (M+H).

[0954] Example 83

[0955] N-((4-(3-(tert-Butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-ethoxyphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0956]

[0957] Step A. Preparation of Intermediate 83A: N-(3-bromophenyl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0958]

[0959] The title compound was synthesized according to the method described for the synthesis of Intermediate 1D by substituting Intermediate 33E and (Z)-N'-hydroxypivalimidamide in the appropriate places. (200 mg, 0.377 mmol, 68% yield) was obtained as a brown gummy solid. MS (ESI) 530 (M+H).

[0960] Step B. Example 83: Preparation of N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-ethoxyphenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0961] To a stirred solution of intermediate 83A (30 mg, 0.057 mmol) in 1,4-dioxane (2 mL) was added 4-ethoxyaniline (8 mg, 0.057 mmol), cesium carbonate (46 mg, 0.141 mmol) and Xantphos (4 mg, 5.66 μmol) at room temperature. The reaction mixture was degassed and backfilled three times with argon, and bis(dibenzylideneacetone)palladium (2 mg, 2.83 μmol) was added. The reaction bottle was sealed. The reaction mixture was heated to 110 ° C and stirred overnight. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude material was purified by preparative LC / MS using the following conditions: Column: Waters XBridge C18, 150 mm x 19 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water containing 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water containing 10 mM ammonium acetate; Gradient: 40% B for 0 minutes, 40% to 84% B over 20 minutes, then 100% B for 5 minutes; Flow rate: 15 mL / min; Column temperature: 25°C. Fraction collection was triggered by the MS signal. Product-containing fractions were combined and dried via centrifugal evaporation to afford the title compound (12 mg, 0.019 mmol, 34% yield). 1H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.22(t,J=7.9Hz,1H),7.05(d,J=8.8Hz,2H),6.96-6.80(m,3H),6.79-6.70(m,1H),6.67(d,J= 7.6Hz,1H),3.99(q,J=6.9Hz,2H),3.49(d,J=4.9Hz,2H),1.90(s,6H),1.87-1.67(m,6H),1.55-1.37(m,6H),1.35-1.17(m,12H); FXR EC 50 (nM) = 1131; MS (ESI) 587 (M+H).

[0962] Example 84

[0963] N-((4-(5-(tert-Butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-(difluoromethoxy)phenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0964]

[0965] Step A. Preparation of Intermediate 84A: N-(3-bromophenyl)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0966]

[0967] The title compound was synthesized by substituting Intermediate 33H and the corresponding acid according to the method described for the synthesis of Intermediate 1D. (190 mg, 0.358 mmol, 83% yield) as a pale yellow solid. MS (ESI) 530 (M+H).

[0968] Step B. Preparation of Intermediate 84B: N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-((4-(difluoromethoxy)phenyl)amino)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

[0969] The title compound was synthesized according to the procedure described for the synthesis of Example 83 (Step B) by substituting Intermediate 84A and 4-(difluoromethoxy)aniline where appropriate (0.4 mg, 0.61 μmol, 2% yield). 1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),7.34-6.86(m,8H),6.80(d,J=7.8Hz,1H),3.63- 3.40(m,2H),1.91(br.s.,6H),1.82-1.70(m,6H),1.55-1.39(m,6H),1.34(s,9H); FXR EC 50 (nM) = 84; MS (ESI) 609 (M+H).

[0970] The following examples were synthesized according to the procedure described for the synthesis of Example 83 by substituting Intermediate 84A and the corresponding aryl / heteroaryl amine at the appropriate place.

[0971]

[0972]

[0973]

[0974] Example 89

[0975] Methyl 3-(3-(N-((4-(4-(dimethylamino)phenyl)bicyclo[2.2.2]oct-1-yl)methyl)cyclohexanecarboxamido)phenyl)propanoate

[0976]

[0977] Step A. Preparation of Intermediate 89A. 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carbaldehyde

[0978]

[0979] At -78 ℃ under nitrogen atmosphere, to the stirred solution of oxalyl chloride (0.12mL, 1.219mmol) in anhydrous DCM (3mL), a solution of DMSO (0.21mL, 3.05mmol) in anhydrous DCM (2.5mL) was added dropwise. The reaction mixture was stirred at -78 ℃ for 15min. A solution of intermediate 79D (0.3g, 1.016mmol) in DCM (5mL) was added to the above-mentioned reaction mixture over a period of 10min. The reaction mixture was stirred for 3h at -78 ℃. With Et3N (0.85mL, 6.10mmol) was added to the reaction and continued to stir for 5min at -78 ℃. The reaction mixture was allowed to warm to 0 ℃ and stirred for 1h. The reaction mixture was diluted with DCM (10mL) and poured on crushed ice. The organic layer was separated, and the aqueous layer was extracted with DCM (2x10mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (220 mg, 0.75 mmol, 74% yield). 1 H NMR (300 MHz, CHLOROFORM-d) δ 9.53 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 1.95-1.73 (m, 12H).

[0980] Step B. Preparation of Intermediate 89B. (E)-methyl 3-(3-nitrophenyl)acrylate

[0981]

[0982] To a stirred solution of methyl 2-(dimethoxyphosphoryl)acetate (1.3 mL, 7.94 mmol) in water (6 mL) was added KCO (1.82 g, 13.23 mmol) at room temperature, followed by 3-nitrobenzaldehyde (1 g, 6.62 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1 g, 4.83 mmol, 73% yield). 1 H NMR (300MHz, DMSO-d6) δ8.56(t,J=1.7Hz,1H),8.27-8.18(m,2H),7.81(d,J=16.2Hz,1H),7.71(t,J=8.1Hz,1H),6.87(d,J=16.2Hz,1H),3.75(s,3H).

[0983] Step C. Preparation of Intermediate 89C. (E)-methyl 3-(3-aminophenyl)acrylate

[0984]

[0985] To a stirred solution of intermediate 89B (1.300 g, 6.27 mmol) in water (15 mL) at room temperature, tin chloride di...

Claims

1. A compound of formula (I): or a salt thereof, wherein: X 1 It is CH; X 2 It is CH; X 3 It is CH; X 4 is N or CH; Z 1 and Z 2 are independently CH2 or O; provided that Z 1 and Z 2 At least one of them is CH2; a is 1; b is zero or 1; d is 1; Q is: (i) -C(O)OCH3, -C(O)NH(CH2CH3), -OCH3, -OCH2CH3, -OCHF2, -OCH2C(O)OCH3, -NHC(O)OC(CH3)3, -NHS(O)2CH3, -S(O)2CH3, -S(O)2NH(cyclopropyl) or -S(O)2NH(CH3); R 2 is cyclopropyl, cyclobutyl, cyclohexyl, tetrahydropyranyl, bicyclo[1.1.1]pentyl or dioxotetrahydrothiopyranyl, each of which is substituted with zero to two substituents independently selected from F, hydroxy, oxo, -CH3, -CF3 and -C(CH3)2OH; R 3a It is hydrogen; R 3b It is hydrogen; A is phenyl, pyrazolyl, oxadiazolyl, pyridyl or indazolyl, separated by zero to two R 4a Replace; each R 4a independently Cl, -CH3, -C(CH3)3, -CF3, -CF2CH3, -C(CH3)2F, -N(CH3)2, cyclopropyl or fluorocyclopropyl.

2. The compound or salt thereof according to claim 1, wherein Z 1 is CH2; and Z 2 It's CH2.

3. The compound or salt thereof according to claim 1, wherein Z 1 and Z 2 One of them is CH2, and Z 1 and Z 2 The other one is O.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (12); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (13); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(2-methoxypyridin-4-yl)bicyclo[ 1.1.1]pentane-1-carboxamide (17); N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (18); (1S,3S)-N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (19); N-(3-(N-cyclopropylsulfamoyl)phenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,4-difluorocyclohexane-1-carboxamide (20); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(N-methylsulfamoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (21); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(N-methylsulfamoyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (22); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,4-difluoro-N-(3-(N-methylsulfamoyl)phenyl)cyclohexane-1-carboxamide (23); 3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluorobicyclo[ 1.1.1] pentane-1-carboxamido)benzoic acid methyl ester (27); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(ethylcarbamoyl)phenyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (28); (3-(N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[ 1.1.1] tert-butyl pentane-1-carboxamido)phenyl)carbamate (32); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (52); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3,3-difluorocyclobutane-1-carboxamide (53); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (54); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (55); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (56); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-methoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (57); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-methoxyphenyl)bicyclo[ 1.1.1]pentane-1-carboxamide (58); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluoro-N-(3-methoxyphenyl)cyclobutane-1-carboxamide (59); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-methoxyphenyl)tetrahydro-2H-pyran-4-carboxamide (60); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-methoxyphenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (61); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3,3-difluoro-N-(3-(methylsulfonamido)phenyl)cyclobutane-1-carboxamide (65); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonamido)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (66); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonamido)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (67); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (68); N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4,4-difluoro-N-(3-(methylsulfonyl)phenyl)cyclohexane-1-carboxamide (69); (1S,3S)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (76); N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,4-difluoro-N-(3-(methylsulfonyl)phenyl)cyclohexane-1-carboxamide (77); N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (78); Methyl 2-(3-(N-((4-(3-chloro-4-(dimethylamino)phenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamido)phenoxy)acetate (79); methyl 2-(3-(N-((1-(1-methyl-1H-indazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)tetrahydro-2H-pyran-4-carboxamido)phenoxy)acetate (81); (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(methylsulfonyl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (90); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-N-(3-(cyanomethoxy)phenyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (111); N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-(2-hydroxy-2-methylpropoxy)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (112); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(ethylcarbamoyl)-4-fluorophenyl)-3-fluorobicyclo[ 1.1.1]pentane-1-carboxamide (122); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (123); (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (124); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-methylcyclobutane-1-carboxamide (125); (1S,3S)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-isopropoxyphenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (126); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(3-isopropoxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (127); N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]oct-1-yl)methyl)-3-fluoro-N-(4-fluoro-3-(2-hydroxyprop-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (128); N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-methoxyphenyl)bicyclo[ 1.1.1] pentane-1-carboxamide (129); or N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-ethoxyphenyl)-3-fluorobicyclo[ 1.1.1] Pentane-1-carboxamide (130). 5 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pathological fibrosis associated with farnesoid X receptor (FXR) activity.

7. The use according to claim 6, wherein the pathological fibrosis is liver fibrosis, kidney fibrosis, biliary fibrosis or pancreatic fibrosis.

8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with farnesoid X receptor (FXR) activity, the disease being non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC).

9. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-alcoholic steatohepatitis (NASH) associated with farnesoid X receptor (FXR) activity.

10. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis (IPF) associated with farnesoid X receptor (FXR) activity.

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