EA047337B1 - SUBSTITUTED BICYCLIC COMPOUNDS AS MODULATORS OF THE FARNEZOID X RECEPTOR - Google Patents

Description

The present invention generally relates to compounds useful as farnesoid X receptor (FXR) modulators, pharmaceutical compositions containing such compounds, and their use in therapy, especially in the treatment or prevention of diseases, disorders and conditions for which an FXR modulator is indicated .

FXR or NR1H4 (nuclear receptor subfamily 1, group H, 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, and in the gallbladder and biliary tree in humans. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to specific response elements in target genes to regulate gene transcription (VM Forman et al., Cell 1995; 81: 687; W. Seol et al., Mol Endocrinol 1995; 9:72). The FXR/RXR heterodimer typically binds to an inverted repeat of a consensus hexanucleotide sequence (AGGTCA) separated by a single nucleotide, that is, the IR-1 sequence. Relevant physiological ligands for FXR are bile acids, including chenodeoxycholic acid and its taurine conjugate (D. J. Parks et al., Science 1999; 284: 1365; M. Makishima et al., Science 1999; 284: 1362). Activation of FXR regulates the expression of several genes that encode enzymes and transporters involved in the synthesis, influx, and efflux of bile acids from the liver and intestine, resulting in an overall decrease in the total amount of endogenous bile acids in a negative feedback loop. FXR is involved in paracrine and endocrine signaling by increasing the expression of the cytokine Fibroblast Growth Factor 15 (rodents) or 19 (primates), which may also contribute to the regulation of bile acid concentrations (Holt et al., Genes Dev. 2003; 17: 1581; Inagaki et al. al., Cell Metab 2005; 2: 217). Therefore, FXR is considered a master regulator of bile acid homeostasis.

One use of FXR agonists is to treat diseases in which bile acids are dysregulated, including cholestatic diseases (eg, primary biliary cirrhosis and primary sclerosing cholangitis), which can lead to fibrosis, cirrhosis, cholangiocarcinoma, hepatocellular carcinoma, liver failure, and death. Although elevated concentrations of bile acids in the liver have deleterious effects, bile acids also affect the microflora and integrity of the small intestine. Impaired bile flow in humans or rodents causes the proliferation of intestinal bacteria and damage to the mucosa, which can lead to bacterial translocation across the mucosal barrier and systemic infection (Berg, Trends Microbiol. 1995; 3: 149-154). Mice lacking FXR have increased levels of bacteria in the ileum and a compromised epithelial barrier, while activation of intestinal FXR plays an important role in preventing bacterial overgrowth and maintaining the integrity of the intestinal epithelium (Inagaki et al., Proc Natl Acad Sci 2006; 103 : 3920-3925). Over time, FXR null mice spontaneously develop hepatocellular carcinoma, and this can be reversed by selective reactivation of FXR in the intestine (Degirolamo et al., Hepatology 61: 161-170). Pharmacological activation of FXR with a small molecule agonist or transgenic expression of FXR in the intestine can normalize bile acid concentrations, reduce cellular proliferation in the liver bile ducts, and reduce inflammatory cell infiltration, necrosis, and liver fibrosis in rodent models of cholestasis (Liu et al., J. Clin Invest 2003; 112:1678-1687; Modica et al. 2012; Some of these beneficial effects observed in preclinical models of cholestasis have been translated to human patients, and the FXR agonist obeticholic acid (OCA or OCALIVA™) has been approved for the treatment of primary biliary cirrhosis (https://www.fda.gov/ newsevents/newsroom/pressannouncements/ucm503964.htm).

In addition to controlling bile acid homeostasis, FXR agonists regulate the hepatic expression of hundreds of genes encoding proteins involved in cholesterol and lipid metabolism and transport, glucose homeostasis, inflammation, chemotaxis, and apoptosis among other pathways (Zhan et al., PLoS One 2014;9:e105930 ; Ijssennagger et al., J Hepatol 2016; 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, nonalcoholic fatty liver disease (NAFLD), and metabolic syndrome (Crawley, Expert Opin. Patents 2010; 20:1047-1057).

FXR agonists have also been studied in human clinical trials for the treatment of NAFLD, a more advanced form of fatty liver disease, nonalcoholic steatohepatitis (NASH) and related complications. NAFLD is one of the most common causes of chronic liver disease in the modern world (Vernon et al., Aliment Pharmacol Ther 2011;34:274-285). Risk factors for developing NAFLD include obesity, type 2 diabetes mellitus (T2DM), insulin resistance, hypertension

- 1 047337 and dyslipidemia. In a 6-week clinical trial in T2DM patients with NAFLD, the FXR agonist OCA statistically significantly improved insulin sensitivity and reduced body weight, demonstrating beneficial effects on several of these risk factors (Mudaliar et al., Gastroenterology 2013; 145:574-582). NASH is the most severe and progressive form of NAFLD and includes histologic findings of hepatic steatosis, inflammation, and ballooning degeneration with varying degrees of pericellular fibrosis (Sanyal et al., Hepatology 2015;61:1392–1405). In a 72-week clinical trial in patients with NASH, OCA statistically significantly improved hepatic steatosis, lobular inflammation, hepatocyte ballooning, and fibrosis as assessed by histological analyzes of liver biopsy samples (Neuschwander-Tetri et al., Lancet 2015; 385: 956-965). These data also suggest that FXR agonists may have a beneficial effect on clinical outcomes, given that NASH is the second leading cause of hepatocellular carcinoma (HCC) and liver transplantation in the United States (Wong et al., Hepatology 2014;59:2188-2195 ).

The present invention provides new compounds for treating a disease, disorder or condition associated with farnesoid X receptor (FXR) activity in a patient in need thereof.

Brief description of the invention

In one aspect, the present invention provides compounds of formula (I), as well as subgenera and species thereof, including stereoisomers or pharmaceutically acceptable salts thereof, which are useful as FXR modulators.

In yet another aspect, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers or pharmaceutically acceptable salts thereof.

The compounds of the present invention can be used to treat a disease, disorder or condition associated with farnesoid X receptor (FXR) activity in a patient in need of such treatment by administering to the patient a therapeutically effective amount of the compound or a stereoisomer or pharmaceutically acceptable salt thereof. The disease, disorder or condition may 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, for example, one or two other therapeutic agents.

The compounds of the present invention can be used either as a single agent or in combination with other agents in the treatment of a disease, disorder or condition selected from non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). The compounds of the present invention can be used either as a single agent or in combination with other agents in the treatment of idiopathic pulmonary fibrosis (IPF).

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

Other features and advantages of the invention will be apparent from the following detailed description and claims.

Brief description of drawings

The invention is illustrated by reference to the accompanying drawings described below. In fig. 1 shows a general reaction scheme 12.

In fig. 2 shows a general reaction scheme 13.

In fig. 3 shows a general reaction scheme 15.

Detailed Description of the Invention

The present invention provides compounds, including all stereoisomers, solvates, prodrugs, as well as pharmaceutically acceptable salts and solvate forms thereof, according to formula (I). Also provided herein are pharmaceutical compositions containing at least one compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, and optionally at least one additional therapeutic agent. Further provided herein are methods of treating a patient suffering from an FXR-modulated disease or disorder, such as, for example, biliary 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, by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof, and optionally in combination with at least one additional therapeutic agent.

The first aspect of the present invention provides a compound of formula (I):

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or a stereoisomer or pharmaceutically acceptable salt thereof, wherein

Q is phenyl substituted with 0-1 R ¹ ;

X ¹ represents CH;

X ² represents CH or N;

X ³ represents CH or N;

X ⁴ represents CH; with the proviso that 0 or 1 of X ² and X ³ represent N;

Z ¹ and Z ² are independently CH ₂ or O; with the proviso that at least one of Z ¹ and Z ² is CH ₂ ;

A is oxadiazolyl or pyridinyl substituted with R ^4a ;

a is equal to 1;

b is equal to 1;

d is 1;

each R ¹ independently represents C _1-4 -alkyl, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH ₂ CHF ₂ , -C(CH3)2OH, -CH2OCH3, - C(CH3)2OCH3, -OCH3, -OCH2CH3, -OC(CH3) ₂ CIII, -Ci OHY)CI IF, -C(O)OCH3, -C(O)OCH ₂ CH ₃ , -CH ₂ (cyclopropyl ), ^(O) ₂ CH ₃ , ^(O) ₂ (cyclopropyl), =O, difluorocyclobutyl, fluorobicyclo[1.1.1]pentyl, oxetanyl, methyloxetanyl, pyridinyltetrahydropyranyl or cyclopropyl substituted with 0-1 substituent selected from hydroxyl, -CH ₃ , -OSH ₃ and -NHC(O)CH ₃ ;

R ² represents:

(i) C _1-4 alkyl, C _1-5 alkoxy or -NH(C _1-6 alkyl), wherein each of said alkyl and alkoxy is substituted with 0-4 R ^2a ; or (ii) C _3-5 cycloalkyl substituted with 0-3 R ^2b ;

R ^2a is independently halogen, cyano or hydroxyl;

R ^2b independently represents halogen, cyano, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy, where alkyl is substituted with 0-6 R ^2a ;

R ^3a represents hydrogen or -CH3; And

R ^3b represents hydrogen; And

R ^4a represents cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -CF2CH3, -C( _CH3 ) -C(CH3) ₂ OH, -C( _CH3 ) ₂ CN, -OCH ₃ , -C(O)N(CH ₃ ) ₂ , -CH ₂ (cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetanyl, tetrahydropyranyl or fluorobicyclo[1.1.1]pentyl .

In one embodiment, a compound or a stereoisomer or pharmaceutically acceptable salt thereof is provided having the structure:

In one embodiment, a compound or a stereoisomer or pharmaceutically acceptable salt thereof is provided having the structure:

In one embodiment, a compound or stereoisomer or pharmaceutically acceptable salt thereof is provided having the structure:

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In one embodiment, a compound or stereoisomer or pharmaceutically acceptable salt thereof is provided having the structure:

In one embodiment, a compound or stereoisomerically acceptable salt thereof is provided wherein A is pyridinyl substituted with ^R4a .

or pharmaceutical In one embodiment, a compound or skilfully acceptable salt is provided having the structure:

its stereoisomer or pharmaceutical

In one embodiment, a compound or a stereoisomer or pharmaceutically acceptable salt thereof is provided having the structure:

In one embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof.

In one embodiment, the use of a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is provided for the treatment of pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

In one embodiment, the use of a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is provided, wherein the pathological fibrosis is liver fibrosis, renal fibrosis, biliary fibrosis or pancreatic fibrosis.

In one embodiment, the use of a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is provided for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (BBC).

In one embodiment, the use of a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof is provided for the treatment of idiopathic pulmonary fibrosis (IPF).

One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is:

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or

One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is:

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One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is:

One embodiment provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said compound is:

In one embodiment, the present invention provides a compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is:

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T4-((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(3-methyl1,2,4-oxadiazol-5-yl)phenyl)isobutyramide ( 1);

T4-((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(3-methyl1,2,4-oxadiazol-5-yl)phenyl)cyclopropanecarboxamide ( 2);

T4-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-T4-((4-(3-methyl-1,2,4oxadiazol-5-yl) bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (3);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(methyl difluoro)-M-(3 -( 3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)cyclobutane-1-carboxamide (4);

(18.38)-H-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-( 3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (5);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-ethyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (6);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)T4-(3-(2-ethoxyoxazol-5-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (7);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (8);

(18.38)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3-( 3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamide (9);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (10);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclopentane-1 carboxamide (11);

ethyl 2-(3-(3-fluoro-T4-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1. 1]pentane-1-carboxamido)phenyl)oxazole-4-carboxylate (12);

ethyl 2-(3-(T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)-3-fluorobicyclo[1.1.1 ]pentane-1-carboxamido)phenyl)oxazole-4-carboxylate (13);

N-(3 -(4-(chloromethyl)oxazol-2-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (14);

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18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(4-(2 -hydroxypropan-2-yl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (15);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3-d πφτορ-Ν-(3 -( 4-(2-hydroxypropan-2-yl)oxazol-2-yl)phenyl)cyclobutane-1 carboxamide (16);

N -((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) 3 -(difluoromethyl)-M-(3 -( 4-(2-hydroxypropan-2-yl)oxazol-2-yl)phenyl)cyclobutane-1 carboxamide (17);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3-d πφτορ-Ν-(3 -( 4-(2-hydroxypropan-2-yl)oxazol-2-yl)phenyl)cyclopentane-1 carboxamide (18);

(18.38)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-H- (3-(3-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-5-yl)phenyl)-3(trifluoromethyl)cyclobutan-1-carboxamide (19);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-cyclopropyloxazol-5-yl )phenyl)cyclobutanecarboxamide (20);

(18.38)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-( 2-cyclopropyloxazol-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (21);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)18G-(3-(2-cyclopropyloxazol-5-yl )phenyl)-3,3-difluorocyclobutane-1-carboxamide (22);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-cyclopropyloxazol-5-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (23);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-cyclopropyloxazol-5-yl )phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (24);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(5-ethoxyisoxazol-3-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (25);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-propyloxazol- 5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (26);

- 8 047337 ^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3-difluoro-M-(3 -(2-propyloxazol-5-yl)phenyl)cyclobutane-1-carboxamide (27);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(difluoromethyl)-M-(3-(2 -propyloxazol-5-yl)phenyl)cyclobutane-1-carboxamide (28);

ethyl 4-(3-(18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)-3-fluorobicyclo[1.1.1 ]pentane-1-carboxamido)phenyl)thiazole-2-carboxylate (29);

M-(3-(2-(chloromethyl)thiazol-4-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (30);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-(2 -hydroxypropan-2-yl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (31);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(2methylpyridin-4-yl)bicyclo[2.2.2]octane- 1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (32);

N-(3 -(3-cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-3,3-d πφτορ-Ν-((4-(2methylpyridin-4-yl)bicyclo[2.2. 2]octan-1-yl)methyl)cyclopentane-1-carboxamide (33);

3-Φτορ-Ν-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)18G-(3-(2-( tetrahydro-2H-pyran-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (34);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-(tetrahydro -2H-pyran-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (35);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -d πφτορ-Ν-(3 -( 2-(tetrahydro-2H-pyran-4-yl)oxazol-5 -yl)phenyl)cyclobutan-1 carboxamide (36);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 methyloxazol-2-yl)bicyclo[2.2.2]octane -1 -yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (37);

(18.38)-M-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-M-((4-(5methyloxazol-2-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-(trifluoromethyl)cyclobutan-1carboxamide (38);

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N-(3 -(3-cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-3,3-d πφτορ-Ν-((4-(5methyloxazol-2-yl)bicyclo[2.2. 2]octan-1-yl)methyl)cyclopentane-1-carboxamide (39);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(4-(difluoromethyl)oxazol- 2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (40);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(4-(difluoromethyl)oxazol- 2-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (41);

(15.35)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-( 4-(difluoromethyl)oxazol-2-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxamide (42);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(difluoromethyl)-M-(3 -(4 -(difluoromethyl)oxazol-2-yl)phenyl)cyclobutan-1-carboxamide (43);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(4-(difluoromethyl)oxazol- 2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (44);

M-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-fluoro-M-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl )methyl)bicyclo[1.1.1]pentane-1-carboxamide (45);

(cis)-M-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-hydroxy-M-((4-(5methyloxazol-2-yl)bicyclo[2.2.2]octane-1 -yl)methyl)-3-(trifluoromethyl)cyclobutane-1carboxamide (46);

T\G-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M(3 -(3-ethyl-1 ,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (47);

M-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M(3-(3-ethyl-1,2 ,4-oxadiazol-5-yl)phenyl)cyclobutanecarboxamide (48);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-M-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)cyclobutan-1carboxamide (49);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2. 2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (50);

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M-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M(3-(2-ethoxyoxazol-5-yl) )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (51);

3-fluoro-L-(3-(2-propyloxazol-5-yl)phenyl)-L-((4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1 -yl)methyl )bicyclo[1.1.1]pentane-1-carboxamide (52);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicycle [2.2.2]octan-1-yl)methyl)-L(3 -(5-ethoxy-1,3 ,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (53);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(5-ethoxy-1,3 ,4-oxadiazol-2-yl)phenyl)cyclobutanecarboxamide (54);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-ethoxy-1,3 ,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (55);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(difluoromethyl)-M-(3 -(5 -ethoxy-1,3,4-oxadiazol-2-yl)phenyl)cyclobutane-1-carboxamide (56);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropylisoxazol-3 -yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (57);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropylisoxazol-3 -yl )phenyl)-3-(difluoromethyl)cyclobutane-1 carboxamide (58);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropylisoxazol-3 -yl )phenyl)-3,3-difluorocyclopentane-1-carboxamide (59);

I-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(5-cyclopropylisoxazol-3-yl) )phenyl)-3,3-difluorocyclobutane-1-carboxamide (60);

T\G-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(3 - (cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (61);

T\G-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(3 - (cyclopropylmethyl)-1,2,4-oxad iazol-5-yl)phenyl)-3,3 difluorocyclopentane-1-carboxamide (62);

- 11 047337

T4-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(3 -(cyclopropylmethyl )-1,2,4-oxad iazol-5-yl)phenyl)-3,3 difluorocyclobutane-1-carboxamide (63);

T4-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(3 -(cyclopropylmethyl )-1,2,4-oxadiazol-5-yl)phenyl)cyclobutanecarboxamide (64);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3 -(cyclopropylmethyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (65);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(3-(cyclopropylmethyl)-1 ,2,4-oxadiazol-5-yl)phenyl)cyclobutanecarboxamide (66);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3 -(cyclopropylmethyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclopentane-1 carboxamide (67);

N-(3 -(3-cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-M-((4-(3 (cyclopropylmethyl)-1,2,4-oxadiazol-5-yl) bicyclo[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamide (68);

N-(3 -(3 -cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-M-((4-(3 (cyclopropylmethyl)-1,2,4-oxadiazol-5 -yl) bicyclic o[2.2.2]octan-1-yl)methyl)-3,3 difluorocyclopentane-1-carboxamide (69);

N-(3 -(3 -cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-M-((4-(3 (cyclopropylmethyl)-1,2,4-oxadiazol-5 -yl) bicyclic o[2.2.2]octan-1-yl)methyl)-3,3 difluorocyclobutane-1-carboxamide (70);

N-(3 -(3-cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-M-((4-(3 (cyclopropylmethyl)-1,2,4-oxadiazol-5-yl) bicyclo[2.2.2]octan-1-yl)methyl)cyclobutanecarboxamide (71);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(2-( methoxymethyl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (72);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 (methyl difluoro)-M-(3 -( 2-(methoxymethyl)thiazol-4-yl)phenyl)cyclobutan-1-carboxamide (73);

- 12 047337

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -d πφτορ-Ν-(3 -(2-(methoxymethyl)thiazol-4-yl)phenyl)ring opentan-1-carboxamide (74);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1 -methyl-1H-pyrazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (75);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1 -methyl-1H-pyrazol-3-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (76);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1 -methyl-1H-pyrazol-3-yl)phenyl)-3,3-difluorocyclopentane-1 carboxamide (77);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1 -methyl-1H-pyrazol-3-yl)phenyl)-3-(difluoromethyl)cyclobutane-1 carboxamide (78);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(4 -(2-methoxypropan-2-yl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (79);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-ethyl-2 -oxo-2,3-dihydrooxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (80);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-ethyl-2 -oxo-2,3-dihydrooxazol-5-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (81);

M-((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2cyclopropyloxazol-5-yl)phenyl)-3-fluorobicyclo[1.1 .1]pentane-1-carboxamide (82);

M-((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2cyclopropyloxazol-5-yl)phenyl)-3,3-difluorocyclobutane -1-carboxamide (83);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -d πφτορ-Ν-(3 -(4-(methoxymethyl)oxazol-2-yl)phenyl)ring butan-1-carboxamide (84);

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A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(4-(methoxymethyl )oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (85);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (86);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (87);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4 (3 -(3 - cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (88);

N-(3-(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(3 -isopropyl1,2,4-oxadiazol-5-yl) bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (89);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(3 (tetrahydro-2H-pyran-4-yl)-1 ,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (90);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)pyrrolidine-1-carboxamide (91);

1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1(3-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-neopentylurea (92);

(8)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(3 - cyclopropyl-1,2,4-oxad iazol-5-yl)phenyl)-3-(d imethylamino)pyrrolidine-1-carboxamide (93);

1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1(3 -(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-(1-methylcyclopropyl)urea (94);

1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1(3-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-ethylurea (95);

1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1(3-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-(4-methoxyphenyl)urea (96);

- 14 047337 and (3-(2-cyclopropyloxazol-5-yl)phenyl)A-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3- fluorobicyclo[1.1.1]pentane-1-carboxamide (97);

M-(3-(2-cyclopropyloxazol-4-yl)phenyl)-M-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,3 -difluorocyclobutane-1-carboxamide (98);

M-(3-(2-cyclopropyloxazol-4-yl)phenyl)-M-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,3 -difluorocyclopentane-1-carboxamide (99);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(4cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1 -yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (100);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(4cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1 -yl) methyl)-3,3-difluorocyclobutane-1 carboxamide (101);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(5- (3-fluorobicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (102);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -(3, 3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (103);

N-(3 -(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (104);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -(difluoromethyl) -1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (105);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(5- (1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (106);

N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl) bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (107);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(5- (trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (108);

- 15 047337

A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(5-isopropyl- 1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (109);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(5-( 1 -hydroxycyclopropyl)-1,2,4-oxadiazol-3 -yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (PO);

N-(3 -(5-(1-acetamidocyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(3 cyclopropyl-1,2,4-oxadiazol-5-yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (111);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -(1,1 - difluoroethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (112);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-T4-(3-(5-( 3-methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (113);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(3 fluorobicyclo[1.1.1]pentane-1 - yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (114);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(1methylcyclopropyl)-1,2,4-oxadiazol- 3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (115);

M-((4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (116);

M-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-(difluoromethyl)1,2,4-oxadiazol-3-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (117);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(1(trifluoromethyl)cyclopropyl)-1,2, 4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (118);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(3-cyclopropyl -1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (119);

- 16 047337

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 -isopropyl1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1 carboxamide (120);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-U ((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-1carboxamide (121);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(3 methyloxetan-3-yl)-1,2 ,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (122);

T4-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-(2,2difluorocyclopropyl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide (123);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-cyclopropyl-1 methyl-1 H-pyrazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (124);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-cyclopropyl-1 methyl-1 H-pyrazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3,3-difluorocyclobutane-1 carboxamide (125);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(3-cyclopropyl-1 methyl-1 H-pyrazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (126);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(3-cyclopropyl-1 methyl-1 H-pyrazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3,3-difluorocyclobutane-1 carboxamide (127);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((1 -(4methoxyphenyl)-2-oxabicyclo[2.2.2]octane-4 -yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (128);

N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-M-(( 1 -(4methoxyphenyl)-2-oxabicyclo[2.2.2]octane -4-yl)methyl)cyclobutan-1-carboxamide (129);

H-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-cyclopropyl-1 -methyl - 1H-imidazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (130);

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X((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-cyclopropyl-1 -methyl- 1H-imidazol-4-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (131);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -cyclopropyl-4-methyl -4H-1,2,4-triazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (132);

M-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1 carboxamide (133);

M-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3-(difluoromethyl)cyclobutan-1 carboxamide (134);

M-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (135);

M-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-cyclopropyl-1,3 ,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (136);

N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-cyclopropyl-1,3,4 oxadiazol-2-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (137);

N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-cyclopropyl-1,3,4 oxadiazol-2-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3,3-difluorocyclobutane-1 carboxamide (138);

N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-M-((4-(5-cyclopropyl-1,3,4 oxadiazol-2-yl)bicyclo[ 2.2.2] octan-1 -yl)methyl)-3 -(d fluoromethyl)cyclobutan-1 carboxamide (139);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((1 -(2methoxypyrimidin-5-yl)-2-oxabicyclo[2.2.2 ]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (140);

N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(3 -cyclopropyl-1,2,4-oxadiazole -5-yl)phenyl)-3-(difluoromethyl)cyclobutane-1 carboxamide (141);

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N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(3 -cyclopropyl-1,2,4-oxadiazole -5-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (142);

N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(3 -cyclopropyl-1,2,4-oxadiazole -5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (143);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(5 -cyclopropyl-1,3,4-oxadiazole -2-yl)phenyl)-3-(difluoromethyl)cyclobutane-1 carboxamide (144);

N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(3 -cyclopropyl-1,2,4-oxadiazole -5-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (145);

N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(3 -cyclopropyl-1,2,4-oxadiazole -5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (146);

Т4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(5-( 1-methoxycyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (147);

N-(3 -(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3 -φτορ-Ν-((4-(2methoxypyrimidin-4-yl)bicyclo[2.2.2]octane- 1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (148);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl-3φτορ-Ν-(3 -(1 -(oxetan- 3 -yl)-1H-pyrazol-3 -yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (149);

Т4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(1 -( oxetan-3 -yl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (150);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(4-methylthiazole -2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (151);

Т4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(1 -( pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (152);

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T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(5 -cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (153);

N-(3 -(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(1methylcyclopropyl)-1,2,4-oxadiazol- 3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (154);

N-(3 -(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3 -φτορ-Ν-((4-(5 -(3 methyloxetan-3-yl)-1,2 ,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (155);

M-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-M-((4-(5-(difluoromethyl)1,2,4-oxadiazol-3-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (156);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(5 -cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (157);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(1 -(cyclopropyl sulfonyl )-1 H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (158);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(1- (methylsulfonyl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (159);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(1 -(difluoromethyl) - 1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (160);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(1 -(2, 2-difluoroethyl)-1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (161);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(1 - (2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (162);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(5 -isopropyl-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (163);

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N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(3-(5-(difluoromethyl) -1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (164);

N-(3 -(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-M-((4-(3-cyclopropyl-1 methyl-1 H-pyrazol-5 - yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (165);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(5 -(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (166);

N-(3 -(5-(tert-butyl)-1,2,4-oxadiazol-3 -yl)phenyl)-M-((4-(5-cyclopropyl-1 methyl-1 H-pyrazol-3 - yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (167);

N-((4-(5 -cycloiropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(3 -(5-(difluoromethyl) -1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (168);

N-((4-(5 -cycloiropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(5 -isopropyl-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (169);

N-(3 -(5-cyclopropyl-1,2,4-oxadiazol-3 -yl)phenyl)-M-((4-(5-cyclopropyl-1 methyl-1 H-pyrazol-3 -yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (170);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(5-cyclopropyl -1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (171);

N-(3 -(5-cycloiropyl-1,2,4-oxadiazol-3-yl)phenyl)-M-((4-(3 -(difluoromethyl)1,2,4-oxadiazol-5-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (172);

Т4-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3 -φτορ-Ν-(3 -(5 -(3-methyl oxetan-3 -yl)-1,2,4-oxadiazol-3 -yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (173);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 5-(3-methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (174);

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3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(5- (1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (175);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -( 5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (176);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -( 5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (177);

Т4-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)3 -φτορ-Ν-(3 -(5 -(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (178);

M-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-M- (3-(5-(1 -methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (179);

-φτορ-Ν-(3 -(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5 (3-methyloxetan-3-yl)- 1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (180);

N-(3 -(5-(tert-butyl)-1,2,4-oxadiazol-3 -yl)phenyl)-3 -φτορ-Ν-((1-(2(trifluoromethyl)pyrimidin-5-yl) -2-oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (181);

Ν-(3 -(5-(difluoromethyl)-1,2,4-oxadiazol-3 -yl)phenyl)-3 -φτορ-Ν-((1-(2(trifluoromethyl)pyrimidin-5-yl)-2 -oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (182);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(5 -( tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (183);

T4-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -(difluoromethyl) -1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (184);

N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3 -φτορ-Ν-((4-(5 (trifluoromethyl)pyridin-2-yl)bicyclo[2.2. 2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (185);

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-φτορ-Ν-(3 -(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5 (trifluoromethyl)pyridin-2-yl) bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (186);

3-fluoro-M-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-M-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2. 2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (187);

M-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-M-((4-(5(trifluoromethyl)pyridin-2-yl) bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (188);

N-(3 -(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3 -φτορ-Ν-((4-(5 (trifluoromethyl)pyridin-2-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1. 1]pentane-1carboxamide (189);

M-(3-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-M-((4-(5(trifluoromethyl)pyridin-2- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (190);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(3-cyclopropyl -1,2,4-oxadiazol-5-yl)phenyl)-3-methyloxetane-3-carboxamide (191);

(18.38)-T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N- (3 -(3 -cyclopropyl-1,2,4-oxad iazol-5 -yl)phenyl)-3-methoxycyclobutane-1 carboxamide (192);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(3-cyclopropyl -1,2,4-oxadiazol-5-yl)phenyl)-1 -(2,2,2-trifluoroacetyl)azetidine-3 carboxamide (193);

^-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3-( Ι -(methylsulfonyl)-!H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (194);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(1-( cyclopropylsulfonyl)-1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (195);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )-N-(3 -(3-cyclopropyl -1,2,4-oxad iazol-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (196);

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M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )-N-(3 -(3-cyclopropyl -1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (197);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )-N-(3 -(3-cyclopropyl -1,2,4-oxad iazol-5 -yl)phenyl)-3 -(difluoromethyl)cyclobutane-1-carboxamide (198);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M-(3-(5-cyclopropylisoxazole -3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (199);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(5-cyclopropylisoxazole -3-yl)phenyl)-3,3-difluorocyclobutane-1 carboxamide (200);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(5-cyclopropylisoxazole -3-yl)phenyl)-3-(diforomethyl)cyclobutane-1 carboxamide (201);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(5-cyclopropylisoxazole -3-yl)phenyl)-3,3-difluorocyclopentane-1 carboxamide (202);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M-(3-(5-cyclopropylisoxazole -3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (203);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )-N-(3-(5-( difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (204);

N-(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-M-((4-(3 cyclopropyl-1-methyl-1H-pyrazol-5- yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide (205);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M (5-(3- cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (206);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M (5-(3- cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (207);

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L-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-M-(3 - (1 -(cyclopropylsulfonyl)-1 H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (208);

N-(3-(l H-pyrazol-4-yl)phenyl)-3-fluoro-M-((4-(5-(1-(trifluoromethyl)cyclopropyl) 1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1 -yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (209);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (210);

M-(4-(1H-pyrazol-4-yl)pyridin-2-yl)-M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (211);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-( 1 -(difluoromethyl)-1 H-pyrazol-4-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (212);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(3 -(tert-butyl)-1 -methyl-1 H-pyrazol-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (213);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3 -(5 -(tert-butyl)-1 -methyl-1H-pyrazol-3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (214);

N-(l-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)M-(3-(2-cyclopropyloxazol-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (215-216);

X-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)N-(3 -(3-cyclopropyl-1 ,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (217-218);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(4-cyclopropyl-1H -1,2,3-triazol-1-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (219);

3,3-Difluoro-M-(3'-methoxy-[1,1'-biphenyl]-3-yl)-M-((4-(3-methyl-1,2,4-oxadiazol5-yl)bicyclo [2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide (220);

3-fluoro-M-(3'-methoxy-[1,1'-biphenyl]-3-yl)-L-((4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (221);

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N-((l-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3φτορ-Ν-(3-(2-methoxypyridin- 4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (222);

M-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M (3-(2-methoxypyridin-4-yl) )phenyl)cyclobutanecarboxamide (223);

M-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M (3 -(2-methoxypyridin-4-yl )phenyl)cyclopentanecarboxamide (224);

18G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)18G-(3-(4-ethoxypyridin-2-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (225);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)18G-(3-(2-ethoxypyridin-4-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (226);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(3-(tetrahydro-2H-pyran-4yl)-1,2,4-oxadiazol-5- yl)bicyclo[2.2.2]octan-1 -yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (227);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(3-methyl-1,2,4-oxadiazol-5·yl)bicyclo[2.2.2] octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (228);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3-(2-methoxypyridine -4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (229);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(5-methyl-1,3,4-oxadiazol-2·yl)bicyclo[2.2.2] octan-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (230);

N-(3 -(2-methoxyl irid in-4-yl)phenyl)-N-((4-(5 - methyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)cyclobutanecarboxamide (231);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(5-methyl-1,3,4-thiadiazol-2yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (232);

N-(3 -(2-methoxyl yrid in-4-yl)phenyl)-N-((4-(5 - methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)cyclopentanecarboxamide (233);

3,3-difluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(5-methyl-1,3,4thiadiazol-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)cyclobutan-1-carboxamide (234);

3,3-difluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(5-methyl-1,3,4thiadiazol-2-yl)bicyclo[2.2.2] octan-1 -yl)methyl)cyclopentane-1-carboxamide (235);

(18.38)-3-hydroxy-T\G-(3-(2-methoxypyridin-4-yl)phenyl)-T\G-((4-(5-methyl-1,3,4thiadiazol-2- yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(trifluoromethyl)cyclobutan-1 carboxamide (236);

- 26 047337

3,3-difluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1-yl) methyl)cyclobutane-1-carboxamide (237);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1 -yl)methyl) bicyclo[1.1.1]pentane-1-carboxamide (238);

3-fluoro-T4-(3-(2-methoxypyridin-4-yl)phenyl)-T4-((4-(6-methylpyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl) bicyclo[1.1.1]pentane-1-carboxamide (239);

T4-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutanecarboxamide (240);

3-fluoro-M-(3-(2-methoxypyridin-4-yl)phenyl)-M-((4-(4-(trifluoromethyl)pyridin2-yl)bicyclo[2.2.2]octan-1 -yl)methyl )bicyclo[1.1.1]pentane-1-carboxamide (241);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(2-methoxypyrimidine -4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (242);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -dπφτορ-Ν-(3 -(2 -methoxypyrimidin-4-yl)phenyl)cyclobutan-1-carboxamide (243);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-methoxypyrimidin-4-yl )phenyl)cyclobutanecarboxamide (244);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3-dπφτορ-N-(3-(2 -methoxypyrimidin-4-yl)phenyl)cyclopentane-1-carboxamide (245);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(4'-(methylsulfonamido) -[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (246);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3 -(6-fluoro -5-methylpyridin-3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (247);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(2-methoxypyrimidine -5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (248);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(6-methoxypyridine -3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (249);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)T4-(3',5'-dichloro-[1 ,G-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (250);

- 27 047337

A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'-(trifluoromethoxy)-[ 1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (251);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 '-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (252);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'-(trifluoromethyl)- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (253);

M-(3'-acetamido[1,G-biphenyl]-3-yl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (254);

N-(3 -(benzo[c1] [1,3] dioxol-5-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol5 -yl)bicyclo[2.2.2 ]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (255);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 '-(methylsulfonamido)- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (256);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3'-sulfamoyl-[1 ,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (257);

Ν-(3'-cyano-[1,1'-biphenyl]-3-ηπ)-Ν-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2 ]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (258);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-T4-(3'-(trifluoromethoxy)- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (259);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'-fluoro-3' -methoxy-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (260);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(2-oxo- 2,3-dihydrobenzo|Hoxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (261);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-(trifluoromethyl )pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (262);

- 28 047337 and ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(8- (trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (263);

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) 3 -φτορ-N-(3 -(8- methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (264);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2,8-dimethyl -[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (265);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(8- methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (266);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'-(( trifluoromethyl)sulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane1-carboxamide (267);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(4'-(( 1 -methylethyl)sulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (268);

T\G-(4'-(cyclopropanesulfonamido)-[1,G-biphenyl]-3-yl)-M-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (269);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(6- (methyl sulfonamide o)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (270);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-cyclopropylpyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (271);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(2-(methyl sulfonamide o)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (272);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'-(methoxymethyl )-[1,G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (273);

- 29 047337

N-((4-(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 φτορ-Ν-(3 -(6-( methoxymethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (274);

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(2-methylbenzo [c!]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (275);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-cyclopropylthiazolo[4,5 -b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide (276);

M-(3-(benzo[c1]thiazol-6-yl)phenyl)-H-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane- 1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (277);

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(2-methylthiazolo [4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (278);

N-(4'-(1-cyanocyclopropyl)-[1,1'-biphenyl]-3-ππ)-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2 .2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (279);

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-N-(3 -(b-( trifluoromethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (280);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3-(6-ethoxypyridin-3-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (281);

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 fluoro-M-(4'-methoxy-[ 1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (282);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(6-ethoxypyridazin-3 -yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (283);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2,2-difluorobenzo[< 1][1,3]dioxol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (284);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)T4-(4'-ethyl-[1,G- biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (285);

- 30 047337

A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3',4'-dichloro-[ 1, 1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (286);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-T4-(3-(5-fluoropyridine -2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (287);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(azo[imide 1,2-a]pyride in-7-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (288);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-ethoxypyrimidin-5-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (289);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(4'-3tokch-[1,1' -biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (290);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(4-( trifluoromethyl)pyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (291);

M-(3-(6-cyanopyridin-2-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (292);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3 -φτορ-Ν-(3 -(3-fluoro -6-(trifluoromethyl)pyridin-2-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (293);

N-(3'-cyano-4'-fluoro-[1,1'-biphenyl]-3-yl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (294);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-N-(3-(6-methylpyridazine -3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (295);

A(3'-cyano-4'-methoxy-[1,G-biphenyl]-3-yl)A-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (296);

M-(3-(5-cyanopyridin-2-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (297);

N-(3 -([ 1,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (298);

- 31 047337

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 '-(1 ,1,2,2-tetrafluoroethoxy)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (299);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(4- methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (300);

PM-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3',4'-dimethoxy-[ 1 , G-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (301);

T\G-(4'-cyano-[1,1'-biphenyl]-3-yl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2 .2]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (302);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-1H-(3-(2- methylbenzo[c1]thiazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (303);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(1 - methyl-1 H-ind azol-5 -yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (304);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2- methylbenzo[c!]oxazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (305);

N-(3 -(3-cyanoimidazo[1,2-b]pyridazin-6-yl)phenyl)-N-((4-(3-cyclopropyl-1,2,4 oxadiazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (306);

N-(3 -([ 1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-M-((4-(3 -cyclopropyl-1,2,4oxadiazol-5-yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (307);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(4'-(λ iforomethoxy)- [1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (308);

M-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (309);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(5-methylpyrazin- 2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (310);

- 32 047337

M-(3-(8-cyanoquinolin-5-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (311);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(7,8-dimethyl-[ 1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (312);

M-(3-(5-cyano-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)-M-((4-(3cyclopropyl-1,2,4-oxadiazol- 5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (313);

N-(3 -(7-cyanoimidazo[1,2-b]pyridazin-3-yl)phenyl)-N-((4-(3-cyclopropyl-1,2,4 oxadiazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (314);

N-(3 -(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol- 5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (315);

M-(3-(6-cyanothieno[3,2-b]pyridin-5-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (316);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(8-fluorimidazo[ 1,2-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (317);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(imidazo[ 1, 2-b]pyridazin-3 -yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (318);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(7-methylimidazo[ 1,2-b]pyridazin-3-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (319);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2,7-dimethylimidazo[ 1 ,2-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (320);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-methyl- 8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (321);

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H-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2,8-dimethylimidazo[ 1 ,2-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (322);

N-(3 -([ 1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)-M-((4-(3-cycloiropil-1,2,4oxadiazol-5-yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (323);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -(2-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (324);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(5-methylpyridin- 2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (325);

T4-(3-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl)-T4-((4-(3-cyclopropyl1,2,4-oxadiazole -5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (326);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-T4-(3-(7-methylthiazolo[ 5,4-b]pyridin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (327);

M-(3-(3-cyano-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)phenyl)-M-((4-(3cyclopropyl-1,2,4- oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (328);

N-(3 -(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl)-M-((4-(3-cycloyropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (329);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(azo[1 imide ,2-a]pyride in-8-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (330);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-hydroxyquinoline- 6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (331);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3-(2-oxoindolin- 5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (332);

X-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5-ethoxypyrimidin-2-yl )phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (333);

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T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-ylmethyl)-3fluoro-M-(3-(5-methoxypyrimidin-2- yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (334);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(5 -(difluoromethoxy)pyrimidin- 2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (335);

T4-(3-(2-acetamidoimidazo[1,2-b]pyrid az in-6-yl)phenyl)-M-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (336);

N-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl )methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (337);

N-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-M-((4-(3-cyclopropyl-1,2,4oxadiazol-5 -yl)bicyclo[2.2.2]octan-1 -yl )methyl)-3,3-difluorocyclobutane-1 carboxamide (338);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-M-(3- (2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide (339);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(2'-methoxy-[ 4,4'-bipyridin]-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (340);

T4-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-N-(3-(2-methoxypyrimidine -5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (341);

T4-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 φτορ-Ν-(3-(2-methoxypyridine -4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (342);

T4-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(3-(6-methoxypyridine -3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (343);

T4-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(4'-(methylsulfonamido) -[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (344);

N-((l-(4-(1-Cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)3-fluoro-M-(4'-(methylsulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentan-1carboxamide (345);

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N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 fluoro-M-(3-(2-methylbenzo[s!] thiazol-6-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (346);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 fluoro-M-(3-(2-methylbenzo[<1] oxazol-6-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (347);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 φτορ-Ν-(3-(2-methoxypyridin-4-yl )phenyl)bicyclo[1.1.1]pentane-1-carboxamide (348);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 φτορ-Ν- (4'-methoxy-[1,1' -biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (349);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 fluoro-M-(3-(6-methoxypyridin-3-yl )phenyl)bicyclo[1.1.1]pentane-1-carboxamide (350);

N-((l-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3 fluoro-M-(3-(2-methoxypyrimidin-5-yl )phenyl)bicyclo[1.1.1]pentane-1-carboxamide (351);

N-((l-(4-(1 -cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)N-(3 -(2-ethoxypyrimidin-5-yl)phenyl)- 3-fluorobicyclo[1.1.1]pentane-1-carboxamide (352);

T4-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )-N-(3-(2-ethoxypyrimidine -5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (353);

M-(4'-(cyclopropanesulfonamido)-[1,G-biphenyl]-3-yl)-3-fluoro-M-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (354);

3-fluoro-M-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)-M-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (355);

3-fluoro-T4-(3-(2-methylbenzo[c1]thiazol-6-yl)phenyl)-T4-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (356);

T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2 -ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (357);

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T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2 -cyclopropylpyrimide in-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (358);

T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4'-ethoxy -[1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (359);

T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(6 -ethoxypyridin-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (360);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'- (methylsulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (361);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-methylbenzo[c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (362);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (363);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -( 6-(methyl sulfonamide o)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide (364);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-methylthiazolo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (365);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (366);

^-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -( 2-(methyl sulfonamide o)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (367);

T\G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4'-( difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (368);

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1H-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 5-methoxypyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (369);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(5-ethoxypyrimidine -2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (370);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(5-( difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (371);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'- ((trifluoromethyl)sulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane1-carboxamide (372);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(5-( difluoromethoxy)pyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (373);

M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (374);

M-(4'-ethoxy-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5·yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (375);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(4'-(methylsulfonamido )-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (376);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(4'-methoxy- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (377);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(2- methylbenzo[c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (378);

M-(4'-(cyclopropanesulfonamido)-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(3isopropyl-1,2,4-oxadiazol-5-yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (379);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4-(4'-(trifluoromethyl )-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (380);

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T4-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5 -yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (381);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3-(6- methoxypyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (382);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2- methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (383);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2- (trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (384);

M-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (385);

N-(3 -(2,2-d iforobenzo[d][1,3]dioxol-5-yl)phenyl)-3-φτορ-Ν-((4-(3-isopropyl1,2,4-oxadiazol- 5-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (386);

M-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (387);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(b- (trifluoromethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (388);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2- methylthiazolo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (389);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4-(4'-(( trifluoromethyl)sulfonamido)-[1,G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (390);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(b- (methoxymethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (391);

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3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4-(4'-(methoxymethyl )-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (392);

3-fluoro-M-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(5- methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (393);

T4-(3-(5-ethylpyrimidin-2-yl)phenyl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5 -yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (394);

T4-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluoro-M-((4-(3-isopropyl-1,2,4oxadiazol-5 -yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (395);

M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(1-methylcyclopropyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (396);

M-(4'-(cyclopropanesulfonamido)-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (397);

3-φτορ-Ν-((4-(5-(1 -methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(4 '-(methylsulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (398);

M-(4'-ethoxy-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(5-(1-methylcyclopropyl)-1,2,4oxadiazol-3-yl )bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (399);

3-fluoro-M-(3-(2-methoxypyrimidin-5-yl)phenyl)-M-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (400);

T4-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-M-((4-(5-(1-methylcyclopropyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide (401);

-φτορ-Ν-(3 -(2-methylbe iso[c!]thiazol-6-yl)phe ηππ)-Ν-((4-(5 -(1methylcyclopropyl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (402);

- 40 047337

L-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-L-((4-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (403);

3-φτορ-Ν-((4-(5-(Ι -methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3 -(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (404);

L-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-fluoro-L-((4-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (405);

N-((4-(5-cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(4'-( methylsulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (406);

N-((4-(5 -cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(3-(2-ethoxypyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (407);

N-((4-(5-cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(4'-methoxy -[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (408);

N-((4-(5-cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(2 -methylbenzo[c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (409);

N-((4-(5-cyclopropyl-1-methyl-1 H-pyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2-cyclopropylthiazolo[4 ,5-b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (410);

N-((4-(5-cyclopropyl-1 -methyl-1 H-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(2 -oxo-2,3-dihydrobenzo[c1]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (411);

N-((4-(3-cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(4'-( methylsulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (412);

N-((4-(3-cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(3-(2-ethoxypyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (413);

- 41 047337

N-((4-(3-cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-T4-(4'-methoxy -[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (414);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3-(2 -methylbenzo[c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (415);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3· φτορ-Ν-(3-( 4-methylpiperazin-1 -yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (416);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3· φτορ-Ν-(3-morpholinophenyl )bicyclo[1.1.1]pentane-1-carboxamide (417);

T\G-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2] octan-4-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (418);

3-fluoro-H-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)-H-((1-(2(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2 .2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (419);

3-fluoro-M-(4'-methoxy-[1,G-biphenyl]-3-yl)-M-((1-(2-(trifluoromethyl)pyrimidin5-yl)-2-oxabicyclo[2.2.2] octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (420);

3-fluoro-T4-(3-(2-methylbenzo[c1]thiazol-6-yl)phenyl)-T4-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2. 2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (421);

T\G-(4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluoro-M-((1-(2-(trifluoromethyl)pyrimidin-5yl)-2-oxabicyclo[2.2. 2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (422);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)T\G-(5-(2-ethoxypyrimidine -5-yl)pyr idin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (423);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)T\G-(5-(4-ethoxyphenyl)pyridine -3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (424);

T\G-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 fluoro-M-(5-( 2-methylbenzo[c1]thiazol-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1carboxamide (425);

- 42 047337 ^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(6'-ethoxy-[3 ,3'-bipyridin]-5-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (426);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-D-(5-(2-(trifluoromethyl )pyrimidin-5-yl)pyridin-3-yl)bicyclo[1.1.1]pentan-1carboxamide (427);

^-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-D-(5-(2-(trifluoromethyl )pyrimidin-5-yl)pyridin-3-yl)bicyclo[1.1.1]pentan-1carboxamide (428);

M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-isopropyl-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (429);

3-fluoro-M-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4-(4'-(methylsulfonamido )-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (430);

M-(4'-ethoxy-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(5-isopropyl-1,2,4-oxadiazol-3·yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (431);

M-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-M-((4-(5-isopropyl-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (432);

3-fluoro-M-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(2- methylbenzo[c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (433);

T4-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-isopropyl-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (434);

3-fluoro-M-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3-(2- (trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (435);

M-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-fluoro-M-((4-(5-isopropyl-1,2,4oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (436);

D-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(3-(2-ethoxypyrimidine -5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (437);

- 43 047337

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'- (methylsulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (438);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4'-ethoxy-[ 1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (439);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(6-ethoxypyridine -3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (440);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-methylbenzo[c!]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (441);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2-cyclopropylpyr imide in-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (442);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (443);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4'-(difluoromethoxy) -[1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (444);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-T4-(4'- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (445);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4'- ((trifluoromethyl)sulfonamido)-[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane1-carboxamide (446);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(3 -( 2-oxo-2,3-dihydrobenzo[(1]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide (447);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3φτορ-Ν-(4'- ((1-methylethyl)sulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1 carboxamide (448);

- 44 047337

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 2-methylthiazolo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (449);

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-H-(3-( 5-methoxypyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (450);

A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-A (3-(5-ethoxypyrimidin- 2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (451);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(3-(5-( difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (452);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(3-(5-ethylpyrimidine -2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (453);

C-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-( 5-methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (454);

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H(3-(5-( difluoromethoxy)pyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (455);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(4'-ethyl-[ 1, G-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (456);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(3 -(2,2 -difluorobenzo[<1][1,3]dioxol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (457);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(4'-ethyl-[ 1, G-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (458);

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H(3 -(2,2 -difluorobenzo[<1][1,3]dioxol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide (457);

T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(3-(2-cyclopropylthiazolo [4,5-b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (458);

- 45 047337

M-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-ethoxypyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (459);

M-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)3-fluoro-M-(4'-( methylsulfonamido)-[1,G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1carboxamide (460);

M-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(4'-3tokch-[ 1, 1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (460);

M-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)3 -φτορ-Ν-(3 -(2 -methylbenzo[<1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (462);

T4-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-M-((4-(5-(difluoromethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (463);

M-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)3-fluoro-M-(3-(2 -(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (464);

N-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-M-((4-(5-(difluoromethyl)-1,2,4 oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (465);

T4-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-M-((4-(3-(difluoromethyl)-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (466); T\G-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-M-(3 -(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (467);

M-(4'-(d fluoromethoxy)-[1,1'-biphenyl]-3-yl)-M-((4-(3 -(difluoromethyl)-1,2,4oxadiazol-5-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (468);

PM-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3-fluoro-M-(4'-( methylsulfonamido)-[1,G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1carboxamide (469);

- 46 047337

A((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)N-(3 -(2-ethoxypyrimidin-5- yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (470);

M-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3 -φτορ-Ν-(3 -(2 -methylbenzo[<1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (471);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(2-ethoxypyrimidine -5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (472);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(2-cyclopropylpyrimidine -5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (473);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(5-( 2-methylbenzo[c!]thiazol-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1carboxamide (474);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(5-( 4-(methylsulfonamido)phenyl)pyride in-3-yl)bicyclo[1.1.1]pentane-1carboxamide (475);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(4-ethoxyphenyl) )pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (476);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(6'-ethoxy-[ 3,3'-bipyridin]-5-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (477);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(2-ethoxypyrimidine -5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (478);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-F*G-(5 -(2-oxo-2,3-dihydrobenzo[c1]oxazol-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (479);

Y1-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(2-cyclopropylthiazolo [4,5-b]pyridin-6-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (480); T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo [2.2.2]octan-1-yl)methyl)-3-fluoro-H -(5-(4-(methylsulfonamido)phenyl)pyridin-3-yl)bicyclo[1.1.1]pentan-1-carboxamide (481);

- 47 047337 ^((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H (5-(4 -ethoxyphenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (482);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M (5-( 4-(difluoromethoxy)phenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (483);

14-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(5-( 2-methylbenzo[c!]thiazol-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1carboxamide (484);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M (5-( 5-(difluoromethoxy)pyrimidin-2-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (485);

^((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H (5-(difluoromethoxy)-[ 2,3'-bipyridin]-5'-yl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (486);

T\G-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (487);

3-fluoro-M-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)-M-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)bicyclo[1.1.1]pentan-1·carboxamide (488);

M-(4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (489);

M-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl )methyl)bicyclo[1.1.1]pentane-1-carboxamide (490);

3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(3-(2-(trifluoromethyl)pyrimidin-5 -yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (491);

M-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl )bicyclo[1.1.1]pentane-1-carboxamide (492);

T4-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-fluoro-T4-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2. 2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (493);

- 48 047337

3-fluoro-M-(3-(2-methoxypyrimidin-5-yl)phenyl)-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl )methyl)bicyclo[1.1.1]pentane-1-carboxamide (494);

18G-(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2 octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (495);

M-(3-(5-ethylpyrimidin-2-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1 -yl) methyl)bicyclo[1.1.1]pentane-1-carboxamide (496);

T4-(4'-ethyl-[1,G-biphenyl]-3-yl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (497);

T\G-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (498);

N-(3 -(5 -(difluoromethoxy)pyrimidin-2-yl)phenyl)-3 -φτορ-Ν-((4-(5 (trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane- 1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide (499);

3-fluoro-M-(3-(5-methoxypyrimidin-2-yl)phenyl)-M-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl )methyl)bicyclo[1.1.1]pentane-1-carboxamide (500);

18G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2-ethoxypyrimidine -5-yl)phenyl)-3-hydroxycyclobutane-1-carboxamide (501);

(18,38)-18G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M- (3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxycyclobutane-1-carboxamide (502);

18G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2-ethoxypyrimidine -5-yl)phenyl)-3-methyloxetane-3-carboxamide (503);

(18,38)-18G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M- (3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methylcyclobutane-1carboxamide (504);

tert-butyl (3-(((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)(3-(2- ethoxypyrimidin-5-yl)phenyl)carbamoyl)bicyclo[1.1.1]pentan-1-yl)carbamate (505);

- 49 047337

3-ημηηο-Ν-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(3 -(2-ethoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (506);

(18,38)-18G-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M- (3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (507);

(cis)-M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methylcyclobutane-1carboxamide (508);

(1S, 38)^-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)-M- (3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (509);

18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(3-(2-ethoxypyrimidine -5-yl)phenyl)-3-methyloxetane-3-carboxamide (510);

(18,38)-18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M- (3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxycyclobutane-1-carboxamide (5I);

(cis)-M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy- 3-methyl-M-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)cyclobutan-1-carboxamide (512);

(18,38)-18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3- hydroxy-M-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (513);

(18,38)-18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3- methoxy-M-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)cyclobutan-1carboxamide (514);

18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4'-(difluoromethoxy) -[1,G-biphenyl]-3-yl)-3-methyloxetane-3-carboxamide (515);

(18,38)-18G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M- (4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (516);

- 50 047337 (18.38)-T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) -M-(4'-(difluoromethoxy)-[1, G-biphenyl]-3-yl)-3-hydroxy-3-methylcyclobutane-1carboxamide (517);

(cis)-M-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxy-N-((4-(5 -(3 methyloxetan-3-yl)-1,2,4-oxadiazole -3-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide (518);

(18.38)-M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methyl-M-((4-(5-(3methyloxetan-3-yl)-1, 2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide (519);

(18,38)-M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-M-((4-(5-(3methyloxetan-3-yl)-1,2,4- oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(trifluoromethyl)cyclobutan-1-carboxamide (520);

T4-(4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluoro-18G-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole -3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (521);

M-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-fluoro-M-((4-(5-(1-(trifluoromethyl) cyclopropyl)-1,2 ,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (522);

3-fluoroA-(4'-(methylsulfonamido)-[1,G-biphenyl]-3-yl)A-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (523);

-φτορ-Ν-(3 -(2-methylbenzo[c!]thiazol-6-yl)phe ηππ)-Ν-((4-(5 -(1 -(trifluoromethyl)cyclopropyl)-1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (524);

M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl )bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (525);

M-(3-(2-cyclopropylthiazolo[4,5-b]pyridin-6-yl)phenyl)-3-fluoro-M-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2, 4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (526);

M-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(4'- 3tokch-[1,1'-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (527);

- 51 047337

T\G-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-M-(4 '-(difluoromethoxy)-[1, G-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (528);

T\G-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-N-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (529);

M-(3-(2-cyclopropylthiazolo[4,5-b]pyridin-6-yl)phenyl)-M-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (530);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(2 -ethoxypyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (531);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(4 -ethoxyphenyl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (532);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(4 -(difluoromethoxy)phenyl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (533);

^-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4-( 4-(methyl sulfonamide o)phenyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1 carboxamide (534);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(2 -cyclopropylthiazolo[4,5-b]pyridin-6-yl pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (535);

T\G-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(6-ethoxy- [3,4'-bipyridin]-2'-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (536);

^-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4-( 2-methylbenzo[c!]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1carboxamide (537);

^-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4-( 2-methoxypyrimidin-5-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1 carboxamide (538);

- 52 047337

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H(4-(2-cyclopropylpyrimidine -5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (539);

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4-( 2-oxo-2,3-dihydrobenzo[c1]oxazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (540);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(5-( difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide (541);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(4-(5-ethoxypyrimidine -2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (542);

H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-H(4-(5-ethylpyrimidine -2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (543);

M-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M(5-(difluoromethoxy)- [2,4'-bipyridin]-2'-yl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide (544);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-M-(4-(4-(d fluoromethoxy )phenyl)pyridin-2-yl)-3-fluorobicycle o[1.1.1]pentan-1 carboxamide (545);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]-octan-1 yl)methyl)-3-fluoro-M-(4-(2 -methylbenzo[c1]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (546);

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo-[2.2.2]octan-1 yl)methyl)-3-fluoro-M-(4-(4 -(methylsulfonamido)phenyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (547);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)M-(4-(2-ethoxypyrimidin-5-yl )pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (548);

M-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(4-(2-methylbenzo[ <1]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1carboxamide (549);

- 53 047337

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoroA-(4-(2-methylbenzo[c1] Oxazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1carboxamide (550);

T4-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-X-(4-( 2-methylbenzo[<1]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1. 1]pentane-1carboxamide (551);

M-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-methoxypyrimidin-2yl)bicyclo[2.2.2]octan-1 -yl)methyl)bicyclo[ 1.1.1 ]pentane-1-carboxamide (552);

M-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-M-(3- (2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (553);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3-difluoro-M-(3-(2 -methylbenzo[<1]thiazol-6-yl)phenyl)cyclobutane-1-carboxamide (554);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-methylbenzo[ c1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (555);

3-fluoro-M-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M-(3-(2methylbenzo[(1]thiazol-6-yl) phenyl)bicyclo[1.1.1]pentane-1-carboxamide (556);

3,3-difluoro-M-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-M(3 -(2-methylbenzo[<1]thiazol-6 -yl)phenyl)cyclobutane-1-carboxamide (557);

3-φτορ-Ν-((1 -(2-methoxypyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-1H-(3-(2-methylbenzo[c1]thiazole -6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (558);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(5-fluorobenzo[ <1]oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide (559);

T4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -d πφτορ-Ν-(3 -( 5-fluorobenzo[<1]oxazol-2-yl)phenyl)cyclobutan-1-carboxamide (560);

T4-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluoro-M-(3-(2-methylbenzo[ c!]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (561);

- 54 047337

1H-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3(difluoromethyl)-N-(3-(2 -methylbenzo[c1]thiazol-6-yl)phenyl)cyclobutane-1-carboxamide (562);

T\G-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)3,3 -d πφτορ-Ν-(3 -(2-methylbenzo[c1]thiazol-6-yl)phenyl)ring opentan-1-carboxamide (563);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-M-(3- (2-methylbenzo[<1]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (564);

N-((l-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl) methyl)-3,3-difluoro-M- (3-(2-methylbenzo[c1]thiazol-6-yl)phenyl)cyclobutane-1carboxamide (565);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(difluoromethyl)-M-( 3-(2-methylbenzo[c1]thiazol-6-yl)phenyl)cyclobutane-1carboxamide (566);

M-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3,3-difluoro-M-( 3-(2-methylbenzo[c1]thiazol-6-yl)phenyl)ring opentan-1carboxamide (567);

T\G-((1-(4-cyanophenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-M-(3-(2methylbenzo[(1]thiazol-6- yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (376);

M-((1-(4-(dimethylcarbamoyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3fluoro-D-(3-(2-methylbenzo[c1]thiazol-6- yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (377);

T\G-cyclopropyl-4-((3 -φτορ-Ν-(3 -(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2] octane-1-carboxamide (570);

N-(3-cyclopropylphenyl)-1H-((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 (571);

N-(3-cyclopropylphenyl)-3-fluoro-T\G-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octan-1-yl) methyl)bicyclo[1.1.1]pentane-1-carboxamide (572):

Ν-(3 -cyclopropylphenyl)-3 -φτορ-Ν-((4-(5-( 1 -fluorocyclopropyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl )bicyclo[1.1.1]pentane-1-carboxamide (573);

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N-(3-cyclopropyl-4-fluorophenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (574);

N-(3 -(azetidin-1 -yl)-4-fluorophenyl)-M-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol3 -yl)bicyclo[2.2,2 ]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide (575);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3(trifluoromethyl)cyclobutan-1-carboxamide (576);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3methylcyclobutan-1-carboxamide (577);

(cis)-H-(4'-(1-cyanocyclopropyl)-3'-fluoro-[1,G-biphenyl]-3-yl)-H-((4-(5-(1fluorocyclopropyl)-1,2 ,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy3-(trifluoromethyl)cyclobutan-1-carboxamide (578);

T\G-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(1fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (579);

M-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-M-((4-(5-(trifluoromethyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide (580);

(cis)-H-(6-fluoro-4'-isopropoxy-[1,G-biphenyl]-3-yl)-H-((4-(5-(1fluorocyclopropyl)-1,2,4-oxadiazol- 3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy3-(trifluoromethyl)cyclobutan-1-carboxamide (581);

(unc)-N-(4 '-((2-cyanopropan-2-yl)oxy)-6-fluoro-[1,G-biphenyl]-3-yl)-M-((4-(5 (2 -fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxamide (582) ;

(cis)-M-(4'-((2-cyanopropan-2-yl)xy)-[1,1'-biphenyl]-3 -yl)-M-((4-(5-( 1 fluorocyclopropyl) -1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy3-(trifluoromethyl)cyclobutan-1-carboxamide (583);

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol3 -yl)bicyclo[2.2,2]octane- 1 -yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate (584);

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3-cyano-T4-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 yl)methyl)-H-( 4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentan-1 carboxamide (585);

-(tert-butyl)-1 -(6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3 -yl)-1-((4-(5-(1fluorocyclopropyl)-1,2, 4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (586);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(4'-(2-hydroxypropan-2-yl)-2',3',4',5'-tetrahydro-[1,Hbiphenyl]-3-yl)-3-(trifluoromethyl)cyclobutan- 1-carboxamide (587);

(cis)-M-(3-(3,6-dihydro-2H-pyran-4-yl)phenyl)-M-((4-(5-(2-fluoropropan-2-yl)1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (588);

N-((4-(5-(l, 1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-M- (3-(4-hydroxypiperidin-1-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide (589);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(3-(6-(2-hydroxypropan-2-yl)spiro[3.3]hept-1-en-2-yl)phenyl)-3-(trifluoromethyl)cyclobutan-1-carboxamide (590);

1,1,1-trifluoro-2-methylpropan-2-yl (4'-(1-cyanocyclopropyl)-3'-fluoro-[1, G biphenyl]-3-yl)((4-(5-(2 -fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamate (591);

(cis)-M-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-M-((4-(5-(2-fluoropropan-2yl)-1,2, 4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-hydroxy-3 (trifluoromethyl)cyclobutan-1-carboxamide (592);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(3-(6-(2-hydroxypropan-2-yl)pyridazin-3-yl)phenyl)-3(trifluoromethyl)cyclobutan-1-carboxamide (593);

3-fluoro-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- M-(3-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (594);

(cis)-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3- hydroxy-M-(6-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-3(trifluoromethyl)cyclobutane-!-carboxamide (595);

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T4-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-T4(2-(2-ethoxypyrimidine -5-yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (596);

X((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X (2-(2-cyclopropylpyrimidin- 5-yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide (597);

2-cyanopropan-2-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) (4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)carbamate (598);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-((trans )-4-hydroxy-4-methylcyclohexyl)-1-(4'-(2-hydroxypropan-2-yl)[1,G-biphenyl]-3-yl)urea (599);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(4- hydroxy-4-(trifluoromethyl)cyclohexyl)-1-(4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl)urea (600-601);

isopropyl (4-(((cis)-3-hydroxy-M-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]3-yl)-3-(trifluoromethyl)cyclobutane)- 1-carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (602);

(cis)-M-(4'-(d fluoromethoxy)-[1,1'-biphenyl]-3 -yl)-3-hydroxy-3-(trifluoromethyl)N-((4-((trifluoromethyl)sulfonamido) bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1carboxamide (603);

(cis)-3-hydroxy-T4-(4'-isopropoxy-[1,G-biphenyl]-3-yl)-T4-((4-(3isopropylureido)bicyclo[2.2.2]octan-1-yl) methyl)-3-(trifluoromethyl)cyclobutane-1carboxamide (604);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)pyridin-2-1)bicyclo[2.2.2]octan-1-yl)methyl)( 4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate (605);

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-((2-cyanopropan-2-yl)oxy)phenyl)pyride in-2-yl)((4-(5 -( 1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (606);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 5-(2-hydroxypropan-2-yl)-[2,4'-bipyridin]-2'-yl)carbamate (607);

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1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)pyridin-2-yl)carbamate (608);

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2yl)carbamate (609);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5 -(1,1-difluoroethyl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate (610);

-(tert-butyl)-1 -(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)-1 -((4-(5(trifluoromethyl)-1 ,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (611);

-(tert-butyl)-1 -(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-1 -((4-(5(trifluoromethyl)-1,2,4-oxadiazole -3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (612);

3-(tert-butyl)-1 -(4'-(2-(difluoromethoxy)propan-2-yl)-[1,1'-biphenyl]-3-yl)-1 ((4-(5-( trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (613);

1-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-(spiro[2.3]hexan-5ylmethyl)-1 -((4-(5 - (trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (614);

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-(chlorodifluoromethoxy)phenyl)pyridin-2yl) ((4-(5-(1,1-difluoroethyl)-1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (615);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) (5-fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin2-yl)carbamate (616);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) (5-fluoro-4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate (617);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) (5-fluoro-4-(3-fluoro-4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate (618);

neopentyl ((4-(5-( 1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 yl)methyl)(5-fluoro-4-(4 -(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate (619);

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1,1,1-trifluoro-2-methylpropan-2-yl (5-fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl) pyrid in-2-yl)((4-( 5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate (620);

1,1,1 -trifluoro-2-methylpropan-2-yl (5 -fluoro-4-( 1 -(oxetan-3 -ylmethyl)-1Hpyrazol-4-yl)pyridin-2-yl)((4-( 5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (621);

1,1,1 -trifluoro-2-methylpropan-2-yl (4-(4 -((2-cyanopropan-2-yl)oxy)phenyl) pyrid in-2-yl)((4-(3 -cyclopropyl-1,2,4-oxad iazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (622);

1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) (4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)carbamate (623);

1,1,1 -trifluoro-2-methylpropan-2-yl (4-(4-(difluoromethoxy)phenyl)pyridin-2-yl) ((4-(5-(1-fluorocyclopropyl)-1,2, 4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (624);

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-((2-cyanopropan-2-yl)oxy)phenyl) pyridin-2-yl)((4-(5-( 1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamate (625);

T4-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(4-( 4-isopropoxyphenyl)pyridin-2-yl)morpholine-4-carboxamide (626);

tetrahydro-2H-pyran-4-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)(4-(4 -isopropoxyphenyl)pyridin-2-yl)carbamate (627);

(cis)-M-(4'-(2,2-difluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-ηπ)-N-((4-(5-(1,1difluoroethyl) -1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1-carboxamide (628);

(cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl(4-(4-(difluoromethoxy)phenyl)-5fluoropyridin-2-yl)((4-(5 -(2-fluoropropan-2-yl)-1 ,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (629);

3,3-difluorocyclobutyl (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4 (5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazole -3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (630);

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4,4-difluorocyclohexyl (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4 (5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazol- 3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (631);

-(trifluoromethyl)oxetan-3-yl ((4-(5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octan-1-yl)) methyl)(4'-isopropoxy-[1,G-biphenyl]-3-yl)carbamate (632);

-(bicyclo[1.1.1]pentan-1-yl)-1 -((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2] octan-1 -yl)methyl)-1 -(4-fluoro-3 -(1 -(2-hydroxy-2-methylpropyl)-1Hpyrazol-4-yl)phenyl)urea (633);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol 3-yl)bicyclo[2.2.2] octan-1-yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2yl)carbamate (634);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol 3-yl)bicyclo[2.2.2] octan-1-yl)methyl)(2-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)carbamate (635);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol 3-yl)bicyclo[2.2.2] octan-1-yl)methyl)(4-(4-isopropoxyphenyl)pyrimidin-2-yl)carbamate (636);

№(4-(((cis)-PM-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo [2.2.2]octan-1-yl)-4fluorobenzamide (637);

M-(cyclopropylsulfonyl)-4-(((cis)-M-(4'-(difluoromethoxy)-[1,G-biphenyl]-3yl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamido) methyl)bicyclo[2.2.2]octane-1-carboxamide (638);

(cis)-M-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-M-((4-(5-(4-fluorophenyl)-1,2,4oxadiazol-3 - yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxamide (639);

(cis)-M-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)3-(difluoromethoxy)-M-(4 -(4-isopropoxyphenyl)pyridin-2-yl)-3-methylcyclobutan-1carboxamide (640);

M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M-(4 '-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-2-thia-6-azaspiro[3.3]heptane-6-carboxamide 2,2-dioxide (641);

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-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-1 -(4' -(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-3-((1-methylsulfonyl)cyclopropyl)methyl)urea (642);

H-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy- M-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3(trifluoromethyl)azetidine-1-carboxamide (643);

3-(1,1-otetrahydro-2H-thiopyran-4-yl dioxide)-1 -((4-(5-(2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl)bicyclo [2.2.2]octan-1-yl)methyl)-1-(4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl)urea (644);

-(2,2-difluoro-3-hydroxypropyl)-1 -((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane- 1-yl)methyl)-1-(4'-(2-hydroxypropan-2-yl)-[1,Hbiphenyl]-3-yl)urea (646);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-((4 -(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methyl)-1-(4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)urea (647);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -((1 -hydroxycyclopropyl)methyl)-1 -(4'-(2-hydroxypropan-2-yl)-[1, Hbiphenyl]-3-yl)urea (648);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-1-(4' -(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-(2-morpholinoethyl)urea (649);

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(2- (1-hydroxycyclopentyl)ethyl)-1-(4'-(2-hydroxypropan-2-yl)-[1, Hbiphenyl]-3-yl)urea (650);

T4-(4'-((2-cyanopropan-2-yl)oxy)-[1,G-biphenyl]-3-yl)-M-((4-(5-(2-fluoropropan2-yl)-1 ,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-(2-hydroxypropan-2yl)piperidin-1-carboxamide (651);

-((4-(5-( 1,1 -d iforoethyl)-1,2,4-oxad iazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-1 -(4' -isopropoxy-[1,1'-biphenyl]-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (652);

3-((trans)-4-(difluoromethoxy)-4-methylcyclohexyl)-1-(6-fluoro-4'-isopropoxy[1,1'-biphenyl]-3-yl)-1 -((4-( 5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)urea (653);

- 62 047337 (cis)-M-(4'-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)-[1,1'-biphenyl]-3 -yl)-M( (4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3hydroxy-3-(trifluoromethyl) cyclobutane-1-carboxamide (654);

(cis)-H-(4'-((2-cyanopropan-2-yl)oxy)-[1,1'-biphenyl]-3-yl)-M-((4-(5-(2fluoropropan-2 -yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy3-(trifluoromethyl)cyclobutan-1-carboxamide (654A);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3 -(1-fluorocyclopropyl)-1 -methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl) methyl)(4'-isopropoxy-[1,G-biphenyl]-3-yl)carbamate (655);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)isoxazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 4'-isopropoxy-[1,G-biphenyl]-3-yl)carbamate (656);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-(1,1-difluoroethyl)-1 -methyl-1H-pyrazol5-yl)bicyclo[2.2.2]octane-1- yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate (657);

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)-1 -methyl-1H-pyrazol3-yl)bicyclo[2.2.2]octane-1- yl)methyl)(4'-isopropoxy-[1,G-biphenyl]-3-yl)carbamate (658);

-(tert-butyl)-1-((4-(3-(1,1-difluoroethyl)-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1-yl)methyl )-1-(4'-isopropoxy-[1,G-biphenyl]-3-yl)urea (659);

-(tert-butyl)-1 -(5 -(4-(difluoromethoxy)phenyl)pyride azin-3-yl)-1 -((4-(5-(2fluoropropan-2-yl)-1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea (660);

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-(2-hydroxypropan-2-yl)phenyl-)pyridin-2-yl)((4-(3-isopropyl- 1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)carbamate (661);

(cis)-H-(4'-(4-amino-1,2,5-oxadiazol-3-yl)-[1,G-biphenyl]-3-yl)-M-((4-(5- (2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy3-(trifluoromethyl)cyclobutan-1-carboxamide (662) ;

3-fluoro-M-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1 -yl)methyl)- N-(3 -(1-(2-hydroxy-2-methylpropyl)-1,2,3,6-tetrahydropyridin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (663);

- 63 047337 tert-butyl 4-(3-(3 -φτορ-Ν-((4-(5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamido)phenyl)-3,6dihydropyridine-1 (2H)-carboxylate (663C);

3-fluoro-U-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- M-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)bicyclo[1.1.1]pentane1-carboxamide (663D);

1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1-(4 '-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-((28,48,68)-6hydroxyspiro[3.3]heptan-2-yl)urea (664) ;

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-cyanobicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)((4-(3-cyclopropyl-1, 2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (665); methyl 4-(2-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)((( 1,1,1-trifluoro -2-methylpropan-2-yl)oxy)carbonyl)amino)pyrimidin-4yl)bicyclo[2.2.2]octane-1-carboxylate (665E);

4-(2-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)((( 1,1,1- trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)pyrimide in-4-yl)bicyclo[2.2.2]octane-1-carboxylic acid (665F);

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-carbamoylbicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)((4-(3-cyclopropyl-1, 2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate (665G); or

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl) (4-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1yl)pyrimidin-2-yl)carbamate (666).

II. Pharmaceutical compositions, therapeutic uses and combinations.

In yet another embodiment, the present invention provides a composition containing at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

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

In yet another embodiment, the present invention provides a method of treating a disease, disorder or condition associated with farnesoid X receptor (FXR) activity 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 thereof or pharmaceutically acceptable salt.

In yet another embodiment, the present invention provides a method of treating a disease, disorder or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone or, optionally, in combination with another compound of the present invention. the invention and/or with at least one other type of therapeutic agent.

In yet another embodiment, the present invention provides a method of causing an agonistic effect at the farnesoid X receptor (FXR) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, a disease, disorder, or condition associated with impaired FXR function includes pathological fibrosis, cancer, inflammatory disorders, metabolic

- 64 047337 social or cholestatic disorders.

In some embodiments, the disease, disorder, or condition is associated with fibrosis, including fibrosis of the liver, biliary tract, kidney, heart, skin, eye, and pancreas.

In other embodiments, the disease, disorder, or condition is associated with cell proliferative disorders, such as cancer. In some embodiments, the cancer includes solid tumor growth or neoplasia. In other embodiments, the cancer includes tumor metastases. In some embodiments, the cancer affects the liver, gallbladder, small intestine, colon, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, genitalia , genitourinary tract, head, larynx, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testicle or thyroid gland. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

Examples of diseases, disorders or conditions associated with FXR activity that may be prevented, modulated or treated in accordance with the present invention include, but are not limited to, transplant rejection, fibrotic disorders (eg, liver fibrosis, kidney fibrosis), inflammatory disorders (eg , acute hepatitis, chronic hepatitis, nonalcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and cell proliferative disorders (eg, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, cancer prostate gland, leukemia, Kaposi's sarcoma, solid tumors).

Fibrotic disorders, inflammatory disorders, and cell proliferative disorders that may be prevented or treated by the compounds of the present invention include, but are not limited to, nonalcoholic fatty liver disease (NAFLD), alcoholic or nonalcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, liver cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, liver hypofunction, impaired blood flow in the liver, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretion disorder, benign prostatic hyperplasia, neuropathic 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 kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, viral fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumor, intervertebral disc herniation, 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, scarring corneas, diabetic retinopathy (PVR), cicatricial pemphigoid, scarring after filtration glaucoma surgery, Crohn's disease or systemic lupus erythematosus; formation of keloids as a result of improper wound healing; fibrosis occurring after organ transplantation, myelofibrosis and fibroids. In one embodiment, the present invention provides a method of treating a fibrotic disorder, inflammatory disorder, or cell proliferative disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone or, optionally, in combination with another compound of the present invention and/or with at least one other type of therapeutic agent.

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

In yet another embodiment, the present invention provides a compound of the present invention for use in therapy for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder.

In yet another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder.

In yet another embodiment, the present invention provides a method of treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of the first and

- 65 047337 second therapeutic agents, wherein the first therapeutic agent is a compound of the present invention.

In yet another embodiment, the present invention provides a combination preparation containing a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In yet another embodiment, the present invention provides a combination preparation containing a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment of a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder.

The compounds of the present invention can be used in combination with additional therapeutic agent(s), such as one or more anti-fibrotic and/or anti-inflammatory therapeutic agents.

In one embodiment, the additional therapeutic agent(s) used in combination pharmaceutical compositions or combination methods or combination applications are selected from one or more, preferably one to three, of the following therapeutic agents: TGFe receptor inhibitors (eg, galunisertib), inhibitors TGFe synthesis (eg, pirfenidone), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase inhibitors (eg, nintedanib), humanized monoclonal antibody against ave6 integrin (eg, 3G9), recombinant human pentraxin-2, recombinant human serum amyloid P, recombinant human anti-TGFe-1, -2 and -3 antibody, endothelin receptor antagonists (eg, macitentan), interferon gamma, c-Jun amino-terminal kinase (JNK) inhibitor ( for example, 4-[[9-[^)-tetrahydro-3-furanyl]8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]trans-cyclohexanol, 3-pentylbenzeneacetic acid (PBI-4050), tetrasubstituted porphyrin derivative containing manganese(III), monoclonal antibody targeting eotaxin-2, anti-interleukin-13 (IL-13) antibody (eg, lebrikizumab, tralokinumab), bispecific antibody targeting interleukin ^and _​ fully human IgG1 kappa antibody selective for CC chemokine ligand 2 (eg, carlumab, CCX140), antioxidants (eg, N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (eg, sildenafil), agents for the treatment of obstructive airway diseases such as muscarinic receptor antagonists (eg, tiotropium, ipatropium bromide), β2 adrenergic agonists (eg, salbutamol, salmeterol), corticosteroids (eg, triamcinolone, dexamethasone, fluticasone), immunosuppressants (eg, tacrolimus, rapamycin, and pimecin) and therapeutic agents , useful for the treatment of fibrotic conditions such as liver, biliary and kidney fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF) and systemic sclerosis. Therapeutic agents useful for treating such fibrotic conditions include, but are not limited to, FXR agonists (eg, OCA, GS-9674 and LJN452), LOXL2 inhibitors (eg, simtuzumab), LPA1 antagonists (eg, BMS-986020 and SAR 100842) , PPAR modulators (eg, elafibrinor, pioglitazone and saroglitazar, IVA337), SSAO/VAP-1 inhibitors (eg, PXS-4728A and SZE5302), ASK-1 inhibitors (eg, GS-4997 or selonvertib), ACC inhibitors (eg, CP-640186 and NDI-010976 or GS-0976), FGF21 mimetics (eg, LY2405319 and BMS-986036), caspase inhibitors (eg, emrican), NOX4 inhibitors (eg, GKT137831), MGAT2 inhibitor (eg, BMS-963272) , aV integrin inhibitors (eg, abituzumab) and bile acid/fatty acid conjugates (eg, aramchol). FXR agonists of various embodiments of the present invention can also be used in combination with one or more therapeutic agents, such as CCR2/5 inhibitors (eg, cenicriviroc), galectin-3 inhibitors (eg, TD-139, GR-MD-02), antagonists leukotriene receptors (eg, tipelukast, montelukast), SGLT2 inhibitors (eg, dapagliflozin, remogliflozin), GLP-1 receptor agonists (eg, liraglutide and semaglutide), FAK inhibitors (eg, GSK-2256098), CB1 inverse agonists (eg, JD -5037), CB2 agonists (eg, APD-371 and JBT-101), autotaxin inhibitors (eg, GLPG1690), prolyl tRNA synthetase inhibitors (eg, halofugenone), FPR2 agonists (eg, ZK-994), and THR agonists (eg MGL:3196). In yet another embodiment, the additional therapeutic agent(s) used in combination pharmaceutical compositions or combination methods or combination applications are selected from one or more, preferably one to three, immuno-oncology agents such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab , pembrolizumab and rituximab.

The compounds of the present invention for any of the uses described herein can be administered by any suitable route, for example, orally via tablets, capsules (each of which includes sustained release or defined release formulations).

- 66 047337 time), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions; sublingual; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrathoracic injection, or by infusion methods (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration into the mucous membranes of the nasal cavity, for example, using an inhalation spray; topically, for example, in the form of a cream or ointment; or rectally, for example, in the form of suppositories. They can be administered separately, but are usually administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The term pharmaceutical composition means a composition containing a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to vehicles conventional in the art for the delivery of biologically active agents to animals, particularly mammals, including, for example, an adjuvant, excipient or carrier such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, antibacterial agents, antifungal agents, lubricating agents and dosage agents, depending on the nature of the mode of administration and dosage forms. Pharmaceutically acceptable carriers are formulated in accordance with a number of factors well known to those skilled in the art. These include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the agent-containing composition is to be administered; intended route of administration of the composition; and target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as various solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included for a variety of reasons, eg, to stabilize the active agent, as binders, etc., well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors influencing their selection can be found in various readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

As used herein, the terms treat or treatment refer to an approach to obtain beneficial or desired results, including clinical results, by using a compound or composition of the present invention. For purposes of this invention, beneficial or desirable clinical results include, but are not limited to, one or more of the following: a reduction in the severity and/or frequency of one or more symptoms resulting from a disease, disorder or condition; reducing the severity or causing regression of a disease, disorder or condition; stabilizing a disease, disorder or condition (eg, preventing or slowing the worsening of a disease, disorder or condition); delaying or slowing the progression of a disease, disorder or condition; improvement of a disease, disorder or condition; reducing the dose of one or more other medications needed to treat a disease, disorder or condition; and/or improving quality of life.

The dosage regimen of the compounds of the present 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; species, age, sex, health status, medical condition and body weight of the recipient; nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, patient's kidney and liver function, and desired effect.

As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will range from about 0.01 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and most preferably from about 0.01 to about 250 mg per day. When administered intravenously, the most preferred doses will be in the range of about 0.01 to about 10 mg/kg/min during a constant rate infusion. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be administered in divided doses two, three or four times daily.

The compounds are typically administered in mixtures with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected according to the intended form of administration, for example, in the form of oral tablets, capsules, elixirs and syrups, and in in accordance with generally accepted pharmaceutical practice.

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

A typical capsule for oral administration contains at least one of the compounds

- 67 047337 the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

A typical injection preparation is prepared by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the bottle are mixed with 2 ml of saline to obtain an injection.

The present invention includes within its scope pharmaceutical compositions containing as an active ingredient a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more, preferably one or three, other therapeutic agents, for example, ASK-1 inhibitors, CCR2/5 antagonists, autotaxin inhibitors, LPA1 receptor antagonists or other pharmaceutically active substance.

The above-mentioned other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in such amounts as specified in the Physicians' Desk Reference, in the patents set forth above, or as otherwise determined by one skilled in the art.

In particular, when presented as a single dosage unit, there is a potential for chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and the second therapeutic agent are combined into a single dosage unit, they are formulated in such a way that although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (i.e., reduced ). For example, one active ingredient may be enteric coated. By enteric coating of one of the active ingredients, it is not only possible to minimize contact between the combined active ingredients, but also the release of one of these components in the gastrointestinal tract can be controlled, so that the release of one of these components occurs not in the stomach, but in the intestines. One of the active ingredients may also be coated with a material that effects sustained release throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. In addition, the sustained release component may be further coated with an enteric coating so that release of the component occurs only in the intestines. Another approach may be to formulate 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 low viscosity hydroxypropyl methylcellulose (HPMC), or other suitable materials known in the art. this area, for additional separation of active components. The polymer coating serves as an additional barrier to interaction with another component.

These, as well as other methods of minimizing contact between the components of the combined products of the present invention, administered in a single dosage form or administered in separate forms, but at the same time in the same way, will be obvious to those skilled in the art, familiar with this disclosure.

The compounds of the present invention can be administered alone or in combination with one or more, preferably one to three, additional therapeutic agents. By administration in combination or combination therapy is meant that a compound 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 may be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately, but close enough in time to provide the desired therapeutic effect.

The compounds of the present invention are also useful as standard or reference compounds, for example, as a quality standard or control in tests or assays that use FXR agonists. Such compounds may be provided in a commercial kit, for example, for use in a pharmaceutical study involving FXR agonist activity. For example, a compound of the present invention can be used as a standard in an assay to compare its known activity with a compound of unknown activity. This will allow the experimenter to perform the assay properly and provide a basis for comparison, especially if the compound being tested is a derivative of the reference compound. The compounds of the present invention can be used in the development of new assays or protocols to test their effectiveness.

The present invention also includes a finished product. The term finished product as used herein is intended to include, but is not limited to, kits and packages. Goto

- 68 047337 The article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition placed in a first container, the composition containing: a first therapeutic agent containing a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and their consequences. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as previously defined) with a second therapeutic agent for the treatment of fibrosis and its consequences. The finished product may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located inside or outside the second container. Being located inside the first and second containers means that the corresponding container holds the item within its confines.

The first container is a container used to contain the pharmaceutical composition. This container may be intended for manufacturing, storage, transportation and/or individual/wholesale sale. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (eg, for a cream formulation) or any other container used for the manufacture, containment, storage or distribution of a pharmaceutical product.

The second container is used to contain the first container and, optionally, the insert sheet. Examples of the second container include, but are not limited to, boxes (eg, cardboard or plastic), crates, cartons, bags (eg, paper or plastic bags), bags, and pouches. The insert may be physically attached to the outside of the first container using tape, adhesive, staples, or other method of attachment, or it may be located inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When placed on the outside of the second container, it is preferred that the package insert be physically attached using tape, adhesive, staples, or other method of attachment. Alternatively, it may be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that provides information related to the pharmaceutical composition located within the first container. The information provided is usually determined by the regulatory agency that controls the territory in which the product will be sold (for example, the US Food and Drug Administration). Preferably, the package insert specifically sets forth the indications for which the pharmaceutical composition is approved. The insert may be made of any material on which a person can read the information contained in or on it. Preferably, the insert is a printed material (eg paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information is formed (eg printed or applied).

III. Definitions.

The features and advantages of the invention may be more easily understood by those skilled in the art upon reading the following detailed description. It should be appreciated that certain features of the invention which, for reasons of clarity, are described above and below in the context of individual embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention, which for reasons of brevity are described in the context of one embodiment, can also be combined to form subcombinations thereof. It is intended that embodiments defined herein as typical or preferred are illustrative and non-limiting.

Unless specifically stated otherwise herein, references made to the singular may also include the plural. For example, terms that indicate an indefinite quantity may refer to either one or one or more than one.

As used herein, the phrase compounds and/or salts thereof refers to at least one compound, at least one salt of these compounds, or a combination thereof. For example, compounds of formula (I) and/or salts thereof include a compound of formula (I); two compounds of formula (I); a salt of the 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 the compound of formula (I).

Unless otherwise stated, any atom with unfilled valences is assumed to have a sufficient number of hydrogen atoms to fill the valence.

The definitions set forth herein supersede the definitions set forth in any patent, patent application, and/or patent application publication, which may be incorporated herein by reference.

Listed below are definitions of various terms used to describe the present invention. These definitions apply to terms that are used throughout the specification (unless otherwise limited in special cases) either individually or as part of a

- 69 047337 neck group.

Throughout the description, groups and their substituents may be selected by one skilled in the art to provide stable moieties and compounds.

As used in the art, is used in structural formulas herein to denote a bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

The terms halogen and halogen as used herein refer to F, Cl, Br and I.

The term cyano refers to the -CN group.

The term hydroxy refers to the -OH group.

The term amino refers to the -NH2 group.

The term oxo refers to the =O group.

As used herein, the term alkyl refers to saturated, branched and straight chain aliphatic hydrocarbon groups containing, for example, 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (eg, n-propyl and isopropyl), butyl (eg, n-butyl, isobutyl, sec-butyl and tert-butyl) and pentyl (e.g. n-pentyl, isopentyl, neopentyl), ngexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl and 4-methylpentyl. When numbers appear subscripted after the symbol C, the subscript more accurately defines the number of carbon atoms that a particular group may contain. For example, 'D^-alkyl' denotes straight and branched chain alkyl groups containing from one to four carbon atoms.

As used herein, the term haloalkyl is understood to include saturated aliphatic hydrocarbon groups, both branched and straight chain, substituted by one or more halogen atoms. For example, Ci-4-haloalkyl is understood to include C1, _C2 , _C3 and _C4 alkyl groups substituted by one or more halogen atoms. Typical examples of haloalkyl groups include, but are not limited to, -CF ₃ , -CCl ₃ , -CHF2 and -CF2CC13.

As used herein, the term fluoroalkyl is understood to include saturated aliphatic hydrocarbon groups, both branched and straight chain, substituted by one or more fluorine atoms. For example, 'D^-fluoroalkyl' is understood to include C1, _C2 , _C3 and _C4 alkyl groups substituted by one or more fluorine atoms. Typical examples of fluoroalkyl groups include, but are not limited to, -CF ₃ and -CH ₂ CF ₃ .

As used herein, the term hydroxyalkyl is understood to include saturated aliphatic hydrocarbon groups, either branched or straight chain, substituted by one or more hydroxyl groups. For example, C _1-4 -hydroxyalkyl is understood to include C 1 , C 2 , C ₃ and C ₄ alkyl groups substituted by one or more hydroxyl groups. Typical examples of fluoroalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH and -C(CH3)2OH.

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. Examples of such groups include ethenyl or allyl. For example, C _2-6 -alkenyl refers to straight and branched chain alkenyl groups containing from two to six carbon atoms.

The term alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Examples of such groups include ethynyl. For example, C _2-6 -alkynyl refers to straight and branched chain alkynyl groups containing from two to six carbon atoms.

As used herein, the term alkoxy refers to an alkyl group attached to a moiety of the parent molecule via an oxygen atom, for example, a methoxy group (-OCH3). For example, u-alkoxy denotes alkoxy groups with one to three carbon atoms.

The terms haloalkoxy and -O(haloalkyl) represent a haloalkyl group, as defined above, attached via an oxygen bond (-O-). For example, the term C _1-4 haloalkoxy is understood to include C 1 , C ₂ , C ₃ and C ₄ haloalkoxy groups.

The terms fluoroalkoxy and -O(fluoroalkyl) represent a fluoroalkyl group, as defined above, attached via an oxygen bond (-O-). For example, the term C _1-4 -fluoroalkoxy is understood to include C 1 , C ₂ , C ₃ and C ₄ fluoroalkoxy groups.

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. Typical examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl and cyclohexyl. When numbers appear in a subscript after the symbol C, the subscript defines more specifically the number of carbon atoms that a particular cycloalkyl group may contain. For example, C _3-6 -cycloalkyl refers to cycloalkyl groups with three to six carbon atoms.

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The terms carbocyclo, carbocyclic or carbocyclyl can be used interchangeably and refer to cyclic groups having at least one saturated or partially saturated non-aromatic ring, all atoms of all rings being carbon, and includes groups having one or more bridged rings, in of which a bridging ring occurs when one or more carbon atoms join 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]octanyl, adamantyl and tetrahydronaphthyl.

As used herein, the term bicycloalkyl refers to a carbocyclyl group having at least one bridge. Typical examples of bicycloalkyl groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octanyl, and adamantyl.

As used herein, the term aryl refers to a group of atoms derived from a molecule containing aromatic ring(s) by removing one hydrogen atom that is attached to the aromatic ring(s). Typical examples of aryl groups include, but are not limited to, phenyl and naphthyl. The aryl ring may be unsubstituted or may contain one or more substituents as valency permits.

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

The terms heterocyclo, heterocyclic or heterocyclyl can be used interchangeably and refer to cyclic groups having at least a saturated or partially saturated non-aromatic ring, and wherein one or more rings have at least one heteroatom (O, S or N), wherein said heteroatom-containing ring preferably has 1 to 3 heteroatoms independently selected from O, S and/or N. The ring of such heteroatom-containing group may contain one or two oxygen or sulfur atoms and/or one to four nitrogen atoms at 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 atoms may optionally be quaternized. The heterocyclo group can be attached to any available nitrogen or carbon atom. The heterocyclo ring may be unsubstituted or may contain one or more substituents as valency permits.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, yl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dihydroisoindolyl and tetrahydroquinolinyl.

The terms spirobicyclyl and spirobicyclo can be used interchangeably and refer to bicyclic groups in which two rings are attached to one carbon atom that is a member of each of the two rings. The term includes both spirobicycloalkyls, in which the two rings are cycloalkyl rings attached to one carbon atom that is a member of each of the two rings, and spirobicycloheteroalkyls, in which one ring is a heterocyclyl ring and the other ring is a cycloalkyl ring attached to one carbon atom that is a member of each of two rings, or in which both rings are heterocyclyl rings attached to one carbon atom that is a member of each of two rings. Examples of spirobicyclyl groups include spiro[3.3]heptenyl, spiro[3.4]octanyl, azaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl, oxaazaspiro[3.3]heptanyl and azaspiro[3.4]octanyl.

The term heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups and 9- or 10-membered bicyclic groups that have at least one heteroatom (O, S or N) on at least one of the rings, wherein said heteroatom-containing ring preferably has 1, 2 or 3 heteroatoms independently selected from O, S and/or N. Each heteroaryl ring containing a heteroatom may contain one or two oxygen or sulfur atoms and/or one to four nitrogen atoms at 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 that complete the bicyclic group are aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Bicyclic heteroaryl groups must contain only aromatic rings. A heteroaryl group can 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.

Examples of monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

Typical bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioc

- 71 047337 solyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl and pyrrolopyridyl.

The term glycosyl means a monovalent free radical or substituent moiety obtained by removing the hydroxyl group of a hemiacetal from the cyclic form of a monosaccharide and, accordingly, a lower oligosaccharide. In one embodiment, the glycosyl group has the following structure:

nsd he .

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 interconvertible by migration of an atom or group within the molecule. For example, one skilled in the art will readily appreciate that 1,2,3-triazole exists in two tautomeric forms as defined above:

[-N AND | 'N - - I NH

Η

1H-1,2,3-triazole 2H-1,2,3-triazole,

Thus, this disclosure is intended to cover all possible tautomers, even if the structure of only one of them is reflected. For example, compounds of formula (Ia) in which, when R ^5c is hydroxy and R ^5a , R ^5b and R ^5d are each hydrogen, may exist in tautomeric forms:

The phrase pharmaceutically acceptable is used herein to designate those compounds, materials, compositions and/or dosage forms which, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic reaction or other problem. or complications commensurate with a reasonable benefit/risk ratio.

The compounds of formula (I) can form salts, which are also included in the scope of this invention. Unless otherwise indicated, reference to a compound of the invention is intended to include reference to one or more salts thereof. The term salt(s) means acidic and/or basic salts formed by inorganic and/or organic acids and bases. In addition, the term salt(s) may include zwitterions (internal salts), for example, when the compound of formula (I) contains both a basic component, such as an amine or pyridine or imidazole ring, and an acidic component, such as a carboxylic acid. Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be useful, for example in isolation or purification steps that may be used in the preparation of compounds, and are thus within the scope of the invention. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is incorporated herein by reference.

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Examples of acid addition salts include acetates (eg, those formed with acetic acid or trihaloacetic acid, e.g. trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentane propionates, digluconates , dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, you (formed with methanesulfonic acid), 2-naphthalene sulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates and the like.

Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; or similar pharmaceutically acceptable amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be quaternized by agents such as lower alkyl halides (for example, methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl and diamyl sulfates), long-chain halides (for example, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides) and others. Preferred salts include monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate or nitrate.

The compounds of formula (I) may be provided as amorphous solids or crystalline solids. Lyophilization can be used to obtain the compounds of formula (I) in solid form.

In addition, it should be understood that solvates (eg, hydrates) of the compounds of formula (I) are also included within the scope of the present invention. The term solvate means the physical association of a compound of formula (I) with one or more solvent molecules, organic or inorganic. This physical association involves hydrogen bonds. In some cases the solvate will be able to be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. Solvate covers both solution phase solvates and insoluble solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates and ethyl acetate solvates. Solvation methods are known in the art.

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

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

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

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); And

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

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

In addition, the compounds of formula (I), once prepared, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of the compound of formula (I) (substantially pure), which is then used or formulated as described in this document. Such essentially pure compounds of formula (I) are also contemplated herein as part of the present invention.

A stable compound and a stable structure indicate that the compound is strong enough to withstand isolation to a useful degree of purity from the reaction mixture and formulation into an effective therapeutic agent. The present invention is intended to provide stable compounds.

A therapeutically effective amount is intended to include an amount of a compound of the present invention taken alone, or an amount of a combination of the claimed compounds, or an amount of a compound of the present invention in combination with other active ingredients effective as an FXR agonist, or effective for treating or prevention of disorders associated with dysregulation of bile acids, such as pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

The compounds of the present invention are intended to include all isotopes of atoms found in the compounds of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example and without limitation, iso

- 73 047337 elements of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically labeled compounds of the invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described herein, using a suitable isotopically labeled reagent in place of the unlabeled reagent used in other cases. Such compounds have many potential uses, for example, as standards and reagents in determining the ability of a potential pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of the present invention associated with biological receptors in vivo or in vitro.

In another embodiment, the present invention provides a composition containing at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a method for preparing a compound of the present invention.

In yet another embodiment, the present invention provides an intermediate for preparing a compound of the present invention.

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

Utility.

In one embodiment, the present invention provides a method of treating a disease, disorder or condition associated with dysregulation of bile acids in a patient in need of such treatment, and the method includes administering to the patient a therapeutically effective amount of a compound of the present invention or a stereoisomer or pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a method of treating a disease, disorder or condition associated with farnesoid X receptor (FXR) activity 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 thereof or a pharmaceutically acceptable salt.

In yet another embodiment, the present invention provides a method of treating a disease, disorder or condition, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or optionally in combination with another compound of the present invention. the present invention and/or with at least one other type of therapeutic agent.

In yet another embodiment, the present invention provides a method of causing an agonistic effect at the farnesoid X receptor (FXR) in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

In some embodiments, the disease, disorder or condition associated with FXR dysfunction includes pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders.

In some embodiments, the disease, disorder, or condition is associated with fibrosis, including fibrosis of the liver, biliary tract, kidney, heart, skin, eye, and pancreas.

In other embodiments, the disease, disorder, or condition is associated with cell proliferative disorders, such as cancer. In some embodiments, the cancer includes solid tumor growth or neoplasia. In other embodiments, the cancer includes tumor metastases. In some embodiments, the cancer affects the liver, gallbladder, small intestine, colon, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, genitalia , genitourinary tract, head, larynx, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testicle or thyroid gland. In other embodiments, the cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

Examples of diseases, disorders or conditions associated with FXR activity that may be prevented, modulated or treated in accordance with the present invention include, but are not limited to:

- 74 047337 restrictions, graft rejection, fibrotic disorders (eg liver fibrosis, kidney fibrosis), inflammatory disorders (eg acute hepatitis, chronic hepatitis, non-alcoholic steatohepatitis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) ), as well as cell proliferative disorders (eg, cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

Fibrotic disorders, inflammatory disorders, and cell proliferative disorders that may be prevented or treated by the compounds of the present invention include, but are not limited to, nonalcoholic fatty liver disease (NAFLD), alcoholic or nonalcoholic steatohepatitis (NASH), acute hepatitis, chronic hepatitis, liver cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, biliary cirrhosis, portal hypertension, regenerative failure, liver hypofunction, impaired blood flow in the liver, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic dysfunction, benign prostatic hyperplasia, neuropathic 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 kidney disease (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, viral fibrosis, idiopathic pulmonary fibrosis (IPF), interstitial lung disease, nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), radiation-induced induced fibrosis, familial pulmonary fibrosis, airway fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumor, intervertebral disc herniation, 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, scarring corneas, diabetic retinopathy (PVR), cicatricial pemphigoid, scarring from glaucoma filtration surgery, Crohn's disease or systemic lupus erythematosus; formation of keloids as a result of improper wound healing; fibrosis occurring after organ transplantation, myelofibrosis and fibroids. In one embodiment, the present invention provides a method of treating a fibrotic disorder, inflammatory disorder, or cell proliferative disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone or, optionally, in combination with another compound of the present invention and/or with at least one other type of therapeutic agent.

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

In yet another embodiment, the present invention provides a compound of the present invention for use in therapy for treating a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder.

In yet another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of a fibrotic disorder, an inflammatory disorder, or a cell proliferative disorder.

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

In yet another embodiment, the present invention provides a combination preparation containing a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In yet another embodiment, the present invention provides a combination preparation containing a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment of a fibrotic disorder, an inflammatory disorder or a cell proliferative disorder.

The compounds of the present invention can be used in combination with additional therapeutic agent(s), such as one or more anti-fibrotic and/or anti-inflammatory therapeutic agents.

In one embodiment, the additional therapeutic agent(s) used in the combination pharmaceutical compositions or combination methods or combination applications are selected from one or more, preferably one to three, of the following:

- 75 047337 therapeutic agents: TGFe receptor inhibitors (for example, galunisertib), TGFe synthesis inhibitors (for example, pirfenidone), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptor kinase inhibitors (for example , nintedanib), humanized monoclonal antibody against ave6 integrin (eg, 3G9), recombinant human pentraxin-2, recombinant human serum amyloid P, recombinant human anti-TGFe-1, -2 and -3, endothelin receptor antagonists (eg, macitentan) , interferon gamma, c-Jun amino-terminal kinase (JNK) inhibitor (e.g., 4-[[9-[^)-tetrahydro-3-furanyl]8-[(2,4,6-mfluorophenyl)amino]-9H -purin-2-yl]amino]trans-cyclohexanol, 3-pentylbenzeneacetic acid (PBI-4050), tetrasubstituted porphyrin derivative containing manganese(III), monoclonal antibody targeting eotaxin-2, interleukin-13 antibody (IL- 13) (eg, lebrikizumab, tralokinumab), bispecific antibody targeting interleukin 4 (IL-4) and interleukin 13 (IL13), tachykinin receptor NK1 agonist (eg, Sar ⁹ , Met(O ₂ )-Substance P), Cintredekin Besudotox, human recombinant DNA, connective tissue growth factor IgG1 kappa monoclonal antibody and fully human CC chemokine ligand 2 selective IgG1 kappa antibody (eg, carlumab, CCX140), antioxidants (eg, N-acetylcysteine), phosphodiesterase 5 inhibitors (PDE5) (eg, sildenafil), drugs for the treatment of obstructive airway diseases such as muscarinic receptor antagonists (eg, tiotropium, ipatropium bromide), β2 adrenergic agonists (eg, salbutamol, salmeterol), corticosteroids (eg, triamcinolone, dexamethasone, fluticasone), immunosuppressants (eg, tacrolimus, rapamycin and pimecin) and therapeutic agents useful for the treatment of fibrotic conditions such as liver, biliary and kidney fibrosis, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF) and systemic sclerosis. Therapeutic agents useful for treating such fibrotic conditions include, but are not limited to, FXR agonists (eg, OCA, GS-9674 and LJN452), LOXL2 inhibitors (eg, simtuzumab), LPA1 antagonists (eg, BMS-986020 and SAR 100842) , PPAR modulators (eg, elafibrinor, pioglitazone and saroglitazar, IVA337), SSAO/VAP-1 inhibitors (eg, PXS-4728A and SZE5302), ASK-1 inhibitors (eg, GS-4997 or selonvertib), ACC inhibitors (eg, CP-640186 and NDI-010976 or GS-0976), FGF21 mimetics (eg, LY2405319 and BMS-986036), caspase inhibitors (eg, emrican), NOX4 inhibitors (eg, GKT137831), MGAT2 inhibitor (eg, BMS-963272) , aV integrin inhibitors (eg, abituzumab) and bile acid/fatty acid conjugates (eg, aramchol). FXR agonists of various embodiments of the present invention can also be used in combination with one or more therapeutic agents, such as CCR2/5 inhibitors (eg, cenicriviroc), galectin-3 inhibitors (eg, TD-139, GR-MD-02), antagonists leukotriene receptors (eg, tipelukast, montelukast), SGLT2 inhibitors (eg, dapagliflozin, remogliflozin), GLP-1 receptor agonists (eg, liraglutide and semaglutide), FAK inhibitors (eg, GSK-2256098), CB1 inverse agonists (eg, JD -5037), CB2 agonists (eg, APD-371 and JBT-101), autotaxin inhibitors (eg, GLPG1690), prolyl tRNA synthetase inhibitors (eg, halofugenone), FPR2 agonists (eg, ZK-994), and THR agonists (eg MGL:3196). In another embodiment, the additional therapeutic agent(s) used in combination pharmaceutical compositions or combination methods or combination applications are selected from one or more, preferably one to three, immuno-oncology agents such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, ofatumumab, pembrolizumab and rituximab.

The compounds of the present invention for any of the uses described herein can be administered by any suitable route, for example, orally via tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions; sublingual; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrathoracic injection, or by infusion methods (for example, as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration into the mucous membranes of the nasal cavity, for example, using an inhalation spray; topically, for example, in the form of a cream or ointment; or rectally, for example, in the form of suppositories. They can be administered separately, but are usually administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The term pharmaceutical composition means a composition containing a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to vehicles conventional in the art for the delivery of biologically active agents to animals, particularly mammals, including, for example, an adjuvant, excipient or carrier such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, flavoring agents,

- 76 047337 antibacterial agents, antifungal agents, lubricating agents and dosing agents, depending on the nature of the mode of administration and dosage forms. Pharmaceutically acceptable carriers are formulated in accordance with a number of factors well known to those skilled in the art. These include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the agent-containing composition is to be administered; intended route of administration of the composition; and target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as various solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included for a variety of reasons, eg, to stabilize the active agent, as binders, etc., well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors influencing their selection can be found in various readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

As used herein, the terms treat or treatment refer to an approach to obtain beneficial or desired results, including clinical results, by using a compound or composition of the present invention. For purposes of this invention, beneficial or desirable clinical results include, but are not limited to, one or more of the following: a reduction in the severity and/or frequency of one or more symptoms resulting from a disease, disorder or condition; reducing the severity or causing regression of a disease, disorder or condition; stabilizing a disease, disorder or condition (eg, preventing or slowing the worsening of a disease, disorder or condition); delaying or slowing the progression of a disease, disorder or condition; improvement of a disease, disorder or condition; reducing the dose of one or more other medications needed to treat a disease, disorder or condition; and/or improving quality of life.

Pharmaceutically acceptable carriers are formulated in accordance with a number of factors well known to those skilled in the art. These include, but are not limited to: the type and nature of the active agent formulated; a subject to whom the agent-containing composition is to be administered; intended route of administration of the composition; and target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid vehicles, as well as various solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included for a variety of reasons, eg, to stabilize the active agent, as binders, etc., well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors influencing their selection can be found in various readily available sources, such as, for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen of the compounds of the present 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; species, age, sex, health status, medical condition and body weight of the recipient; nature and extent of symptoms; type of concomitant treatment; frequency of treatment; route of administration, patient's kidney and liver function, and desired effect.

As a general guide, the daily oral dosage of each active ingredient, when used for the indicated effects, will range from about 0.01 to about 5000 mg per day, preferably from about 0.01 to about 1000 mg per day, and most preferably from about 0.01 to about 250 mg per day. When administered intravenously, the most preferred doses will be in the range of about 0.01 to about 10 mg/kg/min during a constant rate infusion. The compounds of the present invention may be administered as a single daily dose, or the total daily dose may be administered in divided doses two, three or four times daily.

The compounds are typically administered in mixtures with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected according to the intended form of administration, for example, in the form of oral tablets, capsules, elixirs and syrups, and in in accordance with generally accepted pharmaceutical practice.

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

A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

A typical injection preparation is prepared by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying

- 77 047337 sealing and sealing. For use, the contents of the bottle are mixed with 2 ml of saline to obtain an injection.

The present invention includes within its scope pharmaceutical compositions containing as an active ingredient a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, the compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more, preferably one or three, other therapeutic agents, for example, ASK-1 inhibitors, CCR2/5 antagonists, autotaxin inhibitors, LPA1 receptor antagonists or other pharmaceutically active substance.

The above-mentioned other therapeutic agents, when used in combination with the compounds of the present invention, can be used, for example, in such amounts as specified in the Physicians' Desk Reference, in the patents set forth above, or as otherwise determined by one skilled in the art.

In particular, when presented as a single dosage unit, there is a potential for chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and the second therapeutic agent are combined into a single dosage unit, they are formulated in such a way that although the active ingredients are combined in a single dosage unit, physical contact between the active ingredients is minimized (i.e., reduced ). For example, one active ingredient may be enteric coated. By enteric coating of one of the active ingredients, it is not only possible to minimize contact between the combined active ingredients, but also the release of one of these components in the gastrointestinal tract can be controlled, so that the release of one of these components occurs not in the stomach, but in the intestines. One of the active ingredients may also be coated with a material that effects sustained release throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. In addition, the sustained release component may be further coated with an enteric coating so that release of the component occurs only in the intestines. Another approach may be to formulate 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 low viscosity hydroxypropyl methylcellulose (HPMC), or other suitable materials known in the art. this area, for additional separation of active components. The polymer coating serves as an additional barrier to interaction with another component.

These, as well as other methods of minimizing contact between the components of the combined products of the present invention, administered in a single dosage form or administered in separate forms, but at the same time in the same way, will be obvious to those skilled in the art, familiar with this disclosure.

The compounds of the present invention can be administered alone or in combination with one or more, preferably one to three, additional therapeutic agents. By administration in combination or combination therapy is meant that a compound 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 may be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately, but close enough in time to provide the desired therapeutic effect

Combination therapy is intended to include the administration of these therapeutic agents in a sequential manner, that is, each therapeutic agent being administered at a different time, as well as the administration of these therapeutic agents or at least two therapeutic agents substantially simultaneously. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage unit having a fixed ratio of each therapeutic agent, or in a plurality of unit dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be accomplished by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination may be administered by intravenous injection, while other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Combination therapy may also involve the administration of therapeutic agents as described above, in additional combination with other biologically active ingredients and non-drug treatments (eg, surgery or radiation

- 78 047337 howling therapy). If the combination therapy additionally includes a non-drug treatment, the non-drug treatment may be administered at any appropriate time provided that a beneficial effect is achieved from the combined action of the combination of therapeutic agents and the non-drug treatment. For example, in appropriate cases, a beneficial effect is still achieved when the non-drug treatment is removed in time from the administration of the therapeutic agents, perhaps by days or even weeks.

The compounds of the present invention are also useful as standard or reference compounds, for example, as a quality standard or control in tests or assays that use FXR agonists. Such compounds may be provided in a commercial kit, for example, for use in a pharmaceutical study involving FXR agonist activity. For example, a compound of the present invention can be used as a standard in an assay to compare its known activity with a compound of unknown activity. This will allow the experimenter to perform the assay properly and provide a basis for comparison, especially if the compound being tested is a derivative of the reference compound. The compounds of the present invention can be used in the development of new assays or protocols to test their effectiveness.

The present invention also includes a finished product. The term finished product as used herein is intended to include, but is not limited to, kits and packages. The finished product of the present invention includes: (a) a first container; (b) a pharmaceutical composition placed in a first container, the composition containing: a first therapeutic agent containing a compound of the present invention or a pharmaceutically acceptable salt form thereof; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemias and their consequences. In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as previously defined) with a second therapeutic agent for the treatment of fibrosis and its consequences. The finished product may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container, and component (c) is located inside or outside the second container. Being located inside the first and second containers means that the corresponding container holds the item within its confines.

The first container is a container used to contain the pharmaceutical composition. This container may be intended for manufacturing, storage, transportation and/or individual/wholesale sale. The first container is intended to encompass a bottle, jar, vial, flask, syringe, tube (eg, for a cream formulation) or any other container used for the manufacture, containment, storage or distribution of a pharmaceutical product.

The second container is used to contain the first container and, optionally, the insert sheet. Examples of the second container include, but are not limited to, boxes (eg, cardboard or plastic), crates, cartons, bags (eg, paper or plastic bags), bags, and pouches. The insert may be physically attached to the outside of the first container using tape, adhesive, staples, or other method of attachment, or it may be located inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When placed on the outside of the second container, it is preferred that the package insert be physically attached using tape, adhesive, staples, or other method of attachment. Alternatively, it may be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that provides information related to the pharmaceutical composition located within the first container. The information provided is usually determined by the regulatory agency that controls the territory in which the product will be sold (for example, the US Food and Drug Administration). Preferably, the package insert specifically sets forth the indications for which the pharmaceutical composition is approved. The leaflet may be made of any material on which the information contained in or on it can be read by a person. Preferably, the insert is a printed material (eg paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information is formed (eg printed or applied).

Methods of obtaining.

The compounds of the present invention can be synthesized by a variety of methods available to those skilled in the art of organic chemistry. General synthetic schemes for preparing the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible techniques that a person skilled in the art may use to prepare the compounds disclosed herein. Various methods for preparing the compounds of the present invention will be apparent to those skilled in the art. Examples of connections according to

- 79 047337 of the present invention, obtained by the methods described in the general schemes, are given in the examples section below. The preparation of homochiral compounds according to the examples can be carried out by methods known to a person skilled in the art. For example, homochiral compounds can be prepared by resolving racemic products or diastereomers by preparative HPLC using a chiral phase. Alternatively, the compounds of the examples can be prepared using methods known to provide products in enantiomerically or diastereomerically enriched form.

The reactions and methods described in this section are carried out in solvents appropriate to the reagents and substances used and suitable for the transformations being carried out. In addition, it should be understood that in the synthetic methods described below, all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, run time, and workup procedures, are selected to correspond to standard conditions for that reaction that should be readily recognized by one skilled in the art. areas. One skilled in the art of organic synthesis will appreciate that the functional group present on various parts of the starting molecule in a reaction must be compatible with the proposed reagents and reactions. Such restrictions on substituents that are compatible with the reaction conditions will be apparent to one skilled in the art, and alternatives required when incompatible substituents are present may be used. Sometimes this will require a decision to change the order of the synthetic steps or to select one particular process scheme over another to produce the compound of the present invention. It should also be recognized that another important consideration when planning any synthetic route in this area is the judicious choice of the protecting group used to protect the reactive functional groups present in the compounds described in the present invention. An authoritative review describing many alternative methods for the skilled practitioner is presented in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wiley and Sons (2007).

Examples

The following examples illustrate specific and preferred embodiments of the present invention and do not limit the scope of the present invention. Chemical abbreviations and symbols and scientific abbreviations and symbols have their usual and generally accepted meanings unless otherwise noted. Additional abbreviations used in the examples and elsewhere in this application are defined below. Conventional intermediates are typically used to prepare more than one example compound and are identified sequentially (eg, Intermediate 1, Intermediate 2) and abbreviated Int. 1 or I1, Int. 2 or I2. Compounds of the Examples are identified by the example and the step in which they are prepared (e.g., 1-A is Example 1, Step A), or by example only when the compound is the title compound of the Example (e.g., 1 is the one shown in header connection according to example 1). In some cases, alternative methods for preparing intermediates or examples are described. Often, chemists skilled in the art of synthesis can develop alternative synthetic routes that may be desirable based on one or more considerations, such as shorter reaction times, less expensive starting materials, ease of operation or isolation, improved yield, susceptibility to catalysis, avoidance toxic reagents, availability of specialized equipment and reduction in the number of linear stages. The purpose of describing alternative synthetic methods is to provide additional possibilities for preparing the compounds of the examples of the present invention. In some cases, certain functional groups in the examples and claims may be replaced by well-known bioisosteric substitutions known in the art, such as replacing a carboxylic acid group with a tetrazole or phosphate moiety. 1H NMR data collected in deuterated dimethyl sulfoxide used water suppression in data processing. Spectra shown are not corrected for water suppression effects. Protons adjacent to the 3.35 ppm water suppression frequency show reduced signal intensity.

Abbreviations.

The abbreviations used herein are defined as follows: 1 x for once, 2 x for twice, 3 x for three times, °C for degrees Celsius, eq for equivalent or equivalents, g for gram or gram, mg for milligram or milligram, L for liter or liters, ml for milliliter or milliliters, μL for microliter or microliters, N for normal, M for molar, mmol for millimole or millimoles, min for minute or minutes, h for hour or hours, rt for room temperature, RBF for round bottom flask, atm for atmosphere, psi for pounds per square inch, conc. for concentrated, RCM for ring-closing metathesis, sat or sat'd for saturated, SFC for supercritical liquid chromatography, MW for molecular weight, mp for melting point, ee for enantiomeric excess, MS or Mass Spec for mass spectrometry, ESI for electrospray ionization mass spectroscopy, HR for high resolution, HRMS for high resolution mass spectrometry

- 80 047337 solutions, LCMS for liquid chromatography with mass spectrometry, HPLC for high pressure liquid chromatography, RP HPLC for reverse phase HPLC, TLC or tlc for thin layer chromatography, NMR for nuclear magnetic resonance spectroscopy, nOe for nuclear Overhauser effect spectroscopy, 1H for proton, δ for delta, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, br for broad, Hz for hertz, and α, β, R, S, E and Z are stereochemical notations familiar to one skilled in the art.

The following abbreviations are used in diagrams, examples, and elsewhere in this document:

EtOAc = ethyl acetate;

PE = petroleum ether;

DMF = dimethylformamide;

THF = tetrahydrofuran;

K2CO3 = potassium carbonate;

Na2CO ₃ = sodium carbonate;

MgSO ₄ = magnesium sulfate;

DCM = CH2Cl2 = methylene chloride;

DCE = 1,2-dichloroethane;

MeOH = methanol;

HCl = hydrochloric acid;

AcOH = acetic acid;

Cs ₂ CO ₃ = cesium carbonate;

DMSO = dimethyl sulfoxide;

TEA = triethylamine;

BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate;

DMAc = dimethylacetamide;

DMAP = 4-dimethylaminopyridine;

2-DMAP = 2-dimethylaminopyridine;

PCC = pyridinium chlorochromate;

PDC = pyridinium dichromate;

DIBAL-H = diisobutylaluminum hydride;

rotovap = rotary evaporation;

min = minute(s);

h = hour(s);

d = day(days);

rt = room temperature;

ml = milliliter;

g = gram(s);

mg = milligram(s);

mmol = millimole(s);

LRMS = low resolution mass spectrometry;

NMR = nuclear magnetic resonance;

HPLC = high performance liquid chromatography.

Synthesis.

The compounds of the present invention can be prepared by a number of methods 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, as well as methods known in the field of synthetic organic chemistry, or variations thereof that are appreciated by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein by reference in their entirety.

New compounds of formula I can be prepared using the reactions and procedures described in this section. Reactions are carried out in solvents appropriate to the reagents and substances used and suitable for the transformations being carried out. In addition, it should be understood that in the synthetic methods described below, all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, run time, and workup procedures, are selected to correspond to standard conditions for that reaction that should be readily recognized by one skilled in the art. areas. One skilled in the art of organic synthesis will appreciate that the functional group present on various parts of the starting molecule in a reaction must be compatible with the proposed reagents and reactions. Not all compounds of formula I falling within this class may be compatible with some of the reaction conditions required in some

- 81 047337 which of the described methods. Such restrictions on substituents that are compatible with the reaction conditions will be apparent to one skilled in the art, and alternative methods may be used.

Scheme 1

Scheme 1 describes the synthesis of compounds of formula I. Intermediate 3 can be synthesized by treating intermediate 1 and intermediate 2 under reductive amination conditions, which are known methods recognized by one skilled in the art. Imine synthesis can occur in the presence of an acid such as acetic acid in a suitable polar protic solvent (e.g. MeOH or EtOH) at room temperature or boiling point, followed by reduction of the imine with reducing agents (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride) to produce the intermediate 3. Intermediate 3 can be subjected to a variety of different transformations using numerous known methods recognized by one skilled in the art, including, but not limited to, the following methods for preparing variants of Formula I:

Amides. Intermediate 4 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (eg, phosphorus oxychloride, thionyl chloride, oxalyl chloride, and methyl or ethyl chloroformate), in a polar aprotic solvent (eg, DCM or THF) at a temperature ranging from 130°C to 0°C. The activated acid intermediate can then react with intermediate 3 in the presence of a base (e.g., 2-(dimethylamino)pyridine, N-methylmorpholine, pyridine, or DMAP) to form compounds of formula I.

Urea. Intermediate 3 can be treated with isocyanates in the presence of a base (eg Et ₃ N, DIPEA or pyridine) in a polar aprotic solvent (eg DCM or DCE) at room temperature to produce the urea represented by Formula I. Alternatively, intermediate 3 can treat with triphosgene in the presence of a base (eg _Et3N or DIPEA) in a solvent (eg DCM or DCE) at a temperature ranging from 0°C to room temperature followed by treatment with an amine in the presence of a base (eg Et3N or DIPEA) in the solvent (for example, DCM or DCE) at room temperature to obtain urea represented by formula I.

Carbamates. Intermediate 3 can be treated with chloroformates (or alcohols activated as carbonates) in the presence of a base (eg Et3N, DIPEA or pyridine) in a polar aprotic solvent (eg DCM, DCE or THF) at a temperature ranging from 0°C to room temperature temperature to obtain carbamates represented by formula I.

Intermediates 1(a-n) (Scheme 1) can be prepared in a variety of ways, as shown in Schemes 2-10, using numerous known methods recognized by one skilled in the art, including, but not limited to, the following methods.

- 82 047337

Scheme 2

Scheme 2 describes the synthesis of intermediate 1a. Intermediates 5 and 6 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediate 5 or 6 can be coupled with various substituted amide oximes (derived from the corresponding nitriles by reaction with hydroxylamine; see Hirawat, S., et al. WO 2006/110483) using an amide bond-forming coupling reagent (e.g. CDI , BOP and EDC) in a polar aprotic solvent (eg THF, 1,4-dioxane or DMF) at room temperature. The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C) to yield intermediate 1a or intermediate 7. Alternatively, in situ cyclization can be accomplished by coupling compound 5 or 6 with amide oximes at elevated temperatures (from 60°C to 100°C). The thus obtained nitro intermediate 7 can be reduced 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 gas at ambient pressure and temperature to yield intermediate 1a.

Scheme 3

Scheme 3 describes the synthesis of intermediate 1b. Intermediate 8 can be prepared from intermediate 6 using any number of reagents recognized by one skilled in the art, but not limited to those described herein (e.g., phosphorus oxychloride, thionyl chloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate), in a polar aprotic solvent (e.g. , DCM or THF) at temperatures from -30°C to boiling point. Intermediate 8 can be treated with methyl acetate, pretreated with a base such as n-BuLi, in a solvent such as, but not limited to, THF or ether to give intermediate 9 (as described by Douglass, T. et al. J. Am. Chem. Soc., 1987, 109, 7488-7494). Alternatively, intermediate 9 can be synthesized as described in France, S. et al. Org. Lett. 2016, 18, 4218-4221. Intermediate 9 can be treated with hydroxylamine hydrochloride in a polar protic solvent such as MeOH, EtOH or water in the presence of a base such as K ₂ CO ₃ to give the intermediates represented by Formula 10 (as described in Wittman, MD, et al. WO 2015/195880 A1). Intermediate 10 can be treated with reagents such as POCl ₃ and SOCl ₂ in the presence of a base such as Et ₃ N or DIPEA for chlorination (as described in Wittman, MD, et al. WO 2015/195880 A1) followed by treatment with alkoxides metals to yield the corresponding substituted intermediates, which can be reduced in the presence of a catalyst such as Pd and hydrogen gas at ambient pressure and temperature to yield intermediate 1b.

- 83 047337

Scheme 4

Scheme 4 describes the synthesis of intermediate 1c. Intermediate 11 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediate 11 can be condensed with a serine ester in the presence of a base (eg Et ₃ N or DIPEA) and a dehydrating agent such as MgSO ₄ to give intermediate 12. Intermediate 12 can be converted to intermediate 13 by treatment with BrCCl ₃ and a base such as DBU in a chlorinated solvent (CH ₂ Cl ₂ or DCE) at ambient temperature as described in Graham, T. H., Org. Lett, 2010, 12, 3614-3617. Nitro intermediate 13 can be reduced 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 gas at ambient pressure and temperature, to yield intermediate 1c.

Scheme 5

Scheme 5 describes the synthesis of intermediate 1d. Intermediates 14 may be obtained from commercial sources or may be synthesized by known methods readily recognized by one skilled in the art. Intermediates 14 can be treated with iodobenzene diacetate in the presence of trifluoromethanesulfonic acid and a substituted nitrile to give oxazoles, as described in Varma, R. S. et al J. Heterocyclic Chem. 1998, 35, 1533. The nitro intermediate 15 thus obtained can be reduced 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 gas at ambient pressure and temperature, yielding intermediates 1d.

Scheme 6

Scheme 6 describes the synthesis of intermediates 1e and 1f. Intermediate 16 can be obtained from commercial sources or synthesized by known methods or modifications thereof readily recognized by one skilled in the art (described as in Bioorg. & Med. Chem. Lett, 2017, 27, 2192-2196). Intermediate 16 can be treated with methyl thioxamate under heating conditions in a protic polar solvent (eg, MeOH or EtOH) to produce the compounds represented by intermediate 17, as described in Wright, SW, J. Med. Chem. 2002, 45, 3865-3877. The thus obtained nitro intermediate 17 can be reduced 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 gas at ambient pressure and temperature, to yield intermediates 1e. Alternatively, intermediate 16 can be treated with an amidine in a polar aprotic solvent (MeCN or DMF) in the presence of a base such as K ₂ CO ₃ under heating conditions to give intermediate 18. Intermediate 18 can be alkylated using numerous known methods recognized one skilled in the art, including, but not limited to, treatment under basic conditions in the presence of an alkylating agent to produce a Nalkylimidazole intermediate, which can be reduced in the presence of a catalyst such as Pd and hydrogen gas at ambient pressure and temperature to produce the intermediate connections 1f.

Scheme 7

Intermediates 1g, 1h or 1i can be synthesized from intermediate 8 following the synthesis method shown in Scheme 7. Intermediate 8 can be coupled with an acid hydrazide in a polar aprotic solvent (e.g. THF, 1,4-dioxane DMF or MeCN ) and in the presence of a base (eg Et ₃ N or DIPEA) to give intermediate 19. Intermediate 19 can then be cyclized with 1,3,4-oxadiazole or 1,3,4-thiadiazole using 4- toluenesulfonic acid (Stabile, P. et al. Tetrahedron Lett. 2010, 57, 4801-4805) or Lawson's reagent (Kitamura, S., et al. PCT Int. Appl., 2008011130, 2008). The cyclized intermediate thus obtained can be reduced in the presence of a catalyst such as Pd and hydrogen gas at ambient pressure and temperature to yield intermediate 1g.

Methyl ketones can be pretreated with a base and then reacted with intermediate 8 to produce intermediate 20, as described in France, S. et al. Org. Lett. 2016, 18, 4218-4221. Intermediate 20 can be treated with a hydrazine salt

- 85 047337 on in a polar protic solvent (such as MeOH and EtOH) under heating conditions to obtain pyrazole. (As described in Cadilla, R., et al. WO 03/074495 A1). The nitro intermediate thus obtained can be reduced in the presence of a catalyst such as Pd and hydrogen gas at ambient pressure and temperature to obtain intermediate 1 i.

Intermediate 20 can also be reacted with a hydroxylamine hydrochloride salt in a polar protic solvent such as ethanol at boiling point to produce a substituted isoxazole (as described in Cadilla, R., et al. WO 03/074495 A1). The nitro intermediate thus obtained can be reduced in the presence of a catalyst such as Pd and hydrogen gas at ambient pressure and temperature to yield intermediate 1h.

Scheme 8

Intermediate 8 can be coupled with hydrazine hydrate in a polar aprotic solvent (eg THF, 1,4-dioxane DMF or MeCN) and in the presence of a base (eg Et ₃ N or DIPEA) to give intermediate 21. Intermediate 21 can be reacted with the substituted amide in the presence of trifluoromethanesulfonic anhydride and 2-fluoropyridine under heating conditions to give intermediate 22 as described by Charette, A. B. et al. Org. Lett., 2015, 77, 1184-1187. Intermediate 22 thus obtained can be reduced 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 gas at ambient pressure and temperature to yield intermediate 1j.

Scheme 9

Scheme 9 describes the synthesis of intermediate 1k. Intermediate 16 can be obtained from commercial sources or can be synthesized by known methods or modifications thereof readily recognized by one skilled in the art (described as in Bioorg. & Med. Chem. Lett, 2017, 27, 2192-2196). Intermediate 16 can be treated with a thiazolidinedione in polar solvents such as DMF or DMAc, in the presence of a base such as K2CO3 and Na ₂ CO ₃ at room temperature or under heating conditions to obtain intermediate 24 (as described in Brown, ML et al WO 2004/032882 A2). Intermediate 24 can be treated with reagents such as POCl ₃ or SOCl ₂ in the presence of a base such as Et ₃ N and DIPEA for chlorination (as described in Brown, ML et al. WO 2004/032882 A2) followed by treatment

- 86 047337 metal alkoxides to give the corresponding substituted intermediates, which after reduction as described in Scheme 3 give intermediate 1k.

Circuit 10A

Scheme 10A describes the synthesis of intermediate 11 (where Y ² is an N''-atom). Intermediates 85 and 86 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediates 85 and 86 can be subjected to various metal-catalyzed reactions (including, but not limited to, reactions such as the Ullmann and Buchwald reactions) in the presence of a metal catalyst (eg, CuI, CuBr, Cu(OAc) ₂ , Cu ₂ O, Pd( OAc) ₂ , Pd ₂ (dba) ₃ or Pd(dppf)Cl ₂ ) and a corresponding ligand (including, but not limited to, ligands such as 1,10-phenanthroline, L-proline, tricyclohexylphosphine, dppf or β-ketoesters) if necessary. Ullmann and Buchwald coupling reactions of intermediates 85 and 86 can be carried out with a variety of coupling partners, including, but not limited to, substituted or unsubstituted pyrrole, pyrazole, imidazole, triazole, indole, indazole, benzimidazole, benzotriazole, and cyclic amides. Coupling reactions can be carried out in the presence of a base, when necessary (bases including, but not limited to, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , K3PO4, NaOtBu or DBU), and a solvent (for example, dioxane, THF, DME, MeCN, DMSO, DMF or MeOH) under heating conditions to obtain intermediate 11 from intermediate 86. The coupled N-linked heteroaryl nitro intermediate obtained from 85 can be subjected to reduction 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 gas, or Zn and ammonium chloride, or Fe and acetic acid to produce intermediate 11.

Circuit 10V

1) combination

2) recovery

^{1t 86 * * 89}

Intermediate 1 m can be prepared in a variety of ways, as shown in Diagram 10B. Intermediates 86, 88 and 89 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediates 86, 88 and 89 can be subjected to metal-catalyzed cross-coupling reactions using numerous known methods recognized by one skilled in the art, including, but not limited to, methods described in the book Metal-Catalyzed CrossCoupling Reactions, Armin de Meijere, Francois Diederich, 2 Volumes, Second, Revised and Enlarged Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and references cited therein. Intermediates 86, 88, and 89 can be subjected to various metal-catalyzed reactions (including, but not limited to, reactions such as the Ullmann, Buchwald, Suzuki, and Stille coupling). These coupling reactions can be carried out in the presence of a metal catalyst (for example, CuBr, Pd(OAc) ₂ , Pd ₂ (dba) ₃ , Pd(PPh3)4, Pd(PPh3)2Cl2 or Pd(dppf)Cl2) and an appropriate ligand (including but not limited to, ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine and dppf), as necessary. Ullmann and Buchwald coupling reactions of intermediate 86 can be carried out with various coupling partners such as heterocyclyl or heteroarylamines. The Suzuki, Chan-Lama coupling reaction of intermediates 88 and 89 can be carried out with various coupling partners such as cycloalkenyl, aryl halides, heteroaryl halides and triflates. Intermediate 86 can be subjected to Suzuki and Stille cross-coupling with coupling partners such as cycloalkyl or alkenyl or aryl or heteroarylboronic acids, boronic acid esters and organotin reagents. Coupling reactions can be carried out in the presence of a base, as appropriate (including, but not limited to, _Na2CO3 , K2CO3, _NaHCO3 , K3PO4 or NaOtBu), and a solvent (for example, dioxane, THF, DME, toluene, methanol, DMF or water, or mixtures of two or three of these solvents) under heating conditions to give intermediate 1m. Alternatively, intermediate 86 can be converted to an organotin reagent using hexamethyltin in the presence of a palladium catalyst and in a solvent (e.g., toluene or THF) at boiling point, which, after coupling with suitable coupling partners such as cycloalkenyl, aryl or heteroaryl halides, and triflates in the Stille coupling reaction (Sherer, V., et al. PCT Int. Appl., 2016/039734, 2016) gives intermediate 1m. Intermediate 86 can be converted to an organoboron reagent using bis(pinacolato)diboron and bis(neopentylglycolato)diboron, for example in the presence of a palladium catalyst such as Pd(dppf)Cl2 and a base such as potassium acetate in a solvent (eg , dioxane or DMSO) at boiling point, which can then be coupled with suitable coupling partners such as cycloalkenyl, aryl halides, heteroaryl halides and triflates in a Suzuki coupling reaction to give intermediate 1m. Intermediate 88 followed by coupling reactions as described above provided a nitro intermediate that can be reduced using conditions recognized by one of ordinary skill in the art, including, but not limited to, reduction in the presence of a catalyst such as Pd and hydrogen gas under pressure and ambient temperature to obtain intermediate 1m.

Scheme 10C

Scheme 10C describes the synthesis of intermediates 1n. Intermediate 11 can be obtained from commercial sources or can be synthesized by known methods readily recognized by one skilled in the art. Intermediate 11 can be reacted with alkyl 2-(dimethoxyphosphoryl) acetate in the presence of a base (eg K2CO3 or Na ₂ CO ₃ ) in a polar protic solvent (eg water, methanol or ethanol) to give intermediate 83. Intermediate 83 can be subjected to a cyclopropanation reaction by treating it with a solution of diazomethane at -78°C in a solvent mixture containing diethyl ether and DCM in the presence of Pd(OAc) ₂ to obtain a nitro intermediate which can be reduced to intermediate 1n using conditions recognized by those skilled in the art in the art, including, but not limited to, described conditions such as heating in the presence of a reagent such as tin(II) chloride in a polar protic solvent. Intermediate 1n can be converted to compounds of formula I using the steps described in Scheme 1.

Intermediates 2 (Scheme 1) can be prepared in various ways, as shown in Scheme 11, using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, the following methods.

- 88 047337

Scheme 11

Synthesis

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 ring synthesis to yield compounds of intermediate 26.

Formation of heterocycle (A). The carboxylic acid moiety of compound 25 can be converted into various heterocycles (A) using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, the following methods:

A = 1,2,4-oxadiazole. Intermediate 25 can be coupled with various amidoximes (derived from the corresponding nitriles by reaction with hydroxylamine; see Hirawat, S., et al. WO 2006/110483) using an amide bond-forming coupling reagent (e.g. CDI, BOP or EDC) in a polar aprotic solvent (such as THF, 1,4-dioxane or DMF) at room temperature. The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C). Alternatively, in situ cyclization can be accomplished by coupling acid 25 with amidoximes at elevated temperatures (60°C to 100°C).

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

A = 1,3,4-oxadiazole or A = 1,3,4-thiadiazole. Intermediate 25 can be coupled to acetic acid hydrazide (described in WO 2014/071247, Bradner, JE, et al.) using an amide bond coupling reagent (e.g. CDI, BOP or EDC) in a polar aprotic solvent (e.g. THF, 1,4-dioxane DMF or MeCN). The acyclic hydrazide intermediate can then be cyclized to 1,3,4-oxadiazole or 1,3,4-thiadiazole using 4-toluenesulfonic acid, respectively (Stabile, P. et al. Tetrahedron Lett. 2010, 57, 4801-4805 ) or Lawesson's reagent (Kitamura, S., et al. PCT Int. Appl., 2008011130, 2008).

A = 3-substituted 5-alkyl-1-methyl-III-pyrazole. Methyl ketones can be treated with a base and an acid chloride of intermediate 25 to produce a diketone, which upon reaction with a substituted or unsubstituted hydrazine salt in a polar protic solvent such as ethanol at boiling point yields ester 26, wherein A is an alkyl substituted or unsubstituted pyrazole. (As described in Cadilla, R., et al. WO 03/074495 A1).

A = isoxazole. The diketone prepared from intermediate 25 as described above can, upon reaction with the hydroxylamine hydrochloride salt in a polar protic solvent such as ethanol at boiling point, yield ester 26, where A is an alkyl-substituted isoxazole (as described in Cadilla, R. , et al. WO 03/074495 A1).

A = 5-(3-alkyl-1-methyl-III-pyrazole). The diketone prepared from intermediate 25 as described above can react with an alkylhydrazine in a polar protic solvent such as ethanol at boiling point to give ester 26, where A is an alkyl-substituted pyrazole.

A = substituted heteroaryl. Intermediate 25 can be subjected to a Miniski reaction with substituted heteroaryl compounds (including, but not limited to, heteroaryl rings such as pyridine, pyrimidine, pyridazine, pyrazine, quinoline, pyrazole) in the presence of silver nitrate and potassium persulfate or ammonium persulfate in a mixture of DCM ( or any other conditions that can be used to form a carbon-centered radical) and water as solvent at ambient temperature to give ester 26 (as described in LingBo, Qu et al. Org. Biomol. Chem., 2015, 73 , 2750-2755 and Review: Duncton, M. A. J. Med. Chem. Commun., 2011, 2, 1135-1161, and references therein).

A = 2-benzothiazole. Method A Intermediate 25 can be coupled with a substituted 2-aminobenzenethiol (see generally Chedekel, MR, et al. Synth. Commun. 1980, 10, 167-173; synthesis of various 2-aminobenzenethiols) using a coupling reagent to form amide bond (eg BOP, T ₃ P or EDC) in a polar aprotic solvent (eg DCE or THF). The coupling reaction can be carried out at elevated temperatures (60°C to 80°C), thereby

- 89 047337 providing the formation of cyclized 2-benzothiazole in situ.

Method B: Alternatively, intermediate 25 can be coupled to a substituted 2-chloroaniline (commercially available) using a coupling reagent to form an amide bond (e.g. T3P or BOP) or by activating intermediate 25 for acylation using any number of reagents (e.g. , oxalyl chloride or POCl ₃ ). The resulting carboxamide can be treated with Lawesson's reagent at elevated temperature (120°C), thereby carrying out in situ cyclization to 2-benzothiazole.

A = 2-benzoxazole. Intermediate 25 can be coupled to a substituted 2-aminophenol (commercially available) using an amide coupling reagent (eg, BOP or EDC) in a polar aprotic solvent (eg, DMF or THF). Cyclization can be accomplished by refluxing toluene in the presence of paratoluenesulfonic acid (tosic acid).

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

A = 2-quinazoline. Intermediate 25 can be coupled with 4-amino-3-(aminomethyl)benzoate dihydrochloride (Pascal, R. et al. Eur. J. Org. Chem. 2000, 22, 3755-3761) using a coupling reagent to form an amide bond (eg HBTU, EDC or RuBOP) in a polar aprotic solvent (eg MeCN or THF). Cyclization can be carried out under acidic conditions (pure AcOH) at elevated temperatures (115°C). The resulting dihydroquinazoline intermediate can be oxidized to 2-quinazoline using an oxidizing agent such as DDQ.

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

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

A may represent other heterocycles such as substituted as well as 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 functionality of intermediate 25 can be converted to heterocycles as shown in Schemes 2-9 using the methods and literature references described therein.

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

Scheme 12 (Fig. 1) describes an alternative synthesis of compounds of formula I with 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 reducing agent (e.g. LAH, DIBAL-H or NaBH4) to yield intermediate 28. Intermediate 28 can be oxidized to intermediate 29 by methods known to those skilled in the art using oxidation conditions (eg, Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC). Intermediate 1 and intermediate 29 can be reacted in the presence of an acid such as acetic acid in a suitable polar protic solvent (e.g. MeOH or EtOH) at room temperature or boiling point, followed by reduction with reducing agents (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride) to yield intermediate 30. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) at temperatures ranging from -30°C to 0°C.

The activated acid intermediate can react with intermediate 30 in the presence of a base to form the corresponding amide. Subsequent hydrolysis of the methyl ester with an alkali metal hydroxide base can provide intermediate 31. Intermediate 31 can be converted into various heterocycles (A) using numerous known methods recognized by one of ordinary skill in the art, including

- 90 047337 tea, but without limitation, the methods described in Scheme 11 for the preparation of compounds of formula I.

Alternatively, intermediate 29 and intermediate 86 can be subjected to reductive amination using numerous known methods recognized by one skilled in the art. Synthesis of the imine in the presence of an acid such as acetic acid in a suitable polar protic solvent (e.g. MeOH or EtOH) at room temperature or boiling point followed by reduction of the imine with reducing agents (e.g. sodium cyanoborohydride or sodium triacetoxyborohydride) gives intermediate 30a. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) at temperatures ranging from -30 °C to 0°C. The activated acid intermediate can react with intermediate 30a in the presence of a base to form the corresponding amide. Subsequent hydrolysis of the methyl ester with an alkali metal hydroxide base can yield intermediate 31a. Intermediate 31a can be converted to various heterocycles (A) using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, the methods described in Scheme 11 to produce intermediate 31b. Intermediate 31b can be subjected to metal-catalyzed cross-coupling reactions using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, methods described in Metal-Catalyzed Cross-Coupling Reactions, Armin de Meijere, Francois Diederich, 2 Volumes, Second, Revised and Enlarged Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and references therein.

Intermediate 31b can also be subjected to various metal catalyzed reactions (including, but not limited to, reactions such as the Ullmann, Buchwald, Suzuki and Stille coupling). These coupling reactions can be carried out in the presence of a metal catalyst (for example, CuBr, Pd(OAc)2, _Pd2 (dba _{) 3} , Pd( _PPh3 ) ₄ , Pd( _PPh3 ) _2Cl2 or Pd(dppf) _Cl2 ) and an appropriate ligand (including, but not limited to, ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine and dppf) as needed. Ullmann and Buchwald coupling reactions of intermediate 31b can be carried out with various coupling partners such as heterocyclylamines and heteroarylamines. Intermediate 31b can be subjected to Suzuki and Stille cross-coupling reactions with coupling partners such as, for example, cycloalkylboronic acids, alkenylboronic acids, arylboronic acids, heteroarylboronic acids, boronic acid esters and organotin reagents. Coupling reactions can be carried out in the presence of a base, if necessary (including, but not limited to, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , K ₃ PO ₄ or NaOtBu), and a solvent (eg, dioxane, THF, DME, toluene , methanol, DMF or water, or a mixture of two or three of these solvents) under heating conditions to obtain compounds of formula I. Alternatively, intermediate 31b can be converted into an organotin reagent using hexamethyltin in the presence of a palladium catalyst and in a solvent (for example, toluene or THF) at boiling point, which after coupling with suitable coupling partners such as cycloalkenyl, aryl or heteroaryl halides, and triflates in the Stille coupling reaction (Sherer, V., et al. PCT Int. Appl., 2016/039734, 2016) gives the compounds represented by Formula I. Intermediate 31b can be converted to an organoboron reagent using bis(pinacolato)diboron or bis(neopentylglycolato)diboron, for example, in the presence of a palladium catalyst such as Pd(dppf)Cl ₂ and a base such as potassium acetate, in a solvent (e.g. dioxane or DMSO) at boiling point, which when combined with suitable coupling partners such as cycloalkenyl, aryl or heteroaryl halides and triflates in a Suzuki coupling reaction gives the compounds represented by Formula I.

Scheme 13 (Fig. 2) describes an alternative synthesis of compounds of formula I with a modified sequence of steps.

Intermediate 30 (described in Scheme 12) can be subjected to hydrolysis of the methyl ester with an alkali metal hydroxide base to yield intermediate 32. Intermediate 32 can be converted into various heterocycles (A) using numerous known methods recognized by one of ordinary skill in the art, including but not limited to, the methods described in Scheme 11 to produce compounds of Formula 33. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (for example, DCM or THF) at a temperature from -30°C to 0°C. The activated acid intermediate can react with intermediate 33 in the presence of a base to form compounds of formula I.

Alternatively, intermediate 30a (described in Scheme 12) can be subjected to hydrolysis of the methyl ester with an alkali metal hydroxide base to give the intermediate

- 91 047337 precise connection 32a. Intermediate 32a can be converted to various heterocycles (A) using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, the methods described in Scheme 11, to obtain compounds of formula 33a. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) over a temperature range of -30° From to 0°C. The activated acid intermediate can react with intermediate 33a in the presence of a base to form intermediate 33b. Intermediate 33b can be subjected to metal-catalyzed cross-coupling reactions using numerous known methods recognized by one of ordinary skill in the art, including, but not limited to, methods described in MetalCatalyzed Cross-Coupling Reactions, Armin de Meijere, Francois Diederich, 2 Volumes. Second, Revised and Enlarged Edition, 2004, ISBN: 3-527-30518-1, Wiley-VCH and references cited therein. The intermediate amide can be subjected to various metal-catalyzed reactions (including, but not limited to, Ullmann, Buchwald, Suzuki and Stille coupling reactions). These coupling reactions can be carried out in the presence of a metal catalyst (for example, CuBr, Pd(OAc)2, _Pd2 (dba _{) 3} , Pd( _PPh3 ) ₄ , Pd( _PPh3 ) _2Cl2 or Pd(dppf) _Cl2 ) and an appropriate ligand (including, but not limited to, ligands such as proline, 1,10-phenanthroline, tricyclohexylphosphine or dppf) as needed. Ullmann and Buchwald coupling reactions of intermediate 33b can be carried out with various coupling partners such as heterocyclylamines and heteroarylamines. Intermediate 33b can be subjected to Suzuki and Stille cross-coupling reactions with coupling partners such as cycloalkyl, alkenyl, aryl or heteroarylboronic acids, boronic acid esters and organotin reagents. Coupling reactions can be carried out in the presence of a base, if necessary (including, but not limited to, Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ , K ₃ PO ₄ or NaOtBu), and a solvent (eg, dioxane, THF, DME, toluene , methanol, DMF or water, or a mixture of two or three of these solvents) under heating conditions to give compounds of formula I. Alternatively, intermediate 33b can be converted into an organotin reagent using hexamethylditin in the presence of a palladium catalyst and in a solvent (for example, toluene and THF) at boiling point, which when combined with suitable coupling partners such as cycloalkenyl halides, aryl halides, heteroaryl halides and triflates in the Stille coupling reaction (Sherer, V., et al. PCT Int. Appl., 2016/039734, 2016) gives compounds represented by Formula I. Intermediate 33b can be converted to an organoboron reagent using bis(pinacolato)diboron or bis(neopentylglycolato)diboron, for example in the presence of a palladium catalyst such as Pd(dppf)Cl ₂ and a base such as acetate potassium, in a solvent (eg dioxane or DMSO) at boiling point, which when reacted with suitable coupling partners such as cycloalkenyl halides, aryl halides, heteroaryl halides and triflates in a Suzuki coupling reaction gives the compounds represented by Formula I.

Scheme 14

Scheme 14 describes the synthesis of intermediate 40, where 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 or HATU in the presence of a solvent,

- 92 047337 such as DCM and DMF, and an organic base such as Et ₃ N or DIPEA, at ambient temperature in the presence of ammonium chloride to obtain intermediate 34. Intermediate 34 can be converted to intermediate 35 by treatment with trifluoroacetic anhydride in pyridine at 0°C or by treatment with POCl ₃ and a base such as imidazole. Intermediate 36 can be synthesized by reacting intermediate 35 with hydroxylamine; see Hirawat, S., et al. WO 2006/110483. Variably substituted intermediates 37 can be coupled to intermediates 36 using an amide bond-forming coupling reagent (e.g. CDI, BOP or EDC) in a polar aprotic solvent (e.g. THF, 1,4-dioxane or DMF) at room temperature. The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C). Alternatively, in situ cyclization can be accomplished by coupling acids 37 with amidoximes 36 at elevated temperatures (60°C to 100°C) to yield intermediates of formula 38. Subsequent hydrolysis of intermediate 38 with an alkali metal hydroxide base can provide the acid that can be reduced in the presence of hydride reducing agents (e.g. LAH, DIBALH or NaBH4) in a chlorinated or ethereal solvent such as DCM, ether, 1,4-dioxane or THF to give intermediate 39 Intermediate 39 can be oxidized to intermediate 40 by methods known to those skilled in the art using oxidation conditions (eg, Dess-Martin periodane, Swern oxidation conditions, PDC or PCC). Intermediates 40 can be converted to compounds of Formula I using the steps described in Scheme 1.

Scheme 15 (Fig. 3) describes the synthesis of compounds of formula I (ad). The intermediates represented by Formula 31 (synthesis described in Scheme 12) can be esterified. Intermediate 31 can be activated for acylation using any number of reagents known to one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) at temperatures ranging from - 30°C to 0°C. The activated acid intermediate can react with alcohols in the presence of a base to form compounds of formula Ia. Intermediate 31 can be subjected to amide synthesis by activating the acid with an activating agent (eg BOP, CDI or HATU) in a solvent (eg DCM or DMF) in the presence of a base (eg Et ₃ N or DIPEA) at ambient temperature or under heating conditions in the presence of ammonium chloride or a substituted amine (eg, alkyl, cycloalkyl, aryl and heteroaryl) to produce amides of formula Ib. Intermediate 31 can be subjected to primary amide synthesis by treatment with an activating agent (eg BOP, CDI or HATU) in a solvent (eg DCM or DMF) in the presence of a base (eg Et3N or DIPEA) and ammonium chloride at ambient temperature. The primary amide thus obtained can be treated with i) trifluoroacetic anhydride in pyridine at 0° C. or ii) POCl ₃ and imidazole to give nitriles of formula Ic. Intermediate 31 can be activated using any number of reagents known to one skilled in the art (eg, thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate and ethyl chloroformate) in a polar aprotic solvent (eg, DCM or THF) at temperatures ranging from -30 °C to 0°C. The activated acid intermediate can react with sulfonamides in the presence of a base (e.g. pyridine, DMAP, 2(dimethylamino)pyridine or N-methylmorpholine) in a polar aprotic solvent (e.g. DCM or THF) at temperatures ranging from 0°C to 90°C C to form acyl sulfonamides of formula Id.

- 93 047337

Scheme 16

Scheme 16 describes the synthesis of intermediate 2a. Intermediate 52 can be synthesized according to methods described by Singh, S. B. et al. (ACS Med. Chem. Lett. 2014, 5, 609-614). Intermediate 53 can be deprotonated with n-BuLi in an ethereal solvent (e.g. THF and 1,4-dioxane) at -78°C to 0°C and then reacted with intermediate 52 to give intermediate 54 Intermediate 54 can be cyclized in the presence of an alkali metal hydroxide base at elevated temperature (70°C) to form intermediate 55. Thioacetal deprotection can be accomplished using any number of reagents (eg, NCS, Hg(ClO ₄ ) ₂ , or DDQ) to produce an aldehyde, which can be oxidized to an acid using an oxidizing agent (NaClO2, PCC, PDC or _KMnO4 ) and then esterified by reaction with iodomethane to produce intermediate 56. Subsequent hydrolysis of intermediate 56 with an alkali metal hydroxide base may yield intermediate 57. Intermediate 57 can be converted to various heterocycles (A) using a variety of known methods recognized by one of ordinary skill in the art, including, but not limited to, the methods described in Scheme 11, to produce the compounds of intermediate 58. Intermediate 58 can be treated with an acetate salt (e.g., CsOAc or KOAc) in a polar aprotic solvent (e.g., DMF or NMP) at elevated temperatures (120°C) to yield the corresponding acetate, which upon subsequent hydrolysis under acidic conditions (HCl) yields intermediate 59. Intermediate 59 can be oxidized by methods recognized by one skilled in the art using oxidation conditions (eg, Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC) to give compounds of formula 2a. Intermediates 2a can be converted to compounds of formula I using the steps described in Scheme 1.

- 94 047337

Scheme 17

Scheme 17 describes an alternative synthesis of intermediate 2b. Intermediate 52 can be synthesized according to methods described by Singh, S. B. et al. (ACS Med. Chem. Lett. 2014, 5, 609-614). Halogenated heterocycles 60 (commercially available or prepared by methods known to those skilled in the art) can be treated with a base (such as, for example, n-BuLi, s-BuLi or MeLi) in an ethereal solvent (for example, THF or 1,4dioxane) at temperature in the range from -78°C to 0°C and then reacted with ketone 52 to obtain intermediate 61. Intermediate 61 can be cyclized in the presence of an alkali metal hydroxide base at elevated temperature (70°C) to obtain intermediate 62 Intermediate 62 can be treated with an acetate salt (eg CsOAc or KOAc) in a polar aprotic solvent (eg DMF or NMP) at elevated temperatures (120°C) to yield the corresponding acetate, which is subsequently hydrolyzed under acidic conditions (HCl). yields intermediate 63. Intermediate 63 can be oxidized by methods known to those skilled in the art using oxidation conditions (eg, Dess-Martin periodinane, Swern, PDC, or PCC oxidation conditions) to yield intermediate 2b. Intermediate 2b is converted to compounds of formula I using the steps described in Scheme 1.

Scheme 18A

Scheme 18A describes an alternative synthesis of compounds of formula I. Intermediate 57 (synthesis described in Scheme 16) is reduced in the presence of a hydride reducing agent (eg LAH, DIBAL-H or NaBH ₄ ) to give intermediate 64. Intermediate 64 can be oxidized to aldehyde 65 by methods recognized by one skilled in the art using oxidation conditions (eg, Dessa Martin periodinane, Swern oxidation conditions, PDC or PCC). Intermediate 1 and Intermediate 65 are subjected to reductive amination using numerous known methods recognized by one skilled in the art in the presence of an acid such as acetic acid in a suitable polar protic solvent (eg MeOH or EtOH) at room temperature

- 95 047337 temperature or boiling point, followed by reduction of the imine with reducing agents (eg sodium cyanoborohydride or sodium triacetoxyborohydride) to give intermediate 66. Intermediate 66 can be treated with an acetate salt (eg CsOAc or KOAc) in a polar aprotic solvent ( e.g. DMF or NMP) at elevated temperatures (120°C) to yield the corresponding acetate, which upon subsequent hydrolysis under acidic conditions (HCl) gives intermediate 67. Intermediate 67 can be oxidized to an acid by using an oxidizing agent ( _NaClO2 , PCC, PDC or KMnO) followed by the synthesis of various heterocycles (A) using numerous known methods recognized by one skilled in the art, including, but not limited to, the methods described in Scheme 11, to obtain intermediate 68. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) at temperatures ranging from -30°C to 0 °C. The activated acid intermediate can react with intermediate 68 in the presence of a base to form compounds of formula I.

Circuit 18V

Scheme 18B describes an alternative synthesis of compounds of formula I. Intermediate 86 and intermediate 65 (as shown in Scheme 18A) can be subjected to reductive amination using numerous known methods recognized by one skilled in the art, in the presence of an acid such as acetic acid, in a suitable polar protic solvent (eg MeOH or EtOH) at room temperature or boiling point, followed by reduction of the imine with reducing agents (eg sodium cyanoborohydride or sodium triacetoxyborohydride) to give intermediate 66a. Intermediate 66a can be treated with an acetate salt (e.g. CsOAc or KOAc) in a polar aprotic solvent (e.g. DMF or NMP) at elevated temperatures (120°C) to yield the corresponding acetate, which upon subsequent hydrolysis under acidic conditions (HCl) gives intermediate 67a. Intermediate 67a can be oxidized to acid using an oxidizing agent (NaClO ₂ , PCC, PDC or KMnO ₄ ) followed by the synthesis of various heterocycles (A) using numerous known methods recognized by one skilled in the art, including, but not limited to, methods described in Scheme 11 to yield intermediate 68a. Intermediate 68a can be converted to compounds of formula I by following the steps described in Scheme 13.

- 96 047337

Scheme 19

Scheme 19 describes an alternative synthesis of compounds of formula I. Intermediate 2 can be treated with organic magnesium reagents in an ethereal solvent (such as Et ₂ O or THF) at a temperature ranging from -78°C to 0°C to give intermediate 70 Intermediate 70 can be oxidized to intermediate 71 by techniques recognized by one skilled in the art under oxidation conditions using oxidizing agents such as Dess-Martin periodinane, PDC or PCC. Intermediate 71 and intermediate 1 in a polar protic solvent such as MeOH or EtOH can be treated with triethylsilane and indium chloride at ambient temperature to give intermediates of formula 72. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art. in the art (eg, thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate or ethyl chloroformate) in a polar aprotic solvent (eg, DCM or THF) at a temperature ranging from -30°C to 0°C. The activated acid intermediate can react with intermediate 72 in the presence of a base to form compounds of formula I.

Scheme 20

- 97 047337

Scheme 20 describes the synthesis of compounds of formula I (eg) (where A is an amide, sulfonamide, urea or carbamate). Intermediate 25 can be converted to intermediate 73 by 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 reducing agent (e.g., LAH, DIBAL-H, or NaBH ₄ ) to yield intermediate 74. Intermediate 74 can be oxidized to aldehyde 75 using techniques recognized by one of ordinary skill in the art. using oxidation conditions (eg, Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC). Intermediate 1 and Intermediate 75 can be subjected to reductive amination using numerous 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 or EtOH) at room temperature or boiling point followed by reduction of the imine with reducing agents (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to yield intermediate 76. Intermediate 4 can be activated for acylation using any number of reagents recognized by one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate or ethyl chloroformate), in a polar aprotic solvent (for example, DCM or THF) at a temperature ranging from -30°C to 0°C. The activated acid intermediate can react with intermediate 76 in the presence of a base to form the corresponding amide. The amide intermediate can be deprotected in a polar aprotic solvent (eg DCM or THF) with trifluoroacetic acid at room temperature to give intermediate 77. Intermediate 77 can be subjected to a variety of different transformations using numerous known methods recognized one skilled in the art, including, but not limited to, the following methods to produce variants of Formula I.

Amides. Intermediate 77 can react with activated acid intermediates in the presence of a base (eg, pyridine, DMAP, 2(dimethylamino)pyridine, or N-methylmorpholine) in a polar aprotic solvent (eg, DCM or THF) to form amides of formula Ie.

- 98 047337

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

Urea. Intermediate 77 can be treated with isocyanates in the presence of a base (eg Et ₃ N, DIPEA or pyridine) in a polar aprotic solvent (eg DCM or DCE) at room temperature to give urea represented by formula Ig. Alternatively, intermediate 77 can be activated by treatment with triphosgene in the presence of a base (eg Et ₃ N or DIPEA) in a solvent (eg DCM or DCE) at a temperature ranging from 0° C. to room temperature. Activated intermediate 3 can then be treated with a substituted alkylamine, arylamine or heteroarylamine in the presence of a base (eg Et ₃ N or DIPEA) in a solvent (eg DCM or DCE) at room temperature to produce urea represented by formula Ig.

Carbamates. Intermediate 77 can be treated with chloroformates in the presence of a base (eg Et3N, DIPEA or pyridine) in a polar aprotic solvent (eg DCM, DCE or THF) at temperatures ranging from 0°C to room temperature to give the carbamates represented by formula Ih .

Scheme 21

82

Scheme 21 describes the synthesis of intermediates 82, where A is a 3-(5-substituted-1,2,4-oxadiazolyl) ring. Intermediate 30a (synthesized as described in Scheme 12) can be hydrolyzed with an alkali metal hydroxide base to yield intermediate 78. Intermediate 78 can be subjected to primary amide synthesis by acid activation with an activating agent (e.g. BOP, CDI or HATU) in a polar aprotic solvent (e.g. DCM or DMF) in the presence of a base (e.g. Et3N or DIPEA) at ambient temperature in the presence of ammonium chloride to give 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 a reagent (eg, POCl ₃ , SOCl ₂ or TFAA) and base (eg, imidazole, Et ₃ N and DIPEA). 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 readily recognized by one skilled in the art. Intermediates 37 can be coupled to intermediates 81 using an amide bond coupling reagent (eg, CDI, BOP, or EDC) in a polar aprotic solvent (eg, THF, 1,4-dioxane, or DMF) at room temperature. The acyclic intermediate can then be cyclized at elevated temperatures (60°C to 100°C). Alternatively, in situ cyclization can be accomplished by coupling intermediates 37 with intermediates 81 at elevated temperatures (60°C to 100°C) to produce oxadiazoles 82. Intermediates 82 can be converted to compounds of formula I by sequential amide and combinations as described in diagram 13.

- 99 047337

Scheme 22

Scheme 22 describes the synthesis of compounds of formula I (where A is aryl). Commercially available 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be subjected to bromine bromination in the presence of mercuric oxide in dibromomethane as a solvent under heating conditions to yield intermediate 90 (as described by Owen et. al . PCT Int. Appl., 2014113485, 2014). Intermediate 90 can be converted to intermediate 91 in benzene in the presence of AlCl ₃ under the conditions described by Piyasena et. al. PCT Int. Appl., 2015005901, 2015. Intermediate 91 can be brominated in the presence of silver trifluoroacetate and bromine in CHCl ₃ at room temperature to give intermediate 92 (described by Piyasena et. al. PCT Int. Appl., 2015005901, 2015). Intermediate 92 can be reduced in the presence of a hydride reducing agent (eg LAH, DIBALH or NaBH ₄ ) to give intermediate 93. Intermediate 93 can be oxidized to aldehyde 94 by techniques recognized by one of skill in the art using oxidation conditions (eg Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC). Intermediate 1 and Intermediate 94 can be subjected to reductive amination using numerous known methods recognized by one skilled in the art in the presence of an acid such as acetic acid in a suitable polar protic solvent (eg MeOH or EtOH) at room temperature or boiling point followed by reduction of the imine with reducing agents (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to yield intermediate 95. Intermediate 4 can be activated for acylation using any number of reagents known to one skilled in the art (e.g., thionyl chloride, phosphorus oxychloride, oxalyl chloride, methyl chloroformate or ethyl chloroformate) in a polar aprotic solvent (eg DCM or THF) at a temperature ranging from -30°C to 0°C. The activated acid intermediate can react with intermediate 95 in the presence of a base to form intermediate 96. Intermediate 96 can be subjected to various metal-catalyzed reactions (including, but not limited to, reactions such as Ullmann, Suzuki, Buchwald and Stille coupling reactions) in the presence of a metal catalyst (for example, CuBr, Pd(OAc) ₂ , Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ , Pd(PPh ₃ ) ₂ Cl ₂ or Pd(dppf)Cl ₂ ) and an appropriate ligand (including , but not limited to ligands such as tricyclohexylphosphine or dppf) as appropriate. Ullmann and Buchwald coupling reactions of intermediate 96 can be carried out with various coupling partners such as alkylamines, arylamines, heteroarylamines, thiols and alcohols. The Suzuki or Stille coupling reaction of intermediate 96 can be carried out with various coupling partners such as alkenylboronic acids, arylboronic acids, heteroa

- 100 047337 rilboronic acids, boronic acid esters and organotin reagents. Coupling reactions can be carried out in the presence of a base, when necessary (including, but not limited to, _Na2CO3 , K2CO3, _NaHCO3 , K3PO4 or NaOtBu), and a solvent (for example, dioxane, THF, DME, toluene, methanol, DMF or water, or a mixture of two or three of these solvents) under heating conditions to obtain compounds of formula I.

Scheme 23 describes the synthesis of intermediate 99. Commercially available 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 25 can be subjected to bromination followed by Friedel-Crafts arylation in the presence of suitably substituted arenes as described in Scheme 22 to yield intermediate 97. Alternatively, intermediate 97 can be synthesized via Negishi or Suzuki type decarboxylating cross-coupling reactions. Intermediate 25 can be activated as an N-hydroxyphthalimide ester or an N-hydroxybenzotriazole ester, a redox-active ester, and can be treated with organozinc or organoboron acids, or Grignard reagents of differently substituted aryls in the presence of metal catalysts ( for example, Fe(acac) ₃ , FeCl ₃ or NiCl2-glyme), as described in Torriyama, F. et al J. Am. Chem. Soc. 2016, 138, 11132-11135, and references cited therein, to yield intermediate 97. Intermediate 97 can be reduced in the presence of a hydride-based reducing agent (e.g., LAH, DIBAL-H, or NaBH4) to yield intermediate 98. Intermediate 98 can be oxidized to aldehyde 99 by techniques recognized by one skilled in the art using oxidation conditions (eg, Dess-Martin periodinane, Swern oxidation conditions, PDC or PCC). Intermediate 99 can be converted to compounds of Formula I (where A is aryl) using the steps described in Scheme 1.

The sequence of steps, including the introduction of groups Q and A, can be carried out interchangeably in the schemes depending on the situation.

Example 1.

N((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octan-1 -yl)methyl)-N-(3 -(3-methyl-1,2,4-oxadiazol-5yl)phenyl)isobutyramide

Step A. Intermediate 1 A. Preparation of 3-methyl-5-(3-nitrophenyl)-1,2,4-oxadiazole

To a solution of 3-nitrobenzoic acid (1 g, 5.98 mmol) in DMF (10 ml) was added (E)-N'hydroxyacetimidamide (0.887 g, 11.97 mmol) (commercially available), BOP (2.65 g, 5.98 mmol) followed by TEA (2.502 ml, 17.95 mmol). The reaction mixture was stirred for 1 hour at room temperature and then heated to 100°C and stirred for 2 hours. The reaction mixture was poured into water (10 ml) and extracted with EtOAc (2x30 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain

- 101 047337 the crude product, which was purified by flash chromatography (silica gel, 0-20% EtO Ac/PE). Fractions containing the compound were concentrated under reduced pressure to obtain the title compound (0.3 g, 1.389 mmol, 23% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.50-8.54 (m, 2H), 7.94 (t, J=8.00 Hz, 1H), 2.47 (s, 3H).

Stage B. Intermediate 1B. Preparation of 3-(3-methyl-1,2,4-oxadiazol-5-yl)aniline

To a solution of intermediate 1A (0.15 g, 0.731 mmol) in ethanol (5 ml) and water (0.2 ml) was added tin(II) chloride (0.693 g, 3.66 mmol). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in EtOAc (30 ml) and washed with 10% aqueous NaHCO ₃ (10 ml) and brine (25 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-20% EtOAc/PE) to give the title compound (0.13 g, 0.705 mmol, 96% yield) as an off-white solid.

^1H NMR (400 MHz, DMSO-d6) δ 7.35-7.15 (m, 3H), 6.83 (ddd, J= 7.8, 2.3, 1.3 Hz, 1H), 5.54 (s, 2H), 2.39 (s, 3H) . MS (ESI) 176 (M+H).

Stage C. Intermediate 1C. Preparation of methyl 4-bromobicyclo[2.2.2]-octane-1carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1 g, 4.71 mmol) in CH ₂ Br ₂ (10 ml) was added red mercuric oxide (1.735 g, 8.01 mmol ) and heated to 80°C. Bromine (0.364 mL, 7.07 mmol) was added dropwise to the above reaction mixture and the reaction mixture was stirred for 3 hours. The reaction mixture was cooled to room temperature, filtered, and the solids were washed with dibromomethane. The filtrate was concentrated under reduced pressure to give the title compound (1 g, 4.05 mmol, 86% yield).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.56 (s, 3H), 2.25-2.15 (m, 6H), 1.94-1.85 (m, 6H).

Stage D. Intermediate 1D. Preparation of methyl 4-phenylbicyclo[2.2.2]-octane-1carboxylate

H ₃ C-0 /—h

Aluminum chloride (2.70 g, 20.23 mmol) was transferred to a 50 mL two-neck round bottom flask under nitrogen and cooled to -10°C. Benzene (12.72 mL, 142 mmol) was added to the reaction flask and the resulting mixture was stirred for 5 minutes. A solution of intermediate 1C (1 g, 4.05 mmol) in benzene (12.72 mL, 142 mmol) was then added to the reaction mixture at -10°C, and the reaction mixture was warmed to room temperature and stirred for 12 hours. the mixture was poured into crushed ice and the layers were separated. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (0.82 g, 2.097 mmol, 52% yield).

1H 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), 1.991.84 (m, 12H). MS (ESI) 445 (M+H).

Step E. Intermediate 1E. Preparation of methyl 4-(4-bromophenyl)bicyclo[2.2.2]octane1-carboxylate

Intermediate 1D (0.8 g, 3.27 mmol) was transferred to a 50 mL two-neck round bottom flask under nitrogen at room temperature and CHCl ₃ (20 mL) was added. Silver trifluoroacetate (0.868 g, 3.93 mmol) was added to the stirred reaction mixture and stirred for 5 minutes. A solution of Br ₂ (0.169 ml, 3.27 mmol) in CHCl ₃ (40 ml) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through a pad of celite, and the celite layer was washed with CHCl ₃ (50 ml ). The filtrate was concentrated under reduced pressure and the solids were triturated with n-hexane to give the title compound (0.74 g, 1.580 mmol, 48% yield). MS (ESI) 323 (M + N).

1H 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), 1.991.78 (m, 12H) .

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Step F. Intermediate 1F. Preparation of methyl 4-(4cyclopropylphenyl)bicyclo[2.2.2]octane-1-carboxylate

O /—h /=\

N ₃ S-S) '—'

A stirred suspension of intermediate 1E (500 mg, 1.547 mmol), cyclopropylboronic acid (199 mg, 2.320 mmol) and tribasic potassium phosphate (985 mg, 4.64 mmol) in 1,4dioxane (10 ml) was degassed and refilled with argon for 10 min. Palladium(P) acetate (34.7 mg, 0.155 mmol) and tricyclohexylphosphine (87 mg, 0.309 mmol) were added to this mixture. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature and then poured into cold water. The aqueous layer was extracted with EtOAc (2x50 ml) and the combined organic layers were dried over MgSO ₄ . The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-20% ESA/PE) to give the title compound (330 mg, 0.580 mmol, 38% yield). MS (ESI) 285 (M+H).

Stage G. Intermediate 1G. Preparation of (4-(4cyclopropylphenyl)bicyclo[2.2.2]octan-1-yl)methanol

Intermediate 1F (330 mg, 1.160 mmol) was placed in a two-neck round bottom flask under nitrogen and THF (10 mL) was added. The solution was cooled to -78°C and then DIBAL-H (2.3 mL, 2.321 mmol) was added. After stirring for 2 hours, the reaction mixture was poured into a saturated aqueous NH4Cl solution. The aqueous layer was extracted with EtOAc (2x50 ml) and the combined organic layers were dried over MgSO ₄ . The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-20% EtOAc/PE) to give the title compound (250 mg, 0.975 mmol, 84% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 2H), 4.34 (d, J=5.5 Hz, 1H), 3.07 ( d, J=5.4 Hz, 2H), 1.91-1.79 (m, 1H), 1.78-1.64 (m, 6H), 1.49-1.36 (m, 6H), 0.89 (dd, J=2.2, 8.4 Hz, 2H) , 0.65-0.51 (m, 2H).

Step H: Intermediate 1H. Preparation of 4-(4cyclopropylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

To a stirred solution of intermediate 1G (260 mg, 1.014 mmol) in DCM (10 ml) was added Dess-Martin periodinane (516 mg, 1.217 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-20% EtOAc/PE) to give the title compound (200 mg, 0.786 mmol, 78% yield).

1H NMR (400 MHz, Chloroform-d) δ 9.61-9.42 (m, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 1.91-1.83 (m, 7H), 1.81-1.73 (m, 6H), 0.95-0.91 (m, 2H), 0.67 (dd, J=1.6, 5.0 Hz, 2H).

Stage I. Intermediate 1I. Preparation of N-((4-(4cyclopropylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)aniline

To a stirred solution of intermediate 1B (34.4 mg, 0.197 mmol) and intermediate 1H (50 mg, 0.197 mmol) in MeOH was added AcOH (5.63 μL, 0.098 mmol) followed by molecular sieves 4Λ (5 mg). The reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was cooled to 0°C, sodium cyanoborohydride (37.1 mg, 0.590 mmol) was added and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 ml). The EtOAc solution was poured into cold water (5 ml) and the aqueous layer was extracted with EtOAc (2x10 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (4 g silica gel cartridge, gradient 0-30% EtOAC in hexane as eluent) to give the title compound (45 mg, 0.074 mmol, 38% yield). MS (ESI) 414 (M-N).

Step J. Example 1. Preparation of A((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-No-(3-103 047337 (3-methyl-1,2,4- Oxadiazol-5-yl)phenyl)isobutyramide

To a solution of intermediate 1I (15 mg, 0.036 mmol) in anhydrous DCM (2 mL) was added Et ₃ N (0.020 mL, 0.145 mmol) and the resulting mixture was stirred for 5 min. Isobutyryl chloride (7.73 mg, 0.073 mmol) was added to the above reaction mixture and stirring was continued for 2 hours at room temperature. The reaction mixture was concentrated and the crude product was purified by preparative LC/MS using the following conditions: column: Waters XBridge C18, 19 x 150 mm, 5 µm particles; mobile phase A: 10 mM ammonium acetate; mobile phase B: acetonitrile; gradient: 40-80% B for 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (4.9 mg, 10.1 μmol, 28%).

1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.82-7.63 (m, 2H), 7.12 (d, J=8.1 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H) , 3.64 (br. s., 2H), 2.44 (s, 3H), 1.91-1.75 (m, 1H), 1.73-1.55 (m, 6H), 1.49-1.30 (m, 6H), 1.02-0.76 (m , 9H), 0.64-0.47 (m, 2H). FXR EU ₅₀ (nM) 1826; MS (ESI) 484 (M+H).

The following compound was synthesized in accordance with the method described for the synthesis of the compound of example 1, by replacing intermediate 1I and the corresponding acid chloride.

Etc. No. Structure MS (ESI) (M+H) FXR EC50 (hM) 2 ABOUT Ν-0 482 3063 2 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.75-7.62 (m, 1H), 7.20-7.02 (m, J= 8.1 Hz, 2H), 6.99-6.81 (m, J= 8.6 Hz, 2H), 3.71 (br. s., 2H), 2.44 (s, 3H), 1.86- 1.78 (m, 1H), 1.69-1.58 (m, 6H), 1.47-1.32 (m, 7H), 0.92-0.79 (m, 4H), 0.66 (br. s., 2H), 0.61-0.53 (m, 2H)

Example 3.

^(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N(4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo [2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 3A. Preparation of methyl 4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1-carboxylate

To a 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 (1.396 g, 18.85 mmol ), BOP (4.17 g, 9.42 mmol), and then TEA (3.94 ml, 28.3 mmol). The reaction mixture was stirred at room temperature for 2 hours and then heated to 110°C overnight. The reaction mixture was cooled to room temperature and poured into water. The aqueous layer was extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-30% EtOAc/PE). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound (0.6 g, 2.277 mmol, 24% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.60 (s, 3H), 2.29 (s, 3H), 1.95-1.86 (m, 6H), 1.86-1.78 (m, 6H).

Stage B. Intermediate 3B. Preparation of (4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methanol

- 104 047337

The title compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 3A where necessary. The crude product was purified by flash column chromatography (Combiflash, 4 g, silica gel, 0-30% EtOAc/petroleum ether) to give the desired product (0.58 g, 2.348 mmol, 98% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 4.41 (br. s., 1H), 3.08 (s, 2H), 2.29 (s, 3H), 1.90-1.80 (m, 6H), 1.50-1.40 (m, 6H).

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

To a solution of intermediate 3B (0.58 g, 2.61 mmol) in dichloromethane (10 ml) at 0°C was added Dess-Martin periodinane (2.213 g, 5.22 mmol) under nitrogen and stirred for 1 h at 0°C. The reaction mixture was filtered through a pad of celite and the filtrate was washed with 10% aqueous sodium bicarbonate solution (2x50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (Combiflash, silica gel, 12 g, 0-20% EtOAc/PE). Fractions containing the desired product were combined and concentrated to give the title compound (0.46 g, 1.984 mmol, 76% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 2.30 (s, H), 1.96-1.84 (m, 6H), 1.73-1.66 (m, 6H).

Stage D. Intermediate connection 3D. Preparation of 3-ethyl-5-(3-nitrophenyl)-1,2,4-oxadiazole

NO ₂

IssAgAchM

N-C>\=/

To a stirred solution of (E)-Y-hydroxypropionimidamide (0.522 g, 5.93 mmol) and DIPEA (1.882 ml, 10.78 mmol) in dichloromethane (10 ml) was added 3-nitrobenzoyl chloride (1 g, 5.39 mmol) at temperature 0°C, and the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in EtOAc. The organic solution was washed with water and then with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A solution of the above residue in tetrahydrofuran (10 ml) was cooled to 0°C. A solution of 1 M TBAF in THF (5.06 mL, 5.06 mmol) was added under nitrogen and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-15% EtOAc/PE). Fractions containing the desired compound were combined and concentrated under reduced pressure to give the title compound (0.8 g, 3.47 mmol, 69% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78-8.74 (m, 1H), 8.57-8.50 (m, 2H), 7.98-7.91 (m, 1H), 2.90-2.80 (m, 2H), 1.37 -1.28 (m, 3H).

Step E. Intermediate 3E. Preparation of 3-(3-ethyl-1,2,4-oxadiazol-5-yl)aniline

NH ₂ ^N (D\=/

To a solution of intermediate 3D (1 g, 4.56 mmol) in ethanol (10 mL) was added tin(II) chloride (2.60 g, 13.69 mmol) at room temperature. The reaction mixture was heated at 90°C and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with 10% aqueous NaHCO ₃ solution and then with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.6 g, 2.85 mmol, 63% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 7.33-7.29 (m, 1H), 7.27-7.17 (m, 2H), 6.88-6.80 (m, 1H), 5.53 (s, 2H), 2.78 (q, J =7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H). MS (ESI) 190 (M+N).

Step F. Intermediate 3F. Preparation of 3-(3-ethyl-1,2,4-oxadiazol-5-yl)-U-((4-(3methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane- 1-yl)methyl)aniline

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The compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing intermediate 3E and intermediate 3C where necessary: (0.13 g, 0.297 mmol, 52% yield) as an off-white solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.34-7.24 (m, 2H), 7.22-7.17 (m, 1H), 6.92 (dd, J=7.9, 1.8 Hz, 1H), 5.99 (t, J= 5.5 Hz, 1H), 2.89 (d, J=5.9 Hz, 2H), 2.78 (q, J=7.6 Hz, 2H), 2.30 (s, 3H), 1.95-1.85 (m, 6H), 1.65-1.55 ( m, 6H), 1.28 (t, J=7.6 Hz, 3H). MS (ESI) 394 (M+H).

Step G. Example 3. Preparation of X(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(3-methyl1,2,4- Oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

To a solution of intermediate 3F (20 mg, 0.051 mmol) and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid (6.61 mg, 0.051 mmol) (synthesized as described in Organic & Biomolecular Chemistry, 2015, 73, 11597 -11601) in dichloromethane (2 ml) was added pyridine (0.012 ml, 0.152 mmol). The reaction mixture was cooled to 0°C and POCl ₃ (9.47 μl, 0.102 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM, washed with 10% aqueous sodium bicarbonate, and then with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters XBridge C18, 19x150 mm, 5 µm particles; mobile phase A: 10 mM ammonium acetate; mobile phase B: acetonitrile; gradient: 1045% B for 25 minutes, then 5 minutes retention at 100% B; flow rate: 15 ml/min). Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain the title compound (20 mg, 0.040 mmol, 78% yield) as an off-white solid (40 mg, 0.079 mmol, 89% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.15-8.08 (m, 1H), 8.06 (t, J=1.6 Hz, 1H), 7.79-7.67 (m, 2H), 3.63 (br. s., 2H) , 2.83 (q, J=7.5 Hz, 2H), 2.28 (s, 3H), 1.89 (br. s., 6H), 1.85-1.73 (m, 6H), 1.53-1.37 (m, 6H), 1.31 ( t, J=7.6 Hz, 3H). FXR EC ₅₀ (nM) 346; MS (ESI) 506 (M+H).

Example 4.

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

Step A: Intermediate 4A. Preparation of methyl 4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1-carboxylate

This compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid and (7)-N-hydroxycyclopropanecarboximidamide (commercially available). The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-30% EtOAc/PE) to give the title compound (490 mg, 1.667 mmol, 71% yield). MS (ESI) 277 (M+H).

Stage B. Intermediate 4B. Preparation of (4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methanol /—y OH

T \\_Z-X—/ M-s/ \—/

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G by replacing intermediate 4A where necessary: (500 mg, 1.087 mmol, 61% yield). MS (ESI) 249 (M+H).

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

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The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C by replacing intermediate 4B where necessary: (350 mg, 1.421 mmol, 71% yield). MS (ESI) 247 (M+H).

Stage D. Intermediate 4D. Preparation of A((4-(3-cyclopropyl-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-ethyl-1,2,4- Oxadiazol-5-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 3E and intermediate 4C where necessary: (40 mg, 0.086 mmol, 42% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-7.22 (m, 2H), 7.22-7.15 (m, 1H), 6.91 (dd, J=7.5, 2.0 Hz, 1H), 5.95 (t, J =6.0 Hz, 1H), 2.87 (d, J=6.0 Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.11-2.01 (m, 1H), 1.92-1.80 (m, 6H), 1.631 .52 (m, 6H), 1.28 (t, J=8.00 Hz, 3H), 1.07-0.98 (m, 2H), 0.88-0.82 (m, 2H). MS (ESI) 420 (M+H).

Step E. Example 4. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-3 -(difluoromethyl)-N- (3 -(3 -ethyl-1,2,4-oxadiazol-5-yl)phenyl)cyclobutane-1-carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of the compound in example 3 by replacing intermediate 4D and the corresponding acid where necessary: (17 mg, 0.031 mmol, 64.6% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.08-7.94 (m, 2H), 7.81-7.57 (m, 2H), 6.23-5.68 (m, 1H), 3.71-3.60 (m, 2H), 3.16- 2.96 (m, 1H), 2.90-2.75 (m, 2H), 2.30 (br. s., 1H), 2.16-1.95 (m, 2H), 1.82-1.58 (m, 9H), 1.41 (d, J= 7.1 Hz, 6H), 1.31 (td, J=7.6, 0.7 Hz, 3H), 1.09-0.93 (m, 2H), 0.91-0.69 (m, 2H). FXR EC ₅₀ (nM) 322. MS (ESI) 552 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3 by replacing intermediate 4D and the corresponding acids where necessary:

Etc. No. Structure & Name MS (ESI) (M+H) FXR ec ₅₀ (hM) 5 OH ^CF ₃ oAAA yL k/CN Νλ/С/ °~n НзС^Х-О 586 182

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (br. s., 2H), 7.76 (d, J= 7.3 Hz, 1H), 7.70 (t, J= 7.5 Hz, 1H), 6.54 (s, 1H), 3.67 (br. s., 2H), 2.91-2.78 (m, 2H), 2.77-2.63 (m, 1H), 2.41-2.29 (m, 2H), 2.05 (td, J= 8.4, 3.8 Hz , 3H), 1.76 (d, J= 8.1 Hz, 6H), 1.41 (br. s., 6H), 1.33-1.24 (m, 3H), 1.08-0.94 (m, 2H), 0.91-0.72 (m, 2H). ^NMR (400 MHz, DMSO-d ₆ ) δ 8.16-8.07 (m, 1H), 8.07-8.02 (m, 1H), 7.857.61 (m, 2H), 3.61 (br. s., 2H), 2.83 (q, 7= 7.5 Hz, 2H), 2.11-1.99 (m, 1H), 1.89 (br. s., 6H), 1.81-1.67 (m, 6H), 1.53-1.35 (m, 6H), 1.31 ( t, 7= 7.6 Hz, 3H), 1.120.95 (m, 2H), 0.90-0.75 (m, 2H).

Example 7.

Y-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-U-(3-(2ethoxyoxazol-5- yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 7A. Preparation of 5-(3-nitrophenyl)oxazol-2(3H)-one

To a stirred solution of 2-bromo-1-(3-nitrophenyl)ethan-1-one (5.0 g, 20.49 mmol) and thiazolidine-2,4-dione (2.78 g, 23.77 mmol) in DMF (22 ml), potassium carbonate (3.96 g, 28.7 mmol) was added and stirred for 1.5 hours at room temperature. The reaction mixture was poured into ice water (200 ml). The solution was filtered, the solids were washed with water (100 ml) and dried under high vacuum. The resulting solids were dissolved in water (45 ml) and THF (45 ml) and lithium hydroxide monohydrate (3.44 g, 82 mmol) was added thereto. The reaction mixture was stirred for 30 minutes at room temperature. The resulting reaction mixture was poured into acetic acid (4.69 ml, 82 mmol) in ice water (200 ml). The solution was filtered and the solids were washed with water (50 mL) and dried in vacuo to give the title compound (2.2 g, 10.67 mmol, 52% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (br. s, 1H), 8.29 (t, J=2.0 Hz, 1H), 8.13-8.09 (m, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.74-7.69 (m, 1H). MS (ESI) 205 (MH).

Stage B. Intermediate 7B. Preparation of 2-chloro-5-(3-nitrophenyl)oxazole

To a stirred solution of intermediate 7A (1.0 g, 4.85 mmol) in acetonitrile (10 ml) was added tetraethylammonium chloride (1.929 g, 11.64 mmol) and N-diethylaniline (0.724 g, 4.85 mmol). Phosphorus oxychloride (4.61 g, 30.1 mmol) was then added dropwise and then refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The product was added to crushed ice and extracted with ethyl acetate (2x50 ml). The organic layer was washed with water (50 mL), then brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg, 0.980 mmol, 20% yield) as pale -yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J=2.0 Hz, 1H), 8.25 (dt, J=7.4, 1.6 Hz, 1H), 8.16-8.13 (m, 1H),

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8.08 (s, 1H), 7.80 (t, J=8.0 Hz, 1H). MS (ESI) 226 (M+H).

Step C. Intermediate 7C. Preparation of 2-ethoxy-5-(3-nitrophenyl)oxazole

To a cooled (0-5°C) and stirred solution of sodium ethoxide (144 mg, 0.445 mmol) in THF (1.0 ml) was added dropwise a solution of intermediate 7B (100 mg, 0.445 mmol) in THF (1.0 ml ) and left to stir at room temperature for 30 min. The reaction mixture was quenched with water (1 ml) and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (10 ml), washed with water (5 ml) and brine (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (80 mg, 0.342 mmol, 77% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.34 (t, J=2.0 Hz, 1H), 8.16-8.09 (m, 1H), 8.04-7.97 (m, 1H), 7.77-7.68 (m, 2H), 4.49 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H). MS (ESI) 235 (M+H).

Stage D. Intermediate 7D. Preparation of 3-(2-ethoxyoxazol-5-yl)aniline

Intermediate 7C (80 mg, 0.342 mmol) was dissolved in a mixture of ethanol (0.8 ml), THF (0.4 ml) and water (0.2 ml). Zinc (335 mg, 5.12 mmol) followed by ammonium chloride (274 mg, 5.12 mmol) was added to the stirred reaction mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (2 ml). The aqueous layer was extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with water (5 ml), then brine (5 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (60 mg, 0.294 mmol, 86% yield) as a brown solid. .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.19 (s, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.77-6.69 (m, 2H), 6.50 (ddd, J=8.0, 2.0 , 1.0 Hz, 1H), 5.20 (s, 2H), 4.43 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.3 Hz, 3H). MS (ESI) 205 (M+H).

Step E. Intermediate 7E. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-ethoxyoxazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 7D and intermediate 4C where necessary: (50 mg, 0.115 mmol, 59% yield) as a brown wax.

1H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.07 (t, J=7.9 Hz, 1H), 6.80-6.74 (m, 1H), 6.70 (d, J=7.6 Hz, 1H) , 6.56 (d, J=9.8 Hz, 1H), 5.61 (t, J=6.0 Hz, 1H), 4.43 (q, J=7.0 Hz, 2H), 2.84 (d, J=6.1 Hz, 2H), 2.12 -2.00 (m, 1H), 1.91-1.77 (m, 6H), 1.62-1.51 (m, 6H), 1.37 (t, J=7.1 Hz, 3H), 1.07-0.98 (m, 2H), 0.89-0.81 (m, 2H). MS (ESI) 435 (M+H).

Step F. Example 7. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)-N-(3 -(2- ethoxyoxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 7E and the corresponding acid where necessary: (12.8 mg, 0.023 mmol, 25.4% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.64-7.54 (m, 3H), 7.54-7.43 (m, 1H), 7.32 (d, J=7.6 Hz, 1H), 4.47 (q, J=7.1 Hz, 2H), 3.57 (d, J=5.1 Hz, 2H), 2.09-2.01 (m, 1H), 1.87 (br. s., 6H), 1.82-1.67 (m, 6H), 1.51-1.30 (m, 9H ), 1.07-0.96 (m, 2H), 0.92-0.79 (m, 2H). FXR EC ₅₀ (nM) 22. MS (ESI) 547 (M+H).

Example 8.

A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(3cyclopropyl-1,2,4 -oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 8A. Preparation of yl)aniline

-(3-cyclopropyl-1,2,4-oxadiazole-5-

The title compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing 3-aminobenzoic acid and (Z)-N'hydroxycyclopropanecarboximidamide where necessary: (2.3 g, 10.40 mmol, 71% yield) in the form of a solid.

¹ HNMR (400 MHz, DMSO-d6) δ 7.30-7.21 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 6.89 (dd, J=8.3, 1.8 Hz, 1H), 5.95 (t, J=6.0 Hz, 1H), 2.86 (d, J=6.0 Hz, 2H), 2.20-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.81 (m, 6H), 1.621.52 (m, 6H), 1.13-1.06 (m, 2H), 1.06-0.99 (m, 2H), 0.99-0.94 (m, 2H), 0.89-0.82 (m, 2H), MS (ESI) 432 (M+ N).

Stage B. Intermediate 8B. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane -1 -yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 4C where necessary: (100 mg, 0.232 mmol, 57% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.30-7.21 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 6.89 (dd, J=8.3, 1.8 Hz, 1H), 5.95 (t , J=6.0 Hz, 1H), 2.86 (d, J=6.0 Hz, 2H), 2.20-2.12 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.81 (m, 6H), 1.621. 52 (m, 6H), 1.13-1.06 (m, 2H), 1.06-0.99 (m, 2H), 0.99-0.94 (m, 2H), 0.89-0.82 (m, 2H). MS (ESI) 432 (M+H).

Step C. Example 8. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-N-(3-(3- cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 8B and the corresponding acid where necessary: (15 mg, 0.028 mmol, 59.5% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.81-7.64 (m, 2H), 3.63 (br. s., 2H), 2.30-2.15 (m, 1H), 2.11-2.00 (m, 1H), 1.88 (br. s., 6H), 1.82-1.69 (m, 6H), 1.54-1.31 (m, 6H), 1.14 (dd, J=8.4, 2.6 Hz, 2H), 1.08-0.92 (m, 4H), 0.88-0.77 (m, 2H).

FXR EC ₅₀ (nM) 137. MS (ESI) 544 (M+H).

The following compounds were synthesized in accordance with the method described for the synthesis of the compound of example 3, by replacing intermediate 8B and the corresponding acids.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 9 OH ^CF ₃ θ'Ν Г** X f Ν-° 598 153 10 ABOUT U D l __°'N N'° 550 425 AND ABOUT ,Λ J0 564 282 9 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.12-7.94 (m, 2H), 7.75 (d, J= 7.8 Hz, 1H), 7.68 (t, J= 7.9 Hz, 1H), 6.54 (s, 1H), 3.66 (br. s., 2H), 2.78-2.69 (m, 1H), 2.372.28 (m, 2H), 2.24-2.16 (m, 1H), 2.14-1.96 (m, 3H), 1.85 -1.68 (m, 6H), 1.511.29 (m, 6H), 1.19-1.08 (m, 2H), 1.08-0.90 (m, 4H), 0.87-0.76 (m, 2H). 10 ΉΉΜΡ (400 MHz, DMSO-d ₆ ) δ 8.13-7.94 (m, 2H), 7.75 (d, J= 8.1 Hz, 1H), 7.68 (t, J= 7.7 Hz, 1H), 3.66 (br. s. , 2H), 2.97-2.70 (m, 3H), 2.34 (br. s., 2H), 2.24-2.14 (m, 1H), 2.10-1.98 (m, 1H), 1.88-1.65 (m, 6H), 1.53-1.28 (m, 6H), 1.17-1.08 (m, 2H), 1.07-0.88 (m, 4H), 0.87-0.79 (m, 2H). AND ΉΉΜΡ (400 MHz, DMSO-d ₆ ) δ 8.16-7.89 (m, 2H), 7.78 (d, J= 7.6 Hz, 1H), 7.68 (t, ./= 7.6 Hz, 1H), 3.64 (br. s., 2H), 2.98-2.80 (m, 1H), 2.31-2.16 (m, 2H), 2.15-1.96 (m, 3H), 1.94-1.69 (m, 8H), 1.65 (br. s., 1H), 1.50-1.29 (m, 6H), 1.12 (dd, J= 8.2, 2.6 Hz, 2H), 1.07-0.88 (m, 4H) , 0.88-0.70 (m, 2H).

Example 12.

Ethyl

2-(3-(3-fluoro-N((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1.1] pentane-1-carboxamido)phenyl)oxazole-4-carboxylate

Step A: Intermediate 12A. Preparation of ethyl ^)-3-hydroxy-2-((3nitrobenzylidene)amino)propanoate

To a stirred solution of L-serine ethyl ester hydrochloride (2.81 g, 16.54 mmol) in THF (160 ml) at room temperature was added Et ₃ N (4.61 ml, 33.1 mmol), magnesium sulfate (1.991 g ,

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16.54 mmol) and 3-nitrobenzaldehyde (2.5 g, 16.54 mmol) (commercially available). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through a pad of celite and the residue was washed with MTBE (10 ml). The filtrate was concentrated under reduced pressure to give the title compound (4.5 g, 8.28 mmol, 50% yield), which was used as such in the next step without further purification. MS (ESI) 265 (M-N).

Stage B. 12V intermediate connection. Preparation of ethyl 2-(3-nitrophenyl)oxazole-4carboxylate

To a stirred solution of intermediate 12A (5 g, 18.78 mmol) in DCM (160 mL) was added bromotrichloromethane (5.58 mL, 56.3 mmol) and DBU (8.49 mL, 56.3 mmol) at 0° WITH. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into cold water and the aqueous layer was extracted with EtOAc (2x100 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 120 g, silica gel, 0-50% EtOAc/PE) to give the title compound (3 g, 11.33 mmol, 60% yield). MS (ESI) 263 (M+H).

Step C. Intermediate 12C. Preparation of ethyl 2-(3-aminophenyl)oxazole-4carboxylate

To a stirred solution of intermediate 12B (1 g, 3.81 mmol) in 1,4-dioxane (20 ml) was added 10% Pd on carbon (0.203 g, 1.907 mmol) and stirred at room temperature for 12 h in ambient atmosphere hydrogen. The reaction mixture was filtered through a pad of celite and the residue was washed with ethyl acetate. The ethyl acetate solution was concentrated under reduced pressure to give the title compound (800 mg, 3.31 mmol, 87% yield). MS (ESI) 233 (M+H).

Stage D. Intermediate 12D. Preparation of ethyl 2-(3-(((4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)oxazole-4-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 12C and intermediate 3C where necessary: (40 mg, 0.092 mmol, 27% yield). MS (ESI) 437 (M+H).

Step E. Example 12. Preparation of ethyl 2-(3-(3-fluoro4U-((4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl )bicyclo[1.1.1]pentane-1-carboxamido)phenyl)oxazole-4-carboxylate

This compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 12D and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (3.5 mg, 6.38 µmol , yield 14%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.03 (d, J=6.8 Hz, 1H), 7.96 (s, 1H), 7.71-7.61 (m, 2H), 4.35 (q , J=7.3 Hz, 2H), 3.65 (br. s., 1H), 3.59 (br. s., 1H), 2.28 (s, 3H), 1.89 (br. s., 6H), 1.85-1.73 ( m, 6H), 1.46 (d, J=8.1 Hz, 6H), 1.33 (t, J=7.1 Hz, 3H); FXR EC ₅₀ (nM) 1714; MS (ESI) 549 (M+H).

Example 13.

Ethyl 2-(3-(N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1] pentane-1-carboxamido)phenyl)oxazole-4-carboxylate

Step A: Intermediate 13A. Preparation of ethyl 2-(3-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)-oxazol-4- carboxylate

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This compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 12C and intermediate

4C where needed: (550 mg, 1.153 mmol, 54% yield). MS (ESI) 463 (M+H).

Step B. Example 13. Preparation of ethyl 2-(3-(N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 -fluorobicyclo[1.1.1]pentane-1-carboxamido)phenyl)oxazole-4carboxylate

This compound was synthesized in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 13A and 3-fluorobicyclo[1.1.1]pentane-1 carboxylic acid where necessary: (13.9 mg, 0.24 mmol, yield 55%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.95 (s, 1H), 7.72-7.60 (m, 2H), 4.35 ( q, J=7.0 Hz, 2H), 3.64 (br. s., 2H), 2.11-2.00 (m, 1H), 1.89 (br. s., 6H), 1.82-1.67 (m, 6H), 1.53- 1.36 (m, 6H), 1.33 (t, J=7.1 Hz, 3H), 1.08-0.97 (m, 2H), 0.88-0.76 (m, 2H); FXR EC50 (nM) 512; MS (ESI) 575 (M+H).

Example 14.

N(3-(4-(chloromethyl)oxazol-2-yl)phenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1 - yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 14A. Preparation of (2-(3-(((4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)oxazol-4-yl )methanol

ΗΝ^ΧΧι

To a stirred solution of intermediate 13A (100 mg, 0.216 mmol) in THF (5 ml) cooled to -78°C, DIBAL-H (0.432 ml, 0.432 mmol) was added and stirred for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (60 mg, 0.110 mmol, 51% yield). MS (ESI) 421 (M+H).

Step B. Example 14. Preparation of N(3-(4-(chloromethyl)oxazol-2-yl)phenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2 .2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Pyridine (0.046 mL, 0.571 mmol) and POCl ₃ (0.027 ml, 0.285 mmol). The reaction mixture was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 15% B, 15-70% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signal. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (5.6 mg, 10.03 μmol, 11% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 8.00 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.70-7.57 (m, 2H), 4.78 (s , 2H), 3.63 (br. s., 1H), 3.58 (br. s., 1H), 2.08-2.00 (m, 1H), 1.89 (br. s., 6H), 1.82-1.70 (m, 6H ), 1.50-1.34 (m, 6H), 1.06-0.96 (m, 2H), 0.87-0.79 (m, 2H); FXR EC ₅₀ (nM) 166; MS (ESI) 551 (M+H).

Example 15.

N-((4-(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -fluoro-N-(3 -(4- (2hydroxypropan-2-yl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 15A. Preparation of 2-(2-(3-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)oxazol-4 -yl)propan-2-ol

To a stirred solution of intermediate 13A (50 mg, 0.108 mmol) in THF (2 mL) was added methyl magnesium bromide (0.108 mL, 0.324 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (30 mg, 0.067 mmol, 62% yield). MS (ESI) 449 (M+H).

Step B. Example 15. Preparation of N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro-N-( 3-(4-(2-hydroxypropan-2-yl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide

This compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 15A and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (3.0 mg, 5.14 µmol , yield 12%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.03-7.95 (m, 2H), 7.86 (s, 1H), 7.62 (t, J=7.9 Hz, 1H), 7.57(d, J=8.1 Hz, 1H ), 5.15 (s, 1H), 3.75-3.48 (m, 2H), 2.07-2.01 (m, 1H), 1.89 (br.s., 6H), 1.82-1.65 (m, 6H), 1.53-1.34 ( m, 12H), 1.06-0.97 (m, 2H), 0.88-0.78 (m, 2H); FXR EC ₅₀ (nM) 88; MS (ESI) 561 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 15A and the corresponding acids where necessary:

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H), 7.94 (d, J= 7.6 Hz, 1H), 7.88 (s,

1H), 7.64-7.53(m, 2H), 5.15 (s, 1H), 3.66 (br. s., 2H), 2.94-2.73 (m, 3H), 2.34 (d, J= 2.0 Hz, 2H), 2.08-2.01 (m, 1H), 1.83-1.72 (m, 6H), 1.46 (s, 6H), 1.44-1.35 (m, 6H), 1.03-0.97 (m, 2H), 0.86-0.79 (m, 2H )

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H), 7.92 (d, J= 5.9 Hz, 1H), 7.85

7.76 (m, 1H), 7.61-7.45 (m, 2H), 6.01 (t, J= 56 Hz, 1H), 5.14 (s, 1H), 3.63 (br.

s., 2H), 3.02 (d, 7= 9.0 Hz, 1H), 2.27 (s, 1H), 2.14-2.01 (m, 2H), 1.76 (d, 7=8.8

Hz, 8H), 1.68 (br. s., 1H), 1.52-1.31 (m, 12H), 1.01 (dd,7= 8.2, 2.6 Hz, 2H), 0.89-0.78 (m, 2H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.92 (m, 2H), 7.90 (s, 1H), 7.62 (d, 7 = 4.2 Hz, 2H), 5.15 (s, 1H), 3.62 (br . s., 2H), 2.29 (br. s., 1H), 2.18-1.99 (m, 3H),

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1.92 (br. s., 1H), 1.89-1.59 (m, 9H), 1.52-1.32 (m, 12H), 1.07-0.97 (m, 2H), 0.89-0.76 (m, 2H)

Ή NMR (400 MHz, DMSO-de) δ 7.97 (s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.85 (s, 1H), 7.65-7.50 (m, 2H), 6.57 (s, 1H), 5.15 (s, 1H), 3.66 (br. s., 1H), 3.60 (s, 1H), 19

2.76-2.69 (m, 1H), 2.40-2.34 (m, 2H), 2.18-1.97 (m, 3H), 1.87-1.68 (m, 6H),

1.52-1.28 (m, 12H), 1.06-0.94 (m, 2H), 0.89-0.72 (m, 2H)

Example 20.

^((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)A-(3-(2cyclopropyloxazol-5-yl) phenyl)cyclobutanecarboxamide

Ycou ^N 1^(20)

Step A: Intermediate 20A. Preparation of 2-cyclopropyl-5-(3-nitrophenyl)oxazole Δ /°2 ϊΧ

To a stirred solution of (diacetoxyiodo)benzene (1170 mg, 3.63 mmol) in cyclopropanecarbonitrile (50 ml) was added trifluoromethanesulfonic acid (2045 mg, 13.62 mmol) and stirred for 20 minutes at room temperature. 1-(3-nitrophenyl)ethan-1one (500 mg, 3.03 mmol) was added to the reaction mixture and refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with DCM (100 ml) and washed with 10% saline solution (5x30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-40% EtOAc/PE) to give the title compound (800 mg, 0.556 mmol, 18% yield) as an orange-red liquid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (t, J=2.0 Hz, 1H), 8.18-8.13 (m, 1H), 8.13-8.06 (m, 1H), 7.81-7.70 (m, 2H ), 1.93 (dd, J=7.8, 6.8 Hz, 1H), 1.16-1.01 (m, 2H), 0.97-0.88 (m, 2H). MS (ESI) 231 (M+H).

Stage B. Intermediate connection 20V. Preparation of 3-(2-cyclopropyloxazol-5-yl)aniline A NH ₂

Intermediate 20A (300 mg, 1.303 mmol) was dissolved in a mixture of ethanol (8 ml), THF (2 ml) and water (4 ml). Zinc (1278 mg, 19.55 mmol) was added to the stirred reaction mixture, followed by ammonium chloride (1046 mg, 19.55 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was suspended in water (10 ml) and EtOAc (10 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with water (10 ml), then brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg, 1.099 mmol, 84% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.85-6.77 (m, 2H), 6.52 (dt, J=8.0, 1.3 Hz , 1H), 5.21 (s, 2H), 2.18-2.08 (m, 1H), 1.11-1.02 (m, 2H), 1.02-0.93 (m, 2H). MS (ESI) 201 (M+N).

Step C. Intermediate 20C. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-cyclopropyloxazol-5-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 20B and intermediate 4C where necessary: (220 mg, 0.511 mmol, 68% yield) as a brown wax.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 7.34 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.87 (d, J=1.5 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.58 (dd, J=8.0, 1.5 Hz, 1H), 5.62(t, J=5.8 Hz, 1H), 2.85 (d, J=6.0 Hz, 2H), 2.19-2.10 (m, 1H ), 2.10-2.03 (m, 1H), 1.92-1.79 (m, 6H), 1.64-1.53 (m, 6H), 1.11-0.94 (m, 6H), 0.88-0.83 (m, 2H). MS(ESI)431 (M+H).

Step D. Example 20. Preparation of X-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3-( 2-cyclopropyloxazol-5-yl)phenyl)-cyclobutanecarboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 20C and the corresponding acid where necessary: (11.5 mg, 0.022 mmol, 47.8% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.65-7.54 (m, 3H), 7.48 (t, J=8.1 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 3.61 (s, 2H ), 3.09 (d, J=7.6 Hz, 1H), 2.22-1.98 (m, 4H), 1.82-1.71 (m, 6H), 1.64 (m, 4H), 1.46-1.34 (m, 6H), 1.12- 0.94 (m, 6H), 0.87-0.78 (m, 2H). FXR EC ₅₀ (nM) 138; MS (ESI) 513 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 20C and appropriate acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 21 О ^F 3 ^c yZ I Л g, ^but (I ?Ν Гк Ν-Ζ J К Ν-^ О 597 80 22 ABOUT I LJ . o j3 U J to N·^[> 549 133 23 jn, Г 1 » /, ^N NJ k ΐΉ i> 543 72

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 7.65-7.57 (m, 2H), 7.50 (t, J= 7.7 Hz, 1H), 7.35 (d, J= 7.3 Hz, 1H ), 6.55 (s, 1H), 3.64 (br. s., 2H), 2.80-2.73 (m, 1H), 2.34 (t, J= 11.4 Hz, 2H), 2.21-2.14 (m, 1H), 2.11 -2.00 (m, 3H), 1.84-1.67 (m, 6H), 1.41 (br. s., 6H), 1.12-0.98 (m, 6H), 0.87-0.79 (m, 2H).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.64-7.55 (m, 2H), 7.51 (t, J= 7.8 Hz, 1H), 7.35 (d, J= 8.6 Hz, 1H ), 3.64 (br. s., 2H), 2.96-2.83 (m, 1H), 2.83-2.69 (m, 2H), 2.34 (br. s., 2H), 2.23-2.12 (m, 1H), 2.10 -1.99 (m, 1H), 1.87-1.66 (m, 6H), 1.53-1.30 (m, 6H), 1.13-0.96 (m, 6H), 0.89-0.76 (m, 2H).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.60 (m, ZN), 7.52 (t, J= 7.8 Hz, 1H), 7.36 (d, J= 7.8 Hz, 1H), 3.72-3.58 (m , 1H), 3.58-3.44 (m, 1H), 2.24-2.13 (m, 1H), 2.10-1.99 (m, 1H), 1.87 (s, 6H), 1.77 (t, J= 7.7 Hz, 6H), 1.54-1.27 (m, 6H), 1.16-0.93 (m, 6H), 0.89-0.74 (m, 2H).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.63-7.54 (m, 2H), 7.49 (t, J= 7.9 Hz, 1H), 7.36-7.26 (m, 1H), 5.90 (d, 7= 3.9 Hz , 1H), 3.61 (br. s., 2H), 3.14-3.00 (m, 1H), 2.30 (d, 7= 8.8 Hz, 1H), 2.18 (d, J= 4.9 Hz, 1H), 2.11-2.00 (m, 3H), 1.82-1.72 (m, 6H), 1.68 (d, J= 11.5 Hz, 2H), 1.40 (m, 6H), 1.14-0.95 (m, 6H), 0.89-0.77 (m, 2H ). (1H was buried under DMSO peak)

Example 25.

A((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)A-(3-(5ethoxyisoxazol-3-yl) phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 25A. Preparation of 3-(3-nitrophenyl)isoxazol-5(4H)-one

To a stirred solution of methyl 3-(3-nitrophenyl)-3-oxopropanoate (1.0 g, 4.48 mmol) in ethanol (8 ml) was added hydroxylamine hydrochloride (0.342 g, 4.93 mmol) in water (8 ml) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (50 ml) and then filtered. The solids were washed with water (50 ml) and dried under reduced pressure to give the compound (800 mg, 3.88 mmol, 87% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58-8.50 (m, 1H), 8.35 (br. s., 1H), 8.22 (d, J=7.5 Hz, 1H), 7.88-7.78 (m, 1H), 5.93 (br. s., 1H), 4.44 (br. s., 1H). MS (ESI) 207 (M+H).

Stage B. 25V intermediate connection. Preparation of 5-chloro-3-(3-nitrophenyl)isoxazole

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To a stirred solution of intermediate 25A (0.8 g, 3.88 mmol) in POCl ₃ (2.170 mL, 23.28 mmol) was added TEA (0.595 mL, 4.27 mmol) and stirred at 120°C for 2 h The reaction mixture was concentrated under reduced pressure and the resulting residue was added to crushed ice and then extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with water (20 ml), then with saturated aqueous brine (20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-30% EtOAc/PE) to give the title compound (130 mg, 0.579 mmol, 15% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J=2.0 Hz, 1H), 8.41 (ddd, J=8.3, 2.3, 1.0 Hz, 1H), 8.34 (dt, J=7.9, 1.3 Hz, 1H ), 7.87 (t, J=8.0 Hz, 1H), 7.60 (s, 1H). MS (ESI) 242 (M+H).

Step C. Intermediate 25C. Preparation of 5-ethoxy-3-(3-nitrophenyl)isoxazole

To a cooled (0-5°C) and stirred solution of sodium ethoxide (151 mg, 2.226 mmol) in THF (5 ml) was added dropwise a solution of intermediate 25B (500 mg, 2.226 mmol) in THF (5 ml), and the reaction the mixture was left stirring at room temperature for 30 min. The reaction mixture was quenched with water (1 ml) and concentrated under reduced pressure. The residue was diluted with ethyl acetate (5 ml), washed with water (5 ml) and then brine (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (450 mg, 1.921 mmol, 86% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (t, J=2.0 Hz, 1H), 8.34 (d, J=1.0 Hz, 1H), 8.30-8.23 (m, 1H), 7.82 (t, J=8.0 Hz, 1H), 6.45 (s, 1H), 4.38 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H). MS (ESI) 235 (M+H).

Stage D. Intermediate 25D. Preparation of 3-(5-ethoxyisoxazol-3-yl)aniline

Intermediate 25C (450 mg, 1.921 mmol) was dissolved in a mixture of ethanol (4 ml), THF (1 ml) and water (2 ml). Zinc (1884 mg, 28.8 mmol) was added to the stirred reaction mixture, followed by ammonium chloride (1542 mg, 28.8 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite, and the celite layer was washed with methanol (5 ml). The combined filtrate was evaporated under reduced pressure to leave a residue, which was diluted with ethyl acetate (10 ml). The subsequent solution was washed with water (2x5 ml), brine (10 ml), then dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg, 1.077 mmol, 56% yield) as a brown wax.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.15-7.07 (m, 1H), 7.00 (t, J=2.0 Hz, 1H), 6.91-6.86 (m, 1H), 6.69-6.62 (m, 1H) , 5.96 (s, 1H), 5.25 (s, 2H), 4.32 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H). MS (ESI) 205 (M+N).

Step E. Intermediate 25E. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(5-ethoxyisoxazol-3-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 25D and intermediate 4C where necessary: (200 mg, 0.460 mmol, 63% yield) as a brown wax. MS (ESI) 435 (M+H).

Step F. Example 25. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3-(5- ethoxyisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 25E and the corresponding acid where necessary: (2.1 mg, 3.84 μmol, 8% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 6.33 (s, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 2.09-1.96 (m, 1H), 1.86 (s, 6H), 1.81-1.67 (m, 6H), 1.52-1.36 (m, 9H), 1.08-0.97 (m, 2H), 0.88-0.76 (m, 2H). FXR EU ₅₀ (pm) = 87; MS (ESI) 547 (M+H).

Example 26.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3 -(2- 119 047337 propyloxazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 26A. Preparation of 5-(3-nitrophenyl)-2-propyloxazole

To a stirred solution of (diacetoxyiodo)benzene (2.340 g, 7.27 mmol) in butyronitrile (10 ml) was added trifluoromethanesulfonic acid (4.09 g, 27.2 mmol) and the reaction mixture was stirred at room temperature for 20 min. 1-(3nitrophenyl)ethan-1-one (1.0 g, 6.06 mmol) was added to the reaction mixture and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (100 ml ). The subsequent organic solution was washed with 10% aqueous saline solution (3x50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Comblash, 24 g, silica gel, 0-50% EtOAc/PE, gradient elution) to give the title compound (300 mg, 1.292 mmol, 21% yield) as a brown liquid.

1H NMR (400 MHz, DMSO-de) δ 8.76 (s, 1H), 8.59-8.53 (m, 1H), 8.24-8.11 (m, 2H), 7.73 (t, J=8.0 Hz, 1H), 2.80 ( t, J=7.5 Hz, 2H), 1.82-1.70 (m, 2H), 0.97 (t, J=7.3 Hz, 3H). MS (ESI) 233 (M+H).

Stage B. Intermediate connection 26V. Preparation of 3-(2-propyloxazol-5-yl)aniline

Intermediate 26A (300 mg, 1.292 mmol) was dissolved in a mixture of ethanol (8 ml), THF (2 ml) and water (4 ml). Zinc (1267 mg, 19.38 mmol) followed by ammonium chloride (1036 mg, 19.38 mmol) was added to the stirred reaction mixture and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 ml) and extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with water (10 ml), then brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg, 1.088 mmol, 84% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.09-6.97 (m, 2H), 6.91-6.84 (m, 1H), 6.52-6.46 (m, 1H), 5.12 (s, 2H), 2.75 (t, J=7.3 Hz, 2H), 1.74 (q, J=7.4 Hz, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (ESI) 203 (M+N).

Step C. Intermediate 26C. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-propyloxazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 26B and intermediate 4C where necessary: (140 mg, 0.324 mmol, 66% yield) as a brown wax.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 7.10-7.06 (m, 1H), 7.04 (d, J=5.5 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H ), 6.56 (dd, J=8.3, 1.8 Hz, 1H), 5.53 (t, J=6.0 Hz, 1H), 2.85 (d, J=5.5 Hz, 2H), 2.76 (t, J=7.3 Hz, 2H ), 2.11-2.03 (m, 1H), 1.92-1.82 (m, 6H), 1.80-1.69 (m, 2H), 1.63-1.54 (m, 6H), 1.07-1.00 (m, 2H), 0.96 (t , J=7.3 Hz, 3H), 0.89-0.83 (m, 2H). MS (ESI) 433 (M+H).

Step D. Example 26. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro-N-(3 -(2-propyloxazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 26C and the corresponding acid where necessary: (8.2 mg, 0.015 mmol, 33% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.1 Hz, 1H), 3.59 (br. s., 2H), 2.79 (t, J=7.5 Hz, 2H), 2.10-2.01 (m, 1H), 1.87 (s, 6H), 1.82-1.69 (m, 8H), 1.52-1.35 (m, 6H), 1.04-0.92 (m, 5H), 0.87-0.79 (m, 2H). FXR EC ₅₀ (nM) = 72; MS (ESI) 545 (M+H).

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The title compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 26C and the corresponding acids where necessary:

etc No Structure MS (ESI) (M+H) FXR ec ₅₀ (nM)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 7.80-7.68 (m, 2H), 7.50 (t, J= 7.9 Hz, 1H), 7.33(d, J= 7.1 Hz, 1H ), 3.64 (br. s., 2H), 2.94-2.82 (m, 1H), 2.82-2.69 (m, 4H), 2.39-2.32 (m, 2H), 2.09-2.00 (m, 1H), 1.76 ( q, J= 7.3 Hz, 8H), 1.481.36 (m, 6H), 1.05-0.99 (m, 2H), 0.97 (t, J= 7.3 Hz, 3H), 0.88-0.79 (m, 2H) Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.57 (d, 7= 6.1 Hz, 1H), 7.76-7.63 (m, 2H), 7.48 (t, J= 7.8 Hz, 1H), 7.29 (dd, J= 14.7 , 8.3 Hz, 1H), 6.2-5.7 (m, 1H), 3.61 (br. s., 2H), 3.12-3.02 (m, 1H), 2.78 (t, 7=7.3 Hz, 2H), 2.33-2.21 (m, 1H), 2.11-1.94 (m, 3H), 1.84-1.55 (m, 10H), 1.49-1.33 (m, 6H), 1.08-0.90 (m, 5H), 0.89-0.79 (m, 2H)

Example 29.

Ethyl 4-(3-A-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-3fluorobicyclo[1.1. 1]pentane-1-carboxamido)phenyl)thiazole-2-carboxylate

Step A: Intermediate 29A. carboxylate

Preparation of ethyl 4-(3-nitrophenyl)thiazol-2-

Ethyl thiooxamate (0.818 g, 6.15 mmol) was added to a stirred solution of 2-bromo-1-(3-nitrophenyl)ethan-1-one (1.5 g, 6.15 mmol) in EtOH (15 mL) at room temperature. and the reaction mixture was stirred for 2 hours at 90°C. The reaction mixture was concentrated and the residue was suspended in cold water. The aqueous layer was extracted with EtOAc (2x50 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (1.2 g, 4.23 mmol, 69% yield). MS (ESI) 279 (M+H).

Stage B. Intermediate connection 29V. Preparation of ethyl 4-(3-aminophenyl)thiazol-2-121 047337 carboxylate

To a stirred solution of intermediate 29A (500 mg, 1.797 mmol) in EtOH (10 mL) was added tin(II) chloride dihydrate (1338 mg, 5.93 mmol) and conc. HCl (1.8 ml, 59.2 mmol) at 0°C. The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated and cold water was added. The aqueous solution was made basic with 10% aqueous sodium bicarbonate and the aqueous layer was extracted with EtOAc (2x70 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (250 mg, 0.886 mmol, 49% yield). MS (ESI) 249 (M+H).

Step C. Intermediate 29C. Preparation of ethyl 4-(3-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)-thiazol-2- carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 29B and intermediate 4C where necessary: (Combiflash, 12 g, silica gel, 0-30% EtOAc/PE) to obtain the indicated in title compound (240 mg, 0.466 mmol, 58% yield). MS (ESI) 479 (M+H).

Step D. Example 29. Preparation of ethyl 4-(3-(N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 -fluorobicyclo[1.1.1]pentane-1-carboxamido)phenyl)thiazole-2carboxylate

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3 by replacing intermediate 29C and the corresponding acid where necessary: (15 mg, 0.025 mmol, 60% yield).

¹ H NMR (400 MHz, DMSO-de) δ 8.70 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.66 (br. s., 1H), 3.57 (br. s., 1H), 2.07 -1.99 (m, 1H), 1.88 (br. s., 6H), 1.83-1.70 (m, 6H), 1.46 (d, J=8.1 Hz, 6H), 1.37 (t, J=7.1 Hz, 3H) , 1.09-0.95 (m, 2H), 0.910.76 (m, 2H); FXR EU ₅₀ (nM) 1094; MS (ESI) 591 (M+H).

Example 30.

No.(3-(2-(chloromethyl)thiazol-4-yl)phenyl)-No.-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 30A. Preparation of (4-(3-(((4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)thiazol-2-yl )methanol

To a stirred solution of intermediate 29C (110 mg, 0.230 mmol) in THF (5 ml), cooled to -78°C, DIBAL-H (0.460 ml, 0.460 mmol) was added and stirred for 1 hour. The reaction mixture was poured into a biphasic a mixture of saturated aqueous ammonium chloride and EtOAc (50 ml), and the layers were separated. The aqueous layer was further extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (70 mg, 0.151 mmol, 66% yield). MS (ESI) 437 (M+H).

Step B. Example 30. Preparation of No.(3-(2-(chloromethyl)thiazol-4-yl)phenyl)-No.-((4-(3-cyclopropyl)

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1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Pyridine (0.044 mL, 0.550 mmol) and POCl ₃ (0.026 ml, 0.275 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the crude product 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 with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0-minute hold at 15% B, 15-70% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (9.4 mg, 0.016 mmol, 17% yield).

1H NMR (400 MHz, DMSO-de) δ 8.37 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 5.19 (s, 2H), 3.63 (br. s., 1H), 3.57 (br. s., 1H), 2.09-2.00 (m, 1H), 1.88 (br . s., 6H), 1.821.69 (m, 6H), 1.46 (d, J=7.8 Hz, 6H), 1.07-0.96 (m, 2H), 0.88-0.78 (m, 2H); FXR EU ₅₀ (nM) 112; MS (ESI) 567 (M+H).

Example 31.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3 -(2- (2hydroxypropan-2-yl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

ABOUT

Step A: Intermediate 31A. Preparation of 2-(4-(3-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)thiazol-2 -yl)propan-2-ol

HnXT

To a stirred solution of intermediate 29C (60 mg, 0.125 mmol) in THF (2 mL) cooled to 0°C, methyl magnesium bromide (0.251 mL, 0.752 mmol) was added and the reaction mixture was stirred for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (40 mg, 0.067 mmol, 54% yield). MS (ESI) 465 (M+H).

Step B. Example 31. Preparation of M((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-3-fluoro-N-(3 -(2-(2-hydroxypropan-2-yl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentan-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 31A and the corresponding acid where necessary: (7.2 mg, 0.012 mmol, 28% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.52 (t, J=7.8 Hz, 1H) , 7.35 (d, J=5.1 Hz, 1H), 6.06 (s, 1H), 3.60 (br. s., 2H), 2.10-2.01 (m, 1H), 1.89 (br. s., 6H), 1.82 -1.68 (m, 6H), 1.58 (s, 6H), 1.50-1.35 (m, 6H), 1.05-0.96 (m, 2H), 0.87-0.78 (m, 2H); FXR EC50 (nM) 260; MS (ESI) 577 (M+H).

Example 32.

M(3-(3-cyclopropan-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-U-((4-(2-methylpyridin-4yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

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Stage A. Intermediate

yl)bicyclo[2.2.2]octane-1-carboxylate carboxylate

32A1 and methyl

32A2. Preparation of methyl 4-(6-methylpyridin-24-(2-methylpyridin-4-yl)bicyclo[2.2.2]octane-1 &

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2 g, 9.42 mmol) and 2-methylpyridine (1.053 g, 11.31 mmol) in DCM (60 ml) and water (60 ml), silver nitrate (0.320 g, 1.885 mmol) was added, followed by potassium persulfate (2.55 g, 9.42 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 ml) and the organic layer was washed with water (2x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give intermediate 66A1 (200 mg, 0.771 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61-7.54 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.43 (s, 3H), 1.90-1.77 (m, 12H). MS (ESI) 260 (m+H) and intermediate 32A2 (650 mg, 2.506 mmol).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J=5.5 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.12 (dd, J=5.3, 1.8 Hz, 1H) , 3.60 (s, 3H), 2.43 (s, 3H), 1.87-1.73 (m, 12H). MS (ESI) 260 (M+H).

Stage B. Intermediate connection of 32B1 and 32B2. Preparation of 4-(2-methylpyridin-4yl)bicyclo[2.2.2]octan-1-carbaldehyde and (4-(2-methylpyridin-4-yl)bicyclo-[2.2.2]octan-1-yl)methanol

A stirred solution of intermediate 32A2 (650 mg, 2.506 mmol) in DCM (20 ml) was cooled to -78°C. DIBAL-H in heptane (5.22 ml, 6.27 mmol) was added and the reaction mixture was stirred at -78°C for 20 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride and stirred for 2 hours. The DCM layer was separated and the aqueous layer was extracted with DCM (2x25 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography to give intermediate 32B1 (110 mg, 0.480 mmol, 19% yield) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.33 (d, J=5.5 Hz , 1H), 7.21 (s, 1H), 7.15-7.12 (m, 1H), 2.43 (s, 3H), 1.83-1.77 (m, 6H), 1.73-1.66 (m, 6H). MS (ESI) 230 (M+H), and intermediate 32B2 (250 mg, 1.081 mmol, 43% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (d, J=5.0 Hz, 1H), 7.21-7.15 (m, 1H), 7.11 (dd, J=5.5, 1.5 Hz, 1H), 4.39 ( t, J=5.5 Hz, 1H), 3.09 (d, J=5.5 Hz, 2H), 2.43 (s, 3H), 1.79-1.68 (m, 6H), 1.51-1.39 (m, 6H). MS (ESI) 232 (M+H).

Step C. Intermediate 32C. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 32B1 where necessary: (70 mg, 0.169 mmol, 43% yield).

¹ H NMR (400 MHz, DMSO-de) δ 8.31 (d, J=5.0 Hz, 1H), 7.32-7.23 (m, 2H), 7.19 (s, 1H), 7.17-7.11 (m, 2H), 6.93 -6.88 (m, 1H), 6.00-5.95 (m, 1H), 2.87 (d, J=5.5 Hz, 2H), 2.44 (s, 3H), 2.22-2.16 (m, 1H), 1.77 (m,

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6H), 1.64-1.56 (m, 6H), 1.14-1.08 (m, 2H), 1.00-0.95 (m, 2H). MS (ESI) 415 (M+H).

Step D. Example 32. Preparation of ^(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro^-((4(2-methylpyridin-4-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 32C and the corresponding acid where necessary: (8 mg, 0.0151 mmol, 41% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=5.4 Hz, 1H), 8.06 (dt, J=7.3, 1.5 Hz, 1H), 7.99 (t, J=1.6 Hz, 1H) , 7.78-7.63 (m, 2H), 7.12 (s, 1H), 7.05 (dd, J=5.4, 1.5 Hz, 1H), 2.39 (s, 3H), 2.26-2.15 (m, 1H), 1.99-1.75 (m, 6H), 1.73-1.54 (m, 6H), 1.50-1.31 (m, 6H), 1.07-0.91 (m, 4H). 2 Protons are hidden under the humidity peak. FXR EC ₅₀ (nM) = 756; MS (ESI) 527 (M+H).

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 32C and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 33 O f JL GaChaa f Ί Г N-Ο CH ₃ 547 4315 33 ^Χ Η NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J= 5.4 Hz, 1H), 8.12-7.89 (m, 2H), 7.79 (d, J= 8.1 Hz, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.13 (s, 1H), 7.05 (dd, J= 5.4, 1.5 Hz, 1H), 3.65 (br. s., 2H), 2.93 (t, J= 8.4 Hz, 1H) , 2.44-2.35 (m, 3H), 2.352.16 (m, 2H), 2.14-1.96 (m, 4H), 1.95-1.77 (m,lH), 1.74-1.53 (m, 6H), 1.49-1.29 ( m, 6H), 1.20-1.08 (m, 2H), 1.05-0.93 (m, 2H)

Example 34.

3-fluoro^-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N(3-(2-(tetrahydro2H -pyran-4-yl)oxazol-5 -yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 34A. Preparation of 5-(3-nitrophenyl)-2-(tetrahydro-2H-pyran4-yl)oxazole

To a stirred solution of (diacetoxyiodo)benzene (1170 mg, 3.63 mmol) in oxane-4carbonitrile (10 ml) was added trifluoromethanesulfonic acid (2045 mg, 13.62 mmol) and stirred at room temperature for 20 min. 1-(3nitrophenyl)ethan-1-one (500 mg, 3.03 mmol) was added to the reaction mixture and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with DCM (100 ml) and washed with 10% aqueous saline solution (3x50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-60% EtOAc/PE) to give the title compound (200 mg, 0.729 mmol, 24% yield) as a brown wax. MS (ESI) 275 (M+H).

Stage B. Intermediate 34V. Preparation of 3-(2-(tetrahydro-2H-pyran-4-yl)oxazol-5yl)aniline

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Intermediate 34A (200 mg, 0.729 mmol) was dissolved in a mixture of ethanol (4 ml), THF (2 ml) and water (1 ml). Zinc (715 mg, 10.94 mmol) was added to the stirred reaction mixture, followed by ammonium chloride (585 mg, 10.94 mmol) and stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml). The organic layer was washed with water (20 ml), then 10% aqueous sodium bicarbonate (20 ml) and brine (20 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-70% EtOAc/PE) to give the title compound (100 mg, 0.409 mmol, 56% yield) as a brown wax. MS (ESI) 245 (M+H).

Step C. Intermediate 34C. Preparation of A((4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-(tetrahydro-2H-pyran-4- yl)oxazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 34B and intermediate 3C where necessary: (40 mg, 0.089 mmol, 44% yield) as a brown wax. MS (ESI) 449 (M+H).

Step D. Example 34. Preparation of 3-fluoro-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-( 3-(2-(tetrahydro-2H-pyran-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 34C and the corresponding acid where necessary: (6.4 mg, 0.011 mmol, 26% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (s, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 3.95-3.88 (m, 2H), 3.66 (d, J=13.9 Hz, 1H), 3.49 (td, J=11.3, 2.1 Hz, 2H), 3.23-3.14 (m, 2H), 2.28 (s, 3H), 1.99 (d, J=11.2 Hz, 2H), 1.88 (m, 6H), 1.85-1.74 (m, 8H), 1.46 (m, 6H); FXR EC50 (nM) = 1523; MS (ESI) 561 (M+H).

Example 35.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3 -(2( tetrahydro-2H-pyran-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 35A. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-(tetrahydro-2H-pyran-4- yl)oxazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 34B and intermediate 4C where necessary: (60 mg, 0.126 mmol, 62% yield) as a brown wax. MS (ESI) 475 (M+H).

Step B. Example 35. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro-N-(3 -(2-(tetrahydro-2H-pyran-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentan-1carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 35A and the corresponding acid where

- 126 047337 this is necessary: (4.2 mg, 7.16 µmol, yield 17%).

1H NMR (400 MHz, DMSO-d ₀ ) δ 7.73 (s, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 3.91 (d, J=11.0 Hz, 2H), 3.63 (br. s., 1H), 3.55-3.44 (m, 3H), 3.23-3.15 (m, 1H), 2.09-1.96 (m , 3H), 1.88 (m, 6H), 1.82-1.72 (m, 8H), 1.44 (m, 6H), 1.05-0.98 (m, 2H), 0.87-0.80 (m, 2H); FXR EC ₅₀ (nM) = 251; MS (ESI) 587 (M+H).

Example 36.

A((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-3,3-difluoroA-(3-(2 (tetrahydro-2H-pyran-4-yl)oxazol-5-yl)phenyl)cyclobutan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 35A and the corresponding acid where necessary: (1.9 mg, 3.21 μmol, 8% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.69 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 3.91 (d, J=10.5 Hz, 2H), 3.65 (br. s., 2H), 3.54-3.42 (m, 2H), 3.24-3.12 (m, 2H) , 2.90 (m, 1H), 2.76 (d, J=18.3 Hz, 2H), 2.34 (d, J=2.0 Hz, 1H), 2.08-1.90 (m, 3H), 1.83-1.69 (m, 6H), 1.52-1.30 (m, 6H), 1.06-0.96 (m, 2H), 0.88-0.78 (m, 2H), Note: 2H merged in DMSO peak. FXR EC ₅₀ (nM) = 497. MS (ESI) 593 (M+H).

Example 37.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-methyloxazol-2yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Ν

V ⁰ _,N

ABOUT

CH ₃ (37)

Step A: Intermediate 37A. Preparation of methyl 4-((2hydroxypropyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylate

HE

H ₃ C

N.H.

O-CH ₃

A solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1 g, 4.71 mmol), 1-hydroxybenzotriazole hydrate (0.722 g, 4.71 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.806 g, 9.42 mmol) in DCM (20 ml) was stirred at 0°C for 30 min. 1-Aminopropan-2-ol (0.369 mL, 4.71 mmol) was added to the reaction mixture. The resulting mixture was stirred at 0°C for 2 hours and overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 ml) and EtOAc (30 ml) and the layers were separated. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to obtain the title compound (1.2 g, 4.37 mmol, 93% yield) from the reaction mixture. MS (ESI) 268 (M-N).

Stage B. Intermediate 37B. Preparation of methyl 4-((2oxopropyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylate

Oh Oh,

O-CH ₃

H ₃ C

To a stirred solution of intermediate 37A (1.2 g, 4.46 mmol) in DCM (15 ml) was added Dess-Martin periodinane (1.701 g, 4.01 mmol) and the reaction mixture was stirred at room temperature for 1 hour. Reaction the mixture was diluted with DCM (15 ml) and washed with saturated aqueous NaHCO ₃ solution (3x10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (950 mg, 80% yield). MS (ESI) 268 (M+H).

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Step C. Intermediate 37C. Preparation of X(3-(2-methoxypyridin-4yl)phenyl)pyrimidin-2-amine

A solution of intermediate 37B (0.4 g, 1.496 mmol) in DCM (10 mL) and POCl ₃ (5.58 mL, 59.9 mmol) was refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove all volatiles. The residue was diluted with EtOAc (30 ml) and washed with saturated aqueous NaHCO ₃ solution (2x20 ml). The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the compound (0.25 g, 0.842 mm, 56% yield), which was further used without any purification.

^1H NMR (400 MHz, DMSO- _d0 ) δ 6.77 (s, 1H), 3.59 (s, 3H), 2.24 (s, 3H), 1.9-1.7 (m, 12H). MS (ESI) 250 (M+H).

Stage D. Intermediate 37D. Preparation of (4-(5-methyloxazol-2yl)bicyclo[2.2.2]octan-1-yl)methanol

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G, by replacing intermediate 37C where necessary: (65 mg, 0.294 mmol, 73% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.57 (s, 1H), 3.77 (s, 2H), 3.32 (s, 1H), 2.24 (s, 3H), 1.9-1.7 (m, 12H). MS (ESI) 222 (M+H).

Step E. Intermediate 37E. Preparation of 4-(5-methyloxazol-2yl)bicyclo[2.2.2]octane-1-carbaldehyde ^n.s. _o /—\ O

T/VCA

The title compound was synthesized according to the method described for the synthesis of intermediate 1H by replacing intermediate 37D where necessary: (110 mg, 0.477 mmol, 56% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 6.68 (s, 1H), 2.24 (s, 3H), 1.87-1.83 (m, 6H), 1.68-1.65 (m, 6H ). MS (ESI) 220 (M+H).

Step F: Intermediate 37F. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline ^sn z

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 37E where necessary: (105 mg, 0.259 mmol, 81% yield).

^1H NMR (400 MHz, DMSO-d6) δ 7.29-7.08 (m, 3H), 6.89-6.83 (m, 1H), 6.65 (s, 1H), 5.95 (s, 1H), 3.32 (s, 2H) , 2.33 (s, 3H), 2.23 - 2.16 (m, 1H), 1.84-1.80 (m, 6H), 1.57-1.53 (m, 6H), 1.11 - 1.08 (m, 4H). MS (ESI) 405 (M+H).

Step G. Example 37. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-U-((4(5-methyloxazol-2-yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The said compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 37F and the corresponding acid where necessary: (12.5 mg, 0.024 mmol, 49% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J=7.3 Hz, 1H), 7.98 (s, 1H), 7.76-7.62 (m, 2H), 6.60 (d, J=1.2 Hz, 1H), 3.61-3.55 (m, 2H), 2.25-2.12 (m, 4H), 1.87 (br. s., 6H), 1.77-1.61 (m, 6H), 1.49-1.28 (m, 6H), 1.12 (dd, J=8.1, 2.4 Hz, 2H), 1.05-0.94 (m, 2H). FXR EU ₅₀ (nM) 82; MS (ESI) 517 (M+H).

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 74F and the corresponding acid where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ECso (nM) 38 0 Γ-ί M uD ^РзС У X YXctN X4 ^CH = 632 571 39 0 ; C ^x > X D CH ₃ N-0 ³ 308 537 38 ^NMR (400 MHz, DMSO-d6) δ 8.00 (br s, 2H), 7.76 (d, J= 8.1 Hz, 1H), 7.68

(t, J= 8.1 Hz, 1H), 6.62 (d, J= 1.2 Hz, 1H), 6.56 (s, 1H), 3.65 (m, 2H), 2.73 (t, J = 8.7 Hz, 1H), 2.40 -2.30 (m, 2H), 2.27-2.15 (m, 4H), 2.09 (br. s., 2H), 1.82-1.60 (m, 6H), 1.50-1.29 (m, 6H), 1.18-1.10 (m , 2H), 1.05-0.96 (m, 2H).

^X H NMR (400 MHz, DMSO-d6) δ 8.11-7.94 (m, 2H), 7.79 (d, J= 7.8 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 6.62 (d, J = 1.2 Hz, 1H), 3.63 (br. s., 2H), 2.97-2.86 (m, 1H), 2.35-2.16 (m, 5H), 2.06 (dd, J = 10.8,4.6 Hz, 2H), 1.97 -1.77 (m, 2H), 1.77-1.51 (m, 7H), 1.49-1.26 (m, 6H), 1.19-1.08 (m, 2H), 1.05-0.92 (m, 2H)

Example 40.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(4(difluoromethyl)oxazol- 2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Intermediate connection 40A. Preparation of (2-(3-nitrophenyl)oxazol-4-yl)methanol

To a stirred solution of intermediate 12B (1 g, 3.81 mmol) in THF (30 ml) at -78°C was added DIBAL-H (7.63 ml, 7.63 mmol) and the reaction mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (10 ml) and EtOAc (50 ml), and the layers were separated. The aqueous layer was further extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (400 mg, 1.798 mmol, 47% yield). MS (ESI) 221 (M+H).

Stage B. 40V intermediate connection. Preparation of 2-(3-nitrophenyl)oxazole-4-carbaldehyde

Dess-Martin periodinane (925 mg, 2.180 mmol) was added to a stirred solution of intermediate 40A (400 mg, 1.817 mmol) in DCM (15 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (370 mg, 1.594 mmol, 88% yield). MS (ESI) 219 (M+N).

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Step C. Intermediate 40C. Preparation of 4-(difluoromethyl)-2-(3-nitrophenyl)oxazole

To a stirred solution of intermediate 40B (370 mg, 1.696 mmol) in DCM (10 mL) at -78°C was added DAST (0.560 mL, 4.24 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with cold water and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (330 mg, 1.374 mmol, 81% yield). 1H NMR; 400 MHz, DMSO-d ₀ : δ 8.91 (s, 1H), 8.33-8.41 (m, 2H), 8.01 (d, J=4.00 Hz, 1H), 7.69 (t, J=16.00 Hz, 1H), 6.74 (t, J=54.00 Hz, 1H).

Stage D. Intermediate 40D. Preparation of 3-(4-(difluoromethyl)oxazol-2-yl)aniline

To a stirred solution of intermediate 40C (50 mg, 0.208 mmol) in EtOH (2.5 ml) at 0 °C was added tin(II) chloride dihydrate (164 mg, 0.729 mmol) and conc. HCl (0.190 ml, 6.25 mmol). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was neutralized with aqueous sodium bicarbonate and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (30 mg, 0.131 mmol, 63% yield). MS (ESI) 211 (M+H).

Stage E. Intermediate 40E. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(4-(difluoromethyl)oxazol-2-yl) aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 40D and intermediate 4C where necessary: (290 mg, 0.658 mmol, 69% yield). MS (ESI) 441 (M+H).

Step F. Example 40. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3-(4- (difluoromethyl)oxazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 40E and the corresponding acid where necessary: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (t, J=2.6 Hz, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.94 (s, 1H), 7.70-7.59 (m, 2H), 7.16 (t J=54 Hz, 1H), 3.61 (d, J= 15.9 Hz, 2H), 2.10-1.99 (m, 1H), 1.89 (br. s., 6H), 1.82-1.68 (m, 6H), 1.53-1.34 (m, 6H), 1.05-0.96 (m, 2H ), 0.86-0.76 (m, 2H). FXR EU ₅₀ (nM) 243; MS (ESI) 553 (M+H).

The title compounds were synthesized according to the method described for the synthesis of Example 3, substituting intermediate 40E and appropriate acids where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 41 XX 559 465 42 Hq^pF ₃ A fVo 607 613 43 XX. 573 851 44 573 646 41 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.76-8.64 (m, 1H), 8.10-7.89 (m, 2H), 7.727.56 (m, 2H), 7.16 (dd, J= 53.1, 51.1 Hz, 1H), 3.67 (br. s., 2H), 2.96-2.85 (m, 1H), 2.84-2.70 (m, 2H), 2.34 (br. s., 2H), 2.10-1.98 (m, 1H), 1.86-1.62 (m, 6H), 1.52-1.30 (m, 6H), 1.08-0.92 (m, 2H), 0.89-0.70 (m, 2H) 42 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (t, J= 2.7 Hz, 1H), 8.05-7.85 (m, 2H), 7.64 (d, 7= 4.4 Hz, 2H), 7.15 (dd,7 = 55.3, 51.1 Hz, 1H), 6.56 (s, 1H), 3.66 (br. s., 2H), 2.77-2.71 (m, 1H), 2.34 (br. s., 2H), 2.16-1.96 (m , 3H), 1.86-1.66 (m, 6H), 1.42 (d, 7= 7.8 Hz, 6H), 1.08-0.95 (m, 2H), 0.90-0.77 (m, 2H)

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43 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (t, J= 2.7 Hz, 1H), 7.96 (d, J= 7.3 Hz, 1H), 7.91 (d, 7= 8.3 Hz, 1H), 7.72- 7.55 (m, 2H), 7.15 (t, 7= 54 Hz, 1H), 6.195.69 (m, 1H), 3.63 (br. s., 2H), 3.07 (dt, 7= 18.6, 9.0 Hz, 1H ), 2.33-2.23 (m, 1H), 2.11-1.99 (m, 2H), 1.82-1.56 (m, 8H), 1.51-1.29 (m, 6H), 1.10-0.95 (m, 2H), 0.89-0.73 (m, 2H) 44 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 1H), 8.00 (br. s., 2H), 7.72-7.53 (m, 2H), 7.16 (dd, 7= 54.0, 52.6 Hz, 1H ), 3.63 (br. s., 2H), 3.00-2.89 (m, 1H), 2.161.98 (m, 3H),1.91 (br. s., 1H), 1.88-1.71 (m, 7H), 1.67 (br. s., 1H), 1.52-1.30 (m, 6H), 1.25 (s, 1H), 1.09-0.92 (m, 2H), 0.91-0.71 (m, 2H)

Example 45.

N(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-fluoro-N-((4-(5-methyloxazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl) bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 45A. Preparation of 3-(4-(difluoromethyl)oxazol-2-yl)A-((4-(5methyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 40D and intermediate 37E where necessary: (45 mg, 0.109 mmol, 57% yield). MS (ESI) 414 (M+H).

Step B. Example 45. Preparation of A(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-fluoro-N-((4-(5methyloxazol-2-yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]-pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 45A and the corresponding acid where necessary: (12.6 mg, 0.024 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (t, J=2.6 Hz, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.94 (s, 1H), 7.72-7.57 (m, 2H ), 7.16 (t, J=54.0 Hz, 1H), 6.63 (d, J=1.2 Hz, 1H), 3.63 (br. s., 1H), 3.58 (br. s., 1H), 2.21 (d, J=1.2 Hz, 3H), 1.89 (br. s., 6H), 1.78-1.61 (m, 6H), 1.50-1.29 (m, 6H); FXR EC ₅₀ (nM) 258; MS (ESI) 526 (M+H).

Example 46.

(cis)A-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-hydroxy-N-((4-(5-methyloxazol-2yl)bicyclo[2.2.2]octane-1 - yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

BUT CF ₃

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 45A and the corresponding acid where necessary: (5.6 mg, 9.57 μmol, 16% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.73-8.64 (m, 1H), 8.02-7.86 (m, 2H), 7.64 (d, J=4.2 Hz, 2H), 7.15 (t, J=54.5 Hz , 1H), 6.62 (d, J=1.2 Hz, 1H), 6.55 (s, 1H), 3.65 (br. s., 2H), 2.74 (t, J=9.2 Hz, 1H), 2.37-2.28 (m , 2H), 2.21 (d, J=1.0 Hz, 3H), 2.09 (br. s., 2H), 1.80-1.60 (m, 6H), 1.49-1.29 (m, 6H); FXR EC50 (nM) 437 MS (ESI) 580 (M+H).

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Example 47.

N((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)A-(3 -(3-ethyl-1,2, 4oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 47A. Preparation of (4-(4-(2-cyanopropan-2-yl)phenyl)-4hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

To a stirred solution of 2-(4-bromophenyl)-2-methylpropanenitrile (1.441 g, 6.43 mmol) in THF (25 ml) at -78°C was added n-butyllithium (2.79 ml, 6.97 mmol) and stirred for 1 hour. To the above mixture was added dropwise a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4methylbenzenesulfonate) (synthesized as described in ACS Med. Chem. Lett. 2014, 5, 609-614) (2.5 g, 5.36 mmol) in THF (12 ml) and stirred at -78°C for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (3.2 g, 2.93 mmol, 55% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83-7.81 (m, 2H), 7.78-7.76 (m, 2H), 7.50 (d, J=8.0 Hz, 6H), 7.29-7.24 (m, 2H ), 4.79 (s, 1H), 4.01 (s, 2H), 3.75 (s, 2H), 2.45-2.42 (m, 3H), 2.36 (s, 3H), 1.70-1.65 (m, 6H), 1.62- 1.54 (m, 2H), 1.34-1.21 (m, 6H). MS (ESI) 629 (M+H) NH3 adduct.

Stage B. Intermediate 47B. Preparation of (1-(4-(2-cyanopropan-2-yl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate n ₃ with AA /5A ^NC Y\ /A /A ° / =\

H ₃ C \=/ OS-ά /-CH ₃

About ^λ '

To a stirred solution of intermediate 47A (3.6 g, 5.88 mmol) in THF (100 mL) was added NaOH (0.706 g, 17.65 mmol) and refluxed overnight. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (1.4 g, 2.61 mmol, 44% yield) as an off-white solid (1.4 g, 2.61 mmol, 44% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.79 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.45-7.37 (m, 4H), 3.81 (s, 2H), 3.70 (s, 2H), 2.43 (s, 3H), 2.08-1.99 (m, 2H), 1.82-1.75 (m, 2H), 1.65 (s, 6H), 1.61-1.58 (m, 4H). MS (ESI) 440 (M+H).

Step C. Intermediate 47C. Preparation of (1-(4-(2-cyanopropan-2-yl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl acetate o

H ₃ c ^=/ ογ

CH ₃

Cesium acetate (1.474 g, 7.68 mmol) was added to a stirred solution of intermediate 47B (1.35 g, 3.07 mmol) in DMF (20 mL) and heated to 120 °C for 6 h. The reaction mixture was concentrated at under reduced pressure, the residue was diluted with water (25 ml) and extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.0 g, 2.93 mmol, 95% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.40 (m, 4H), 3.81 (s, 4H), 2.11-2.04 (m, 2H), 2.03 (s, 3H) 1.88

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1.78 (m, 2H), 1.70-1.65 (m, 4H), 1.66 (s, 6H) MS (ESI) 345 (M+H) NH3 adduct.

Stage D. Intermediate 47D. Preparation of 2-(4-(4-(hydroxymethyl)-2oxabicyclo[2.2.2]octan-1-yl)phenyl)-2-methylpropanenitrile

To a stirred solution of intermediate 47C (1.1 g, 3.36 mmol) in THF (15 ml) was added sodium methoxide (0.073 g, 0.336 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (25 ml ), and the organic layer was washed with water (15 ml) and then with saline (25 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (600 mg, 2.081 mmol, 62% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.43 (s, 4H), 4.53 (t, J=5.5 Hz, 1H), 3.80 (s, 2H), 3.16 (d, J=5.0 Hz, 2H), 2.10-2.01 (m, 2H), 1.85-1.76 (m, 2H), 1.70-1.62 (m, 8H), 1.56-1.50 (m, 2H). MS (ESI) 286 (M+H).

Step E. Intermediate 47E. Preparation of 2-(4-(4-formyl-2-oxabicyclo[2.2.2]octan1 -yl)phenyl)-2-methylpropanenitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1H, replacing intermediate 47D where necessary: (430 mg, 1.517 mmol, 77% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 7.46-7.40 (m, 5H), 4.00 (s, 2H), 2.16-2.08 (m, 2H), 1.921.85 (m, 6H ), 1.66 (s, 6H). MS (ESI) 284 (M+H).

Step F: Intermediate 47F. Preparation of 2-(4-(4-(((3-(3-ethyl-1,2,4-oxadiazol-5yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl) phenyl)-2-methylpropanenitrile

A A]

H ₃ C ^? V° CH?

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 3E and intermediate 47E where necessary: (60 mg, 0.106 mmol, 60% yield) as a yellow resinous liquid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.41 (m, 4H), 7.35-7.27 (m, 2H), 7.24-7.20 (m, 1H), 6.96-6.92 (m, 1H), 6.02 ( t, J=5.8 Hz, 1H), 3.90 (s, 2H), 2.95 (d, J=6.0 Hz, 2H), 2.83-2.75 (m, 2H), 2.15-2.04 (m, 2H), 1.881.72 (m, 6H), 1.67 (s, 6H), 1.31-1.26 (m, 3H). MS (ESI) 457 (M+H).

Step G. Example 47. Preparation of N((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan4-yl)methyl)-N-(3-(3- ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.G1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 47F and the corresponding acid where necessary: (9 mg, 0.016 mmol, 24% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20-8.08 (m, 2H), 7.87-7.78 (m, 1H), 7.77-7.68 (m, 1H), 7.40 (q, J=8.8 Hz, 4H ), 3.71 (s, 2H), 3.66 (br. s., 2H), 2.83 (q, J=7.6 Hz, 2H), 2.07-1.96 (m, 2H), 1.90 (br. s., 6H), 1.81-1.70 (m, 2H), 1.65 (s, 8H), 1.59 (d, J=12.7 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H). FXR EU ₅₀ (nM) = 299; MS (ESI) 569 (M+H).

Example 48.

No((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-No(3 -(3-ethyl-1,2, 4oxadiazol-5-yl)phenyl)cyclobutanecarboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 47F and the corresponding acid where necessary: (0.7 mg).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.10-7.95 (m, 2H), 7.80-7.58 (m, 2H), 7.47-7.30 (m, 4H), 3.67 (br. s.,

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4H), 3.08 (br. s., 2H), 2.81 (q, J=7.6 Hz, 2H), 2.14 (br. s., 2H), 1.98 (t, J=10.9 Hz, 2H), 1.72 (d , J=11.2 Hz, 3H), 1.67-1.43 (m, 12H), 1.30 (t, J=7.5 Hz, 3H). FXR EU ₅₀ (nM) = 299; MS (ESI) 539 (M+H).

Example 49.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((4-(4-(trifluoromethyl)pyridin-2yl)bicyclo [2.2. 2]octan-1-yl)methyl)cyclobutan-1-carboxamide

Step A: Intermediate 49A. Preparation of methyl 4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1 g, 4.71 mmol) and 4-(trifluoromethyl)pyridine (0.832 g, 5.65 mmol) in DCM (30 ml) and water (30 ml), silver nitrate (0.160 g, 0.942 mmol) was added at room temperature, followed by potassium persulfate (0.160 g, 0.942 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with DCM (25 ml) and filtered through celite. The organic layer was separated and washed with brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (600 mg, 1.915 mmol, 41% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.0 Hz, 1H), 7.64 (d, J=1.0 Hz, 1H), 7.59 (d, J=5.0 Hz, 1H), 3.61 (s, 3H), 1.96-1.88 (m, 6H), 1.88-1.81 (m, 6H). MS (ESI) 314 (M+H).

Stage B. Intermediate 49B. Preparation of (4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methanol

CF ₃ \—' ν=7

The title compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 49A where necessary: (370 mg, 1.271 mmol, 80% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (d, J=5.0 Hz, 1H), 7.62-7.51 (m, 2H), 4.36 (t, J=5.5 Hz, 1H), 3.10 (d, J =5.5 Hz, 2H), 1.93-1.80 (m, 6H), 1.52-1.41 (m, 6H). MS (ESI) 286 (M+H).

Step C. Intermediate 49C. Preparation of 4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carbaldehyde /—\ ^N= \

CF ₃

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 49B where necessary: (220 mg, 0.777 mmol, 60% yield) as a colorless resinous solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 78 (d, J=5.0 Hz, 1H), 7.62-7.51 (m, 2H), 1.93-1.80 (m, 6H), 1.52 -1.41 (m, 6H). MS (ESI) 284 (M+H).

Stage D. Intermediate 49D. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-N((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl) methyl)aniline

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing intermediate 8A and intermediate 49C where necessary: (80 mg, 0.155 mmol, 63% yield) as a brown tarry solid

- 135 047337 substances. MS (ESI) 469 (M+H).

Step E. Example 49. Preparation of u(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N((4-(4-(trifluoromethyl)pyridin- 2-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of the compound of example 3 by replacing intermediate 49D and 3,3-difluorocyclobutane-1-carboxylic acid where necessary: (9.9 mg, 0.017 mmol, 40% yield) .

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=4.9 Hz, 1H), 8.08-7.94 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.68 (t, J =7.9 Hz, 1H), 7.59-7.47 (m, 2H), 3.68 (br. s., 2H), 2.98-2.85 (m, 1H), 2.83-2.65 (m, 2H), 2.42-2.25 (m, 2H), 2.24-2.16 (m, 1H), 1.90-1.68 (m, 6H), 1.52-1.35 (m, 6H), 1.18-1.08 (m, 2H), 1.05-0.93 (m, 2H). FXR EC50 (nM) = 1374; MS (ESI) 587 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 3 by replacing intermediate 49D and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 50 CO 0 C* 581 462 50 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J= 5.1 Hz, 1H), 8.07 (d, J= 7.8 Hz, 1H), 8.01 (s, 1H), 7.81-7.65 (m, 2H ), 7.61-7.48 (m, 2H), 3.66 (br. s., 2H), 2.262.20 (m, 1H), 1.89 (br. s., 6H), 1.85-1.72 (m, 6H), 1.46 (d, J= 8.3 Hz, 6H), 1.14 (dd, 7= 8.1, 2.4 Hz, 2H), 1.01 (d, 7= 2.2 Hz, 2H)

Example 51.

N((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)A-(3-(2ethoxyoxazol-5-yl)phenyl) -3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Stage A. Intermediate

51A. Preparation of 2-(4-(4-(((3-(4-ethoxyoxazol-2yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)-2-methylpropanenitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 7D and intermediate 47E where necessary: (30 mg, 0.064 mmol, 45% yield) as a gummy liquid. MS (ESI) 471 (M+H).

Step B. Example 51. Preparation of u((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan4-yl)methyl)-X-(3-(2- ethoxyoxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3 by replacing intermediate 51A and the corresponding acid where necessary: (1.8 mg, 0.00308 mmol, 6% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (s, 1H), 7.60-7.54 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.45-7.23 (m, 4H), 4.46 (q, J=6.9 Hz, 2H), 3.70 (s, 2H), 3.59 (s, 2H), 2.07-1.93 (m, 2H), 1.88 (br.s., 6H), 1.80-1.70 (m, 2H),

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1.69-1.45 (m, 11H), 1.43-1.33 (m, 3H). FXR EC ₅₀ (nM) = 25. MS (ESI) 584 (M+H).

Example 52.

3-fluoro-N-(3-(2-propyloxazol-5-yl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl )bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 52A. Preparation of 3-(2-propyloxazol-5-yl)-4-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 26B and intermediate 49C where necessary: (78 mg, 0.158 mmol, 64% yield) as a brown gum solid. MS (ESI) 470 (M+H).

Step B. Example 52. Preparation of 3-fluoro-N-(3-(2-propyloxazol-5-yl)phenyl)-N-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)bicyclo[1.1.1]-pentan-1-carboxamide

This compound was synthesized in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 52A and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (17.5 mg, 0.03 mmol , yield 40%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J=4.9 Hz, 1H), 8.64 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.74 (d, J= 1.7 Hz, 1H), 7.61-7.45 (m, 3H), 7.34 (d, J=8.8 Hz, 1H), 3.61 (s, 2H), 2.79 (t, J=7.3 Hz, 2H), 1.88 (br. s., 6H), 1.78 (td, J=15.0, 7.7 Hz, 8H), 1.54-1.39 (m, 6H), 0.98 (t, J=7.3 Hz, 3H). FXR EC ₅₀ (nM) = 242; MS (ESI) 582 (M+H).

Example 53.

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

53A.

Step A: Carboxylate Intermediate

Preparation of ethyl 2-(3-nitrobenzyl)hydrazine-1-

K ₂ CO ₃ (1.772 g, 12.82 mmol) followed by sodium iodide (0.349 g, 2.331 mmol). The reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate (25 ml). The organic solution was washed with ice water (2x50 ml) and then with saline (30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (1.05 g, 4.39 mmol, 38% yield) as a colorless gummy solid .

1H NMR (400 MHz, DMSO-d6) δ 8.53 (br. s., 1H), 8.22 (br. s., 1H), 8.14-8.09 (m, 1H), 7.78 (d, J=7.6 Hz, 1H ), 7.64-7.58 (m, 1H), 5.22 (q, J=4.2 Hz, 1H), 4.05-3.95 (m, 4H), 1.13 (t, J=7.1 Hz, 3H). MS (ESI) 240 (M+H).

Stage B. Intermediate 53B. Preparation of 2-ethoxy-5-(3-nitrophenyl)-1,3,4oxadiazole

- 137 047337

To a stirred solution of intermediate 53A (0.9 g, 3.76 mmol) in MeCN (90 ml) heated to 40°C, iodobenzene diacetate (2.67 g, 8.28 mmol) was added and heating continued for 2 h. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with saline (2x10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography to give the title compound (700 mg, 2.68 mmol, 71% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.58-8.54 (m, 1H), 8.42 (dd, J=8.4, 1.1 Hz, 1H), 8.34-8.29 (m, 1H), 7.88 (t, J= 8.1 Hz, 1H), 4.60 (q, J=7.3 Hz, 3H), 1.45 (t, J=7.20 Hz, 3H). MS (ESI) 236 (M+H).

Step C. Intermediate 53C. Preparation of 3-(5-ethoxy-1,3,4-oxadiazol-2-yl)aniline

IjOl ₀ L- ^СНз H2N^^Xf ^U \_O

N-ν

To a stirred solution of intermediate 53B (600 mg, 2.55 mmol) in ethanol (6 mL) was added a solution of ammonium chloride (2047 mg, 38.3 mmol) in water (6 mL) followed by zinc (2502 mg, 38.3 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with DCM (20 ml) and filtered through celite. The filtrate was washed with water (10 ml) and then with saline. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (480 mg, 2.199 mmol, 86% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.17 (t, J=7.8 Hz, 1H), 7.11-7.06 (m, 1H), 7.01-6.95 (m, 1H), 6.73 (dt, J=8.0 , 1.3 Hz, 1H), 5.44 (br. s., 2H), 4.53 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H). MS (ESI) 206 (M+H).

Stage D. Intermediate 53D. Preparation of M((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(5-ethoxy-1,3,4-oxadiazole -2-yl)aniline

The title compound was synthesized according to the method described for Synthesis 1I by replacing intermediate 53C and intermediate 4C where necessary: (320 mg, 0.735 mmol, 60% yield) as a brown gum solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.25-7.16 (m, 1H), 7.11 (d, J=1.7 Hz, 1H), 6.98 (d, J=6.8 Hz, 1H), 6.836.78 (m , 1H), 4.54 (q, J=7.0 Hz, 2H), 2.86 (d, J=6.1 Hz, 2H), 2.10-2.01 (m, 1H), 1.90-1.80 (m, 6H), 1.61-1.51 ( m, 6H), 1.42 (t, J=7.0 Hz, 3H), 1.06-1.00 (m, 2H), 0.89-0.82 (m, 2H). MS (ESI) 206 (M+H).

Step E. Example 53. Preparation of M((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-U-(3-(5- ethoxy-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 53D and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (7.9 mg, 0.014 mmol, yield 18%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J=6.6 Hz, 1H), 7.84 (s, 1H), 7.70-7.57 (m, 2H), 4.58 (q, J=7.1 Hz, 2H ), 3.60 (br. s., 2H), 2.08-2.02 (m, 1H), 1.88 (br. s., 6H), 1.81-1.68 (m, 6H), 1.54-1.32 (m, 9H), 1.24 (s, 1H), 1.07-0.96 (m, 2H), 0.86-0.80 (m, 2H). FXR EU ₅₀ (nM) = 81; MS (ESI) 548 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 53D and appropriate acids where necessary:

- 138 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 54 O ^NzS ~L O~N m A ν-ν 518 215 55 0 ^f vJ A Wa λ oUU ON /°~Ch i n ₃ s—/ NN 568 127 56 O 'OU /°~CH Η n ₃ s—/ ν—ν 568 275 54 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (d, J= 7.3 Hz, 1H), 7.77 (s, 1H), 7.677.53 (m, 2H), 4.58 (q, J= 7.1 Hz, 2H ), 3.62 (s, 2H), 3.05 (br. s., 1H), 2.20-2.08 (m, 2H), 2.07-1.98 (m, 1H), 1.83-1.71 (m, 6H), 1.64 (br. s., 4H), 1.51-1.31 (m, 9H), 1.07-0.97 (m, 2H), 0.89-0.77 (m, 2H) 55 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.79 (m, 2H), 7.77-7.51 (m, 2H), 4.58 (q, J= 6.9 Hz, 2H), 3.79-3.50 (m, 2H) , 2.92-2.96 (m, 1H), 2.39-2.20 (m, 1H), 2.191.97 (m, 3H), 1.88-1.71 (m, 9H), 1.71-1.64 (m, 1H), 1.52-1.26 ( m,9H), 1.070.94 (m, 2H), 0.89-0.74 (m, 2H) 56 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 7.90-7.73 (m, 2H), 7.67-7.48 (m, 2H), 5.955.78 (m, 1H), 4.57 (q, J= 7.0 Hz, 2H) , 3.62 (d, J= 5.6 Hz, 2H), 3.11-2.95 (m, 1H), 2.13-1.98 (m, 2H), 1.74 (d, J= 8.6 Hz, 6H), 1.67 (br. s., 2H), 1.50-1.27 (m, 9H), 1.00 (dd, J= 8.3, 2.4 Hz, 2H), 0.90-0.75 (m, 2H)

Example 57.

N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-M3-(5cyclopropylisoxazol-3-yl)phenyl)-3 -fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 57A. Preparation of 1-cyclopropyl-3-(3-nitrophenyl)propane1,3-dione

To a stirred solution of LiHMDS in THF (1M solution) at -78°C (23.78 ml, 23.78 mmol) was added 1-cyclopropylethan-1-one (1.0 g, 11.89 mmol) and stirred for 45 min. A solution of 3-nitrobenzoyl chloride (2.101 g, 11.32 mmol) in THF (11 ml) was added dropwise to the reaction mixture over 20 minutes, and the reaction mixture was stirred for 1 hour at -78°C. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2x50 ml).

- 139 047337

The combined organic layers were washed with water (50 ml), then brine (50 ml) and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (1.6 g, 6.86 mmol, 61% yield) as a yellow solid .

¹ H NMR (400 MHz, chloroform-d) δ 16.16 (br. s., 1H), 8.75-8.60 (m, 1H), 8.43-8.27 (m, 1H), 8.20 (dt, J=7.9, 1.3 Hz , 1H), 7.65 (t, J=7.8 Hz, 1H), 6.36 (s, 1H), 1.90-1.77 (m, 1H), 1.28-1.15 (m, 2H), 1.06 (dq, J=7.8, 3.7 Hz, 2H). MS (ESI) 232 (M-N).

Stage B. Intermediate 57B. Preparation of 5-cyclopropyl-3-(3-nitrophenyl)isoxazole

L no ₂ °'N \=/

To a stirred solution of intermediate 57A (0.8 g, 3.43 mmol) in MeOH (30 mL) was added hydroxylamine hydrochloride (0.953 g, 13.72 mmol) and stirred at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure. pressure, the residue was diluted with water (30 ml) and extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (600 mg, 2.61 mmol, 76% yield) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60-8.56 (m, 1H), 8.36-8.31 (m, 1H), 8.30-8.23 (m, 1H), 7.86-7.79 (m, 1H), 6.98 (s, 1H), 2.26-2.18 (m, 1H), 1.17-1.11 (m, 2H), 1.00-0.94 (m, 2H). MS (ESI) 231 (M+H).

Step C. Intermediate 57C. Preparation of 3-(5-cyclopropylisoxazol-3-yl)aniline

L nh ₂

To a stirred solution of intermediate 57B (700 mg, 3.04 mmol) in a mixture of ethanol (8 ml), THF (4 ml) and water (2 ml) was added zinc (2982 mg, 45.6 mmol) followed by ammonium chloride. (2440 mg, 45.6 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (10 ml). The solution was filtered through a pad of celite and the residue was washed with ethyl acetate (10 ml). The resulting filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (200 mg, 0.999 mmol, 33% yield) as a brown wax.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.10 (t, J=8.0 Hz, 1H), 7.03-6.99 (m, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.64 (dd, J=8.0, 1.5 Hz, 1H), 6.57-6.51 (m, 1H), 5.24 (s, 2H), 2.20-2.09 (m, 1H), 1.12-1.04 (m, 2H), 0.96-0.88 (m, 2H). MS (ESI) 201 (M+N).

Stage D. Intermediate 57D. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(5-cyclopropylisoxazol-3-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 57C and intermediate 4C where necessary: (350 mg, 0.813 mmol, 81% yield) as a brown wax. MS (ESI) 431 (M+H).

Step E. Example 57. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3-(5- cyclopropylisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3 by replacing intermediate 57D and the corresponding acid where necessary: (19.7 mg, 52% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=7.8 Hz, 1H), 7.80 (s, 1H), 7.64-7.56 (m, 1H), 7.56-7.49 (m, 1H), 6.88 (s, 1H), 3.59 (s, 2H), 2.26-2.15 (m, 1H), 2.12-2.00 (m, 1H), 1.86 (br. s., 6H), 1.81-1.71 (m, 6H), 1.501.36 (m, 6H), 1.17-1.07 (m, 2H), 1.05-0.98 (m, 2H), 0.98-0.91 (m, 2H), 0.88-0.79 (m, 2H). FXR EC ₅₀ (nM) = 19.80 MS (ESI) 543 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 57D and the existing acid where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 58 O -A o- ^N 563 39 59 O '+ΪΛ. O-Ν |> 563 70 60 ABOUT -ΆΑ-ν, AG 549 230 58 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.84-7.67 (m, 2H), 7.60-7.40 (m, 2H), 6.906.81 (m, 1H), 6.18-5.81 (m, 1H), 3.62 ( br. s., 2H), 3.13-2.99 (m, 1H), 2.30 (br. s., 1H), 2.23-2.15 (m, 1H), 2.12-1.97 (m, 2H), 1.86-1.70 (m , 6H), 1.65 (d, J = 10.3 Hz, 2H), 1.41 (d, J = 4.2 Hz, 6H), 1.18-1.07 (m, 2H), 1.05-0.97 (m, 2H), 0.97-0.89 ( m, 2H), 0.88-0.75 (m, 2H) (1H is hidden under the DMSO peak) 59 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.94-7.73 (m, 2H), 7.66-7.49 (m, 2H), 6.86 (s, 1H), 3.65 (br. s., 2H), 2.94 (t , J = 8.7 Hz, 1H), 2.29 (br. s., 1H), 2.20 (ddd, J = 13.4, 8.3, 5.1 Hz, 1H), 2.15-1.97 (m, 3H), 1.90-1.71 (m, 8H), 1.67 (m, 1H), 1.50-1.32 (m, 6H), 1.18-1.07 (m, 2H), 1.06-0.98 (m, 2H), 0.98-0.90 (m, 2H), 0.87-0.75 ( m, 2H) 60 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.89-7.72 (m, 2H), 7.58 (t, J = 7.9 Hz, 1H), 7.54-7.45 (m, 1H), 6.84 (s, 1H), 3.65 (s, 2H), 2.95-2.84 (m, 1H), 2.81-2.70 (m, 2H), 2.34 (d, J = 2.0 Hz, 2H), 2.22-2.14 (m, 1H), 2.08-2.01 (m , 1H), 1.86-1.68 (m, 6H), 1.51-1.32 (m, 6H), 1.16-1.09 (m, 2H), 1.06-0.98 (m, 2H), 0.98-0.91 (m, 2H), 0.88 -0.77 (m, 2H)

Example 61.

No.((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-No.(3-(3 (cyclopropylmethyl)-1 ,2,4-oxadiazol-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 61A.

Preparation of (E)-2-cyclopropyl-N-hydroxyacetimidamide

h ₂ n he

To a stirred solution of 2-cyclopropylacetonitrile (1.111 ml, 12.33 mmol) in ethanol (10 ml) was added hydroxylamine (3.78 ml, 61.6 mmol) and stirred at reflux.

- 141 047337 for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with water and filtered to give the title compound (1200 mg, 10.51 mmol, 85% yield) as a pale gray solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 5.32 (br. s., 2H), 1.84 (d, J=7.0 Hz, 2H), 1.00-0.87 (m, 1H), 0.48-0.33 (m, 2H), 0.14-0.07 (m, 2H). MS (ESI) 115 (M+H).

Stage B. Intermediate 61B. Preparation of 3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol5-yl)aniline nh ₂

A\=/

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1B by replacing intermediate 57A and 3-aminobenzoic acid where necessary: (350 mg, 1.593 mmol, 87% yield) as a yellow resinous liquid.

1H NMR (400 MHz, DMSO-de) δ 7.31 (t, J=1.8 Hz, 1H), 7.27-7.17 (m, 2H), 6.87-6.80 (m, 1H), 5.55 (s, 2H), 2.68 ( d, J=6.80 Hz, 2H), 1.15-1.07 (m, 1H), 0.57-0.48 (m, 2H), 0.30-0.22 (m, 2H). MS (ESI) 216 (M+H).

Step C. Intermediate 57C. Preparation of methyl 4-(3-(cyclopropylmethyl)-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate

1Н3С-О o- _N -У 1L А о ⁴ -'

The title compound was synthesized according to the method described for the synthesis of intermediate 1F by replacing intermediate 57A and 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid where necessary: (1000 mg, 2.411 mmol, yield 68%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.60 (s, 3H), 2.58 (d, J=7.0 Hz, 2H), 1.97-1.87 (m, 6H), 1.87-1.77 (m, 6H), 1.09 -0.98 (m, 1H), 0.52-0.45 (m, 2H), 0.23-0.16 (m, 2H). MS (ESI) 291 (M+H).

Stage D. Intermediate 61D. Preparation of (4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol5 -yl)bicyclo[2.2.2]octan-1-yl)methanol

HO /-x .O- _N ^λ -x h A

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G by replacing intermediate 61C where necessary: (650 mg, 2.478 mmol, 80% yield). MS (ESI) 263 (M+H).

Step E. Intermediate 61E. Preparation of 4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol5 -yl)bicyclo[2.2.2]octane-1-carbaldehyde

AA _Z °-N

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C by replacing intermediate 61D where necessary: (500 mg, 1.921 mmol, 78% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 1.97-1.88 (m, 6H), 1.84-1.76 (m, 2H), 1.74-1.66 (m, 6H), 1.09-1.01 ( m, 1H), 0.53-0.46 (m, 2H), 0.23-0.18 (m, 2H). MS (ESI) 261 (M+H).

Step F: Intermediate 61F. Preparation of 3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol5 -bh)-N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5 -yl)bicyclo [2.2. 2] octan-1 -yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediates 61B and 61E where necessary: (180 mg, 0.392 mmol, 73% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-7.15 (m, 2H), 6.92 (dd, J=7.7, 2.1 Hz, 1H), 6.83 (ddd, J=7.6, 2.4, 1.5 Hz, 1H) , 6.00 (s, 1H), 2.89 (d, J=5.9 Hz, 2H), 2.68 (dd, J=7.0, 3.3 Hz, 2H), 2.59 (d, J=6.8 Hz, 2H), 1.95-1.85 ( m, 6H), 1.84-1.75 (m, 1H), 1.64-1.54 (m, 6H), 1.17-0.98 (m, 1H), 0.58-0.42 (m, 4H), 0.30-0.17 (m, 4H). MS (ESI) 460 (M+H).

Step G. Example 61. Preparation of N((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-( 3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound

- 142 047337 studies according to example 3, by replacing intermediate 61F and the corresponding acid where necessary: (9.6 mg, 0.017 mmol, 26% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (d, J=7.6 Hz, 1H), 8.05 (s, 1H), 7.83-7.63 (m, 2H), 3.62 (br s, 2H), 2.73 (d, J=6.8 Hz, 2H), 2.55 (d, J=6.8 Hz, 2H), 1.89 (br. s., 6H), 1.84-1.64 (m, 6H),1.59-1.33 (m, 6H) , 1.14 (ddd, J=12.2, 7.4, 4.6 Hz, 1H), 1.06-0.88 (m, 1H), 0.64-0.40 (m, 4H), 0.36-0.23 (m, 2H), 0.17 (q, J= 4.6 Hz, 2H) FXR EC ₅₀ (nM) = 99; MS (ESI) 572 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 61F and existing acids where necessary:

Etc.

No.

MS FXR (ESI) ec ₅₀ (M+H) (hM)

^{X H} NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 8.09 (d, J= 7.8 Hz, 1H), 7.82 (d, J= 8.3 Hz, 1H), 7.72 (t, J= 7.7 Hz, 1H), 3.66 (br. s., 2H), 3.01-2.90 (m, 1H), 2.73 (d, J= 7.1Hz, 2H), 2.56 (d, J= 6.8 Hz, 2H), 2.29 (br. s., 1H), 2.08 (br. s., 2H), 1.96-1.75 (m, 8H), 1.52-1.35 (m, 6H), 1.19-1.10 (m, 1H), 1.08-0.97 ( m, 2H), 0.59-0.51(m, 2H), 0.51-0.42 (m, 2H), 0.33-0.25 (m, 2H), 0.23-0.15 (m, 2H) ^NMR (400 MHz, DMSO-d ₆ ) δ 8.15-8.04 (m, 2H), 7.77 (d, J= 7.6 Hz, 1H), 7.71 (t, J= 7.8 Hz, 1H), 3.68 (br. s., 2H), 2.91 (d, J = 5.9 Hz, 1H), 2.73 (d, J= 7.1 Hz, 3H), 2.56 (d, J= 7.1 Hz, 2H), 2.40-2.27 (m, 3H), 1.91-1.72 (m, 6H), 1.56 -1.32 (m, 6H), 1.21-1.10 (m,lH), 1.06-0.96 (m, 1H), 0.60-0.52 (m, 2H), 0.52-0.44 (m, 2H), 0.33-0.25 (m, 2H), 0.23-0.14 (m, 2H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J= 6.6 Hz, 1H), 8.00 (s, 1H), 7.757.62 (m, 2H), 3.65(s, 2H), 3.08 (br . s., 1H), 2.73 (d, J= 7.1 Hz, 2H), 2.56 (d, J = 7.1 Hz, 2H), 2.14 (br. s., 2H), 1.90-1.75 (m, 6H), 1.65 (br. s., 4H), 1.49-1.32 (m, 6H), 1.19-1.09 (m, 1H), 1.06-0.91 (m, 1H),0.59-0.52 (m, 2H), 0.51-0.43 ( m, 2H), 0.34-0.25 (m, 2H), 0.24-0.14 (m, 2H)

Example 65.

X-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(3(cyclopropylmethyl)-1 ,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

- 143 047337

Step A: Intermediate 65A. Preparation of M(4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-(cyclopropylmethyl)-1,2,4- Oxadiazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediates 61B and 4C where necessary: (180 mg, 0.404 mmol, 71% yield). MS (ESI) 446 (M+H).

Step B. Example 65. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)4U-(3-(3-( cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 65A and the corresponding acid where necessary: (20.4 mg, 0.036 mmol, 40% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=7.3 Hz, 1H), 8.06 (s, 1H), 7.82-7.64 (m, 2H), 3.62 (br. s., 2H), 2.74 (d, J=7.1 Hz, 2H), 2.12-2.00 (m, 1H), 1.90 (br. s., 6H),1.82-1.60 (m, 6H), 1.56-1.32 (m, 6H), 1.21 -1.09 (m, 1H), 1.07-0.92 (m, 2H), 0.90-0.73 (m, 2H), 0.62-0.49 (m, 2H), 0.37-0.22 (m, 2H). FXR EC ₅₀ (nM) = 142; MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 65A and existing acids where necessary:

Etc.

No.

MS (ESI) (M+H)

FXR

EC50 (hM)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J= 6.6 Hz, 1H), 7.99 (s, 1H), 7.767.63 (m, 2H), 3.64(s, 2H), 3.07 (br . s., 1H), 2.73 (d, J= 7.1 Hz, 2H), 2.14 (br. s., 2H), 2.07-2.00 (m, 1H), 1.84-1.70 (m, 6H), 1.65 (br . s., 4H), 1.47-1.30 (m, 6H), 1.18-1.08 (m, 1H), 1.07-0.95 (m, 2H),0.88-0.73 (m, 2H), 0.61-0.50 (m, 2H ), 0.32-0.24 (m, 2H) ^X NMR (400 MHz, DMSO-d ₆ ) δ 8.18-8.01 (m, 2H), 7.80 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 7.8 Hz,1H), 3.65 (br. s., 2H), 2.95 (t, J= 8.3 Hz, 1H), 2.73 (d, J= 6.8 Hz, 2H), 2.41-2.22 (m, 2H), 2.17- 1.97 (m, 3H), 1.91 (br. s., 1H), 1.88-1.71 (m, 6H), 1.67 (br. s., 1H), 1.53-1.31 (m, 6H), 1.20-1.09 (m , 1H), 1.06-0.97 (m, 2H), 0.89-0.79 (m, 2H), 0.61-0.48 (m, 2H), 0.33-0.24 (m, 2H)

- 144 047337

Example 68.

A(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-U-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol5-yl)bicyclo[2.2 .2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

ABOUT

Step A: Intermediate 68A. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-U((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)aniline

HN'^W

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 61E where necessary: (180 mg, 0.404 mmol, 70% yield) as a pale brown solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.32-7.21 (m, 2H), 7.15 (d, J=7.8 Hz, 1H), 6.90 (dd, J=8.2, 1.6 Hz, 1H), 5.98 (t , J=5.5 Hz, 1H), 2.88 (d, J=5.9 Hz, 2H), 2.60-2.56 (m, 2H), 2.23-2.11 (m, 1H), 1.97-1.83 (m, 6H), 1.651. 53 (m, 6H), 1.13-1.06 (m, 2H), 1.00-0.93 (m, 2H), 0.89-0.83 (m, 1H), 0.53-0.45 (m, 2H), 0.23-0.18 (m, 2H ). MS (ESI) 446 (M+H).

Step B. Example 68. Preparation of A(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-U-((4-(3(cyclopropylmethyl)-1,2,4-oxadiazole -5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 68A and the corresponding acid where necessary: (8.4 mg, 0.015 mmol, 22% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J=7.3 Hz, 1H), 8.02 (s, 1H), 7.79-7.73 (m, 1H), 7.73-7.64 (m, 1H), 3.64 (br. s., 1H), 3.58 (br. s., 1H), 2.56 (d, J=7.1 Hz, 2H), 2.22 (tt, J=8.6, 4.2 Hz, 1H), 1.89 (br. s. ., 6H), 1.84-1.68 (m, 6H), 1.55-1.34 (m, 6H), 1.14 (dd, J=8.2, 2.6 Hz, 2H), 1.08-0.94 (m, 3H), 0.54-0.41 ( m, 2H), 0.250.12 (m, 2H). FXR EC ₅₀ (nM) = 110. MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 68A and the corresponding acids where necessary:

- 145 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 69 О У/уМкк ^F J Дх kMM-O ill Υ ,Ν _ N.JkA Ν-4 Ν-Ο ' Υ 578 474 70 Ο ^F k ιΎ Υ ^Ν ιΥ VA '— Ν-0 X/ 564 598 71 Ο ί 1 UN χ __ Ν-A Ν-0 XJ 528 406 69 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (s, 1H), 8.03 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 6.6 Hz, 1H), 7.75-7.62 (m, 1H ), 3.68 (br. s., 2H), 3.00-2.88 (m, 1H), 2.56 (d, J= 7.1 Hz, 2H), 2.33-2.18 (m, 2H), 2.08 (br. s., 2H ), 1.96-1.73 (m, 8H), 1.66 (br. s., 1H), 1.62-1.34 (m, 6H), 1.19-1.09 (m, 2H), 1.07-0.94 (m, 3H), 0.55- 0.41 (m, 2H), 0.29-0.10 (m, 2H) 70 ^X NMR (400 MHz, DMSO-d ₆ ) δ 8.13-7.96 (m, 2H), 7.75 (d, J= 8.1 Hz, 1H), 7.69 (t, 7= 7.7 Hz, 1H), 3.67 (br. s ., 2H), 3.18 (d,7= 5.4 Hz, 1H), 2.95-2.85 (m, 1H), 2.83-2.69 (m, 2H), 2.56 (d, 7= 7.1 Hz, 2H), 2.40-2.29 (m, 2H), 2.26-2.13 (m, 1H), 1.93-1.69 (m, 6H), 1.56-1.30 (m, 6H), 1.18-1.08 (m, 2H), 1.07-0.93 (m, 2H) , 0.53-0.42 (m, 2H), 0.23-0.12 (m, 2H) 71 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, 7= 7.1 Hz, 1H), 7.95 (s, 1H), 7.747.59 (m, 2H), 3.64(s, 2H), 3.07 (br . s., 1H), 2.56 (d, 7 = 7.1 Hz, 2H), 2.26-2.19 (m, 1H), 2.12 (d, 7 = 9.8 Hz, 2H), 1.88-1.73 (m, 6H), 1.64 (br. s., 4H), 1.49-1.30

(m, 6H), 1.17-1.09 (m, 2H), 1.07-0.93 (m, 3H), 0.53-0.41 (m, 2H), 0.23-0.14 (m, 2H)

(m, 6H), 1.17-1.09 (m, 2H), 1.07-0.93 (m, 3H), 0.53-0.41 (m, 2H), 0.23-0.14 (m, 2H)

Example 72.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3 -(2( methoxymethyl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 72A. Preparation of (4-(3-nitrophenyl)thiazol-2-yl)methanol

- 146 047337

To a stirred solution of intermediate 29A (750 mg, 2.70 mmol) in THF (20 ml) at -78°C was added DIBAL-H (10.78 ml, 10.78 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into a biphasic mixture of saturated aqueous ammonium chloride (10 ml) and EtOAc (50 ml), and the layers were separated. The aqueous layer was then extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (400 mg, 1.693 mmol, 63% yield). MS (ESI) 237 (M+H).

Stage B. 72B intermediate. Preparation of 2-(methoxymethyl)-4-(3-nitrophenyl)thiazole

H ₃ C no ₂

To a stirred solution of intermediate 72A (400 mg, 1.693 mmol) in DMF (10 mL) at 0°C was added NaH (135 mg, 3.39 mmol) and MeI (0.212 mL, 3.39 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with cold water and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (380 mg, 1.488 mmol, 88% yield). MS (ESI) 251 (M+H).

Step C. Intermediate 72C. Preparation of 3-(2-(methoxymethyl)thiazol-4-yl)aniline n ₃ with nh ₂

To a stirred solution of intermediate 72B (380 mg, 1.518 mmol) in EtOH (10 mL) at room temperature was added tin(II) chloride dihydrate (1199 mg, 5.31 mmol) and conc. HCl (1.384 ml, 45.6 mmol). The reaction mixture was stirred at 90°C for 2 hours and concentrated. The residue was made basic with saturated aqueous NaHCO ₃ and extracted with EtOAc (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (325 mg, 1.416 mmol, 93% yield). MS (ESI) 221 (M+H).

Stage D. Intermediate 72D. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(2-(methoxymethyl)thiazol-4-yl) aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 72C and intermediate 4C where necessary: (250 mg, 0.388 mmol, 43% yield). MS (ESI) 451 (M+H).

Step E. Example 72. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-3-fluoro-N-(3 -(2-(methoxymethyl)thiazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 72D and the corresponding acid where necessary: (11.3 mg, 0.020 mmol, 36% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.28 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.94-7.88 (m, 1H), 7.53 (t, J=7.8 Hz, 1H ), 7.37 (d, J=9.0 Hz, 1H), 4.79 (s, 2H), 3.60 (d, J=16.4 Hz, 2H), 3.46 (s, 3H), 2.11-1.98 (m, 1H), 1.95 -1.82 (m, 6H), 1.82-1.70 (m, 6H), 1.54-1.36 (m, 6H), 1.11-0.91 (m, 2H), 0.88-0.77 (m, 2H); FXR EC ₅₀ (nM) 166; MS (ESI) 563 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 8, replacing intermediate 72D and appropriate acids where necessary:

- 147 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 73 O Γγ νΑΑ Ms UU-A f III /, ^N [> 583 341 74 I co J Ζ==ξ λp 583 220 7 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J= 7.1 Hz, 1H), 7.99-7.79 (m, 2H), 7.50 (t, J= 7.7 Hz, 1H), 7.33 (dd, J = 15.0, 7.9 Hz, 1H), 5.95-5.78 (m, 1H), 4.83-4.73 (m, 2H), 3.63 (br. s., 2H), 3.49-3.42 (m, 3H), 3.15-2.98 ( m, 1H), 2.34-2.26 (m, 1H), 2.15-1.99 (m, 2H), 1.87 (d, J =9.5 Hz, 1H), 1.82-1.72 (m, 6H), 1.67 (d, J = 8.8 Hz, 1H), 1.60 (d, 7= 7.1 Hz, 1H), 1.43 (d, J =3.7 Hz, 6H), 1.09-0.94 (m, 2H), 0.92-0.78 (m, 2H) 74 Ή NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.01-7.89 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H) , 4.79 (s, 2H), 3.68 (br. s., 2H), 3.45 (s, 3H), 3.02-2.91 (m, 1H), 2.27 (d, J =9.3 Hz, 1H), 2.18-1.99 ( m, 3H), 1.97-1.73 (m, 8H), 1.70 (br. s., 1H), 1.53-1.35 (m, 6H), 1.08-0.96 (m, 2H), 0.89-0.78 (m, 2H)

Example 75.

X-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-X-(3-(5cyclopropyl-1- methyl-1H-pyrazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

ⁿ zS (75)

Step A: Intermediate 75A. Preparation of 5-cyclopropyl-3-(3-nitrophenyl)-1Hpyrazole

To a stirred solution of intermediate 57A (0.8 g, 3.43 mmol) in ethanol (5 ml) was added hydrazine hydrate (0.343 g, 6.86 mmol), acetic acid (10 ml) and stirred for 3 hours at 80° WITH. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (10 ml) and extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (700 mg, 3.05 mmol, 89% yield) as

- 148 047337 yellow solid. MS (ESI) 230 (M+H).

Stage B. 75V intermediate. Preparation of 5-cyclopropyl-1-methyl-3-(3-nitrophenyl)1H-pyrazole

To a stirred solution of intermediate 75A (700 mg, 3.05 mmol) in DMF (7 ml) was added Cs ₂ CO ₃ (2985 mg, 9.16 mmol) and methyl iodide (0.382 ml, 6.11 mmol). The reaction mixture was stirred overnight at room temperature and then diluted with ethyl acetate (20 ml). The organic solution was washed with brine (5x20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (450 mg, 1.850 mmol, 61% yield) as a brown solid. MS (ESI) 244 (M+H).

Step C. Intermediate 75C. Preparation of 3-(5-cyclopropyl-1-methyl-III-pyrazol-3yl)aniline

To a stirred solution of intermediate 75B (450 mg, 1.850 mmol) in ethanol (4 mL), THF (2 mL) and water (1 mL) was added zinc (1814 mg, 27.7 mmol) followed by ammonium chloride (1484 mg, 27.7 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (10 ml). The organic solution was filtered through a pad of celite, and the celite layer was washed with ethyl acetate (10 ml). The filtrate was washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-60% EtOAc/PE) to give the title compound (350 mg, 1.641 mmol, 89% yield) as a brown wax. MS (ESI) 214 (M+H).

Stage D. Intermediate 75D. Preparation of i((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -(5-cyclopropyl-1 -methyl-1 H- pyrazol-3-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 75C and intermediate 4C where necessary: (230 mg, 0.518 mmol, 55% yield) as a brown wax. MS (ESI) 444 (M+H).

Step E. Example 75. Preparation of u((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3-(5- cyclopropyl-1-methyl-1H-pyrazol-3-yl)-phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The said compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 75D and the corresponding acid where necessary: (17.2 mg, 0.029 mmol, 33% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (d, J=7.6 Hz, 1H), 7.66 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 3.89 (s, 3H), 3.58 (br. s., 2H), 2.08-2.00 (m, 1H), 1.95-1.82 (m, 7H), 1.82-1.70 (m, 6H), 1.50-1.35 (m, 6H), 1.07-0.96 (m, 4H), 0.88-0.79 (m, 2H), 0.74-0.64 (m, 2H); FXR EC ₅₀ (nM) = 247; MS (ESI) 556 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 75D and the corresponding acid where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 76 Z jL\ °' h A /=Z / / / ' V Υ ^Ζ Ό Illi ° λ ^τ 562 610 77 0 ichAich ^F X ΑΑ aJXa Gn /, ^Ν /k /aA/ Ν-Χ ί>—< Τ \ N-ν ί> n ₃ s 576 429 78 ο ^F \-X Ca \aao _h F G 1 » /, ^{N F} N-? l>—f T\nn H ₃ C 576 607 76 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (d, J = 7.6 Hz, 1H), 7.67 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.46 (s, 1H), 3.88 (s, 3H), 3.64 (br. s., 2H), 2.93-2.83 (m, 1H), 2.81-2.68 (m, 2H), 2.38-2.28 (m, 2H), 2.10-2.00 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.65 (m, 6H), 1.51-1.32 (m, 6H), 1.07-0.92 (m, 4H) , 0.89-0.78 (m, 2H), 0.76-0.67 (m, 2H) 77 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.79-7.57 (m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 6.46 (s, 1H ), 3.98-3.80 (m, 3H), 3.56 (s, 2H), 3.022.81 (m, 1H), 2.25 (d, J= 13.7 Hz, 1H), 2.16-1.97 (m, 3H), 1.97- 1.70 (m, 9H), 1.66 (m, 1H), 1.41 (br. s., 6H), 0.99 (t, J= 8.3 Hz, 4H), 0.90-0.75 (m, 2H), 0.68 (d, J =4.9 Hz, 2H) 78 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 10.8 Hz, 1H), 7.41 (td, J = 7.9, 1.8 Hz, 1H), 7.28-7.14 (m, 1H), 6.45 (d, J =1.1Hz, 1H), 3.93-3.84 (m, 3H), 3.61 (br. s., 2H), 3.13-3.00 (m, 1H), 2.33 -2.21 (m, 1H), 2.11-1.97 (m, 3H), 1.95-1.88 (m, 1H), 1.83-1.70 (m, 7H), 1.65 (d, J= 10.0 Hz, 1H), 1.42 (d , J = 4.9 Hz, 6H), 1.07-0.93 (m, 4H), 0.88-0.78 (m, 2H), 0.73-0.63 (m, 2H) (Note: 1H is hidden under the DMSO peak)

Example 79.

N-((4-(3 -cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -φτορ-Ν-(3 -(4- (2methoxypropan-2-yl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

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To a stirred solution of the compound of Example 15 (15 mg, 0.027 mmol) in DMF (1 ml) at 0°C was added NaH (2.140 mg, 0.054 mmol) and MeI (3.35 μl, 0.054 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 15% B, 15-60% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (9.1 mg, 0.016 mmol, 59% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.88 (s, 1H), 7.68-7.53 (m, 2H), 3.66 (br . s., 1H), 3.57 (br. s., 1H), 3.06 (s, 3H), 2.09-2.00 (m, 1H), 1.89 (br. s., 6H), 1.83-1.65 (m, 6H ), 1.50 (s, 6H), 1.44 (d, J=7.8 Hz, 6H), 1.07-0.95 (m, 2H), 0.87-0.76 (m, 2H); FXR EU ₅₀ (nM) 194; MS (ESI) 575 (M+H).

Example 80.

U((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(3-ethyl-2-oxo2 ,3-dihydrooxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Ay ν-~4 /—Ν 7\ n ₃ s y-ooO ⁰ (80)

Step A: Intermediate 80A. Preparation of 3-ethyl-5-(3-nitrophenyl)oxazol-2(3H)-one Ο ₂ Ν

To a stirred solution of intermediate 7A (500 mg, 2.425 mmol) in DMF (5 ml) was added iodoethane (0.388 ml, 4.85 mmol) followed by potassium carbonate (670 mg, 4.85 mmol). The reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate (2x20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (440 mg, 1.879 mmol, 77% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (t, J=1.8 Hz, 1H), 8.11 (dt, J=8.2, 1.2 Hz, 1H), 8.01 (s, 1H), 7.967.86 (m , 1H), 7.77-7.66 (m, 1H), 3.63 (q, J=7.5 Hz, 2H), 1.28 (t, J=4.00 Hz, 3H). MS (ESI) 235 (M+H).

Stage B. 80V intermediate connection. Preparation of 5-(3-aminophenyl)-3-ethyloxazol-2(3H)-one

To a stirred solution of intermediate 80A (440 mg, 1.879 mmol) in ethanol (5 ml) was added zinc (1842 mg, 28.2 mmol) and ammonium chloride (1507 mg, 28.2 mmol) in water (5 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM (30 ml), filtered through celite and concentrated under reduced pressure to give the title compound (300 mg, 1.469 mmol, 78% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.49 (s, 1H), 7.04 (t, J=7.8 Hz, 1H), 6.71-6.62 (m, 2H), 6.48 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 5.23 (br. s., 2H), 3.58 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H). MS (ESI) 205 (M+H).

Step C. Intermediate 80C. Preparation of 5-(3-(((4-(3-cyclopropyl-1,2,4-oxadiazol-151 047337

5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)phenyl)-3-ethyloxazol-2(3H)-one

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 80B and intermediate 4C where necessary: (160 mg, 0.368 mmol, 61% yield) as a yellow solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.54 (s, 1H), 7.07 (t, J=7.8 Hz, 1H), 6.71 (s, 1H), 6.64 (d, J=7.5 Hz, 1H), 6.58-6.54 (m, 1H), 5.63 (t, J=6.0 Hz, 1H), 3.58 (q, J=7.0 Hz, 2H), 2.84 (d, J=6.0 Hz, 2H), 2.11-2.03 (m , 1H), 1.94-1.79 (m, 6H), 1.60-1.53 (m, 6H), 1.25 (t, J=13 Hz, 3H), 1.06-1.00 (m, 2H), 0.89-0.84 (m, 2H ). MS (ESI) 435(M+H).

Step D. Example 80. Preparation of ¥-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-X-(3-( 3-ethyl-2-oxo-2,3-dihydrooxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 80C and the corresponding acid where necessary: (18.7 mg, 0.034 mmol, 50% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (s, 1H), 7.50 (d, J=4.2 Hz, 3H), 7.37-7.27 (m, 1H), 3.62 (q, J=7.4 Hz, 2H ), 3.57 (s, 2H), 2.09-2.01 (m, 1H), 1.88 (s, 6H), 1.82-1.67 (m, 6H), 1.51-1.35 (m, 6H), 1.32-1.22 (m, 3H ), 1.08-0.97 (m, 2H), 0.88-0.81 (m, 2H). FXR EC ₅₀ (nM) = 265; MS (ESI) 547 (M+H).

The following compound was synthesized in accordance with the method described for the synthesis of the compound of example 3, by replacing intermediate 80C and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 81 O Ή O Okxo, PO and /—N 7 \ N ₃ C y-0 O O 553 945 81 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.78 (s, 1H), 7.60-7.40 (m, 3H), 7.31 (d, J = 7.1 Hz, 1H), 3.62(q, J = 7.2 Hz, 4H ), 2.95-2.84 (m, 1H), 2.84-2.69 (m, 2H), 2.34 (br. s., 2H), 2.10-1.99 (m, 1H), 1.89-1.67 (m, 6H), 1.53- 1.33 (m, 6H), 1.32-1.23 (m, 3H), 1.08-0.96 (m, 2H), 0.90-0.76 (m, 2H)

Example 82.

N((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(3-(2-cyclopropyloxazol-5yl)phenyl)-3-fluorobicyclo[1.1. 1]pentane-1-carboxamide

Step A: Intermediate 82A. Preparation of methyl 4-(4-cyclopropyloxazol-2yl)bicyclo[2.2.2]octane-1-carboxylate

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To a solution of intermediate 206A (78 mg, 0.368 mmol) in toluene (2 ml) was added 2bromo-1-cyclopropylethan-1-one (50 mg, 0.307 mmol) and the reaction mixture was heated at 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (25 mg, 0.091 mmol, 30% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (s, 1H), 3.58 (s, 3H), 1.91-1.71 (m, 12H), 1.30 - 1.21 (m, 1H), 0.80

0.62 (m, 4H).

Stage B. Intermediate yl)bicyclo[2.2.2]octan-1-yl)methanol compound 82B. Preparation of (4-(4-cyclopropyloxazole-2-

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G, by replacing intermediate 139A where necessary: (40 mg, 0.162 mmol, 56% yield). MS (ESI) 248 (M+H).

Step C Intermediate yl)bicyclo[2.2.2]octane-1-carbaldehyde

82C. Preparation of 4-(4-cyclopropyloxazole-2-

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 82B where necessary: (35 mg, 71% yield). MS (ESI) 246 (M+H).

Stage D. Intermediate 82D. Preparation of M((4-(4-cyclopropyloxazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-cyclopropyloxazol5-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 20B and intermediate 82C where necessary: (20 mg, 0.047 mmol, 57% yield).

^1H NMR (400 MHz, DMSO- _d0 ) δ 7.67 (s, 1H), 7.33 (s, 1H), 7.1-7.08 (m, 1H), 6.89-6.73 (m, 2H), 6.65 (s, 1H ), 5.75 (s, 1H), 2.81-2.75 (m, 2H), 2.15-2.06 (m, 1H), 1.84-1.52 (m, 12H), 1.11-0.71 (m, 8H). MS (ESI) 430 (M+H).

Step E. Example 82. Preparation of M((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octan-1yl)methyl)-U-(3-(2-cyclopropyloxazol-5-yl)phenyl) -3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 82D and the corresponding acid where necessary: (3.8 mg, 7.02 μmol, 30% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 7.78-7.59 (m, 4H), 7.52 (t, J=7.6 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 3.62 (br. s ., 1H), 3.52 (br. s., 1H), 2.19 (ddd, J=13.0, 8.1, 5.1 Hz, 1H), 1.88 (br. s., 6H), 1.78-1.57 (m, 7H), 1.41 (br. s., 6H), 1.14-1.00 (m, 4H), 0.84-0.71 (m, 2H), 0.64-0.50 (m, 2H). FXR EC ₅₀ (nM) 48; MS (ESI) 542 (M+H).

Example 83.

M((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3 -(2-cyclopropyloxazol-5yl)phenyl)-3,3-difluorocyclobutane- 1-carboxamide

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The said compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 82D and the corresponding acid where necessary: (7 mg, 0.013 mmol, 54% yield).

¹ HNMR (400 MHz, DMSO-d6) 7.75-7.55 (m, 4H), 7.50 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 3.62 (br. s., 2H), 2.89 (dd, J=8.2, 5.5 Hz, 1H), 2.82-2.66 (m, 2H), 2.33 (br. s., 2H), 2.22-2.09 (m, 1H), 1.85-1.55 (m , 7H), 1.50-1.23 (m, 6H), 1.15-0.93 (m, 4H), 0.84-0.69 (m, 2H), 0.66-0.46 (m, 2H).FXR EC ₅₀ (nM) 590; MS (ESI) 548 (M+H).

Example 84.

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

NzS-s/ Vo (84)

Step A: Intermediate 84A. Preparation of (2-(3-nitrophenyl)oxazol-4-yl)methanol NO ₂

To a stirred solution of intermediate 12B (1 g, 3.81 mmol) in THF (30 ml) at -78°C was added DIBAL-H (7.63 ml, 7.63 mmol) and then the reaction mixture was stirred for 1 h at - 78°C. The reaction mixture was poured into a biphasic mixture of aqueous ammonium chloride (10 ml) and EtOAc (50 ml) and the layers were separated. The aqueous layer was further extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (400 mg, 1.798 mmol, 47% yield). MS (ESI) 221 (M+H).

Stage B. Intermediate 84B. Preparation of 4-(methoxymethyl)-2-(3-nitrophenyl)oxazole .1%.

NzS-s/ Vo

NO ₂

To a stirred solution of intermediate 84A (370 mg, 1.680 mmol) in DMF (6 mL) at 0°C was added NaH (134 mg, 3.36 mmol) and MeI (0.210 mL, 3.36 mmol). After stirring for 1 hour, the reaction mixture was poured into cold water and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (350 mg, 1.464 mmol, 87% yield). MS (ESI) 235 (M+H).

Step C. Intermediate 84C. Preparation of 3-(4-(methoxymethyl)oxazol-2-yl)aniline .1%.

NzS-o' Vo

NH ₂

To a stirred solution of intermediate 84B (360 mg, 1.537 mmol) in EtOH (10 ml) at 0° C. was added tin(II) chloride dihydrate (1214 mg, 5.38 mmol) and conc. HCl (1.401 ml, 46.1 mmol). The reaction mixture was stirred at 90°C for 2 hours and concentrated under reduced pressure. The residue was made basic with saturated aqueous NaHCO ₃ and extracted with EtOAc (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (310 mg, 1.427 mmol, 93% yield). MS (ESI) 205 (M+H).

Stage D. Intermediate 84D. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(4-(methoxymethyl)oxazol-2-yl) aniline

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The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 84C and intermediate 4C where necessary: (260 mg, 0.592 mmol, 61% yield). MS (ESI) 435 (M+H).

Step E. Example 84. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3,3-difluoro-N- (3-(4-(methoxymethyl)oxazol-2-yl)phenyl)cyclobutane-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 84D and the corresponding acid where necessary: (15 mg, 0.027 mmol, 47% yield).

1H NMR (400 MHz, DMSO-de) δ 8.22 (s, 1H), 8.02-7.87 (m, 2H), 7.69-7.52 (m, 2H), 4.39 (s, 2H), 3.66 (br. s., 2H), 3.33 (s, 3H), 2.89 (d, J=6.4 Hz, 1H), 2.86-2.71 (m, 2H), 2.38-2.29 (m, 2H), 2.08-2.00 (m, 1H), 1.861 .70 (m, 6H), 1.51-1.33 (m, 6H), 1.07-0.95 (m, 2H), 0.88-0.76 (m, 2H); FXR EC ₅₀ (nM) 948; MS (ESI) 553 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 84D and existing acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 85 O G n "/, ^N NzS-s/ [> 547 137 85 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.57 (d, J= 7.8 Hz, 1H), 4.38 (s, 2H), 3.60 (br. s., 2H), 3.33 (s, 3H), 2.07-2.00 (m, 1H), 1.88 (br. s ., 6H), 1.80-1.72 (m, 6H), 1.481.36 (m, 6H), 1.05-0.98 (m, 2H), 0.86-0.79 (m, 2H)

Example 86.

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

Step A: Intermediate 86A. Preparation of 3-nitrobenzohydrazide

To a stirred solution of methyl 3-nitrobenzoate (5 g, 27.6 mmol) in ethanol (75 ml) was added hydrazine hydrate (6.77 ml, 138 mmol) and refluxed for 6 hours. The solids were filtered off, washed with ethanol ( 5 mL) and dried in vacuo to give the title compound (4.2 g, 23.19 mmol, 84% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-de) δ 10.17 (br . s., 1H), 8.65 (t, J=2.0 Hz, 1H), 8.37 (ddd, J=8.3, 2.3, 1.0 Hz, 1H), 8.31-8.23 (m, 1H), 7.78 (t, J= 8.0 Hz, 1H), 4.63 (s, 2H).

Step B: Nitrobenzohydrazide intermediate

86B. Preparation of No.-(cyclopropanecarbonyl)-3-

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To a stirred solution of intermediate 86A (3 g, 16.56 mmol) in DCM (45 ml) at 0°C was added pyridine (2.68 ml, 33.1 mmol), followed by cyclopropanecarbonyl chloride (2.077 g, 19.87 mmol) and stirred at 0°C for 1 hour. The reaction mixture was diluted with DCM (25 ml) and washed with water (2x25 ml), 1.5 N aqueous HCl solution (2x25 ml) and brine (2x25 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (3.8 g, 14.33 mmol, 87% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-de) δ 10.76 (d, J=1.5 Hz, 1H), 10.29 (d, J=1.5 Hz, 1H), 8.72-8.67 (m, 1H), 8.49-8.40 (m , 1H), 8.34-8.27 (m, 1H), 7.83 (t, J=8.0 Hz, 1H), 1.77-1.66 (m, 1H), 0.86-0.70 (m, 4H). MS (ESI) 250 (M+H).

Step C. Intermediate 86C. Preparation of 2-cyclopropyl-5-(3-nitrophenyl)-1,3,4oxadiazole

To a stirred solution of intermediate 86B (3.3 g, 13.24 mmol) in acetonitrile (70 ml) was added CCl ₄ (1.533 ml, 15.89 mmol), then triphenylphosphine (7.29 g, 27.8 mmol) and refluxed for 2 days. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (2x50 ml) and then with brine (30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (1.5 g, 6.49 mmol, 49% yield) as a white solid. MS (ESI) 232 (M+H).

Stage D. Intermediate 86D. Preparation of 3-(5-cyclopropyl-1,3,4-oxadiazol-2yl)aniline

To a stirred solution of intermediate 86C (1.5 g, 6.49 mmol) in ethanol (15 ml) was added zinc (6.36 g, 97 mmol), followed by a solution of ammonium chloride (5.21 g, 97 mmol) in water (15 ml), and stirred overnight. The reaction mixture was diluted with DCM (50 ml) and filtered through celite. The filtrate was washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (650 mg, 3.00 mmol, 46% yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.15-7.21 (m, 2H), 7.04-7.08 (m, 1H), 6.72-6.76 (m, 1H), 5.47 (s, 2H), 2.24-2.25 ( m, 1H), 1.10-1.20 (m, 4H). MS (ESI) 202 (M+N).

Step E. Intermediate 86E. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-(5-cyclopropyl-1,3,4-oxadiazole -2-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 86D and intermediate 4C where necessary: (350 mg, 0.706 mmol, 58% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.26-7.19 (m, 2H), 7.07-7.04 (m, 1H), 6.82 (dd, J=8.0, 2.0 Hz, 1H), 5.88 (t, J= 6.0 Hz, 1H), 2.87 (d, J=5.5 Hz, 2H), 2.32-2.25 (m, 1H), 2.11-2.03 (m, 1H), 1.92-1.80 (m, 6H), 1.63-1.54 (m , 6H), 1.47-1.40 (m, 1H), 1.21-1.14 (m, 2H), 1.12-1.07 (m, 2H), 1.06-1.01 (m, 2H), 0.89-0.84 (m, 2H). MS (ESI) 432 (M+H).

Step F. Example 86. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-U-(3-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The said compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 86E and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (20 mg, 0.037 mmol, 53% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.94 (m, 1H), 7.92 (s, 1H), 7.75-7.60 (m, 2H), 3.61 (br. s., 2H),

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2.37-2.27 (m, 1H), 2.08-2.01 (m, 1H), 1.89 (br. s., 6H), 1.83-1.68 (m, 6H), 1.53-1.33 (m, 6H), 1.29-1.11 ( m, 4H), 1.07-0.96 (m, 2H), 0.88-0.75 (m, 2H). FXR EU ₅₀ (nM) = 123; MS (ESI) 544 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 3, substituting intermediate 86E and appropriate acids where necessary:

Etc.

No.

¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.03-7.83 (m, 2H), 7.65 (d, J = 4.9 Hz, 2H), 3.66 (br. s., 2H), 2.94-2.84 (m, 1H ), 2.84-2.71 (m, 2H), 2.39-2.29 (m, 3H), 2.10-

MS FXR (ESI) eu ₅₀ (M+N) (nM)

2.00 (m, 1H), 1.87-1.65 (m, 6H), 1.52-1.31 (m, 6H), 1.25-1.11 (m, 4H), 1.070.92 (m, 2H), 0.89-0.76 (m, 2H ).

Example 88.

N-((4-(3 -(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-N-(3 -(3 - cyclopropyl1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 88A. Preparation of methyl 4(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate

_BH3.DMS (14.28 mL, 141 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirring was continued for 2 hours at room temperature. The reaction mixture was quenched by slow addition of methanol at 0°C and left to stir overnight at room temperature. The reaction mixture was concentrated and the residue was diluted with water. The aqueous solution was extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-40% EtOAc/PE) to give the title compound (7 g, 35.3 mmol, 75% yield).

1H NMR (400 MHz, DMSO-d ₆ ): δ 4.12 (dd, J=2.8, 4.0 Hz, 1H), 3.65 (s, 3H), 3.29 (s, 2H), 1.82-1.77 (m, 6H), 1.47-1.42 (m, 6H)

Stage B. 88B intermediate. Preparation of methyl 4-formylbicyclo[2.2.2]octane-1carboxylate

The compound was synthesized according to the method described for the synthesis of intermediate 3C by replacing intermediate 88A where necessary: (900 mg, 4.59 mmol, 91% yield) as a gummy solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 3.59 (s, 3H), 1.78-1.57 (m, 12H). MS (ESI) 197 (M+H).

Step C. Intermediate 88C. Preparation of methyl 4-(((3-(3-cyclopropyl-1,2,4- 157 047337 oxadiazol-5-yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 88B where necessary: (550 mg, 1.298 mmol, 67% yield) as a gummy liquid. MS (ESI) 382 (M+H).

Stage D. Intermediate 88D. Preparation of methyl 4-((and(3-(3-cyclopropyl-1,2,4oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1 ]pentane-1-carboxamido)methyl)bicyclo [2.2.2] octane-1 carboxylate

The said compound was synthesized in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 88C and 3-fluorobicyclo[1.1.1]pentane-1carboxylic acid where necessary: (480 mg, 0.632 mmol, 44% yield ) in the form of a resinous liquid. MS (ESI) 494 (M+H).

Step E. Intermediate 88E. Preparation of 4-(A-(3-(3-cyclopropyl-1,2,4-oxadiazol-5yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane -1-carboxylic acid

To a stirred solution of intermediate 88D (480 mg, 0.972 mmol) in MeOH (5 mL) at room temperature was added a solution of NaOH (194 mg, 4.86 mmol) in H2O (2 mL) and stirred overnight. The reaction mixture was concentrated and the residue was diluted with water. The aqueous solution was acidified with 1.5 N aqueous HCl and extracted with ethyl acetate (2x20 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (400 mg, 0.751 mmol, 77% yield) as a white fluffy solid. MS (ESI) 480 (M+H).

Step F: Intermediate 88F. Preparation of N'-hydroxypivalimidamide

To a stirred solution of pivalonitrile (20 g, 241 mmol) in ethanol (200 ml) was added 50% aqueous hydroxylamine (73.7 ml, 1203 mmol) and refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue diluted with water. The mixture was stirred for 15 minutes and solids were filtered off. The product was dried under high vacuum to give (E)-X'-hydroxypivalimidamide (22 g, 189 mmol, 79% yield) as a white solid. MS (ESI) 117 (M+H).

Step G. Example 88. Preparation of u((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-No-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 88E and intermediate 88F where necessary: (13 mg, 0.023 mmol, 37% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.11-8.04 (m, 1H), 8.04-7.97 (m, 1H), 7.79-7.62 (m, 2H), 3.63 (br. s., 2H), 2.28 -2.16 (m, 1H), 1.89 (br. s., 6H), 1.84-1.69 (m, 6H), 1.53-1.35 (m, 6H), 1.33-1.20 (m, 9H), 1.14 (dd, J =8.2, 2.6 Hz, 2H), 1.04-0.93 (m, 2H). FXR EC50 (nM) = 86; MS (ESI) 560 (M+H).

- 158 047337

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 88E and the corresponding amidoximes where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 89 7) I co / \ 1 ^z o ΞΕ CO 546 47 90 A 588 121 89 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.12-8.04 (m, 1H), 8.04-7.95 (m, 1H), 7.807.73 (m, 1H), 7.73-7.64 (m, 1H), 3.62 ( br. s., 2H), 2.99 (quin, J = 7.0 Hz, 1H), 2.28-2.18 (m, 1H), 1.89 (br. s., 6H), 1.84-1.67 (m, 6H), 1.53- 1.34 (m, 6H), 1.28-1.19 (m, 6H), 1.14 (dd, J = 8.2, 2.6 Hz, 2H), 1.06-0.93 (m, 2H) 90 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.7O (t, J = 7.8 Hz, 1H), 3.93-3.80 (m, 2H), 3.63 (br. s., 1H), 3.48-3.38 (m, 2H), 3.18 (d, J= 5.1Hz, 1H), 3.01 (tt, J= 11.2, 3.8 Hz, 1H), 2.27-2.17 (m, 1H), 1.99-1.72 (m, 14H), 1.71-1.57 (m, 2H), 1.54-1.34 (m, 6H), 1.14 (dd, J = 8.2, 2.3 Hz, 2H), 1.06-0.96 (m, 2H)

Example 91.

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

Triphosgene (22.69 mg, 0.076 mmol) was added to a stirred solution of intermediate 8B (30 mg, 0.070 mmol) in DCM (1 mL) at 0° C. and the reaction mixture was stirred overnight at room temperature. A solution of pyrrolidone (4.97 mg, 0.070 mmol) in DCM (1 mL) followed by TEA (0.058 mL, 0.417 mmol) was added to the stirred reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 30% B, 30-67% B for 20 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (18.8 mg, 0.034 mmol, 49% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.31 (dd, J=8.2, 1.6 Hz, 1H), 3.49 (s, 2H), 3.08 (s, 4H), 2.26-2.13 (m, 1H), 2.12-2.00 (m, 1H), 1.97-1.74 (m, 6H), 1.74-1.59 (m, 4H), 1.59-1.39 (m, 6H), 1.17-1.06 (m, 2H), 1.06-0.92 (m, 4H), 0.89-0.81 (m, 2H); FXR EC ₅₀ (nM) = 322;

- 159 047337

MS (ESI) 529 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 91 by replacing intermediate 8B and the corresponding amines where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 92 O ^H3C CH3 ^N D. CA^Och ill n /, ^N H A A k 545 420 93 n ₃ s N-СНз σ хк \/кк il 1 ”/, ^Ν к* dк Ν' ⁰ t> 572 2692 94 Ιίΐ ?Ν Γ. __Ν4 Ν-° b> 529 265 92 ^Χ Η NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (s, 1H), 7.89 (dt, J = 7.0, 1.5 Hz, 1H), 7.69-7.59 (m, 2H), 5.72 (t, J = 6.3 Hz, 1H), 3.60 (s, 2H), 2.83 (d, J = 6.0 Hz, 2H), 2.24-2.15 (m, 1H), 2.09-1.98 (m, 1H), 1.80-1.69 (m, 6H) , 1.44-1.33 (m, 6H), 1.16-1.08 (m, 2H), 1.04-0.95 (m, 4H), 0.85-0.74 (m, 11H). 93 ^X NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (d, J = 7.5 Hz, 1H), 7.61 (s, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 3.62 (d,J= 14.6 Hz, 1H), 3.28-3.19 (m, 1H), 3.06-2.96 (m, 1H), 2.84 (br. s., 1H), 2.20 (ddd, J = 13.1, 8.0, 5.0 Hz, 1H), 2.11-1.99 (m, 6H), 1.85 (t, J = 7.8 Hz, 6H), 1.52 (d, J =6.5 Hz, 6H), 1.171.08 (m, 2H), 1.06-0.96 (m, 4H), 0.89-0.81 (m, 2H) (6 Protons are buried under solvent peaks). 94 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.87-7.80 (m, 2H), 7.59-7.51 (m, 2H), 6.28 (s, 1H), 3.54 (s, 2H), 2.23-2.15 (m, 1H), 2.01 (td, J= 8.7, 4.3 Hz, 1H), 1.78-1.68 (m, 6H), 1.40-1.32 (m, 6H), 1.23 (s, 3H), 1.14-1.07 (m, 2H) , 1.02-0.95 (m, 4H), 0.84-0.78 (m, 2H), 0.59-0.52 (m, 2H), 0.47-0.41 (m, 2H).

Example 95.

-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-1 -(3 -(3-cyclopropyl1,2,4 -oxadiazol-5-yl)phenyl)-3-ethylurea

- 160 047337

To a stirred solution of intermediate 8B (20 mg, 0.046 mmol) in DCM (1 mL) was added ethyl isocyanate (3.67 μL, 0.046 mmol) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 30% B, 30-60% B for 20 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.6 mg, 6.68 μmol, 14% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.95-7.83 (m, 2H), 7.71-7.56 (m, 2H), 6.00-5.92 (m, 1H), 3.59 (s, 2H), 3.02 (dt, J=13.1, 6.5 Hz, 2H), 2.24-2.18 (m, 1H), 2.09-2.01 (m, 1H), 1.84-1.64 (m, 6H), 1.47-1.30 (m, 6H), 1.13 (dd, J=8.1, 2.2 Hz, 2H), 1.06-0.90 (m, 7H), 0.88-0.77 (m, 2H); FXR EC ₅₀ (nM) = 590; MS (ESI) 503 (M+H).

Example 96.

-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-1 -(3 -(3-cyclopropyl1,2,4 -oxadiazol-5-yl)phenyl)-3-(4-methoxyphenyl)urea

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 95, by replacing intermediate compound 8B and the corresponding isocyanate where necessary: (7.4 mg, 0.0127 mmol, 18% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (s, 1H), 7.95-7.86 (m, 2H), 7.74-7.67 (m, 1H), 7.67-7.59 (m, 1H), 7.32-7.22 (m, 2H), 6.86-6.73 (m, 2H), 3.70 (s, 3H), 3.68 (s, 2H), 2.24-2.18 (m, 1H), 2.09-2.01 (m, 1H), 1.831.69 (m, 6H), 1.51-1.37 (m, 6H), 1.18-1.10 (m, 2H), 1.07-0.95 (m, 4H), 0.86-0.80 (m, 2H). FXR EC50 (nM) = 647; MS (ESI) 581 (M+H).

Example 97.

N-(3 -(2-cyclopropyloxazol-5 -yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1yl)methyl)-3-fluorobicyclo[ 1.1.1 ]pentane-1-carboxamide

ABOUT

Step A: Intermediate 97A. Preparation of methyl 4-carbamothioylbicyclo[2.2.2]octane1-carboxylate

About ι—у NH ₂

N ₃ S-S) \\

To a solution of intermediate 213A (850 mg, 4.02 mmol) in THF (10 ml) was added Lawesson's reagent (976 mg, 2.414 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and the residue was diluted with EtOAc (50 ml). The organic layer was washed with saturated aqueous NaHCO ₃ solution and then with brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (0.65 g, 2.86 mmol, 71% yield). MS (ESI) 228 (M+H).

Stage B. Intermediate 97B. Preparation of methyl 4-(4-cyclopropylthiazole-2

- 161 047337 yl)bicyclo[2.2.2]octane-1-carboxylate

Intermediate 97A (150 mg, 0.660 mmol) was transferred to the reaction vessel and toluene (3 mL) was added. To this solution was added 2-bromo-1-cyclopropylethan-1-one (161 mg, 0.990 mmol), and the reaction mixture was heated to 100°C and stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-20% EtOAc/PE) to give the title compound (120 mg, 0.412 mmol, 62% yield).

¹ H NMR (400 MHz, DMSO-d ₀ ) δ 7.05 (s, 1H), 3.58 (s, 3H), 2.76 - 2.71 (m, 1H), 1.87-1.79 (m, 12H), 0.870.67 (m , 4H). MS (ESI) 292 (M+H).

Step C. Intermediate 97C. Preparation of (4-(4-cyclopropylthiazol-2yl)bicyclo[2.2.2]octan-1-yl)methanol

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G by replacing intermediate 97B where necessary: (95 mg, 0.321 mmol, 62% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.02 (s, 1H), 4.38 (s, 1H), 3.07 (s, 2H), 1.99 - 1.97 (m, 1H), 1.82-1.77 (m, 6H ), 1.46-1.41 (m, 6H), 0.87-0.67 (m, 4H). MS (ESI) 264 (M+H).

Stage D. Intermediate 97D. Preparation of 4-(4-cyclopropylthiazol-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C by replacing intermediate 97C where necessary: (50 mg, 0.191 mmol, 72% yield). MS (ESI) 262 (M+H)

Step E. Intermediate 97E. Preparation of 3-(2-cyclopropyloxazol-5-yl)-M((4-(4cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 20B and intermediate 97D where necessary: from the reaction mixture was obtained (25 mg, 0.046 mmol, 60% yield). MS (ESI) 446 (M+H).

Step F. Example 97. Preparation of M(3-(2-cyclopropyloxazol-5-yl)phenyl)-N-((4-(4cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 97E and the corresponding acid where necessary: (4 mg, 7.17 μmol, 32% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.77-7.59 (m, 3H), 7.52 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.02 (s, 1H ), 3.65 (d,J=12.2 Hz, 1H), 3.51 (d, J=13.0 Hz, 1H), 2.25-2.11 (m, 1H), 2.03-1.95 (m, 1H), 1.87 (br. s. , 6H), 1.75 (t, J=1.1 Hz, 6H), 1.57-1.28 (m, 6H), 0.90-0.79 (m, 2H), 0.78-0.65 (m, 2H). FXR EU ₅₀ (nM) 70; MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 97E and the corresponding acid where necessary:

- 162 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 98 ABOUT A A Di. SD 513 564

99 J X 560 578 98 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.65-7.57 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H ), 7.02 (s, 1H), 3.64 (br. s., 2H), 2.89 (br. s., 1H), 2.76 (d, J= 18.1 Hz, 2H), 2.23-2.13 (m, 1H), 2.03-1.93 (m, 1H), 1.81-1.64 (m, 6H), 1.44 (d, J = 8.3 Hz, 6H), 0.84 (dd, J = 8.2, 2.3 Hz, 2H) 99 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (s, 1H), 7.67-7.60 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 6.4 Hz, 1H ), 7.02 (s, 1H), 3.64 (s, 3H), 2.99-2.91 (m, 1H), 2.30 (d, J= 5.6 Hz, 1H), 2.18 (ddd, J= 13.2, 8.3, 4.9 Hz, 2H), 2.09 (s, 2H), 2.03-1.95 (m, 2H), 1.82 (d, J = 10.0 Hz, 2H), 1.80-1.61 (m, 7H), 1.43 (br. s., 6H), 1.13-1.00 (m, 4H), 0.87-0.80 (m, 2H), 0.76-0.67 (m, 2H).

Example 100.

X-(3-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)phenyl)-X-((4-(4-cyclopropylthiazol-2yl)bicyclo[2.2.2]octan-1 -yl )methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Stage A. Intermediate 100A. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)N((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 97D where necessary: (55 mg, 0.101 mmol, 66% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 7.4-7.1 (m, 3H), 7.05 (s, 1H), 6.98-6.92 (m, 1H), 2.85 (s, 2H), 2.21-1.95 (m, 2H), 1.85-1.56 (m, 12H), 1.11-0.71 (m, 8H). MS (ESI) 447 (M+H).

Step B. Example 100. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-X-((4-(4cyclopropylthiazol-2-yl)bicyclo[2.2.2] octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound

- 163 047337 studies according to example 3, by replacing intermediate 100A and the corresponding acid where necessary: (6.3 mg, 0.011 mmol, 25% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.01 (s, 1H), 3.65 (br. s., 1H), 3.56 (br. s., 1H), 2.27-2.17 (m, 1H), 2.04-1.96 (m, 1H) , 1.88 (br. s., 6H), 1.82-1.58 (m, 6H), 1.54-1.30 (m, 6H), 1.14 (dd, J=8.2, 2.3 Hz, 2H), 1.01 (d, J=2.7 Hz, 2H), 0.90-0.78 (m, 2H), 0.78-0.66 (m, 2H). FXR EC ₅₀ (hM) 164; MS (ESI) 559 (M+H).

The following compound was synthesized in accordance with the method described for the synthesis of the compound of example 3, by replacing intermediate 100A and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 101 O A D Length Ν ⁰ 565 635 101 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.10-7.99 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.02 (s, 1H ), 3.66 (br. s., 2H), 2.94-2.84 (m, 2H), 2.83-2.70 (m, 3H), 2.34 (d, J = 2.0 Hz, 3H), 2.22 (ddd, J = 12.9, 8.3, 4.8 Hz, 1H), 2.01-1.93 (m, 1H), 1.82-1.65 (m, 6H), 1.48-1.32(m, 6H), 1.17-1.09 (m, 2H), 1.06-0.96 (m, 2H), 0.88-0.76 (m, 2H), 0.75-0.69 (m, 2H)

Example 102.

A((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-3-fluoro-A(3-(5- (3fluorobicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 102A. Preparation of 3-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)benzonitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 4C where necessary: (600 mg, 1.636 mmol, 67% yield) as an off-white solid. MS (ESI) 349 (M+N).

Stage B. Intermediate 102B. Preparation of N(3-cyanophenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1. 1 ]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 102A and the corresponding acid where necessary: (300 mg, 0.619 mmol, 86% yield) as an off-white solid. MS (ESI) 461

- 164 047337 (M+N).

Step C. Intermediate 102C. Preparation of oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-(Nhydroxycarbamidolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (Z )-N-((4-(3-cyclopropyl-1,2,4-

The title compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 102B where necessary: (250 mg, 0.481 mmol, 85% yield) as a white solid. MS (ESI) 494 (M+H).

Step D. Example 102. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3 -(5-(3-fluorobicyclo[1.E1]pentan-1-yl)-1,2,4-oxadiazol3-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 102C and 3fluorobicyclo[1.1.1]pentane-1-carboxylic acid where necessary: (17 mg, 0.029 mmol, 57% yield) .

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.09-7.99 (m, 1H), 7.91 (d, J=1.2 Hz, 1H), 7.66 (d, J=5.4 Hz, 2H), 3.63 (br. s ., 1H), 3.56 (br. s., 1H), 2.70 (d, J=2.2 Hz, 6H), 2.09-1.97 (m, 1H), 1.87 (br. s., 6H), 1.81-1.65 ( m, 6H), 1.52-1.33 (m, 6H), 1.08-0.95 (m, 2H), 0.84-0.80 (m, 2H). FXR EC ₅₀ (nM) 1040; MS (ESI) 588 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 102C and the corresponding acids where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 103 0 Ary. П » а ^F \>\ N-stХчХ ⁿ 4 F^NZ—» V O' ^N £> 594 227 104 z Α-Δ + ^: V / I 544 60 105 0 Уу n F^''' Ay g HI /, ^{N F} \ NctXSX N-? /~X i> V F b'N 0 554 57 106 0 F^ ⁷ Ay kAx^O ₄ P » /, ^N A N-? /X to H ₃ C O' ^N [> 558 58 107 XCA H»4 nJU Н3С-7-Д/ Y\H ₃ C bN [> 560 18 108 °' ?' V!, 0 572 144

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109 Already. χ y Н ₃ С O-Ν )> 546 55 110 -J ^γθ Ο ^Ν £> 560 88 111 „; a °<yNH O' ^N £> n ₃ s 601 120 112 Dh zhuO 'H HzCo-N (d 568 68 FROM Yes °Μ ^Ν Χθ D N ₃ C Ο' ^Ν ί> 574 121 103 Τι NMR (400 MHz, DMSO-d ₆ ) δ 8.16-7.99 (m, 1H), 7.94 (s, 1H), 7.75-7.58 (m, 2H), 3.96-3.85 (m, 1H), 3.61 (br. s., 2H), 3.26-3.02 (m, 4H), 2.11-1.99 (m, 1H), 1.88 (br. s., 6H), 1.82-1.61 (m, 6H), 1.54-1.33 (m, 6H ), 1.08-0.96 (m, 2H), 0.91-0.75 (m, 2H). 104 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.05-7.92 (m, 1H), 7.87 (s, 1H), 7.74-7.59 (m, 2H), 3.60 (br. s., 2H), 2.48-2.39 (m, 1H), 2.09-2.00 (m, 1H), 1.87 (br. s., 6H), 1.81-1.65 (m, 6H), 1.53-1.36 (m, 6H), 1.35-1.11 (m, 4H ), 1.06-0.94 (m,

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2H), 0.89-0.78 (m, 2H). 105 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.15-8.03 (m, 1H), 7.99 (s, 1H), 7.78-7.64 (m, 2H), 7.58 (s, 1H), 3.61 (s, 2H) , 2.08-2.01 (m, 1H), 1.89 (br. s., 6H), 1.821.66 (m, 6H), 1.54-1.34 (m, 6H), 1.07-0.97 (m, 2H), 0.88-0.77 (m, 2H). 106 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.06-7.94 (m, 1H), 7.87 (s, 1H), 7.73-7.55 (m, 2H), 3.60 (br. s., 2H), 2.12-2.00 (m, 1H), 1.88 (br. s., 6H), 1.83-1.65 (m, 6H), 1.58 (s, 3H), 1.51-1.30 (m, 8H), 1.20-1.10 (m, 2H), 1.06-0.96 (m, 2H), 0.90-0.77 (m, 2H). 107 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.99 (m, 1H), 7.91 (s, 1H), 7.75-7.58 (m, 2H), 3.60 (br. s., 2H), 2.09-2.01 (m, 1H), 1.89 (br. s., 6H), 1.84-1.65 (m, 6H), 1.56-1.27 (m, 15H), 1.08-0.95 (m, 2H), 0.88-0.74 (m, 2H ). 108 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.09-8.05 (m, 1H), 8.01 (s, 1H), 7.75-7.69 (m, 2H), 3.62 (s, 2H), 2.11-1.98 (m, 1H), 1.89 (br. s., 6H), 1.82-1.65 (m, 6H), 1.55-1.33 (m, 6H), 1.01-0.99 (m, 2H), 0.83-0.80 (m, 2H). 109 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.02-7.99 (m, 1H), 7.90 (s, 1H), 7.67-7.62 (m, 2H), 3.60 (br. s., 2H), 3.46-3.35 (m, 1H), 2.11-1.99 (m, 1H), 1.88 (br. s., 6H), 1.82-1.67 (m, 6H), 1.53-1.32 (m, 12H), 1.07-0.96 (m, 2H ), 0.89-0.75 (m, 2H). 110 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.04-7.94 (m, 1H), 7.88 (d, J = 1.0 Hz, 1H), 7.75-7.59 (m, 2H), 7.06 (s, 1H), 3.62 (br. s., 1H), 3.57 (br. s., 1H), 2.11-2.00 (m, 1H), 1.87 (br. s., 6H), 1.83-1.66 (m, 6H), 1.56-1.29 (m, 10H), 1.09-0.96 (m, 2H), 0.89-0.74 (m, 2H). 111 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.05-7.93 (m, 1H), 7.85 (s, 1H), 7.65 (d, J= 5.4 Hz, 2H), 3.62 (br . s., 1H), 3.56 (br. s., 1H), 2.08-2.01 (m, 1H), 1.94-1.83 (m, 9H), 1.83-1.72 (m, 6H), 1.68 (br. s. , 2H), 1.51-1.27 (m, 8H), 1.07-0.95 (m, 2H), 0.89-0.77 (m, 2H) 112 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (br. s., 1H), 7.99 (br. s., 1H), 7.72 (br. s., 2H), 4.00-3.85 (m, 1H) , 3.62 (br. s., 2H), 2.34-2.17 (m, 3H), 2.05 (d, J = 5.1 Hz, 2H), 1.89 (br. s., 6H), 1.77 (br. s., 6H ), 1.59-1.34 (m, 6H), 1.02 (d, J = 2.7 Hz, 2H), 0.83 (br. s., 2H) FROM Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.11-8.00 (m, 1H), 7.95 (s, 1H), 7.75-7.62 (m, 2H), 5.01 (d, J= 6.1 Hz, 2H), 4.61 (d, J= 6.1 Hz, 2H), 3.62 (br. s., 2H), 2.12-2.00 (m, 1H), 1.98-1.82 (m, 9H), 1.82-1.63 (m, 6H), 1.55- 1.32 (m, 6H), 1.08-0.92 (m, 2H), 0.90-0.72 (m, 2H)

Example 114.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-(3-fluorobicyclo[1.1.1]pentan-1yl) -1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 114A. Preparation of 4-(A-(3-(3-cyclopropyl-1,2,4-oxadiazol5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane -1-carboxamide

To a stirred solution of intermediate 88E (200 mg, 0.417 mmol) in DMF (5 mL) at room temperature was added ammonium chloride (26.8 mg, 0.500 mmol), TEA (0.174 mL, 1.251 mmol) and BOP (203 mg, 0.459 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg, 0.418 mmol, 100% yield). MS (ESI) 479 (M+H).

Stage B: 114V Intermediate. Preparation of N((4-cyanobicyclo[2.2.2]octan-1yl)methyl)-N-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1. 1 ]pentane-1 carboxamide

To a stirred solution of intermediate 114A (200 mg, 0.418 mmol) in pyridine (5 ml) at 0°C was added TFAA (0.295 ml, 2.090 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with cold water and extracted with DCM (2x10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-40% EtOAc/PE) to give the title compound (70 mg, 0.149 mmol, 36% yield) as a pale white solid. MS (ESI) 461 (M+H).

Step C. Intermediate 114C. Preparation of (E)-Na-(3-(3-cyclopropyl-1,2,4-oxadiazol5-yl)phenyl)-3-fluoro-Na-((4-A-hydroxycarbamidoyl)bicyclo[2.2.2]octane- 1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 114B where necessary: (60 mg, 0.122 mmol, 80% yield) as a light gray solid. MS (ESI) 494 (M+H).

Step D. Example 114. Preparation of u(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenyl)-3-fluoro-No((4-(5-(3-fluorobicyclo[1.1 .1 ]pentan-1-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 114C and the corresponding acid where necessary: (11.8 mg, 0.020 mmol, 33% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.75 (d, J=7.6 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.39 (t, J=7.8

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Hz, 1H), 3.34 (br. s., 2H), 2.27 (d, J=2.2 Hz, 6H), 1.96-1.87 (m, 1H), 1.57 (br. s., 6H), 1.48-1.32 ( m, 6H), 1.191.02 (m, 6H), 0.83 (dd, J=8.1, 2.7 Hz, 2H), 0.75-0.67 (m, 2H); FXR EC ₅₀ (nM) = 177; MS (ESI) 588 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 114C and the corresponding acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 115 About YA UVN? ^Nc til » W NC) N° 558 35 116 ABOUT rA A^A\ H I P Y<4 to N-q N'° 544 117 117 0 /''/k^Yk F xk A+XN , ^F ί| η » A x /Ya ⁿ o ^f N° 554 12 118 0 F^^ xk ¥k ^N / ^С1=3 \\ IU Yf> ^N 'O A N'° 612 thirty

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119 0 km to__ ^N ~o ^sn - MJ 560 15 120 0 R ⁿ z Gx/cDM N-ljCHi MM 546 15 121 r-AdHCi| СНз Г\ /kQ N-r/k MM 568 22 122 0 ι\, ^Ν γΜ ⁿ 'O N'O 574 28 123 n /chLx N-o MM 580 73 115 'NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, 7= 7.6 Hz, 1H), 8.01 (s, 1H), 7.817.74 (m, 1H), 7.73- 7.63 (m, 1H), 3.65 (br. s., 2H), 3.54 (d, J = 4.4 Hz, 2H), 2.28-2.16 (m, 1H), 1.88 (br. s., 6H), 1.79-1.60 (m, 6H), 1.49 -1.28 (m, 6H), 1.26-1.19 (m, 3H), 1.14 (dd, 7= 8.2, 2.6 Hz, 2H), 1.08-0.93 (m, 4H) 116 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.72-7.64(m, 1H), 3.64 (s , 2H), 2.24 (dd, J= 9.0, 4.9 Hz, 2H), 1.88 (br. s., 6H), 1.69 (d, 7= 8.6Hz, 6H), 1.41 (d,7= 6.4 Hz, 6H ), 1.21-1.09 (m, 4H), 1.02 (d, 7= 3.9 Hz, 4H)

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117 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 7.6 Hz, 1H), 8.04-7.99 (m, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.42 (s, 1H), 3.59 (br. s., 2H), 2.29-2.15 (m, 1H), 1.89 (br. s., 6H), 1.85-1.65 (m, 6H ), 1.56-1.33 (m, 6H), 1.21-1.09 (m, 2H), 1.06-0.96 (m, 2H) 118 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J =7.8 Hz, lH), 7.70(t, J =7.8 Hz, 1H), 3.64 (br. s., 1H), 3.58 (br. s., 1H), 2.28-2.16 (m, 1H), 1.88 (br. s., 6H), 1.82-1.56 (m, 10H), 1.52-1.30 (m, 6H), 1.14 (dd, J = 8.4, 2.8 Hz, 2H), 1.07-0.95(m, 2H) 119 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 7.3 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J =8.6 Hz, lH), 7.70(t, J =7.8 Hz, 1H), 3.64 (br. s., 2H), 2.30-2.16 (m, 1H), 1.88 (br. s., 6H), 1.79- 1.61 (m, 6H), 1.46-1.36 (m, 6H ), 1.33 (s, 9H), 1.19-1.10 (m, 2H), 1.06-0.96 (m, 2H) 120 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 1.7 Hz, 1H), 7.81-7.72 (m,lH), 7.72-7.65 (m , 1H), 3.65 (br. s., 2H), 3.24-3.17 (m, 1H), 2.29-2.16 (m, 1H), 1.88 (br. s., 6H), 1.78-1.57 (m, 6H) , 1.53-1.33 (m, 6H), 1.32-1.20 (m, 6H), 1.14 (dd, J= 8.1, 2.7 Hz, 2H), 1.05-0.95 (m, 2H) 121 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 7.8 Hz, 1H), 8.04-7.98 (m, 1H), 7.82-7.73 (m,lH), 7.73-7.65 (m, 1H) , 3.65 (br. s., 1H), 3.59 (br. s., 1H), 2.272.20 (m, 1H), 2.14 (t, J = 19.7 Hz, 3H), 1.89 (br. s., 6H ), 1.84-1.60 (m, 6H), 1.57-1.31 (m, 6H), 1.14 (dd, J= 8.2, 2.6 Hz, 2H), 1.07-0.93 (m, 2H) 122 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.79-7.74 (m,lH), 7.74-7.62 (m , 1H), 4.84 (d, J = 6.1 Hz, 2H), 4.52 (d, J = 6.1 Hz, 2H), 3.65 (br.s., 1H), 3.54 (br.s., 1H), 2.28- 2.16 (m, 1H), 1.89 (br. s., 6H), 1.82-1.60 (m, 9H), 1.55-1.33(m, 6H), 1.20-1.07 (m, 2H), 1.06-0.92 (m, 2H) 123 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.15-7.93 (m, 2H), 7.84-7.56 (m, 2H), 3.763.48 (m, 4H), 2.26-2.13 (m, 2H), 1.88 ( br. s., 6H), 1.82-1.59 (m, 6H), 1.51-1.35 (m, 6H), 1.18-1.08 (m, 2H), 1.07-0.91 (m, 2H)

Example 124.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1-methyl-III-pyrazol-3yl)bicyclo [2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 124A. Preparation of methyl 4(chlorocarbonyl)bicyclo[2.2.2]octane-1-carboxylate

4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid was absorbed in SOCl ₂ and refluxed for 2 hours at 60°C. The reaction was monitored by TLC (a small amount of MeOH was quenched and checked by TLC), which showed consumption of the acid. Reak

- 172 047337 tion mixture was concentrated under reduced pressure. The crude product was distilled twice using DCM to give the title compound (1.8 g, 7.80 mmol) as an off-white solid.

Stage B. 124V Intermediate Connection. Preparation of methyl 4-(3-cyclopropyl-3oxopropanoyl)bicyclo[2.2.2]octane-1-carboxylate

ABOUT

To a stirred solution of LiHMDS (9.10 mL, 9.10 mmol) in THF at -78°C was added 1-cyclopropylethan-1-one (0.383 g, 4.55 mmol) and the reaction mixture was stirred for 45 min. A solution of intermediate 124A (1 g, 4.33 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture and stirred for an additional 1 hour at the same temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (800 mg, 2.73 mmol, 63% yield) as an oil. MS (ESI) 279 (M+H).

Stage C. Intermediate compound of 124C1 and 124C2. Preparation of methyl 4-(5-cyclopropyl-1methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate and methyl 4-(3-cyclopropyl-1-methyl-1Hpyrazol-5-yl)bicyclo [2.2.2]octane-1-carboxylate

To a solution of intermediate 124B (800 mg, 2.87 mmol) in methanol (10 mL) was added methylhydrazine sulfate (1036 mg, 7.19 mmol). The reaction mixture was stirred overnight at 80°C. The reaction mixture was concentrated under reduced pressure; the crude product was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Combiflash column, 24 g, silica gel) using 0-20% EtOAc in petroleum ether as eluents. Fractions containing the compound were concentrated to obtain a mixture of compounds. The resulting mixture was purified by preparative HPLC to obtain individual regio-isomers. The isolation of one of the isomers was confirmed by NMR studies (NOE). The first isomer to elute (RT = 4.31 min or peak-1) was intermediate 124C1 (270 mg, 0.889 mmol, 31% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) 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). The second isomer eluted (RT=4.90 min or peak-2) was intermediate 124C2 (320 mg, 1.054 mmol, 37% yield). MS (ESI) 289 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 5.67 (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).

Stage D. Intermediate 124D. Preparation of (4-(5-cyclopropyl-1-methyl-1H-pyrazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was synthesized according to the method described for the synthesis of intermediate 1G by replacing intermediate 124C1 where necessary: (160 mg, 0.584 mmol, 67% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 5.63 (s, 1H), 4.30 (t, J=7.20 Hz, 1H), 3.33 (s, 3H), 3.04 (d, J=7.20 Hz, 2H), 1.74-1.79 (m, 1H), 1.62-1.65 (m, 6H), 1.34-1.39 (m, 6H), 0.86-0.91 (m, 2H), 0.57-0.60 (m, 2H).

Step E. Intermediate 124E. Preparation of 4-(5-cyclopropyl-1-methyl-1H-pyrazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

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The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 124D where necessary: (160 mg, 0.557 mmol, 91% yield) as an off-white solid.

1I NMR (400 MHz, DMSO-d ₆ ) δ 9.44 (s, 1H), 5.67 (s, 1H), 3.72 (s, 3H), 1.59-1.76 (m, 13H), 0.88-0.92 (m, 2H) , 0.57-0.60 (m, 2H).

Step F: Intermediate 124F. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)A((4-(5-cyclopropyl-1 -methyl-1 I-pyrazol-3 -yl)bicyclo[2.2.2]octane -1 -yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing intermediate 8A and intermediate 124E where necessary: (95 mg, 0.203 mmol, 33% yield) as an off-white solid. MS (ESI) 444 (M+H).

Step G. Example 124. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenyl)-X-((4-(5cyclopropyl-1 -methyl-1 H-pyrazol- 3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 124F and the corresponding acid where necessary: (14 mg, 0.025 mmol, 44% yield).

1I NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J=7.3 Hz, 1I), 7.98 (s, 1I), 7.78-7.65 (m, 2I), 5.59 (s, 1I), 3.69 (s , 3N), 3.61 (br. s., 1I), 3.53 (br. s., 1I), 2.26-2.18 (m, 1I), 1.88 (br. s., 6I), 1.79-1.72 (m, 1I ), 1.67-1.47 (m, 6H), 1.44-1.25 (m, 6H), 1.14 (dd, J=8.3, 2.7 Hz, 2H), 1.04-0.96 (m, 2H), 0.91-0.81 (m, 2I ), 0.58-0.49 (m, 2H). FXR EC ₅₀ (nM) 89; MS (ESI) 556.3 (M+I).

The following compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 124F and appropriate acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 125 О ^F /' xk ^F Η I Т N-СНз Ν' ⁰ 562 480 125 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.10-7.94 (m, 2H), 7.74 (d, J= 8.1 Hz, 1H), 7.68 (t, J= 7.9 Hz, 1H), 5.59 (s, 1H), 3.69 (s, 3H), 3.63 (br. s., 2H), 2.97-2.84 (m, 1H), 2.84-2.68 (m, 2H), 2.34 (d, J = 1.7 Hz, 2H), 2.26-2.14 (m, 1H), 1.801.68 (m, 1H), 1.68-1.46 (m, 6H), 1.46-1.28 (m, 6H), 1.19-1.09 (m, 2H), 1.060.95 (m , 2H), 0.94-0.80 (m, 2H), 0.60-0.47 (m, 2H).

Example 126.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-X-((4-(3-cyclopropyl-1-methyl-1I-pyrazol-5yl)bicyclo [2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 126A. Preparation of (4-(3-cyclopropyl-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 124C2 where necessary: (120 mg, 0.438 mmol, 42% yield) as a pale yellow solid.

ΉNMR (400 MHz, DMSO-d ₆ ): δ 5.65 (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).

Stage B. 126V intermediate connection. Preparation of 4-(3-cyclopropyl-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 126A where necessary: (90 mg, 0.348 mmol, 76% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.45 (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).

Step C. Intermediate 126C. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2] octan-1-yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 126B where necessary: (70 mg, 0.142 mmol, 41% yield) as an off-white solid. MS (ESI) 444 (M+H).

Step D. Example 126. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenyl)-N-((4-(3cyclopropyl-1-methyl-1 H-pyrazol- 5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 126C and the corresponding acid where necessary: (20.5 mg, 0.037 mmol, 65% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (d, J=7.6 Hz, 1H), 8.03-7.97 (m, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.70 (t, J =7.7 Hz, 1H), 5.62 (s, 1H), 3.72 (s, 3H), 3.63 (br. s., 1H), 3.55 (br. s., 1H), 2.27-2.18 (m, 1H), 1.88 (br. s., 6H), 1.78-1.58 (m, 7H), 1.41 (d, J=7.1 Hz, 6H), 1.14 (dd, J=8.2, 2.8 Hz, 2H), 1.06-0.96 (m , 2H), 0.79-0.69 (m, 2h), 0.59-0.48 (m, 2H). FXR EC ₅₀ (nM) 87; MS (ESI) 556 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 126C and the corresponding acid where necessary:

- 175 047337

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.12-8.01 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 8.1 Hz, 1H), 5.62 (s, 1H ), 3.72 (s, 3H), 3.65 (br. s., 2H), 2.96-2.83 (m, 1H), 2.82-2.69 (m, 2H), 2.34 (d, J= 1.7 Hz, 2H), 2.21 (td, J= 8.6, 4.2 Hz, 1H), 1.81-1.57 (m, 7H), 1.50-1.26 (m, 6H), 1.18-1.07 (m, 2H), 1.06-0.94 (m, 2H), 0.81 -0.70 (m, 2H), 0.57-0.48 (m, 2H).

MS FXR (ESI) eu ₅₀ (M+N) (nM)

Example 128.

N(3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-X-((1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octane-4- yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 128A. Preparation of (4-hydroxy-4-(4methoxyphenyl)cyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

(4-Methoxyphenyl)magnesium was added to a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (0.5 g, 1.072 mmol) in THF (15 ml) at -78°C bromide (3.21 ml, 3.21 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with EtOAc (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (0.6 g, 0.992 mmol, 93% yield) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 7.81-7.71 (m, 4H), 7.37 (d, J=8.5 Hz, 4H), 7.27-7.24 (m, 2H), 6.906.83 (m, 2H), 4.00 (s, 1H), 3.84-3.77 (m, 5H), 2.49-2.44 (m, 6H), 1.70-1.60 (m, 5H), 1.58-1.48 (m, 2H), 1.301.27 (m, 1H ).

Stage B. 128V intermediate connection. Preparation of (1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

Sodium hydride (0.125 g, 3.13 mmol) was added to a solution of intermediate 128A (0.6 g, 1.044 mmol) in anhydrous 1,2-dimethoxyethane (20 mL) at 0°C. The reaction mixture was stirred for 30 minutes at 0°C and refluxed overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 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 product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-50% EtOAc/PE) to give the title compound (0.4 g, 0.944 mmol, 90% yield) as a white solid. MS (ESI) 403 (M+H).

Step C. Intermediate 128C. Preparation of (1-(4-methoxyphenyl)-2

- 176 047337 oxabicyclo[2.2.2]octan-4-yl)methyl acetate /=\

AcO '—' CH ₃

Cesium acetate (0.572 g, 2.98 mmol) was added to a solution of intermediate 128B (0.4 g, 0.994 mmol) in DMF (5 mL). The reaction mixture was heated at 120°C and stirred overnight in a hermetically sealed tube. The reaction mixture was cooled to room temperature and poured into water (10 ml). The aqueous layer was extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (0.3 g, 0.982 mmol, 99% yield) as an off-white solid. MS (ESI) 291 (M+H).

Stage D. Intermediate 128D. Preparation of (1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octan-4-yl)methanol / ⁼ \but ⁴ - 'CH ₃

To a solution of intermediate 128C (0.3 g, 1.033 mmol) in methanol (5 ml) at 0°C was added a solution of potassium carbonate (0.714 g, 5.17 mmol) in water (7 ml) and the reaction mixture was stirred at room temperature for 2 hours. Methanol was removed under reduced pressure and the aqueous solution was extracted with EtOAc (containing 5% MeOH) (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.25 g, 0.906 mmol, 88% yield) as an off-white solid. MS (ESI) 249 (M+H).

Step E. Intermediate 128E. Preparation of 1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octane-4-carbaldehyde / ⁼ \ J °' o '—' CH ₃

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 128D where necessary: (0.1 g, 0.386 mmol, 96% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 7.32-7.25 (m, 2H), 6.89-6.81 (m, 2H), 3.98 (s, 2H), 3.73 (s, 3H) , 2.14-2.00 (m, 2H), 1.93-1.83 (m, 6H).

Step F: Intermediate 128F. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)N((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 128E where necessary: (75 mg, 0.099 mmol, 61% yield) as a brown gum. MS (ESI) 432 (M+H).

Step G. Example 128. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenyl)-3-fluoro-N((1-(4-methoxyphenyl)-2-oxabicyclo [2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3 by replacing intermediate 128F and the corresponding acid where necessary: (11.6 mg, 0.021 mmol, 37% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (d, J=7.8 Hz, 1H), 8.05 (d, J=1.7 Hz, 1H), 7.82-7.76 (m, 1H), 7.767.67 (m , 1H), 7.30-7.16 (m, 2H), 6.87-6.73 (m, 2H), 3.71-3.68 (m, 7H), 2.28-2.17 (m, 1H), 2.02-1.92 (m, 2H), 1.89 (br. s., 6H), 1.80-1.68 (m, 2H), 1.62 (br. s., 2H), 1.55 (d, J=7.3 Hz, 2H), 1.14 (dd, J=8.2, 2.6 Hz , 2H), 1.02 (dd, J=4.6, 2.4 Hz, 2H); FXR EC ₅₀ (nM) = 403; MS (ESI) 544 (M+H).

Example 129.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octane- 4-yl)methyl)cyclobutan-1-carboxamide

- 177 047337

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 128F and the corresponding acid where necessary: (13.8 mg, 0.025 mmol, 43% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.70 (t, J= 7.8 Hz, 1H), 7.30-7.14 (m, J=9.0 Hz, 2H), 6.92-6.75 (m, J=9.0 Hz, 2H), 3.79-3.59 (m, 7H), 2.96-2.71 (m, 3H ), 2.34 (br.s., 2H), 2.25-2.17 (m, 1H), 2.00-1.87 (m, 2H), 1.74 (br.s., 2H), 1.66-1.57 (m, 2H), 1.53 (d, J=7.1 Hz, 2H), 1.17-1.10 (m, 2H), 1.05-0.92 (m, 2H); FXR EC ₅₀ (nM) = 1136; MS (ESI) 550 (M+H).

Example 130.

N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(2cyclopropyl-1-methyl-1 H-imidazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 130A. Preparation of 2-cyclopropyl-4-(3-nitrophenyl)-1Nimidazole

K2CO3 (6 .80 g, 49.2 mmol), and the reaction mixture was stirred for 3 hours at 90°C in a microwave reactor. The reaction mixture was poured into saturated aqueous NaHCO ₃ solution and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (3.0 g, 13.09 mmol, 80% yield). MS (ESI) 230 (M+H).

Stage B. 130V intermediate connection. Preparation of 2-cyclopropyl-1-methyl-4-(3-nitrophenyl)1H-imidazole

To a stirred solution of intermediate 130A (0.35 g, 1.527 mmol) and NaH (0.073 g, 1.832 mmol) in DMF (5 ml) at 0°C was added iodomethane (0.099 ml, 1.527 mmol). After stirring the reaction mixture for 1 hour at room temperature, the reaction mixture was poured into ice water and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (200 mg, 0.822 mmol, 54% yield). MS (ESI) 244 (M+H).

Step C. Intermediate 130C. Preparation of 3-(2-cyclopropyl-1-methyl-1H-imidazol-4yl)aniline

To a stirred solution of intermediate 130B (250 mg, 1.028 mmol) in EtOH (2 ml) at 0°C was added tin(II) chloride dihydrate (812 mg, 3.60 mmol) and conc. HCl (0.468 ml, 15.42 mmol). The reaction mixture was heated to 90°C and stirred for 2 hours. The reaction mixture

- 178 047337 was centrated under reduced pressure, the residue was made basic with saturated aqueous NaHCO ₃ and extracted with EtOAc (2x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (210 mg, 0.985 mmol, 96% yield). MS (ESI) 214 (M+H).

Stage D. Intermediate 130D. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-cyclopropyl-1-methyl-1H-imidazole -4-yl)aniline

H ₃ C

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 130C and intermediate 4C where necessary: (220 mg, 0.496 mmol, 71% yield). MS (ESI) 444 (M+H).

Step E. Example 130. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(2- cyclopropyl-1-methyl-III-imidazol-4-yl)-phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 130D and the corresponding acid where necessary: (6.4 mg, 0.012 mmol, 17% yield).

¹ H NMR (400 MHz, DMSO-de) δ 7.68 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 3.70 (s, 3H), 3.56 (br. s., 2H), 2.11-1.96 (m, 2H), 1.86 (br. s., 6H), 1.81- 1.67 (m, 6H), 1.53-1.31 (m, 6H), 1.06-0.98 (m, 2H), 0.98-0.85 (m, 4H), 0.85-0.76 (m, 2H); FXR EC ₅₀ (nM) 585; MS (ESI) 556 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 130D and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR EC ₅ o (hM) 131 O Λ G 1 U . Ν ι>-<'Τ V N-^ L> H ₃ C 562 1440 131 ^NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.53 (m, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 3.70 (s, 3H ), 3.62 (s, 2H), 2.91-2.69 (m, 3H), 2.412.28 (m, 2H), 2.10-1.92 (m, 2H), 1.92-1.64 (m, 6H), 1.55-1.28 (m , 6H), 1.070.97 (m, 2H), 0.94 (d, J = 8.1 Hz, 2H), 0.91-0.86 (m, 2H), 0.86-0.76 (m, 2H)

Example 132.

N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(3-(5cyclopropyl-4-methyl-4H -1,2,4-triazol-3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 132A. Preparation of N-methylcyclopropanecarboxamide

- 179 047337

To a stirred solution of cyclopropanecarbonyl chloride (2.174 ml, 23.92 mmol) in THF (20 ml) at room temperature was added methanamine (33.5 ml, 67.0 mmol) and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate (30 ml) and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (1.6 g, 16.14 mmol, 68% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (br. s., 1H), 2.58 (d, J=4.6 Hz, 3H), 1.57-1.43 (m, 1H), 0.70-0.54 (m, 4H).

Stage B. Intermediate 132B. Preparation of 3-cyclopropyl-4-methyl-5-(3-nitrophenyl)4H-1,2,4-triazole

To a stirred solution of intermediate 86A (704 mg, 3.88 mmol) in DCE (12 ml) at 0°C was added 2-fluoropyridine (0.343 ml, 3.88 mmol), trifluoromethanesulfonic acid anhydride (0.685 ml, 3.88 mmol ) and N-methylcyclopropanecarboxamide (350 mg, 3.53 mmol). The reaction mixture was stirred for 10 minutes at room temperature and then stirred for 2 hours at 140°C in a microwave reactor. The reaction mixture was then poured into water and the aqueous layer was extracted with EtOAc (2x25 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (550 mg, 2.252 mmol, 64% yield). MS (ESI) 245 (M+H).

Step C. Intermediate 132C. Preparation of 3-(5-cyclopropyl-4-methyl-4H-1,2,4triazol-3-yl)aniline

To a stirred solution of intermediate 132B (250 mg, 1.024 mmol) in EtOH (10 ml) at 0°C was added tin(II) chloride dihydrate (808 mg, 3.58 mmol) and conc. HCl (0.466 ml, 15.35 mmol). The reaction mixture was heated to 90°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHCO3 and extracted with EtOAc (2x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (200 mg, 0.924 mmol, 90% yield). MS (ESI) 215 (M+H).

Stage D. Intermediate 132D. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -(5-cyclopropyl-4-methyl-4H-1 ,2,4-triazol-3-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 132C and intermediate 4C where necessary: (140 mg, 0.220 mmol, 32% yield). MS (ESI) 445 (M+H).

Step E. Example 132. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(5- cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 132D and the corresponding acid where necessary: (11.5 mg, 0.020 mmol, 30% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.66 (m, 2H), 7.63 (t, J=8.1 Hz, 1H), 7.59-7.48 (m, 1H), 3.77-3.67 (m, 3H) , 3.59 (s, 2H), 2.11-2.00 (m, 2H), 1.99-1.82 (m, 6H), 1.82-1.64 (m, 6H), 1.52-1.31 (m, 6h), 1.10-0.99 (m, 4H), 0.99-0.90 (m, 2H), 0.89-0.76 (m, 2H); FXR EC ₅₀ (nM) 4413; MS (ESI) 557 (M+H).

Example 133.

A((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(5cyclopropyl-1,3,4 -oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (racemate)

- 180 047337

ABOUT

Step A: Intermediate 133A. Preparation of methyl 4-(2(cyclopropanecarbonyl)hydrazine-1-carbonyl)bicyclo[2.2.2]octane-1-carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2.0 g, 9.42 mmol) in DMF (20 mL) was added cyclopropanecarbohydrazide (1.038 g, 10.37 mmol) at room temperature ), DIPEA (4.94 ml, 28.3 mmol), then HATU (4.658 g, 12.25 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated, diluted with water (50 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-30% EtOAc/PE) to give the title compound (2.2 g, 7.47 mmol, 79% yield) as a white solid. MS (ESI) 295 (M+H).

Stage B. Intermediate 133B. Preparation of methyl 4-(5-cyclopropyl-1,3,4-oxadiazol2-yl)bicyclo[2.2.2]octane-1-carboxylate

To a stirred solution of intermediate 133A (1.200 g, 4.08 mmol) in acetonitrile (12 ml) was added CCl ₄ (0.433 ml, 4.48 mmol) followed by triphenylphosphine (2.246 g, 8.56 mmol) and the reaction mixture was heated at 90°C and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-80% EtOAc/PE) to give the title compound (800 mg, 2.90 mmol, 71% yield) as a gray solid. MS (ESI) 277 (M+H).

Step C. Intermediate 133C. Preparation of (4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 133B where necessary: (500 mg, 2.013 mmol, 62% yield) as a white resinous solid. MS (ESI) 249 (M+H).

Stage D. Intermediate 133D. Preparation of 4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 133C where necessary: (380 mg, 1.543 mmol, 77% yield) as a white solid.

^1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 2.15-2.20 (m, 1H), 1.66-1.77 (m, 6H), 1.85-1.92 (m, 6H), 1.10-1.11 (m, 4H).

Step E. Intermediate 133E. Preparation of 3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)N((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane- 1 -yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing intermediate 86D and intermediate 133D where necessary: (120 mg, 0.278 mmol, 86% yield) as a gummy liquid. MS (ESI) 432 (M+H).

Step F. Example 133. Preparation of N((4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(3-(5- cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3,3difluorocyclopentane-1-carboxamide (racemate)

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 133E and the corresponding acid where necessary: (4.8 mg, 8.02 μmol, 14% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.79-7.59 (m, 2H), 3.62 (s, 2H), 2.93 (t , J=8.3 Hz, 1H), 2.36-2.27 (m, 2H), 2.19-1.98 (m, 3H), 1.97-1.79(m, 2H), 1.79-1.66 (m, 6H), 1.60 (br. s ., 1H), 1.52-1.30 (m, 6H), 1.24-1.11 (m, 4H), 1.11-1.01 (m, 2H), 0.99-0.85 (m, 2H); FXR EC ₅₀ (nM) = 293; MS (ESI) 564 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 133E and the corresponding acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 134 O xL LM\xO _x _x JuM N'N N'N 564 636

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135 ABOUT AJJ "A" N'N 550 1109 136 O U _Л _Y'AxY k _N ^Z n-ν 544 141 134 Tl NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.84 (m, 2H), 7.71-7.52 (m, 2H), 6.165.96 (m, 1H), 5.96-5.82 (m, 1H), 3.63 ( d, J =3.7 Hz, 2H), 3.04 (dd,J= 19.1, 9.0 Hz, 1H), 2.39-2.29 (m, 2H), 2.19-2.02 (m, 2H), 1.85-1.57 (m, 8H) , 1.40 (d, J =4.6 Hz, 6H), 1.24-1.11 (m,4H), 1.10-1.02 (m, 2H), 0.97-0.86 (m, 2H) 135 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.87 (m, 2H), 7.66 (d, J = 5.1 Hz, 2H), 3.77-3.56 (m, 2H), 2.96-2.69 (m, 3H) , 2.41-2.25 (m, 3H), 2.17-2.03 (m, 1H), 1.86-1.63 (m, 6H), 1.52-1.29 (m, 6H), 1.23-1.11 (m, 4H), 1.11-1.01 ( m, 2H), 0.98-0.86 (m, 2H) 136 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.94 (m, 1H), 7.93 (s, 1H), 7.66 (d, J = 5.1 Hz, 2H), 3.60 (d, J = 16.9 Hz, 2H ), 2.39-2.28 (m, 1H), 2.21-2.09 (m, 1H), 1.88 (br. s., 6H), 1.79- 1.62 (m, 6H), 1.52-1.33 (m, 6H), 1.29- 1.11 (m, 4H), 1.11-1.02 (m, 2H), 0.98-0.87 (m, 2H)

Example 137.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo [2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 137A. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)X-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane -1 -yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 133D where necessary: (70 mg, 0.162 mmol, 100% yield) as a gummy liquid. MS (ESI) 432 (M+H).

Step B. Example 137. Preparation of No.(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-No.-((4-(5cyclopropyl-1,3,4-oxadiazol-2- yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 137A and the corresponding acid where

- 183 047337 this is necessary: (7.2 mg, 0.013 mmol, yield 19%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=7.6 Hz, 1H), 8.00 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 3.63 (br. s., 1H), 3.55 (br. s., 1H), 2.26-2.17 (m, 1H), 2.17-2.08 (m, 1H), 1.87 (br. s., 6H), 1.80-1.60 (m, 6H), 1.51-1.31 (m, 6H), 1.12 (dd, J=8.2, 2.6 Hz, 2H), 1.09-1.03 (m, 2H), 1.03-0.96 (m, 2H), 0.95-0.82 (m, 2H); FXR EC ₅₀ (nM) = 43; MS (ESI) 544 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 137A and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 138 O ^F f^ A ^F Π » ν- _ν Ν-0 550 158 139 O Γγ Ν'Χχ'ι ^F t ⁷ A Nn Ν° 564 384 138 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.12-7.91 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.9 Hz, 1H), 3.66 (br. s., 2H), 2.96-2.69 (m, 3H), 2.34 (br. s., 2H), 2.25-2.17 (m, 1H), 2.17-2.08 (m, 1H), 1.85-1.60 (m, 6H ), 1.51-1.29 (m, 6H), 1.19-1.11 (m, 2H), 1.11-1.03 (m, 2H), 1.03-0.97 (m, 2H), 0.97-0.83 (m, 2H) 139 NMR (400 MHz, DMSO-d ₆ ) δ 8.10-7.87 (m, 2H), 7.80-7.54 (m, 2H), 6.18-5.65 (m, 1H), 3.62 (br. s., 2H), 3.14- 2.96 (m, 1H), 2.34-2.26 (m, 1H), 2.24-2.16 (m, 1H), 2.16-1.98 (m, 2H), 1.82-1.67 (m, 7H), 1.64 (d, J =9.8 Hz, 1H), 1.49-1.35 (m, 6H), 1.32 (br. s., 1H),1.18-1.09 (m, 2H), 1.09-1.02 (m, 2H), 1.02-0.95 (m, 2H) , 0.95-0.81 (m, 2H)

Example 140.

Y-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-A((1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2] octan-4-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 140A. Preparation of (4-hydroxy-4-(2-methoxypyrimidin-5yl)cyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzene sulfonate)

To a stirred solution of 5-bromo-2-methoxypyrimidine (1.519 g, 8.04 mmol) in THF (50 ml)

- 184 047337 n-butyllithium (3.43 ml, 8.57 mmol) was added at -78°C and stirred for 10 minutes. To the above reaction mixture was added a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4methylbenzenesulfonate) (2.5 g, 5.36 mmol) in THF (12 ml) and the reaction mixture was stirred. at 78°C for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (1.4 g, 1.360 mmol, 25% yield) as a white solid. MS (ESI) 577 (M+H).

Stage B. 140V intermediate connection. Preparation of (1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

NaOH (0.281 g, 7.02 mmol) was added to a stirred solution of intermediate 140A (1.35 g, 2.341 mmol) in THF (40 mL) at room temperature and refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (120 mg, 0.291 mmol, 12% yield) as a brown solid. MS (ESI) 405 (M+H).

Step C. Intermediate 140C. Preparation of (1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl acetate

To a stirred solution of intermediate 140B (120 mg, 0.297 mmol) in DMF (2 ml) was added cesium acetate (142 mg, 0.742 mmol), heated to 120°C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue diluted with water (25 ml) and extracted with ethyl acetate (2x30 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (75 mg, 0.233 mmol, 79% yield) as a brown tarry solid. MS (ESI) 293 (M+H).

Stage D. Intermediate 140D. Preparation of (1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methanol

To a stirred solution of intermediate 140C (70 mg, 0.239 mmol) in methanol (2 mL) was added a solution of sodium methoxide (5.48 μL, 0.024 mmol) in methanol at room temperature. After stirring the reaction mixture for 2 hours, it was diluted with DCM (25 ml) and washed with water (15 ml) and then with brine (25 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (60 mg, 0.209 mmol, 87% yield) as a white solid. MS (ESI) 251 (M+H).

Step E. Intermediate 140E. Preparation of 1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octane-4-carbaldehyde

Ν-". tsl yam fu-gm-l N ₃ C Ν=/ (U O

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 140D where necessary: (50 mg, 0.201 mmol, 84% yield) as a brown tarry solid. MS (ESI) 249 (M+H).

Stage F. Intermediate 140F. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)N((1-(2-methoxypyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl )aniline

- 185 047337

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 140E where necessary: (20 mg, 0.046 mmol, 38% yield) as a brown gum solid.

1H NMR (400 MHz, DMSO-d ₀ ) δ 8.59 (s, 2H), 7.33-7.24 (m, 2H), 7.18 (d, J=7.5 Hz, 1H), 6.93-6.92 (m, 1H), 6.01 (br. s., 1H), 3.93-3.87 (m, 5H), 2.94 (d, J=5.0 Hz, 2H), 2.18-2.09 (m, 5H), 1.93-1.88 (m, 2H), 1.75 ( br. s., 2H), 1.14-1.07 (m, 2H), 1.00-0.96 (m, 2H). MS (ESI) 434 (M+H).

Step G. Example 140. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-phenyl)-3-fluoro-N((1-(2-methoxypyrimidin-5-yl) -2-oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide

The said compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 140F and the corresponding acid where necessary: (11.3 mg, 0.021 mmol, 44% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 2H), 8.15-7.98 (m, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 3.88 (s, 3H), 3.71 (br. s., 3H), 3.61 (br. s., 1H), 2.27-2.17 (m, 1h), 2.08-1.97 (m, 2H), 1.89 ( br. s., 6H), 1.82 (br. s., 2H), 1.65 (br. s., 2H), 1.56 (d, J=6.1 Hz, 2H), 1.14 (dd, J=8.3, 2.7 Hz , 2H), 1.07-0.90 (m, 2H); FXR EC ₅₀ (nM) = 582; MS (ESI) 546 (M+H).

Example 141.

N((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(3cyclopropyl-1,2,4-oxadiazol-5 -yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide

ABOUT

Γϊ ^ν Ο6λ° ^Ν '° (141)

Step A: Intermediate 141A. Preparation of (4-(4-(1-cyanocyclopropyl)phenyl)-4hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

To a stirred solution of 1-(4-bromophenyl)cyclopropane-1-carbonitrile (1.785 g, 8.04 mmol) in THF (25 ml), cooled to -78°C, was added n-butyllithium (3.43 ml, 8. 57 mmol) and left to gradually warm to room temperature over 1 hour. The reaction mixture was again cooled to 78°C and a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate) (2, 5 g, 5.36 mmol) in THF (12 ml). After stirring for 3 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (2.4 g, 3.62 mmol, 67% yield) as a white solid. MS (ESI) 609 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J=8.3 Hz, 2H), 7.80-7.74 (m, 2H), 7.50 (d, J=8.1 Hz, 4H), 7.277.19 (m , 4H), 4.81 (s, 1H), 4.01 (s, 2H), 3.74 (s, 2H), 2.45 (s, 3H), 2.37 (s, 3H), 1.77-1.70 (m, 2H), 1.64- 1.52 (m, 2H), 1.50-1.44 (m, 2H), 1.31-1.21 (m, 6H).

Stage B. Intermediate 141B. Preparation of (1-(4-(1-suapocyclopropyl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzene sulfonate / ⁼ \O

TsO ^/ X—/ P/ s _N

NaOH (0.472 g, 11.81 mmol) was added to a stirred solution of intermediate 141A (2.4 g, 3.94 mmol) in THF (70 mL) at room temperature and refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column

- 186 047337 flash chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (1.5 g, 2.54 mmol, 65% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.24 ( d, J=8.3 Hz, 2H), 3.81 (s, 2H), 3.70 (s, 2H), 2.44 (s, 3H), 2.08-1.98 (m, 2H), 1.83-1.68 (m, 4H), 1.66 -1.50 (m, 4H), 1.49-1.43 (m, 2H).

Step C. Intermediate 141C. Preparation of (1-(4-(1-suapocyclopropyl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl acetate <-O /=\

Ace/ ^-/ cn

Cesium acetate (1.535 g, 8.00 mmol) was added to a stirred solution of intermediate 141B (1.40 g, 3.20 mmol) in DMF (20 mL) and heated to 120°C. After stirring for 3 hours, the reaction mixture was concentrated under reduced pressure, the residue was diluted with water (25 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.1 g, 3.01 mmol, 94% yield) as a brown solid. MS (ESI) 326 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H), 3.80 (s, 4H), 2.11-2.01 (m, 5H), 1.85-1.75 (m, 2H), 1.74-1.57 (m, 6H), 1.50-1.44 (m, 2H).

Stage D. Intermediate 141D. Preparation of 1-(4-(4-(hydroxymethyl)-2oxabicyclo[2.2.2]octan-1 -yl)phenyl)cyclopropane-1-carbonitrile

To a stirred solution of intermediate 141C (1.2 g, 3.69 mmol) in THF (15 ml) at room temperature was added sodium methoxide (0.084 ml, 0.369 mmol) and stirred for 2 hours. The reaction mixture was diluted with DCM (25 ml ) and washed with water (15 ml) and then saline (25 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-30% EtOAc/PE) to give the title compound (500 mg, 1.747 mmol, 47% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.36 (m, J=9.0 Hz, 2H), 7.28-7.23 (m, J=8.5 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H ), 3.79 (s, 2H), 3.15 (d, J=5.5 Hz, 2H), 2.09-1.99 (m, 2H), 1.83-1.70 (m, 4H), 1.65 (td, J=10.8, 4.0 Hz, 2H), 1.59-1.44 (m, 4H). MS (ESI) 284 (M+H).

Step E. Intermediate 141E. Preparation of 1-(4-(4-formyl-2-oxabicyclo[2.2.2]octan1 -yl)phenyl)cyclopropane-1-carbonitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 141D where necessary: (400 mg, 1.123 mmol, 66% yield) as a white solid. MS (ESI) 282 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 7.43-7.33 (m, 2H), 7.30-7.20 (m, 2H), 3.99 (s, 2H), 2.10 (d, J= 11.7 Hz, 1H), 2.04-1.96 (m, 1H), 1.93-1.82 (m, 4H), 1.79-1.61 (m, 4H), 1.50-1.43 (m, 2H).

Step F: Intermediate 141F. Preparation of 1-(4-(4-(((3-(3-cyclopropyl-1,2,4oxadiazol-5-yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl) phenyl)cyclopropane-1carbonitrile

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 141E where necessary: (70 mg, 0.120 mmol, 84% yield) as a white solid. MS (ESI) 467 (M+H).

Step G. Example 141. Preparation of A((1-(4-(1-cyanocyclopropyl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-U-(3-(3-cyclopropyl-1, 2,4-oxadiazol-5-yl)phenyl)-3(difluoromethyl)cyclobutan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 141F and the corresponding acid where necessary: (7.3 mg, 0.012 mmol, 28% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.08-7.96 (m, 2H), 7.82-7.61 (m, 2H), 7.38-7.28 (m, J=8.6 Hz, 2H), 7.277.14 (m, J=8.6 Hz, 2H), 6.21-5.74 (m, 1H), 3.68 (br. s., 4H), 3.15-3.01 (m, 1H), 2.43-2.41 (m, 1H), 2.34 (br. s ., 1H), 2.27-2.18 (m, 1H), 2.14-2.04 (m, 1H), 2.02-1.89 (m, 2H), 1.79-1.52 (m, 10H), 1.47-1.42 (m, 2H), 1.17-1.09

- 187 047337 (m, 2H), 1.01 (br. s., 2H). FXR EC50 (nM) = 643; MS (ESI) 599 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 141F and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 142 O F -7M 1 U Ch x. ^F ril IN N/NXU CA/CN N'° 585 583 143 Λ Vo 0z 579 89 142 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 8.04 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.42-7.30 (m, J = 8.3 Hz, 2H), 7.277.14 (m, J = 8.3 Hz, 2H), 3.70 (br. s., 4H), 2.96-2.71 (m, 3H ), 2.34 (br. s., 2H), 2.25-2.18 (m, 1H), 2.07-1.89 (m, 2H), 1.80-1.67 (m, 4H), 1.66-1.48 (m, 4H), 1.48- 1.41 (m, 2H), 1.18-1.08 (m, 2H), 1.05-0.94 (m, 2H) 143 'NMR (400 MHz, DMSO-d ₆ ) δ 8.15-8.00 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.39-7.28 (m , J= 8.3 Hz, 2H), 7.27-7.14 (m, J= 8.3 Hz, 2H), 3.70 (br. s., 4H), 2.28-2.19 (m, 1H), 2.04-1.93 (m, 2H) , 1.89 (br. s., 6H), 1.79-1.67 (m, 4H), 1.67-1.59 (m, 2H), 1.55 (br. s., 2H), 1.49-1.40 (m, 2H), 1.14 (d, J = 8.3 Hz, 2H), 1.02 (br. s., 2H)

Example 144.

Y-(('1-(4-('1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-U-(3-(5cyclopropyl-1,3,4- Oxadiazol-2-yl)phenyl)-3-(difluoromethyl)cyclobutan-1-carboxamide

Stage A. Intermediate

144A. Preparation of 1-(4-(4-(((3-(5-cyclopropyl-1,3,4oxadiazol-2-yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl) phenyl)cyclopropane-1carbonitrile

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 86D and intermediate 141E where necessary: (65 mg, 0.116 mmol, 81% yield) as a white solid. MS (ESI) 467 (M+H).

- 188 047337

Step B. Example 144. Preparation of No.((1-(4-(1-cyanocyclopropyl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-No.(3-(5-cyclopropyl-1,3) ,4-oxadiazol-2-yl)phenyl)-3(difluoromethyl)cyclobutane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 144A and the corresponding acid where necessary: (7.2 mg, 0.012 mmol, 28% yield).

1H NMR (400 MHz, DMSO-d ₀ ) δ 7.91 (s, 1H), 7.94 (s, 1H), 7.75-7.59 (m, 2H), 7.40-7.30 (m, J=8.6 Hz, 2H), 7.27 -7.14 (m, J=8.3 Hz, 2H), 6.24-5.72 (m, 1H), 3.76-3.60 (m, 4H), 3.06 (dd, J=18.1, 9.0 Hz, 1H), 2.43

2.41 9m, 1H), 2.36-2.30 (m, 2H), 2.16-2.02 (m, 1H), 2.02-1.90 (m, 2H), 1.81-1.67(m, 6H), 1.67-1.48 (m, 4H) , 1.48-1.42 (m, 2H), 1.29-1.05 (m, 4H); FXR EC ₅₀ (nM) = 2157; MS (ESI) 599 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 144A and the corresponding acid where necessary:

Etc.

No.

MS FXR (ESI) EU so (M+N) (nM)

^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.07-7.88 (m, 2H), 7.76-7.58 (m, 2H), 7.417.29 (m, J= 8.6 Hz, 2H), 7.28-7.17 (m , J= 8.3 Hz, 2H), 3.70 (br. s., 4H), 2.972.72 (m, ZN), 2.37-2.24 (m, ZN), 2.03-1.90 (m, 2H), 1.81-1.59 ( m, 4H), 1.561.53 (m, J= 8.6 Hz, 4H), 1.49-1.39 (m, 2H), 1.27-1.09 (m, 4H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (s, 2H), 7.69 (s, 2H), 7.39-7.29 (m, J = 7.8 Hz, 2H), 7.29-7.17 (m, J = 8.3 Hz , 2H), 3.70 (br. s., 2H), 3.62 (br. s., 2H), 2.33 (br. s., 1H), 1.98 (d, J= 9.8 Hz, 2H), 1.90 (br. s., 6H), 1.78-1.67 (m, 4H), 1.67-1.50 (m, 4H), 1.46 (t, J = 6.0 Hz, 2H), 1.27-1.09 (m, 4H)

Example 147.

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

NaH (2.68 mg, 0.067 mmol) and MeI (4.19 μl, 0.067 mmol) were added to a stirred solution of example 110 (25 mg, 0.045 mmol) in DMF (1 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was purified by preparative LC/MS under the following conditions: column: Waters XBridge C18, 150 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 15% B, 1560% B for 25 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min;

- 189 047337 column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (8 mg, 0.014 mmol, 31% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.05-7.95 (m, 1H), 7.91 (s, 1H), 7.67 (d, J=5.1 Hz, 2H), 3.61 (br. s., 2H), 3.49 (s, 3H), 2.10-2.00 (m, 1H), 1.88 (br. s., 6H), 1.84-1.65 (m, 6H), 1.59-1.38 (m, 10H), 1.08-0.98 (m, 2H), 0.87-0.77 (m, 2H); FXR EC ₅₀ (nM) 79; MS (ESI) 574 (M+H).

Example 148.

N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(2-methoxypyrimidin-4yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 148A. Preparation of methyl 4-(2-chloropyrimidin-4yl)bicyclo[2.2.2]octane-1-carboxylate

N ₃ S-0

To a stirred solution of 2-chloropyrimidine (1 g, 8.73 mmol) and 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.483 g, 6.98 mmol) in a mixture of DCM (50 ml) and H2O (50 ml) potassium persulfate (2.360 g, 8.73 mmol) and silver nitrate (0.297 g, 1.746 mmol) were added at room temperature. After stirring the reaction mixture for 12 hours, it was poured into EtOAc (100 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (800 mg, 2.85 mmol, 33% yield). MS (ESI) 281 (M+H).

Stage B. Intermediate connection 148V. Preparation of (4-(2-chloropyrimidin-4yl)bicyclo[2.2.2]octan-1-yl)methanol

BUT

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 148A where necessary: (1 g, 3.96 mmol, 79% yield). MS (ESI) 253 (M+H).

Step C. Intermediate 148C. Preparation of 4-(2-chloropyrimidin-4yl)bicyclo[2.2.2]octane-1-carbaldehyde

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 148B where necessary: (30 mg, 0.120 mmol, 30% yield).

¹ HNMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 8.68 (d, J=8.00 Hz, 1H), 7.54 (d, J=6.80 Hz, 1H), 1.83-1.89 (m, 6H ), 1.66-1.71 (m, 6H).

Stage D. Intermediate 148D. Preparation of N((4-(2-chloropyrimidin-4-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)aniline

HN

N.

v°

N^N

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 8A and intermediate 148C where necessary: (20 mg, 0.046 mmol, 37% yield). MS (ESI) 436 (M+H).

Step E. Intermediate 148E. Preparation No.((4-(2-chloropyrimidine-4

- 190 047337 yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3fluorobicyclo[1.1.1 ]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 148D and the corresponding acid where necessary: (20 mg, 0.036 mmol, 64% yield). MS (ESI) 548 (M+H).

Step F. Example 148. Preparation of N(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4(2-methoxypyrimidin-4-yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Sodium methoxide (15.77 mg, 0.073 mmol) was added to a stirred solution of intermediate 148E (20 mg, 0.036 mmol) in MeOH (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The crude product 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 methanol: water with 10 mM ammonium acetate; mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; gradient: 2 minute hold at 18% B, 18-75% B for 25 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (9 mg, 0.017 mmol, 45% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=5.4 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.01 (d, J=5.4 Hz, 1H), 3.86 (s, 3H), 3.67 (br. s., 1H), 3.57 (br. s., 1H), 2.28-2.17 (m, 1H), 1.89 (br. s., 6H), 1.79-1.63 (m, 6H), 1.52-1.32 (m, 6H), 1.14 (dd, J=8.4 , 2.6 Hz, 2H), 1.070.95 (m, 2H). FXR EC ₅₀ (nM) 687; MS (ESI) 544 (M+H).

Example 149.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3-(1( oxetan-3 -yl)-1 H-pyrazol-3 -yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 149A. Preparation of 3-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by substituting 3-bromoaniline and intermediate 4C where necessary: (700 mg, 1.740 mmol, 86% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.02-6.92 (m, 1H), 6.76 (s, 1H), 6.59 (dd, J=8.0, 2.0 Hz, 2H), 5.80-5.70 (m, 1H) , 2.79 (d, J=6.0 Hz, 2H), 2.05 (m, 1H), 1.89-1.77 (m, 6H), 1.59-1.48 (m, 6H), 1.02 (m, 2H), 0.89-0.80 (m , 2H). MS (ESI) 402 (M+H).

Stage B. Intermediate 149V. Preparation of N(3-bromophenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1. 1 ]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 149A and the corresponding acid where

- 191 047337 this is required: (320 mg, 0.603 mmol, 38% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.45-7.39 (m, 2H), 3.56 (br. s., 1H), 3.48 (br. s., 1H), 2.08-2.00 (m, 1H), 1.86 (br. s., 6H), 1.81-1.72 (m, 6H), 1.40 (br. s., 6H), 1.01 (m , 2H), 0.860.79 (m, 2H). MS (ESI) 514 (M+H).

Step C. Intermediate 149C. Preparation of ^((4-(3-cyclopropyl-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-Na-(3-(5,5-dimethyl-1 ,3,2-dioxaborinan-2-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

To a stirred solution of intermediate 149B (50 mg, 0.097 mmol) in dioxane (1 ml) was added bis(neopentylglycolato)diboron (43.9 mg, 0.194 mmol), followed by potassium acetate (42.9 mg, 0.437 mmol). The reaction mixture was then degassed and refilled with argon and PdCl ₂ (dppf) (3.56 mg, 4.86 µmol) was added. The reaction mixture was heated to 110°C and stirred for 3 hours. The reaction mixture was then diluted with ethyl acetate (25 ml) and washed with water (2x50 ml) and then with brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

The crude product was purified by flash column chromatography (Combiflash, 4 g, silica gel, 050% EtOAc/PE) to give the title compound (45 mg, 0.082 mmol, 85% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.55-7.53 (m, 1H), 7.49-7.43 (m, 2H), 3.79 (s, 4H), 2.052.00 (m, 1H ), 1.84-1.70 (m, 12H), 1.41 (br. s., 6H), 1.01-1.00 (m, 2H), 0.97 (s, 6H), 0.87-0.80 (m, 2H) (2 protons hidden under solvent peak).

Stage D. Intermediate 149D. Preparation of 3-bromo-1-(oxetan-3-yl)-III-pyrazole

To a stirred solution of 3-bromo-III-pyrazole (50 mg, 0.340 mmol) in DMF (2 ml) was added cesium carbonate (149 mg, 0.680 mmol), 3-iodoxetane (62.6 mg, 0.340 mmol) and heated at 150°C in a microwave reactor for 30 minutes. The reaction mixture was then diluted with ethyl acetate (5 ml), washed with water (2x5 ml) and brine (5 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 4 g, silica gel, 0-50% EtOAc/PE) to give the title compound (25 mg, 0.123 mmol, 36% yield) as a white solid, MS (ESI) 205 (M+2H).

Step E. Example 149. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3 -(1-(oxetan-3-yl)-1H-pyrazol-3yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

To a stirred solution of intermediate 149C (30 mg, 0.055 mmol) in 1,4dioxane (1 ml) was added intermediate 149D (11.13 mg, 0.055 mmol), potassium carbonate (15.15 mg, 0.110 mmol) in water (0.250 ml). The resulting reaction mixture was degassed and refilled with argon and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.005 mg, 2.74 μmol) was added. The reaction mixture was heated at 100°C and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (5 ml), washed with water (5 ml) and then with brine (5 ml).

The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 2-minute hold at 18% B, 18-62% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (9.5 mg, 0.017 mmol, 31% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 (d, J=2.4 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 7.79 (s, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 5.72-5.58 (m, 1H), 5.08-4.87 (m, 4H), 3.60 (d , J=19.3 Hz, 2H), 2.10-2.00 (m, 1H), 1.89 (br. s., 6H), 1.84-1.63 (m, 6H), 1.46 (d, J=7.6 Hz, 6H), 1.09 -0.94 (m,

- 192 047337

2H), 0.90-0.74 (m, 2H); FXR EC ₅₀ (nM) =111; MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 149, replacing intermediate 149C and the corresponding heteroaryl/aryl halides where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 150 '/L 558 87 151 o F^^ As kA-V ί 1 » /, ^N H ₃ C--<x T \ %-S £\. 533 79 152 0 F'j'' A AAA ί I » /, ^N /DACH ^ν Ά \ y—N / \ N=/ [> 579 162 150 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.14 (s, 1H), 7.75-7.57 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.21 (d , J = 7.6 Hz, 1H), 5.59 (t, J = 7.1 Hz, 1H), 5.07-4.84 (m, 4H), 3.58 (s, 2H), 2.10-2.00 (m, 1H), 1.87 (br. s., 6H), 1.83-1.59 (m, 6H), 1.55-1.31 (m, 6H), 1.08-0.96 (m, 2H), 0.90-0.76 (m, 2H) 151 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.41 (s, 1H), 3.63 (br. s., 1H), 3.56 (br. s., 1H), 2.45 (s, 3H), 2.09-2.00 (m, 1H), 1.89 ( br. s., 6H), 1.83-1.72 (m, 6H), 1.44 (br. s., 6H), 1.01 (d, J= 7.7 Hz, 2H), 0.86-0.79 (m, 2H). 152 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 9.17 (s, 1H), 8.57 (d, J= 4.5 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.77 (br. s., 2H), 7.60 (dd, J = 8.1,4.8 Hz, 1H), 7.50 (t, J =7.9 Hz, 1H), 7.29 (d, J =7.7 Hz, 1H), 3.61 (d, J = 9.2 Hz, 2H), 2.09-2.00 (m, 1H), 1.89 (br. s., 6H), 1.83-1.73 (m, 6H), 1.53-1.39 (m , 6H), 1.01 (d, J = 7.8 Hz, 2H), 0.83 (br. s., 2H).

Example 153.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(5-cyclopropyl1 ,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 153A. Preparation of methyl 4-(((3-(5-cyclopropyl-1,3,4oxadiazol-2-yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

- 193 047337

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 86D and intermediate 88B where necessary: (250 mg, 0.655 mmol, 86% yield) as a gummy liquid. MS (ESI) 382 (M+H).

Stage B. Intermediate 153B. Preparation of methyl 4-(A-(3-(5-cyclopropyl-1,3,4oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicycle[2.2.2] octane-1carboxylate

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 153A and the corresponding acid where necessary: (180 mg, 0.365 mmol, 56% yield) as a gummy solid. MS (ESI) 494 (M+H).

Step C. Intermediate 153C. Preparation of 4-(A-(3-(5-cyclopropyl-1,3,4-oxadiazol2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane -1-carboxylic acid

To a stirred solution of intermediate 153B (180 mg, 0.365 mmol) in MeOH (5 mL) at room temperature was added a solution of NaOH (72.9 mg, 1.823 mmol) in H ₂ O (2.5 mL) and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (10 ml). The aqueous solution was acidified with 1.5 N aqueous HCl and extracted with ethyl acetate (2x10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (160 mg, 0.334 mmol, 91% yield) as a white fluffy solid. MS (ESI) 480 (M+H).

Step D. Example 153. Preparation of No.((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-No.-(3 -(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The compound was synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 153C and intermediate 88F where necessary: (3.4 mg, 6.07 µmol, 19% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.01-7.94 (m, 1H), 7.93 (s, 1H), 7.72-7.58 (m, 2H), 3.62 (br. s., 2H), 2.38-2.27 (m, 1H), 1.89 (br. s., 6H), 1.86-1.70 (m, 6H), 1.55-1.32 (m, 6H), 1.32-1.22 (m, 9H), 1.22-1.09 (m, 4H ); FXR EC ₅₀ (nM) = 73; MS (ESI) 560 (M+H).

Example 154.

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

ABOUT

Step A: Intermediate 154A. Preparation of 4-((No(3-(5-cyclopropyl-1,3,4-oxadiazole

- 194 047337

2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 114A, replacing intermediate 153C where necessary: (160 mg, 0.147 mmol, 50% yield). MS (ESI) 479 (M+H).

Stage B. Intermediate 154B. Preparation of c-((4-cyanobicyclo[2.2.2]octan-1yl)methyl)-N-(3 -(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1 .1 ]pentane-1 carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 114B, replacing intermediate 154A where necessary: (100 mg, 0.217 mmol, 65% yield) as a pale yellow solid. MS (ESI) 461 (M+H).

Step C. Intermediate 154C. Preparation of (E)-Na-(3-(5-cyclopropyl-1,3,4-oxadiazol2-yl)phenyl)-3-fluoro-Na-((4-(Na-hydroxycarbamidoyl)bicyclo[2.2.2]octane -1 yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 154B where necessary: (70 mg, 0.142 mmol, 59% yield) as a white solid. MS (ESI) 494 (M+H).

Step D. Example 154. Preparation of A(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-phenyl)-3-fluoro-N((4-(5-(1-methylcyclopropyl)- 1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 154C and 1-methylcyclopropane-1carboxylic acid where necessary: (6.5 mg, 0.012 mmol, 38% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.99-7.94 (m, 1H), 7.92 (s, 1H), 7.71-7.61 (m, 2H), 3.61 (br. s., 2H), 2.38-2.27 (m, 1H), 1.89 (br. s., 6H), 1.79-1.59 (m, 6H), 1.52-1.31 (m, 9H), 1.26-1.10 (m, 6H), 1.07-1.00 (m, 2H ); FXR EC ₅₀ (nM) = 27; MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 154C and the corresponding acids where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 155 ABOUT and n-c? m¢. II N-N 574 72 156 1 a > ⁴ 554 103 157 O Di χΧ,/Ν / ^СНз ί| 1 π U-D-snz GK ΟγΑΧ ^N 'O СНз nn 560 43 155 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.99-7.95 (m, 1H), 7.93 (s, 1H), 7.67 (d, J = 5.4 Hz, 2H), 4.84 (d, J = 6.1 Hz, 2H ), 4.52 (d, J= 6.1 Hz, 2H), 3.62 (br. s., 2H), 2.36-2.31 (m, 1H),1.89 (br. s., 6H), 1.83-1.62 (m, 9H ), 1.54-1.34 (m, 6H), 1.24-1.05 (m, 4H) 156 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.02-7.87 (m, 2H), 7.67 (d, 7=5.1 Hz, 2H), 7.42 (s, 1H), 3.63 (br. s., 2H), 2.38-2.29 (m, 1H), 1.89 (br. s., 6H), 1.84-1.68 (m, 6H), 1.55-1.36(m, 6H), 1.30-1.07 (m, 4H) 157 ^X NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.94 (m, 1H), 7.92 (s, 1H), 7.72-7.59 (m, 2H), 3.60 (d, 7= 7.8 Hz, 2H), 2.36 -2.30 (m, 1H), 1.89 (br. s., 6H), 1.811.62 (m, 6H), 1.49-1.36 (m, 6H), 1.33 (s, 9H), 1.23-1.09 (m, 4H )

Example 158.

\-((4-(3-11ic.1O11ro11yl-1.2.4-oxadiazol-5-i.1)bi11ic.yu[2.2.2]octan-1-yl)methyl)-\-(3-(1( cyclopropylsulfonyl)-1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

(158)

Step A: Intermediate 158A. Preparation of 1-(cyclopropylsulfonyl)-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole

To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-pyrazole (1 g, 5.15 mmol) in DMF (15 ml) was added NaH ( 0.309 g, 7.73 mmol) and stirred for 5 min at room temperature. Cyclopropanesulfonyl chloride was added dropwise to the reaction mixture.

- 196 047337 (0.797 g, 5.67 mmol) and stirred for 6 hours at room temperature. The reaction mixture was then quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (2x50 ml). The combined organic extracts were washed with water (50 ml) and brine (2x50 ml). Then, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-80% EtOAc/PE) to give 1(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-III-pyrazole (750 mg, 2.52 mmol, 49% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 8.30 (s, 1H), 3.17-0.00 (m, 1H), 1.31-1.25 (m, 14H), 1.211.17 (m , 2H).

Step B. Example 158. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(3-(1- (cyclopropylsulfonyl)-III-pyrazol-4-yl)-phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149 by replacing intermediate 149B and intermediate 158A where necessary: (17.9 mg, 0.029 mmol, 30% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.57 (s, 1H), 7.92-7.84 (m, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.48 ( t, J=7.9 Hz, 1H), 7.36-7.24 (m, 1H), 3.67-3.51 (m, 2H), 3.22-3.13 (m, 1H), 2.10-1.99 (m, 1H), 1.87 (d, J=5.9 Hz, 6H), 1.83-1.58 (m, 6H), 1.56-1.35 (m, 6H), 1.35-1.28 (m, 2H), 1.26-1.19 (m, 2H), 1.05-0.96 (m, 2H), 0.87-0.77 (m, 2H); FXR EC ₅₀ (nM) = 43; MS (ESI) 606 (M+H).

Example 159.

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

ABOUT

Step A: Intermediate 159A. Preparation of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1 H-pyrazole ^H3C \? ^{NZ NZS} >< 9

H ₃ C 9 | NS-SNz

This compound was synthesized according to the method described for the synthesis of intermediate 158A by replacing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-pyrazole and methanesulfonyl chloride where this is required: (2 g, 7.35 mmol, 57% yield) as a colorless oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.01 (s, 1H), 3.31 (s, 3H), 1.31 (s, 12H).

Step B. Example 159. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(3 -(1-(methylsulfonyl)-III-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149 by replacing intermediate compound 149B and intermediate compound 159A where necessary: (8.4 mg, 0.014 mmol, 14% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.57 (s, 1H), 7.88 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 3.66-3.48 (m, 5H), 2.08-2.01 (m, 1H), 1.87 (br. s., 6H), 1.83- 1.61 (m, 6H), 1.55-1.33 (m, 6H), 1.06-0.95 (m, 2H), 0.89-0.76 (m, 2H); FXR EC ₅₀ (nM) = 73; MS (ESI) 580 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 149, replacing intermediate 149B and the corresponding heteroarylboronates where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 160 O /d \/DD_ \ AU ϊ-A ⁴ /~N T F Ή 552 43 161 O dS __ /— Ν T ^v ~~\ Ν=^ F 566 96 162 ABOUT ΆAU A Ν T 584 116 160 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.39 (s, 1H), 8.00-7.65 (m, 3H), 7.48 (t, J = 7.8 Hz, 1H), 7.34-7.22 (m, 1H), 3.59 (d, J = 6.8 Hz, 2H), 2.08-2.00 (m, 1H), 1.87 (br. s., 6H), 1.83-1.54 (m, 6H), 1.54-1.33 ( m, 6H), 1.05-0.96 (m, 2H), 0.88-0.77 (m, 2H). 161 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.71-7.53 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.21 (d , J =7.6 Hz, 1H), 6.41 (t, J =3.7 Hz, 1H), 4.65 (td, J= 15.2,3.7 Hz, 2H), 3.58 (d, J= 9.3 Hz, 2H), 2.13-1.99 (m, 1H), 1.991.83 (m, 6H), 1.83-1.58 (m, 6H), 1.57-1.33 (m, 6H), 1.10-0.93 (m, 2H), 0.900.75 (m, 2H) . 162 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.16 (s, 1H), 7.72-7.55 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.23 (d , J = 9.0 Hz, 1H), 5.17 (q, J = 9.0 Hz, 2H), 3.71-3.58 (m, 1H), 3.58-3.43 (m, 1H), 2.10-1.99 (m, 1H), 1.98- 1.83 (m, 6H), 1.83-1.59 (m, 6H), 1.55-1.33 (m, 6H), 1.08-0.96 (m, 2H), 0.87-0.78 (m, 2H)

Example 163.

N-((4-(3 -cyclopropyl-1 -methyl-1 H-pyrazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -φτορ-Ν-(3 -(5isopropyl -1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 163A. Preparation of 3-(((4-(3-cyclopropyl-1-methyl-Spirazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)benzonitrile

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The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 126B where necessary: (135 mg, 0.356 mmol, 71% yield) as an off-white solid. MS (ESI) 361 (M+H).

Stage B. Intermediate 163B. Preparation of X-(3-cyanophenyl)-X-((4-(3-cyclopropyl-1methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1 .1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 163A and the corresponding acid where necessary: (110 mg, 0.221 mmol, 61% yield) as an off-white solid. MS (ESI) 473 (M+H).

Step C. Intermediate 163C. Preparation of (/)-N-((4-(3-cyclopropyl-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-X-(3- (X'hydroxycarbamidoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 163B where necessary: (120 mg, 0.225 mmol, 76% yield) as an off-white solid. MS (ESI) 506 (M+N).

Step D. Example 163. Preparation of X-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-X-( 3-(5-isopropyl-1,2,4-oxadiazol-3yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 163C and the corresponding acid where necessary: (7.8 mg, 0.014 mmol, 35% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02-7.99 (m, 1H), 7.89 (s, 1H), 7.66-7.64 (m, 2H), 5.61 (s, 1H), 3.72 (s, 3H) , 3.58 (br. s., 2H), 3.42-3.36 (m, 1H), 1.88 (br. s., 6H), 1.79-1.59 (m, 7H), 1.50-1.31 (m, 12H), 0.74- 0.72 (m, 2H), 0.53-0.51 (m, 2H). FXR EC ₅₀ (nM) 156; MS (ESI) 558 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 163C and the corresponding acids where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 164 O ^F ' ^z ^ ^/ χρ yAyp/j ^F \ mУУ ,ν-ν^ )—</ T ^N z ^s F ON 566 104

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165 O ^N з ^с _х Νχ/DD z ^N N НзС-γ-Ζ/ Y Н ₃ с Н ₃ С QN 572 124 166 O IX,Ν-Ν Υ n ₃ with CH ₃ O ^N 570 82 164 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.07-8.05 (m, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.56 (t, J = 51.60 Hz , 1H), 5.61 (s, 1H), 3.72 (s, 3H), 3.59 (s, 2H), 1.89 (br. s., 6H), 1.77-1.61 (m, 7H), 1.49-1.30 (m, 6H), 0.74-0.71 (m, 2H), 0.53-0.51 (m, 2H). 165 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.02 - 8.00 (m, 1H), 7.90 (s, 1H), 7.66-7.65 (m, 2H), 5.61 (s, 1H), 3.72 (s, 3H) , 3.20 (br. s., 2H), 1.89 (br. s., 6H), 1.801.57 (m, 7H), 1.47 (s, 9H), 1.45-1.28 (m, 6H), 0.76-0.71 ( m, 2H), 0.54-0.50 (m, 2H). 166 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.98 - 7.96 (m, 1H), 7.86 (s, 1H), 7.64-7.63 (m, 2H), 5.61 (s, 1H), 3.72 (s, 3H) , 3.58 (br. s., 2H), 1.88 (br. s., 6H), 1.781.61 (m, 7H), 1.58 (s, 3H), 1.47-1.31 (m, 8H), 1.20-1.11 ( m, 2H), 0.74-0.71 (m, 2H), 0.53-0.51 (m, 2H).

Example 167.

4-(3-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)phenyl)-4-((4-(5-cyclopropyl-'Gmethyl-'1H-pyrazol-3yl )bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 167A. Preparation of 3-(((4-(5-cyclopropyl-1-methyl-1-Ipyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)benzonitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 124E where necessary: (130 mg, 0.361 mmol, 72% yield) as an off-white solid. (ESI) 361 (M+H).

Stage B. Intermediate 167V. Preparation of N(3-cyanophenyl)-N-((4-(5-cyclopropyl-1methyl-1 I-pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluorobicyclo [1.1 .1 ]pentane-1-carboxamide

- 200 047337

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 167A and the corresponding acid where necessary: (95 mg, 0.201 mmol, 56% yield) as an off-white solid. MS (ESI) 473 (M+H).

Step C. Intermediate 167C. Preparation of (E)-U-((4-(5-cyclopropyl-1-methyl-1Hpyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(3- (Nohydroxycarbamidoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 167B where necessary: (100 mg, 0.188 mmol, 93% yield) as an off-white solid. (ESI) 506 (M+N).

Step D. Example 167. Preparation of A(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-U-((4-(5cyclopropyl-1-methyl-1H -pyrazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 167C and the corresponding acid where necessary: (9.7 mg, 0.017 mmol, 43% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (d, J=7.1 Hz, 1H), 7.88 (s, 1H), 7.72-7.56 (m, 2H), 5.59 (s, 1H), 3.69 (s , 3H), 3.57 (br. s., 2H), 1.88 (br. s., 6H), 1.75-1.72 (m, 1H), 1.70-1.50 (m, 6H), 1.47 (s, 9H), 1.41 -1.29 (m, 6H), 0.94-0.82 (m, 2H), 0.60-0.45 (m, 2H). FXR EC ₅₀ (nM) 69; MS (ESI) 572 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 167C and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 168 O F ^/ ^ ^/ /Ах с ί I А у-О x/ХАА ⁿ -n J m сн ₃ F O- ^N 566 111 169 O F''^ ⁷ /Ax /1 _{and r} \\ 1 Η ⁿ 3C__ _/ N^Jx ₄ X Ν~ _ν H3C^oA ^CH3 558 98

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170 O zk May \\ η p u-m A/NMLM n- _n ' ΐ сн ₃ O ^N 556 74 168 DNMR (400 MHz, DMSO-d ₆ ) δ 8.06-80.5 (m, 1H), 7.95 (s, 1H), 7.73-7.68 (m, 2H), 7.56 (t, J= 51.60 Hz, 1H), 5.59 ( s, 1H), 3.69 (s, 3H), 3.58 (s, 2H), 1.96-1.81 (m, 6H), 1.78-1.70 (m, 1H), 1.66-1.52 (m, 6H), 1.45-1.30 ( m, 6H), 0.90-0.82 (m, 2H), 0.56-0.49 (m, 2H). 169 DNMR (400 MHz, DMSO-d ₆ ) δ 8.02 - 8.00 (m, 1H), 7.89-7.88 (m, 1H), 7.67-7.61 (m, 2H), 5.59 (s, 1H), 3.69 (s, 3H ), 3.57 (br. s., 2H), 3.43-3.35 (m, 1H), 1.88 (br. s., 6H), 1.79-1.70 (m, 1H), 1.67-1.51 (m, 6H), 1.48 -1.28 (m, 12H), 1.24 (s, 1H), 0.88-0.86 (m, 2H), 0.54-0.52 (m, 2H). 170 DNMR (400 MHz, DMSO-d ₆ ) δ 7.97-7.95 (m, 1H), 7.90-7.85 (m, 1H), 7.647.61 (m, 2H), 5.59 (s, 1H), 3.69 (s, 3H ), 3.56 (s, 2H), 2.47-2.40 (m, 1H), 1.87 (br. s., 6H), 1.79-1.70 (m, 1H), 1.68-1.45 (m, 6H), 1.45-1.25 ( m, 8H), 1.251.15 (m, 2H), 0.94-0.82 (m, 2H), 0.60-0.48 (m, 2H).

Example 171.

A((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-A(3-(5- cyclopropyl1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

171A.

Step A: Amino)methyl)bicyclo[2.2.2]octane-1-carboxylate intermediate

Preparation of methyl 4-(((3-cyanophenyl)-

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing 3-aminobenzonitrile and intermediate 88B where necessary: (575 mg, 1.908 mmol, 45% yield). MS (ESI) 299 (M+H).

Stage B. Intermediate 171B. Preparation of methyl 4-((A(3-cyanophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo-[2.2.2]octane-1-carboxylate

This compound was synthesized according to the method described for the synthesis of Example 3, by replacing intermediate 171A and the corresponding acid where necessary: (600 mg, 1.432 mmol, 75% yield). MS (ESI) 411 (M+N).

Step C. Intermediate 171C. Preparation of methyl (Ζ)-4-((3-Φτορ-Ν-(3-(Ν'hydroxycarbamidoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1carboxylate

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The indicated compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 171B where necessary: (470 mg, 1.060 mmol, 95% yield). MS (ESI) 444 (M+H).

Stage D. Intermediate 171D. Preparation of methyl 4-((M(3-(5-cyclopropyl-1,2,4oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2] octane-1carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 171C and the corresponding acid where necessary: (300 mg, 0.583 mmol, 70% yield). MS (ESI) 494 (M+H).

Step E. Intermediate 171E. Preparation of 4-((M(3-(5-cyclopropyl-1,2,4-oxadiazol3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo[2.2.2]octane -1-carboxylic acid

To a stirred solution of intermediate 171D (250 mg, 0.507 mmol) in a mixture of THF (5 ml), MeOH (5 ml) and water (2 ml) was added LiOH (36.4 mg, 1.520 mmol) at room temperature, and then the reaction the mixture was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was reconstituted in cold water. The aqueous solution was acidified with 1.5 N aqueous HCl until the solution reached pH = 2. The aqueous solution was extracted with EtOAc (2x50 ml). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (200 mg, 0.400 mmol, 96% yield). MS (ESI) 480 (M+H).

Step F. Example 171. Preparation of M((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-U-(3 -(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 171E and intermediate 88F where necessary: (17.7 mg, 0.031 mmol, 60% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 7.97 (td, J=4.1, 2.1 Hz, 1H), 7.87 (s, 1H), 7.72-7.56 (m, 2H), 3.60 (br. s., 2H ), 2.47-2.40 (m, 1H), 1.88 (br. s., 6H), 1.84-1.68 (m, 6H), 1.54-1.37 (m, 6H), 1.36-1.28 (m, 2H), 1.28- 1.13 (m, 11H); FXR EC ₅₀ (nM) 37.58 MS (ESI) 560.1 (M+H).

Example 172.

M(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-U-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5yl)bicyclo [2.2 .2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of prome

- 203 047337 of the compound 3A, by replacing intermediate 171E and (E)-2,2-difluoro-Nhydroxyacetimidamide where necessary: (12.8 mg, 0.023 mmol, 44% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (td, J=4.5, 1.6 Hz, 1H), 7.88 (d, J=1.0 Hz, 1H), 7.70-7.58 (m, 2H), 7.31 (m , 1H), 3.61 (br. s., 2H), 2.47-2.40 (m, 1H), 2.00-1.74 (m, 12H), 1.58-1.37 (m, 6H), 1.35-1.28 (m, 2H), 1.27-1.16 (m, 2H); FXR EC ₅₀ (nM) 153.69 MS (ESI) 554.3 (M+H).

Example 173.

N((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-(5 -(3methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 173A. Preparation of methyl 4-((3-fluoro-N-(3-(5-(3-methyloxetan3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentan-1- carboxamido)methyl)bicyclo[2.2.2]octane-1carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 171C and the corresponding acid where necessary: (100 mg, 0.189 mmol, 56% yield). MS (ESI) 524 (M+H).

Stage B. Intermediate 173B. Preparation of 4-((3-fluoro-N-(3-(5-(3-methyloxetan-3-yl)1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentan-1- carboxamido)methyl) carboxylic acid bicyclo[2.2.2]octane-1-

The indicated compound was synthesized according to the method described for the synthesis of intermediate 171E, by replacing intermediate 173A where necessary: (100 mg, 0.192 mmol, 40% yield). MS (ESI) 510 (M+H).

Step C. Example 173. Preparation of N((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N- (3-(5-(3-methyloxetan-3-yl)-1,2,4-oxadiazol-3yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 173B and (E)-2,2-difluoro-N-hydroxyacetimidamide where necessary: (11.4 mg, 0.019 mmol, yield 39 %).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.09-8.02 (m, 1H), 7.96 (d, J=1.0 Hz, 1H), 7.74-7.61 (m, 2H), 7.32 (m, 1H), 5.00 (d, J=6.1 Hz, 2H), 4.61 (d, J=6.1 Hz, 2H), 3.63 (br. s., 2H), 2.00-1.75 (m, 15H), 1.56-1.39 (m, 6H ); FXR EC ₅₀ (nM) 139; MS (ESI) 584.1 (M+H).

Example 174.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro<N-(3- (5-(3methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

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The indicated compound was synthesized according to the method described for the synthesis of Intermediate 3A by replacing intermediate 173B and intermediate 88F where necessary: (18.8 mg, 0.032 mmol, 65% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.11-8.01 (m, 1H), 7.95 (s, 1H), 7.76-7.55 (m, 2H), 5.00 (d, J=6.1 Hz, 2H), 4.61 (d, J=6.1 Hz, 2H), 3.62 (br. s., 2H), 2.00-1.86 (m, 6H), 1.86-1.70 (m, 9H), 1.56-1.34 (m, 6H), 1.331. 17 (m, 9H); FXR EC ₅₀ (nM) 40; MS (ESI) 590 (M+H).

Example 175.

3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)<N-(3-(5- (1methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 175A. Preparation of methyl 4-((3-fluoro-N-(3-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamido)methyl)bicyclo[ 2.2.2]octane-1-carboxylate

The compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 171C and the corresponding acid where necessary: (260 mg, 0.512 mmol, 87% yield) as a gummy solid. MS (ESI) 508 (M+H).

Stage B. Intermediate 175V. Preparation of 4-((3-fluoro-N-(3-(5-(1-methylcyclopropyl)1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl) bicyclo[2.2.2]octane-1carboxylic acid

To a stirred solution of intermediate 175A (260 mg, 0.512 mmol) in MeOH (3 mL) was added a solution of NaOH (102 mg, 2.56 mmol) in H2O (1.5 mL) and stirred for 1 hour at 60°C. The reaction mixture was concentrated under reduced pressure and diluted with water (10 ml). The aqueous solution was acidified with 1.5 N aqueous HCl and extracted with ethyl acetate (2x20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (250 mg, 0.507 mmol, 99% yield) as a brownish gummy solid. MS (ESI) 494 (M+H).

Step C. Example 175. Preparation of 3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-( 3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 175B and (Z)-N'hydroxyisobutyrimidamide where necessary: (22 mg, 0.039 mmol, 78% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.99-7.96 (m, 1H), 7.87 (s, 1H), 7.65 (d, J=6.00 Hz, 2H), 3.60 (s, 2H), 3.00 -2.97 (m, 1H), 1.88-1.78 (m, 12H), 1.58 (s, 3H), 1.46-1.40 (m, 8H), 1.24-1.16 (m, 8H); FXR EC ₅₀ (nM) = 54; MS (ESI) 560 (M+H).

The following compound was synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 175B and the corresponding N'hydroxyimimidamides where necessary:

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Etc. No. Structure MS (ESI) (M+H) FXR EC50 (nM) 176 O F^^ xks, ^sn z P G />Х ^CH z ⁿ z ^s , Ν-Χχ O-ν CH ₃ DH II ΝΙ qN 574 24 176 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.00-7.95 (m, 1H), 7.87 (s, 1H), 7.68-7.62 (m, 2H), 3.61 (br. s., 2H), 1.88 (br . s., 6H), 1.84-1.73 (m, 6H), 1.58 (s, 3H), 1.53-1.31 (m, 8H),1.31-1.20 (m, 9H), 1.19-1.15 (m, 2H)

Example 177.

\-((4-(5-(t].11=butyl)-1,2,4-oxadiazol-3-yl)bi11iclo[2.2.2]octan-1-yl)methyl)-3-(]) tor-\-(3-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 177A. Preparation of 4-((3-fluoro-X-(3-(5-(1-methylcyclopropyl)1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl) bicyclo[2.2.2]octane-1carboxamide

ABOUT

The indicated compound was synthesized in accordance with the method described for the synthesis of intermediate 114A, replacing intermediate 175B where necessary:

(250 mg, 0.508 mmol, 100% yield). MS (ESI) 493 (M+H).

Stage B. Intermediate 175V. Preparation of Y-((4-suapobicyclo[2.2.2]octan-1yl)methyl)-3-fluoro-X-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl) phenyl)bicyclo[1.E1]pentane-1carboxamide

The compound was synthesized according to the method described for the synthesis of intermediate 114B by replacing intermediate 177A where necessary: (100 mg, 0.211 mmol, 52% yield) as a white resinous solid. MS (ESI) 475 (M+H).

Step C. Intermediate 177C. Preparation of 3-fluoro-N-((4-(Nohydroxycarbamidoyl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(3-(5-(1-methylcyclopropyl)-1,2,4oxadiazol- 3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

- 206 047337

The indicated compound was synthesized according to the method described for the synthesis of intermediate 88F by replacing intermediate 177B where necessary: (100 mg, 0.197 mmol, 100% yield) as a white solid. MS (ESI) 508 (M+H).

Step D. Example 177. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1 -yl)methyl)-3-fluoro- N-(3 -(5-( 1 -methylcyclopropyl)-1,2,4-oxadiazol-3 -yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 177C and the corresponding acid where necessary: (11.5 mg, 0.020 mmol, 41% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02-7.93 (m, 1H), 7.91-7.83 (m, 1H), 7.69-7.59 (m, 2H), 3.60 (br. s., 2H), 1.88 (br. s., 6H), 1.80-1.63 (m, 6H), 1.58 (s, 3H), 1.46-1.36 (m, 8H), 1.36-1.30 (m, 9H), 1.20-1.12 (m, 2H ); FXR EC ₅₀ (nM) = 33; MS (ESI) 574 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A by substituting intermediate 177C and appropriate acids where necessary:

- 207 047337

180 O H ₃ C N-dCo II \l qN 588 83 178 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (td, J = 4.5, 1.6 Hz, 1H), 7.88 (d, J = 1.0 Hz, 1H), 7.72-7.59 (m, 2H), 7.42 (s , 1H), 3.61 (br. s., 2H), 1.88 (br. s., 6H), 1.83-1.67 (m, 6H),1.58 (s, 3H), 1.53-1.32 (m, 8H), 1.20 -1.12 (m, 2H) 179 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (td, J = 4.4, 1.5 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.71-7.57 (m, 2H), 3.61 (br . s., 2H), 2.25-2.04 (m, 3H), 1.88 (br. s., 6H), 1.82-1.64 (m, 6H), 1.58 (s, 3H), 1.51-1.31 (m, 8H) , 1.20-1.12 (m, 2H) 180 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (td, J = 4.4, 1.5 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.73-7.53 (m, 2H), 4.84 (d , J = 5.9 Hz, 2H), 4.52 (d, J= 6.1 Hz, 2H), 3.61 (br. s., 2H), 1.88 (br. s., 6H), 1.80-1.63 (m, 9H), 1.58 (s, 3H), 1.521.31 (m, 8H),1.21-1.12 (m, 2H)

Example 181.

U(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((1-(2-(trifluoromethyl)pyrimidin-5yl)-2 -oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

Stage A. Intermediate

181A. Preparation of (4-hydroxy-4-(2(trifluoromethyl)pyrimidin-5-yl)cyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

The title compound was synthesized according to the method described for the synthesis of intermediate 141A by replacing 5-bromo-2-(trifluoromethyl)pyrimidine where necessary: (brown gum solid; 2.5 g, 1.139 mmol, 27% yield) . MS (ESI) 614 (M+H).

Stage B. Intermediate 181B. Preparation of (1-(2-(trifluoromethyl)pyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methyl-benzenesulfonate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 141B by replacing intermediate 181A where necessary: (off-white solid; 450 mg, 1.017 mmol, 28% yield). MS (ESI) 443 (M+H).

Step C. Intermediate 181C. Preparation of (1-(2-(trifluoromethyl)pyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl acetate

This compound was synthesized according to the method described for the synthesis of intermediate 141C by replacing intermediate 181B where necessary: (brown gum solid; 300 mg, 0.881 mmol, 89% yield). MS (ESI) 331 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 2H), 3.86 (d, J=11.5 Hz, 4H), 2.28-2.18 (m, 2H), 2.05 (s, 3H), 2.01-1.90 (m, 2H), 1.80-1.63 (m, 4H).

Stage D. Intermediate 181D. Preparation of (1-(2-(trifluoromethyl)pyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methanol

- 208 047337

The indicated compound was synthesized according to the method described for the synthesis of intermediate 141D by replacing intermediate 181C where necessary: (brown solid; 250 mg, 0.824 mmol, 91% yield). MS (ESI) 289 (M+H).

1H NMR (400 MHz, DMSO-de) δ 9.07 (s, 2H), 4.59 (t, J=5.3 Hz, 1H), 3.85 (s, 2H), 3.19 (d, J=5.0 Hz, 2H), 2.26- 2.14 (m, 2H), 1.91 (d, J=4.0 Hz, 2H), 1.76-1.66 (m, 2H), 1.60 (d, J=8.0 Hz, 2H).

Step E. Intermediate 181E. Preparation of 1-(2-(trifluoromethyl)pyrimidin-5-yl)-2oxabicyclo[2.2.2]octane-4-carbaldehyde

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C by replacing intermediate 181D where necessary: (brown solid; 150 mg, 0.524 mmol, 60% yield). MS (ESI) 287 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 9.09 (s, 2H), 4.06 (s, 2H), 2.36-2.22 (m, 2H), 2.06-1.88 (m, 6H) .

Step F: Intermediate 181F. Preparation of 3-(((1-(2-(trifluoromethyl)pyrimidin-5-yl)2-oxabicyclo[2.2.2]octan-4-yl)methyl)amino)benzonitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 181E where necessary: (brown solid; 60 mg, 0.057 mmol, 33% yield). MS (ESI) 389 (M+H).

^1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.28-7.15 (m, 1H), 7.00-6.94 (m, 1H), 6.92-6.83 (m, 2H), 5.59 (s, 1H), 3.91 (s, 2H), 2.96 (d, J=6.0 Hz, 2H), 2.28-2.18 (m, 2H), 1.99-1.89 (m, 2H), 1.77 (d, J=5.0 Hz, 4H ).

Stage G. Intermediate 181G. Preparation of N(3-cyanophenyl)-3-fluoro-N-((1-(2(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1. 1]pentane-1carboxamide

This compound was synthesized according to the method described for the synthesis of Example 3 by replacing intermediate 181F and the corresponding acid where necessary: (brown gum solid; 45 mg, 0.080 mmol, 57% yield). MS (ESI) 501 (M+N).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 8.09 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.71-7.65 (m, 1H), 3.73 (s, 2H), 3.63 (br. s., 2H), 2.20-2.10 (m, 2H), 1.94-1.82 (m, 6H), 1.72-1.61 (m, 2H), 1.58 (br. s., 2H) (2 protons hidden under the solvent peak)

Step H. Intermediate 181H. Preparation of 3-fluoro-N-(3-(N-hydroxycarbamidoyl)phenyl)-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4yl)methyl) bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 88F by replacing intermediate 181G where necessary: (white solid, 30 mg, 0.050 mmol, 56% yield). MS (ESI) 534 (M+H).

Stage I. Example 181. Preparation of N(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((1(2-(trifluoromethyl) pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide

- 209 047337

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 181H and the corresponding acid where necessary: (6.7 mg, 10.84 µmol, 39% yield).

^1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.09-8.00 (m, 1H), 7.95 (s, 1H), 7.76-7.61 (m, 2H), 3.76 (s, 2H) , 3.66 (br. s., 2H), 2.23-2.09 (m, 2H), 2.01-1.75 (m, 8H), 1.74-1.52 (m, 4H), 1.50-1.40 (m, 9H); FXR EC50 (nM) = 828; MS (ESI) 600 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A by substituting intermediate 181H and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 182 Yu m O with 594 2000 182 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 8.10 (dt, J= 7.0, 1.6 Hz, 1H), 8.06-7.99 (m, 1H), 7.82-7.43 (m, 3H ), 3.77 (s, 2H), 3.67 (s, 2H), 2.23-2.07 (m, 2H), 2.01-1.80 (m, 8H), 1.77-1.65 (m, 2H), 1.65-1.54 (m, 2H ).

Example 183.

X-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-X-(3-( 5-(tert-butyl)-

1,2,4-oxadiazol-3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 183A. Preparation of 4-((D-(3-carbamoylphenyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

To a solution of intermediate 171B (200 mg, 0.487 mmol) in a mixture of methanol (2 ml), tetrahydrofuran (2 ml) and water (2 ml) at room temperature was added sodium hydroxide (195 mg, 4.87 mmol) and stirred for nights. The reaction mixture was concentrated under reduced pressure. The residue was acidified with 1.5 N aqueous HCl ~pH=2 and extracted with EtOAc (2x25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (170 mg, 0.369 mmol, 76% yield) as a pale yellow oil. MS (ESI) 415 (M+H).

Stage B. Intermediate 183B. Preparation of 4-((D-(3-carbamoylphenyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of prome

- 210 047337 compound 114A by replacing intermediate 183A where needed: (90 mg, 0.174 mmol, 43% yield) as a pale yellow oil. MS (ESI) 414 (M+H).

Step C. Intermediate 183C. Preparation of Y((4-suapobicyclo[2.2.2]octan-1yl)methyl)-N-(3-cyanophenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 114B by replacing intermediate 183B where necessary: (90 mg, 0.227 mmol, 62% yield). MS (ESI) 378 (M+H).

Stage D. Intermediate 183D. Preparation of 3-fluoro-N-((4-((E)-Nhydroxycarbamidoyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(k)-Nhydroxycarbamidoyl)phenyl)bicyclo[ 1.1.1]pentane-1-carboxamide

The compound was synthesized according to the method described for the synthesis of intermediate 88F by replacing intermediate 183C where necessary: (60 mg, 0.122 mmol, 51% yield) as an off-white solid. MS (ESI) 444 (M+H).

Step E. Example 183. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3 -(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.G1]pentane-1carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 183D and the corresponding acid where necessary: (13.5 mg, 0.023 mmol, 42% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (dd, J=6.2, 2.6 Hz, 1H), 7.90 (s, 1H), 7.66-7.64 (m, 2H), 3.61 (br. s., 2H ), 1.89 (br. s., 6H), 1.81-1.67 (m, 6H), 1.62 (s, 9H), 1.54-1.36 (m, 6H), 1.33 (s, 9H). FXR EC ₅₀ (nM) 18; MS (ESI) 576 (M+H).

Example 184.

No.((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-No.-(3-(5(difluoromethyl)- 1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized in accordance with the method described for the synthesis of intermediate 3A by replacing intermediate 183D and the corresponding acid where necessary: (10.83 mg, 0.113 mmol).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.07-8.05 (m, 1H), 7.99 (s, 1H), 7.71-7.69 (m, 2H), 7.56 (t, J=52.00 Hz, 1H), 7.40 (t, J=48.00 Hz, 1H), 3.62 (s, 2H), 1.89-1.81 (m, 6H),

1.79-1.75 (m, 6H), 1.46-1.42 (m, 6H). FXR EC ₅₀ (nM) 58; MS (ESI) 564 (M+H).

Example 185.

N(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-pyridin-2yl)bicyclo[2.2.2 ]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

- 211 047337

Step A: Intermediate 185A. Preparation of methyl 4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carboxylate

O /—\ ^N =\

HO/Λ # ^CF3 H ₃ C-O ⁴ ''—'

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (3 g, 14.13 mmol) and 3-(trifluoromethyl)pyridine (2.495 g, 16.96 mmol) in DCM (90 ml ) and water (90 ml), ammonium persulfate (3.23 g, 14.13 mmol) was added, followed by silver nitrate (0.480 g, 2.83 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with DCM (25 ml) and filtered through celite. The organic layer was separated and washed with brine (25 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-50% EtOAc/PE) to give the title compound (2.2 g, 6.95 mmol, 49% yield) as a white solid. MS (ESI) 314 (M+H).

Stage B. Intermediate connection 185V. Preparation of (4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methanol /—\ ^N =\ ^CFa but '—' ⁴ —'

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G by replacing intermediate 258A where necessary: (1.6 g, 5.05 mmol, 79% yield) as a white solid. MS (ESI) 286 (M+H).

Step C. Intermediate 185C. Preparation of 4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carbaldehyde /—y N=\

ABOUT '-' '-

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 185B where necessary: (1.2 g, 4.24 mmol, 78% yield) as a white solid. MS (ESI) 284 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.89 (dd, J=2.5, 1.0 Hz, 1H), 8.18-8.07 (m, 1H), 7.60 (d, J=8.5 Hz, 1H), 1.98-1.83 (m, 6H), 1.76-1.65 (m, 6H).

Stage D. Intermediate 185D. Preparation of 3-(((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)benzonitrile ^ΗΝ ^Π/\1 jrj XX NCT^ ^(ЗЭз

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 185C where necessary: (180 mg, 0.462 mmol, 66% yield) as a brown solid. MS (ESI) 386 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.91-8.86 (m, 1H), 8.10 (dd, J=8.5, 2.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.22 (t , J=7.8 Hz, 1H), 6.99-6.92 (m, 2H), 6.85 (dt, J=7.5, 1.3 Hz, 1H), 6.01 (t, J=5.8 Hz, 1H), 2.87(d, J= 5.5 Hz, 2H), 1.93-1.84 (m, 6H), 1.63-1.56 (m, 6H).

Step E. Intermediate 185E. Preparation of N(3-cyanophenyl)-3-fluoro-N-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane -1-carboxamide

The title compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 185D and the corresponding acid where necessary: (190 mg, 0.378 mmol, 81% yield) as a brown solid. MS (ESI) 498 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.12-8.02 (m, 2H), 7.88 (d, J=7.5 Hz, 1H), 7.84-7.78 (m, 1H), 7.70 -7.63 (m, 1H), 7.53 (d, J=8.5 Hz, 1H), 3.61 (br. s., 2H), 1.94-1.84 (m, 6H), 1.84-1.75 (m, 6H), 1.481. 37 (m, 6H).

Step F: Intermediate 185F. Preparation of 3-fluoro-N-(3-(N-hydroxycarbamidoyl)phenyl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo-[2.2.2]octan-1- 212 047337 yl) methyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

NH ₂

The compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 185E where necessary (190 mg, 0.347 mmol, 96% yield) as a white solid. MS (ESI) 531 (M+H).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 8.85 (s, 1H), 8.08 (dd, J=8.5, 2.5 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H ), 7.65 (t, J=1.8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.42-7.38 (m, 1H), 5.95 (s, 2H) , 3.723.65 (m, 1H), 3.54-3.47 (m, 1H), 1.92-1.76 (m, 12H), 1.45 (d, J=4.5 Hz, 6H).

Step G. Example 185. Preparation of M(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-U((4-(5-(trifluoromethyl)pyridin-2- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 185F and the corresponding acid where necessary: (15.6 mg, 0.027 mmol, 47% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.07 (dd, J=8.6, 2.0 Hz, 1H), 7.98 (ddd, J=5.3,3.5, 1.5 Hz, 1H), 7.88 (s, 1H), 7.71-7.57 (m, 2H), 7.52 (d, J=8.6 Hz, 1H), 3.62 (s, 2H), 2.47-2.40 (m, 1H), 1.88 (br. s., 6H), 1.85-1.63 (m, 6H), 1.57-1.36 (m, 6H), 1.34-1.27(m, 2H), 1.25-1.17 (m, 2H); FXR EC50 (nM) = 508; MS (ESI) 581 (M+H).

The following compounds were synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 185F and the corresponding acid where necessary:

- 213 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 186 _CH3O -- ^N 595 625 187 O H ₃ ^CO'N 583 605 188 O H ₃ C O' ^N 597 304 189 O F Ο' ^Ν 591 691 190 ABOUT F%'N 605 281 186 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.07 (dd, J = 8.8, 2.4 Hz, 1H), 8.03-7.94 (m, 1H), 7.88 (s, 1H), 7.72 -7.59 (m, 2H), 7.52 (d, J= 8.6 Hz, 1H), 3.62 (br. s., 2H), 1.88 (br. s., 6H), 1.85-1.65 (m, 6H), 1.58 (s, 3H), 1.53-1.33 (m, 8H), 1.20-1.11 (m, 2H)

- 214 047337

187 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.07 (dd, J = 8.6, 2.4 Hz, 1H), 8.04-7.96 (m, 1H), 7.92 (s, 1H), 7.77 -7.59 (m, 2H), 7.52 (d, J= 8.3 Hz, 1H), 3.63 (br. s., 2H), 3.45-3.35 (m, 1H), 1.89 (br. s., 6H), 1.85 -1.71 (m, 6H), 1.551.31 (m, 12H) 188 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.92-8.78 (m, 1H), 8.07 (dd, J = 8.6, 2.0 Hz, 1H), 8.04-7.96(m, 1H), 7.91 (s, 1H) , 7.76-7.57 (m, 2H), 7.52 (d, J= 8.6 Hz, 1H), 3.63 (br. s., 2H), 1.89 (br. s., 6H), 1.85-1.70 (m, 6H) , 1.58-1.36 (m, 15H) 189 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.19-8.03 (m, 2H), 8.01-7.95 (m, 1H), 7.81-7.64 (m, 2H), 7.64-7.48 ( m, 2H), 3.64 (s, 2H), 1.90 (br. s., 6H), 1.86-1.59 (m, 6H), 1.57-1.35 (m, 6H) 190 ^X NMR (400 MHz, DMSO-d ₆ ) δ 8.91-8.79 (m, 1H), 8.15-8.02 (m, 2H), 7.99 (s, 1H), 7.79-7.62 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 3.64 (br. s., 2H), 2.25 (t, J = 19.8 Hz, 3H), 1.90 (br. s., 6H), 1.86-1.59 (m, 6H), 1.55 -1.34 (m, 6H)

Example 191.

N-((4-(3 -(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-N-(3 -(3 - cyclopropyl1,2,4-oxadiazol-5-yl)phenyl)-3-methyloxetane-3-carboxamide

Step A: Intermediate 191A. Preparation of methyl 4-(3-(tert-butyl)-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid and intermediate 88F where necessary: (2.2 g, 7.52 mmol, 97% yield) as a white solid. MS (ESI) 293 (M+H).

¹ H NMR (400 MHz, DMSO-d6) δ 3.61 (s, 3H), 1.96-1.87 (m, 6H), 1.87-1.79 (m, 6H), 1.29 (s, 9H).

Stage B. Intermediate 191B. Preparation of (4-(3-(tert-butyl)-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methanol

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 191A where necessary: (1.5 g, 5.62 mmol, 75% yield) as a white solid. MS (ESI) 265 (M+H).

¹ H NMR (400 MHz, DMSO-d6) δ 4.43 (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).

Step C. Il)bicyclo[2.2.2]octane-1-carbaldehyde intermediate

191C. Preparation of 4-(3-(tert-butyl)-1,2,4-oxadiazole-5-

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 191B where necessary:

- 215 047337 (1.1 g, 3.44 mmol, 61% yield) as a white solid. MS (ESI) 263 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 1.97-1.88 (m, 6H), 1.76-1.65 (m, 6H), 1.29 (s, 9H).

Stage D. Intermediate 191D. Preparation of A-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -(3-cyclopropyl-1, 2,4-oxadiazol-5-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 191C where necessary: (3 g, 6.70 mmol, 70% yield) as a brown solid. MS (ESI) 448 (M+H).

Step E. Example 191. Preparation of N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-X-(3 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-methyloxetane-3-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of the compound in Example 3, by replacing intermediate 191D and the corresponding acid where necessary: (8 mg, 0.014 mmol, 22% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (t, J=1.7 Hz, 1H), 8.01 (dd, J=9.0, 1.2 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 4.51 (br. s., 2H), 3.74-3.44 (m, 4H), 2.27-2.15 (m, 1H), 1.88-1.72 (m, 6H), 1.59 (s, 3H), 1.48-1.34 (m, 6H), 1.32-1.16 (m, 9H), 1.16-1.08 (m, 2H), 1.06-0.97 (m, 2H); FXR EC ₅₀ (nM) = 824; MS (ESI) 546 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 191D and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 192 O N ₃ С. ₄ 0</ J. _Ν СНз Γη Т/уА-сн, Γκ,Νυ/ΥΑ θ'Ν СН ₃ Ν'° 560 449 193 O ADa:·., O~N CH ₃ Ν'° 627 4871 192 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (t, J= 18.40 Hz, ZH), 7.71-7.64 (m, 2H), 3.63 (s, 2H), 3.44-3.51 (w, 1H), 3.02 (s, ZN), 2.20 (m, 1H), 1.96-1.92 (m, 4H), 1.80-1.76 (m, 6H), 1.41-1.37 (m, 6H), 1.25 (s, 9H), 1.13-1.11 (m, 2H), 1.02-0.99 (m, 2H). 193 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.14-7.90 (m, 2H), 7.79-7.60 (m, 2H), 4.55-

4.39 (m, 1H),4.20-3.95 (m, 2H), 3.80-3.61 (m, 2H), 3.61-3.46 (m, 2H), 2.28- 2.17 (m, 1H),1.88-1.68 (m, 6H), 1.54-1.30 (m, 6H), 1.30-1.17 (m, 9H), 1.17- 1.07 (m, 2H), 1.04-0.93 (m, 2H)

4.39 (m, 1H),4.20-3.95 (m, 2H), 3.80-3.61 (m, 2H), 3.61-3.46 (m, 2H), 2.28

2.17 (m, 1H),1.88-1.68 (m, 6H), 1.54-1.30 (m, 6H), 1.30-1.17 (m, 9H), 1.17

1.07 (m, 2H), 1.04-0.93 (m, 2H)

Example 194.

N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3- (1(methylsulfonyl)-III-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

- 216 047337

Intermediate connection 194A. Receipt

Stage A.

bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate methyl 4-(((3-

The title compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 88B where necessary: (2.0 g, 5.68 mmol, 81% yield) as a brown wax, MS (ESI) 352 (M+H).

Stage B. Intermediate 194B. Preparation of 4-(((3bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

The indicated compound was synthesized according to the method described for the synthesis of intermediate 175B, replacing intermediate 194A where necessary: (1.9 g, 5.62 mmol, 99% yield) as a white solid. MS (ESI) 338 (M+H).

Step C. Intermediate 194C. Preparation of 4-(((3bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 184A, replacing intermediate 194B where necessary: (2.0 g, 5.93 mmol, 100% yield). MS (ESI) 338 (M+H).

Stage D. Intermediate 194D. Preparation of 4-(((3bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carbonitrile

To a stirred solution of intermediate 194C (2.0 g, 5.93 mmol) in pyridine (50 ml) was added imidazole (1.009 g, 14.83 mmol) and cooled to 0-5°C. POCl ₃ (0.608 mL, 6.52 mmol) was added dropwise to the cooled solution and allowed to gradually warm to room temperature over 5 hours. The reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (2x70 mL). The combined organic layers were washed with 1.5 N aqueous HCl (4x50 ml), water (100 ml) and brine (100 ml). Then, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-60% EtOAc/PE) to give the title compound (1.0 g, 3.13 mmol, 53% yield) as a white solid. MS (ESI) 336(M+18) (NH3 adduct).

Step E. Intermediate 194E. Preparation of (7)-4-(((3-bromophenyl)amino)methyl)-N-hydroxybicyclo[2.2.2]octane-1-carboximidamide

The title compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 194D where necessary: (1.0 g, 2.84 mmol, 91% yield) as a white solid. MS (ESI) 352 (M+H).

Step F: Intermediate 194F. Preparation of 3-bromo-N-((4-(5-(tert-butyl)-1,2,4- 217 047337 oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 194E and the corresponding acid where necessary: (900 mg, 2.151 mmol, 95% yield) as a brown wax. MS (ESI) 420 (M+2).

Stage G. Intermediate 194G. Preparation of A(3-bromophenyl)-H-((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

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 194F and the corresponding acid where necessary: (300 mg, 0.566 mmol, 49% yield) as a brown wax. MS (ESI) 530 (M+H).

Step H. Example 194. Preparation of A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro- H-(3-(1-(methylsulfonyl)-1H-pyrazol-4-yl)-phenyl)bicyclo[1.1.1]pentan-1carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 194G and 1-(methylsulfonyl)-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl )-III-pyrazole where needed: (4.8 mg, 8.06 µmol, 17% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 8.59 (s, 1H), 7.94-7.85 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.49 (t , J=7.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.72-3.45 (m, 5H), 1.87 (br. s., 6H), 1.79-1.62 (m, 6H), 1.56 -1.37 (m, 6H), 1.33 (s, 9H). FXR EC50 (nM) = 16; MS (ESI) 596 (M+H).

The following compound was synthesized according to the method described for the synthesis of Example 149, replacing intermediate 194G and the corresponding heteroarylboronate where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 195 О ^N '° ^СНз О hr 622 20 195 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.62-8.54 (m, 1H), 7.89 (s, 1H), 7.81 (d, J =8.1 Hz, 1H), 7.49 (t , J = 7.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 3.64 (d, J = 13.4 Hz, 1H), 3.54 (d, J = 13.7 Hz, 1H), 3.22-3.14 (m , 1H), 1.87 (d, J =6.6 Hz, 6H), 1.79-1.58 (m, 6H), 1.57-1.36 (m, 6H), 1.36-1.27 (m, 11H), 1.26-1.20 (m, 2H ).

Example 196.

N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3 -(3 cyclopropyl- 1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

- 218 047337

Step A: Intermediate 196A. Preparation of (4-(1,3-dithian-2-yl)-4hydroxycyclohexane-1,1-diyl)bis(methylene)bis(4-methylbenzenesulfonate)

S NO

OTs .OTs

To a stirred solution of 1,3-dithiane (4.33 g, 36.0 mmol) in THF (60 ml) at -78°C, n-butyllithium (15.60 ml, 39.0 mmol) was added and allowed to warm to 0 °C for 1 hour. The reaction mixture was cooled again to -78 °C, and then a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene)bis(4methylbenzenesulfonate) (7.0 g, 15.00 mmol) was added ) in THF (20 ml). The reaction mixture was allowed to warm to 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (100 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with water (100 ml) and then with brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 220 g, silica gel, 0-60% EtOAc/PE) to give the title compound (5.5 g, 9.37 mmol, 63% yield) as a white solid. MS (ESI) 604 (M+18) (NH3 adduct).

Stage B. Intermediate 196V. Preparation of (1-(1,3-dithian-2-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 141B, replacing intermediate 196A where necessary: (2.5 g, 6.0 mmol, 71%) as a brown wax. MS (ESI) 432 (M+18) (NH3 adduct).

Step C. Intermediate 196C. Preparation of (1-formyl-2-oxabicyclo[2.2.2]octan-4yl)methyl 4-methylbenzenesulfonate

OTs

To a stirred solution of intermediate 196B (2.3 g, 5.55 mmol) in DCM (90 ml) was added a solution of N-chlorosuccinimide (2.59 g, 19.42 mmol) in H ₂ O (10 ml) and stirred for 2 hours at room temperature. The reaction mixture was then diluted with DCM (100 ml) and washed with water (2x50 ml) and then brine (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (3 g, crude) as a white wax. MS (ESI) 325 (M+H).

Stage D. Intermediate 196D. Preparation of 4-((tosiloxy)methyl)-2oxabicyclo[2.2.2]octane-1-carboxylic acid

BUT

OTs

To a stirred solution of intermediate 196C (2.0 g, 6.17 mmol) in tert-butanol (60 ml) was added 2-methyl-2-butene (1.297 g, 18.50 mmol) followed by sodium chlorite (2.79 g, 30.8 mmol) and then a solution of sodium dihydrogen phosphate monohydrate (8.51 g, 61.7 mmol) in water (20 ml) was added. After stirring the reaction mixture overnight at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 ml). The aqueous solution was acidified with 1.5 N aqueous HCl and extracted with EtOAc (2x50 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.5 g, 4.41 mmol, 72% yield). . MS (ESI) 341 (M+H).

Since the intermediate 196D thus obtained was not pure, it was esterified in step E and purified. Intermediate 196E was then hydrolyzed in Step F to obtain pure acid intermediate 196F as described below.

Step E. Intermediate 196E. Preparation of methyl 4-((tosiloxy)methyl)-2oxabicyclo[2.2.2]octane-1-carboxylate

- 219 047337 n ₃ s-o

OTs

To a stirred solution of intermediate 196D (2.5 g, 7.34 mmol) in DMF (20 mL) at room temperature was added potassium carbonate (2.030 g, 14.69 mmol) and stirred for 5 min. Methyl iodide (0.918 mL, 14.69 mmol) was added to the resulting solution and stirred for 1 hour at room temperature. The reaction mixture was then diluted with ethyl acetate (100 ml) and washed with water (2x50 ml) and then with brine (2x50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-50% EtOAc/PE) to give the title compound (1.4 g, 3.95 mmol, 54% yield) as a white solid. MS (ESI) 372 (M+18) NH3 adduct.

Step F: Intermediate 196F. Preparation of 4-((tosiloxy)methyl)-2oxabicyclo[2.2.2]octane-1-carboxylic acid

BUT

OTs

To a stirred solution of intermediate 196E (1 g, 2.82 mmol) in THF (4 mL) and MeOH (2 mL) was added a solution of sodium hydroxide (0.226 g, 5.64 mmol) in water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water (40 ml). The aqueous solution was acidified with 1.5 N aqueous HCl (5 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (900 mg, 2.64 mmol, 94% yield) as a white solid. MS (ESI) 358 (M+18) NH3 adduct.

Stage G. Intermediate 196G. Preparation of (Z)-(1((((amino(cyclopropyl)methylene)amino)oxy)carbonyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4methylbenzenesulfonate

N-0 // '

OTs

_NH2O

To a stirred solution of intermediate 196F (800 mg, 2.350 mmol) in DMF (8 mL) was added TEA (1.310 mL, 9.40 mmol), N-N-hydroxycyclopropanecarboximidamide (706 mg, 7.05 mmol), BOP (1143 mg, 2.59 mmol) and stirred for 1 hour at room temperature. The reaction mixture was stirred overnight at 110°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (2x5 ml) and then with brine (10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.5 g, crude), which was used as such for the next step without further purification. MS (ESI) 423 (M+1).

Step H. Intermediate 196H. Preparation of (1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

OTs

To a stirred solution of intermediate 196G (1.0 g, 2.367 mmol) in THF (20 mL) at 0°C was added a solution of 1 M TBAF in THF (14.20 mL, 14.20 mmol) at the following times: every 2 equiv . at time points 0, 4 hours and 8 hours. After stirring for an additional 8 hours, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 ml). The organic solution was washed with water (20 ml) and then with saturated saline (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-60% EtOAc/PE) to give the title compound (600 mg, 1.483 mmol, 63% yield) as a brown wax. MS (ESI) 405 (M+l).

Stage I. Intermediate 196I. Preparation of (1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl acetate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 141C, replacing intermediate 196H where necessary: (420 mg, 1.437 mmol, 89% yield) as a brown oil. MS (ESI) 293 (M+1).

- 220 047337

Step J. Intermediate 196J. Preparation of (1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methanol

HE

The compound was synthesized according to the method described for the synthesis of intermediate 141D, replacing intermediate 196I where necessary: (280 mg, 1.119 mmol, 91% yield) as a white solid. MS (ESI) 251 (M+1).

Stage K. Intermediate 196K. Preparation of 1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)2-oxabicyclo[2.2.2]octane-4-carbaldehyde

The title compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 196J where necessary: (200 mg, 0.806 mmol, 67% yield) as a white solid. MS (ESI) 249.2(M+1), 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 3.95 (s, 2H), 2.30-2.20 (m, 1H), 2.15-2.02 ( m, 4H), 1.93-1.86 (m, 4H), 1.101.01 (m, 2H), 0.90-0.84 (m, 2H).

Step L. Intermediate 196L. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)A((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2 ]octan-4-yl)methyl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 8A and intermediate 196K where necessary: (24 mg, 0.053 mmol, 65% yield) as an off-white solid. MS (ESI) 434 (M+H).

Step M. Example 196. Preparation of A((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 196L and the corresponding acid where necessary: (14.9 mg, 0.027 mmol, 47% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.17-7.96 (m, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 3.65 (br. s ., 4H), 2.27-2.19 (m, 1H), 2.18-2.03 (m, 3H), 2.02-1.76 (m, 8H), 1.65 (d, J=9.8 Hz, 2H), 1.57 (d, J= 13 Hz, 2H), 1.14 (dd, J=8.2, 2.6 Hz, 2H), 1.08-0.90 (m, 4H), 0.90-0.80 (m, 2H). FXR EC50 (nM) 205; MS (ESI) 546 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 196L and the corresponding acids where necessary:

- 221 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 197 ABOUT °'Ν D A Ν'° 552 965 198 0 Ν-0 566 909 197 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 3.80-3.55 (m, 4H), 2.97-2.70 (m, 3H), 2.39-2.28 (m, 2H), 2.26-2.19 (m, 1H), 2.16-1.99 (m, 3H), 1.98-1.86 (m, 2H), 1.72-1.60 (m, 2H), 1.55 (d, J = 6.8 Hz, 2H), 1.20-1.10 (m, 2H), 1.090.95 (m, 4H), 0.93- 0.78 (m, 2H). 198 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.10-7.95 (m, 2H), 7.82-7.55 (m, 2H), 6.25.7 (m, 1H), 3.75-3.59 (m, 4H), 3.05 ( dq, J = 16.9, 8.5 Hz, 1H), 2.34-2.26 (m, 1H), 2.26-2.16 (m, 1H), 2.15-2.00 (m, 4H), 1.99-1.86 (m, 2H), 1.79- 1.70 (m, 1H), 1.70-1.58 (m, 3H), 1.54 (d, J =8.3 Hz, 2H), 1.19-1.09 (m, 2H), 1.080.94 (m, 4H), 0.89-0.78 ( m, 2H). (1H is buried under solvent peak)

Example 199.

X-(('1-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-X-(3-(5cyclopropylisoxazole -3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 199A. Preparation of N((1-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(5-cyclopropylisoxazol-3-yl) aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing intermediate 57C and intermediate 196K where necessary: (20 mg, 0.046 mmol, 46% yield) as a brown wax. MS (ESI) 433 (M+1).

Step B. Example 199. Preparation of N((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-X-(3- (5-cyclopropylisoxazol-3-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound

- 222 047337 studies according to example 3, by replacing intermediate 199A and the corresponding acid where necessary: (10.9 mg, 0.019 mmol, 41% yield).

^1H NMR (400 MHz, DMSO-d6) δ 7.94-7.76 (m, 2H), 7.67-7.50 (m, 2H), 6.88 (s, 1H), 3.75-3.53 (m, 4H), 2.24-2.16 ( m, 1H), 2.16-2.01 (m, 3H), 2.00-1.77 (m, 8H), 1.74-1.61 (m, 2H), 1.61-1.42 (m, 2H), 1.17-1.08 (m, 2H), 1.08-1.00 (m, 2H), 1.00-0.90 (m, 2H), 0.89-0.74 (m, 2H); FXR EC ₅₀ (nM) = 281; MS (ESI) 545 (M+H).

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 199A and the corresponding acid where necessary:

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 200 O __/\ K Αν Ο-Ν^ OD II Ο ^Ν 551 526 201 o γΧνΧχΟ c JJ X L>—< T O ^N 565 384 202 oA <\ z =/ '—( ° Vo Ϊ 565 299 200 ^NMR (400 MHz, DMSO-d ₆ ) δ 7.88-7.78 (m, 2H), 7.63-7.48 (m, 2H), 6.84 (s, 1H), 3.67 (d, J = 6.6 Hz, 4H), 2.96 -2.69 (m, 3H), 2.39-2.29 (m, 2H), 2.262.16 (m, 1H), 2.14-2.01 (m, 3H), 1.97-1.85 (m, 2H), 1.72-1.60 (m, 2H), 1.56 (d, J = 5.9 Hz, 2H), 1.18-1.09 (m, 2H), 1.07-0.99 (m, 2H), 0.98-0.89 (m, 2H), 0.88-0.79 (m, 2H) 201 ^NMR (400 MHz, DMSO-d ₆ ) δ 7.89-7.70 (m, 2H), 7.64-7.40 (m, 2H), 6.92- 6.76 (m, 1H), 3.74-3.56 (m, 4H), 3.14- 3.02 (m, 1H), 2.44 (br. s., 1H), 2.34-

2.27 (m, 1H), 2.24-2.17 (m, 1H), 2.15-2.01 (m, 4H), 1.99-1.83 (m, 2H), 1.73 (m, 1H), 1.65 (t, J= 10.0 Hz, 3H), 1.54 (m, 2H), 1.18-1.07 (m, 2H), 1.07-1.00 (m, 2H), 0.96-0.89 (m, 2H), 0.89-0.80 (m, 2H), (1H is buried under DMSO peak). 202 NMR (400 MHz, DMSO-d ₆ ) δ 7.97-7.75 (m, 2H), 7.60 (d, J = 4.4 Hz, 2H), 6.86 (s, 1H), 3.65 (s, 4H), 2.94 (t, J= 8.3 Hz, 1H), 2.32-2.16 (m, 2H), 2.161.99 (m, 5H), 1.99-1.76 (m, 4H), 1.66 (m, 3H), 1.56 (d, J = 8.8 Hz , 2H), 1.171.09 (m, 2H), 1.09-0.97 (m, 2H), 0.97-0.89 (m, 2H), 0.89-0.76 (m, 2H)

Example 203.

U-(('1-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)A-(3-(5cyclopropylisoxazol- 3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

- 223 047337

Step A: Intermediate 203A. Preparation of 3-(((1-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)amino)benzonitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 3-aminobenzonitrile and intermediate 196K where necessary: (30 mg, 0.086 mmol, 25% yield) as a white solid. MS (ESI) 351 (M+H).

Stage B. Intermediate 203B. Preparation of A(3-cyanophenyl)A-(('1-(3-cyclopropyl1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluorobicyclo [1.1.1]pentane-1carboxamide

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 203A and the corresponding acid where necessary: (30 mg, 0.065 mmol, 76% yield) as a brown wax. MS (ESI) 463 (M+H).

Step C. Intermediate 203C. Preparation of ^)-Na-((1-(3-cyclopropyl-1,2,4oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-Na(3 -(Nhydroxycarbamidoyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 203B where necessary: (40 mg, 0.081 mmol, 93% yield) as a brown wax. MS (ESI) 496 (M+H).

Step D. Example 203. Preparation of N((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3 - (5-cyclopropylisoxazol-3-yl)phenyl)-3 fluorobicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 203C and the corresponding acid where necessary: (3.8 mg, 6.96 µmol, 17% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03-7.95 (m, 1H), 7.91 (s, 1H), 7.72-7.60 (m, 2H), 3.75-3.52 (m, 4H), 2.47-2.42 (m, 1H), 2.17-2.03 (m, 3H), 2.01-1.91 (m, 2H), 2.0-1.88 (m, 6H), 1.66-1.56 (m., 2H), 1.60-1.49 (m, 2H ), 1.38-1.2 (m, 4H), 1.09-0.99 (m, 2H), 0.90-0.79 (m, 2H); FXR EU ₅₀ (nM) = 74; MS (ESI) 546 (M+H).

Example 204.

No.((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-No.-(3-(5(difluoromethyl) -1,2,4-oxadiazol-3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

- 224 047337

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 203C and the corresponding acid where necessary: (9.3 mg, 0.017 mmol, 42% yield).

¹ HNMR (400 MHz, DMSO-d6) δ 8.14-8.05 (m, 1H), 8.05-7.99 (m, 1H), 7.79-7.44 (m, 3H), 3.65 (d, J=10.0 Hz, 4H), 2.18-2.03 (m, 3H), 2.03-1.76 (m, 8H), 1.67-1.62 (m, 2H), 1.61-1.49 (m, 2H), 1.09-0.99 (m, 2H), 0.900.75 (m , 2H); FXR EC ₅₀ (nM) = 371; MS (ESI) 556 (M+H).

Example 205.

4-(5-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)pyridin-3-yl)-4-((4-(3-cyclopropyl-'1-methyl-'1Hpyrazol-5 -yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 205A. Preparation of yl)pyridine-3-amine

5-(3-cyclopropyl-1,2,4-oxadiazol-5-

The title compound was synthesized according to the method described for the synthesis of intermediate 3A by substituting 5-aminonicotinic acid (cis)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5- yl)bicyclo[2.2.2]octan-1-yl)methyl)-No-(3-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-phenyl)-3-methoxycyclobutan-1-carboxamide and ( 7)-N-hydroxycyclopropane-carboximidamide where needed: (700 mg, 3.46 mmol, 80% yield) as a brown solid. MS (ESI) 203 (M+N).

Stage B. Intermediate connection 205V. Preparation of 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)N((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane- 1-yl)methyl)pyridin-3-amine

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 205A and intermediate 126B where necessary: (20 mg, 0.045 mmol, 30% yield) as a brown wax. MS (ESI) 445 (M+H).

Step C. Example 205. Preparation of No.(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-No.((4-(3-cyclopropyl-1-methyl-III -pyrazol-5-yl)bicyclo-[2.2.2]octan-1-yl)methyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

To a stirred solution of intermediate 205B (20 mg, 0.045 mmol) in DCM (2 ml) was added 2-dimethylaminopyridine (16.49 mg, 0.135 mmol) and 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (8, 78 mg, 0.067 mmol). After cooling the reaction mixture to 0°C, POCl ₃ (8.39 μl, 0.090 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice water (2 ml) and extracted with DCM (5 ml). The organic layer was washed with water (5 ml), brine (5 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 15% B, 15-75% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing the desired product were combined

- 225 047337 and dried by centrifugal evaporation to obtain the title compound (4.7 mg, 8.11 µmol, 18% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (d, J=1.7 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.50 (t, J=2.3 Hz, 1H), 5.62 ( s, 1H), 3.72 (s, 5H), 2.30-2.21 (m, 1H), 1.92 (br. s., 6H), 1.76-1.64 (m, 7H), 1.54-1.27 (m, 6H), 1.19 -1.10 (m, 2H), 1.08-0.98 (m, 2H), 0.80-0.69 (m, 2H), 0.59-0.45 (m, 2H); FXR EC ₅₀ (nM) = 218; MS (ESI) 557 (M+H).

Example 206.

X((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(5-(3-cyclopropyl) -

1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 206A. Preparation of methyl 4-carbamoylbicyclo[2.2.2]octane-1carboxylate

This compound was synthesized according to the method described for the synthesis of intermediate 114A by replacing 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid where necessary: (9.0 g, 42.6 mmol , yield 90%). MS (ESI) 212 (M+1).

Stage B. Intermediate 206B. Preparation of methyl 4-cyanobicyclo[2.2.2]octane-1carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 114B, replacing intermediate 206A where necessary: (4.3 g, 22.25 mmol, 47% yield) as a white solid. MS (ESI) 211 (M+18) NH3 adduct.

Step C. Intermediate 206C. Preparation of methyl 4-(N'hydroxycarbamidoyl)bicyclo[2.2.2]octane-1-carboxylate

The compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 206B where necessary: (530 mg, 2.342 mmol, 91% yield) as a white solid. MS (ESI) 227 (M+H).

Stage D. Intermediate 206D. Preparation of methyl 4-(5-(tert-butyl)-1,2,4-oxadiazol3 -yl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 206C and the corresponding acid where necessary: (650 mg, 2.223 mmol, 95% yield). MS (ESI) 293 (M+H).

Step E. Intermediate 280E. Preparation of (4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was synthesized according to the method described for the synthesis of intermediate 1G, replacing intermediate 206D where necessary: (500 mg, 1.891 mmol, 89% yield) as a white solid. MS (ESI) 265 (M+H).

Step F: Intermediate 206F. Preparation of 4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

- 226 047337

The compound was synthesized according to the method described for the synthesis of intermediate 3C, replacing intermediate 206E where necessary: (390 mg, 1.487 mmol, 82% yield) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 9.45 (s, 1H), 1.88-1.84 (m, 6H), 1.70-1.66 (m, 6H), 1.35 (s, 9H),

Stage G. Intermediate 206G. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)pyridin-3-amine

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 205A and intermediate 206F where necessary: (20 mg, 0.045 mmol, 27% yield) as a brown wax. MS (ESI) 449 (M+H).

Step H. Example 206. Preparation of No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-No.-(5 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

This compound was synthesized according to the method described for the synthesis of Example 205, replacing intermediate 206G and the corresponding acid where necessary: (5.2 mg, 9.27 µmol, 21% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (d, J=1.7 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 3.72 ( m, 2H), 2.28-2.23 (m, 1H), 1.92 (br. s., 6H), 1.82-1.63 (m, 6H), 1.52-1.36 (m, 6H), 1.36-1.29 (m, 9H) , 1.15 (dd,J=8.1, 2.4 Hz, 2H), 1.06-0.99 (m, 2H); FXR EC50 (nM) = 49; MS (ESI) 561.3 (M+H).

Example 207.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(5-(3-cyclopropyl1 ,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 207A. Preparation of methyl 4-(((5-(3-cyclopropyl-1,2,4oxadiazol-5-yl)pyridin-3-yl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 205A and intermediate 88B where necessary: (250 mg, 0.654 mmol, 44% yield). MS (ESI) 383 (M+H).

Stage B. Intermediate 207B. Preparation of 4-(((5-(3-cyclopropyl-1,2,4-oxadiazol-5yl)pyridin-3-yl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

The indicated compound was synthesized according to the method described for the synthesis of intermediate 175B, replacing intermediate 207A where necessary: (50 mg, 0.115 mmol, 67% yield). MS (ESI) 369 (M+H).

Step C. Intermediate 207C. Preparation of X-((4-(3-('tre'g-bu'gil)-'1,2,4-oxadiazol-5

- 227 047337 yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-amine

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 207B and intermediate 88F where necessary: (20 mg, 0.045 mmol, 55% yield). MS (ESI) 449 (M+H).

Step D. Example 207. Preparation of Y((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1 -yl)methyl)-N-( 5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 207C and the corresponding acid where necessary: (1 mg, 1.784 μmol, 3% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.7 Hz, 1H), 8.51 (s, 1H), 3.3- 3.18 (s, 2H ), 2.29-2.23 (m, 1H), 1.92 (br. s., 6H), 1.84-1.77 (m, 6H), 1.45 (br. s., 6H), 1.26 (s, 9H), 1.19-1.13 (m, 2H), 1.03 (br. s., 2H). FXR EC ₅₀ (nM) 571; MS (ESI) 561 (M+H).

Example 208.

No.((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)-No.-(3-( 1(cyclopropylsulfonyl)-III-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 208A. Preparation of (1-(hydroxymethyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

The compound was synthesized according to the method described for the synthesis of intermediate 88A, replacing intermediate 196F where necessary: (900 mg, 2.76 mmol, 52% yield) as a white solid. MS (ESI) 344 (M+18) NH3 adduct.

Stage B. Intermediate connection 208V. Preparation of (1-formyl-2-oxabicyclo[2.2.2]octan-4yl)methyl 4-methylbenzenesulfonate

O—h

Q'—'OTs

To a stirred solution of oxalyl chloride (0.402 ml, 4.60 mmol) in DCM (2 ml) at -78°C, DMSO (0.326 ml, 4.60 mmol) in DCM (1.7 ml) was added dropwise over 5 minutes. After stirring the reaction mixture for 15 minutes, a solution of intermediate 208A (600.0 mg, 1.838 mmol) in DCM (4 ml) was added dropwise over 10 minutes and the reaction mixture was stirred for 2.5 hours at -78°C. TEA (1.794 mL, 12.87 mmol) was added dropwise to the above reaction mixture over 5 minutes, and the reaction mixture was stirred for an additional 5 minutes at -78°C. The reaction mixture was warmed to room temperature and stirred for an additional 1 hour. The reaction was quenched with water (20 ml) and extracted with DCM (2x20 ml). The combined organic layers were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 24 g, silica gel, 0-90% EtOAc/PE) to give the title compound (430 mg, 1.326 mmol, 72% yield) as a white solid. MS (ESI) 342 (M+18) NH3 adduct.

Step C. Intermediate 208C. Preparation of (1-(((3-bromophenyl)amino)methyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzene sulfonate

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 208B where necessary: (440 mg, 0.916 mmol, 79% yield) as a brown wax. MS (ESI) 480 (M+H).

Stage D. Intermediate 208D. Preparation of (1-((A-(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl methylbenzenesulfonate

The said compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 208C and the corresponding acid where necessary: (330 mg, 0.557 mmol, 61% yield) as a brown wax. MS (ESI) 592 (M+H).

Step E. Intermediate 208E. Preparation of (1-((A-(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl acetate

The compound was synthesized according to the method described for the synthesis of intermediate 141C, replacing intermediate 208D where necessary: (230 mg, 0.479 mmol, 92% yield) as a white solid. MS (ESI) 480 (M+H).

Step F: Intermediate 208F. Preparation of N(3-bromophenyl)-3-fluoro-N-((4(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 141D, replacing intermediate 208E where necessary: (180 mg, 0.411 mmol, 86% yield). MS (ESI) 438 (M+H).

Stage G. Intermediate 208G. Preparation of 1-((No(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid

To a stirred solution of intermediate 208F (160 mg, 0.365 mmol) in acetone (2 ml) at 0°C was added chromium trioxide (0.365 ml, 0.730 mmol) and the reaction mixture was stirred for 15 min at 0°C. The reaction mixture was quenched with isopropanol (5 ml) and concentrated under reduced pressure. The residue was diluted with water (10 ml) and extracted with ethyl acetate (2x20 ml). The combined organic extracts were washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (160 mg, 0.354 mmol, 97% yield). MS (ESI) 452 (M+H).

Step H. Intermediate 208H. Preparation of N(3-bromophenyl)-N-((4-(3-(tert-butyl)1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl )-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The title compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing intermediate 208G and (Z)-N'hydroxypivalimidamide where necessary: (130 mg, 0.244 mmol, 69% yield) as brown

- 229 047337 wax. MS (ESI) 532 (M+H).

Stage I. Example 208. Preparation of No. ((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-1-yl)methyl)-No. -(3-(1-(cyclopropylsulfonyl)-III-pyrazol-4-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 208H and the corresponding boronate ester where necessary: (4.5 mg, 7.05 μmol, 15% yield).

1H NMR (400 MHz, DMSO-d ₀ ) δ 8.93 (s, 1H), 8.55 (s, 1H), 7.89-7.71 (m, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.29 (d , J=8.8 Hz, 1H), 3.85 (br. s., 2H), 3.72 (d, J=17.4 Hz, 2H), 3.21-3.13 (m, 1H), 2.03 (br. s., 4H), 1.87 (br. s., 8H), 1.83-1.66 (m, 2H), 1.39-1.30 (m, 2H), 1.30-1.11 (m, 11H). FXR EC ₅₀ (nM) 618; MS (ESI) 624 (M+H).

Example 209.

and(3-(III-pyrazol-4-yl)phenyl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 209A. Preparation of 3-bromo-N-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-aniline

The compound was synthesized according to the method described for the synthesis of intermediate 3A, replacing intermediate 194E and the corresponding acid where necessary: (450 mg, 0.957 mmol, 96% yield) as a yellow solid. MS (ESI) 470 (M+H).

Stage B. Intermediate connection 209V. Preparation of i(3-bromophenyl)-3-fluoro-N-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl )methyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 209A and the corresponding acid where necessary: (400 mg, 0.687 mmol, 77% yield). MS (ESI) 582 (M+H).

Step C. Example 209. Preparation of irfIII-pyrazolM-yl^enylA-fluoro-IfAAA (trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[ 1.1.1]pentane-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 209B and the corresponding boronate ester where necessary: (7.9 mg, 0.0138 mmol, 26% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 13.00 (br. s., 1H), 8.31 (br. s., 1H), 8.03 (br. s., 1H), 7.71-7.54 (m, 2H) , 7.41 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H),3.67-3.49 (m, 2H),1.87 (br. s., 6H), 1.80-1.57 (m, 10H), 1.55-1.35 (m, 6H). FXR EC ₅₀ (nM) 152; MS (ESI) 570 (M+H).

Example 210.

N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(4-(3-cyclopropyl1 ,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

- 230 047337

Step A: Intermediate 210A. Preparation of 4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)pyridin-2-amine

The title compound was synthesized according to the method described for the synthesis of intermediate 3A by replacing 2-aminoisonicotinic acid and N'hydroxycyclopropanecarboximidamide where necessary: (200 mg, 0.920 mmol, 25% yield) as a yellow solid. MS (ESI) 203 (M+N).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J=5.0 Hz, 1H), 7.06 (s, 1H), 7.00 (dd, J=5.0, 1.5 Hz, 1H), 6.42 (s, 2H ), 2.25-2.17 (m, 1H), 1.17-1.09 (m, 2H), 1.01-0.95 (m, 2H).

Stage B. Intermediate connection 210V. Preparation of M((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-(3-cyclopropyl-1,2 ,4-oxadiazol-5-yl)pyridin-2-amine

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 210A and intermediate 206F where necessary: (30 mg, 0.067 mmol, 35% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=4.5 Hz, 1H), 7.21 (s, 1H), 6.93 (dd, J=5.3, 1.3 Hz, 2H), 4.38 (t, J= 5.3 Hz, 2H), 2.22-2.19 (m, 1H), 1.86-1.75 (m, 6H), 1.57-1.49 (m, 3H), 1.47-1.40 (m, 3H), 1.35 (s, 9H), 1.141 .12 (m, 2H), 1.00-0.95 (m, 2H). MS (ESI) 449 (M+H).

Step C. Example 210. Preparation of M((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-U-(4 -(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

Intermediate 210B (30 mg, 0.067 mmol) was added to a stirred solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (17.40 mg, 0.134 mmol) in acetonitrile (1 mL). The reaction mixture was cooled to 0°C and 4-methylmorpholine (0.038 ml, 0.334 mmol) was added, followed by POCl ₃ (0.016 ml, 0.167 mmol). The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (30 ml), and the organic solution was washed with 10% aqueous citric acid (25 ml), 10% aqueous sodium bicarbonate (25 ml ), and then saline solution (2x20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product 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 with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 2-minute hold at 25% B, 25-70% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (6.2 mg, 0.011 mmol, 17% yield). FXR EU ₅₀ (nM) = 48; MS (ESI) 561 (M+H).

Example 211.

M(4-(III-pyrazol-4-yl)pyridin-2-yl)-U-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo [2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

- 231 047337

Step A: Intermediate 211A. Preparation of 4-bromo-N-((4-(5-(tert-butyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by replacing 4-bromopyridin-2-amine and intermediate 206F where necessary: (250 mg, 0.596 mmol, 41% yield) as a colorless liquid. MS (ESI) 419 (M+N).

Stage B. Intermediate 211B. Preparation of A(4-bromopyridin-2-yl)A-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-fluorobicyclo[1.1.1]pentane-1carboxamide

The compound was synthesized according to the method described for the synthesis of Example 210, replacing intermediate 211A and the corresponding acid where necessary: (130 mg, 0.245 mmol, 57% yield) as a colorless liquid. MS (ESI) 531 (M+H).

Step C. Example 211. Preparation of A(4-('1I-pyrazol-4-yl)pyridin-2-yl)A-((4-(5-(tre'g-bu'gyl)1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 211B and the corresponding boronate ester where necessary: (2.9 mg, 0.006 mmol, 10% yield).

1I NMR (400 MHz, DMSO-d ₆ ) δ 13.25 (br. s., 1I), 8.55 (s, 1I), 8.45 (d, J=5.1 Hz, 1I), 8.21 (s, 1I), 7.75 ( s, 1I), 7.66 (dd, J=5.3, 1.6 Hz, 1I), 3.67 (s, 2I), 1.91 (d, J=2.7 Hz, 6H), 1.80-1.60 (m, 6I), 1.50-1.35 (m, 6I), 1.33 (s, 9I). FXR EC50 (nM) 17; MS (ESI) 519 (M+H).

Example 212.

N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(4-(1(difluoromethyl )-1 I-pyrazol-4-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 211B and the corresponding boronate ester where necessary: (22.9 mg, 0.0402 mmol, 71% yield).

1I NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1I), 8.63-8.46 (m, 2I), 7.90 (s, 2I), 7.84-7.67 (m, 1I), 3.69 (s, 2I) , 1.91 (d, J=2.4 Hz, 6H), 1.80-1.54 (m, 6H), 1.52-1.36 (m, 6H), 1.36-1.16 (m, 9H). FXR EC ₅₀ (nM) 11; MS (ESI) 569 (m+H).

Example 213.

No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-No.-(3-(3-( tert-butyl)1-methyl-1I-pyrazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

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Step A: Intermediate 213A. Preparation of 4,4-dimethyl-1-(3-nitrophenyl)pentane-1,3 dione

To a stirred solution of 1 M LiHMDS in THF (140 ml, 140 mmol) at -78°C was added 3,3dimethylbutan-2-one (7.0 g, 69.9 mmol) and stirred for 45 min. A solution of 3-nitrobenzoyl chloride (12.35 g, 66.6 mmol) in THF (20 ml) was added dropwise to the resulting solution over 20 minutes and stirred for 1 hour at -78°C. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-30% EtOAc/PE) to give the title compound (8.0 g, 32.1 mmol, 48% yield) as a yellow solid . MS (ESI) 252 (M+H).

Stage B. Intermediate connection of 213B1 and 213B2. Preparation of 3-(tert-butyl)-1-methyl-5-(3-nitrophenyl)-1H-pyrazole and 5-(tert-butyl)-1-methyl-3-(3-nitrophenyl)-1H-pyrazole

To a stirred solution of intermediate 213A (3.0 g, 12.04 mmol) in MeOH (30 mL) was added methylhydrazine sulfate (3.47 g, 24.07 mmol) at room temperature and heated to 80°C. After stirring for 3 hours, the reaction mixture 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 brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 40 g, silica gel, 0-50% EtOAc/PE) to obtain a mixture of isomers. Regioisomers were separated by preparative HPLC to yield intermediate 294B1 (900 mg, 3.47 mmol, 29% yield) 1H NMR (400 MHz, DMSO- _d6 ) δ 8.29-8.24 (m, 2H), 8.01-7.99 (m, 1H ), 7.77 (t, J=8.00 Hz, 1H), 6.46 (s, 1H), 3.83 (s, 3H), 1.28 (s, 9H); MS (ESI) 260 (M+H) as yellow solid, and intermediate 294B2 (800 mg, 3.09 mmol, 26% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.53 (m, 1H), 8.20-8.18 (m, 1H), 8.12-8.09 (m, 1H), 7.66 (t, J=8.00 Hz, 1H), 6.72 (s, 1H), 3.98 (s, 3H), 1.38 (s , 9H); MS (ESI) 260 (M+H) as a yellow solid.

Step C. Intermediate 213C. Preparation of 3-(3-(tert-butyl)-1-methyl-III-pyrazol-5yl)aniline

To a stirred solution of intermediate 213B1 (700 mg, 2.70 mmol) in a mixture of ethanol (8 ml) and THF (4 ml) was added zinc (2.65 g, 40.5 mmol), followed by a solution of ammonium chloride (2.167 g , 40.5 mmol) in water (2 ml). After stirring the reaction mixture overnight at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water (20 ml). The aqueous solution was extracted with ethyl acetate (2x20 ml) and the combined organic layers were washed with water (20 ml) and then brine (20 ml). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (Combiflash, 12 g, silica gel, 0-80% EtOAc/PE) to give the title compound (250 mg, 1.090 mmol, 40% yield) as a brown wax. MS (ESI) 230 (M+H).

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Stage D. Intermediate 213D. Preparation of X((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(3-(tert-butyl) )-1-methyl-1H-pyrazol-5-yl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 213C and intermediate 206F where necessary: (60 mg, 0.126 mmol, 72% yield) as a brown wax. MS (ESI) 476 (M+H).

Step E. Example 213. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1 -yl)methyl)-N-(3 -(3 -(tert-butyl)-1 -methyl-1 H-pyrazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 213D and the corresponding acid where necessary: (14.2 mg, 0.024 mmol, 19% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 7.63-7.49 (m, 3H), 7.48-7.40 (m, 1H), 6.36 (s, 1H), 3.81 (s, 3H), 3.73 (d, J= 15.4 Hz, 1H), 3.43 (d, J=13.2 Hz, 1H), 1.92 (br. s., 3H), 1.84 (br. s., 3H), 1.74 (t, J=7.9 Hz, 6H), 1.57-1.36 (m, 6H), 1.36-1.30 (m, 9H), 1.30-1.20 (m, 9H); FXR EC ₅₀ (nM) = 198; MS (ESI) 588 (M+H).

Example 214.

N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(3-(5-( tert-butyl)1-methyl-1H-pyrazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 214A. Preparation of 3-(5-(tert-butyl)-1-methyl-1H-pyrazol-3yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 213C, replacing intermediate 213B2 where necessary: (240 mg, 1.047 mmol, 45% yield) as a brown wax. MS (ESI) 230 (M+H).

Stage B. Intermediate connection 214V. Preparation of X((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(5-(tert-butyl) -1-methyl-1 H-pyrazol-3-yl)aniline

The compound was synthesized according to the method described for the synthesis of intermediate 1I, replacing intermediate 214A and intermediate 206F where necessary: (50 mg, 0.105 mmol, 60% yield) as a brown wax. MS (ESI) 476 (M+H).

Step C. Example 214. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1 -yl)methyl)-N-(3 -(5-(tert-butyl)-1 -methyl-1 H-pyrazol-3 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1 carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate compound 214B and the corresponding acid where necessary: (26 mg, 0.044 mmol, 42% yield).

¹ H NMR (400 MHz, DMSO-de) δ 7.76 (d, J=8.1 Hz, 1H), 7.71 (t, J=1.7 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H),

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7.32-7.24 (m, 1H), 6.63 (s, 1H), 3.97 (s, 3H), 3.62 (br. s., 1H), 3.55 (br. s., 1H), 1.87 (d, J=2.2 Hz, 6H), 1.78-1.67 (m, 6H), 1.51-1.41 (m, 6H), 1.39 (s, 9H), 1.33 (s, 9H); FXR EC50 (nM) = 89; MS (ESI) 588 (M+H).

Examples 215 and 216.

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

Step A. Intermediate yl)bicyclo[2.2.2]octan-1-yl)ethan-1-ol (215-216)

215A. 1-(4-(3-cyclopropyl-1,2,4-oxadiazole-5 compound

A solution of intermediate 4C (1.5 g, 6.09 mmol) in dry tetrahydrofuran (15 ml) was cooled to -78°C and 3 M methylmagnesium bromide in diethyl ether (3.04 ml, 9.13 mmol) was added under an inert atmosphere . The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 hour at room temperature. The reaction mixture was cooled to 0°C and quenched with a saturated aqueous solution of NH4Cl (50 ml). The aqueous solution was extracted with EtOAc (2x50 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (24 g silica gel cartridge, gradient 0-50% EtOAc in PE as eluent) to give the title compound (1.25 g, 4.53 mmol, 74% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d ₆ ) δ 4.29 (d, J=6.80 Hz, 1H), 3.21-3.25 (m, 1H), 2.05-2.11 (m, 1H), 1.78-1.83 (m, 6H), 1.35-1.58 (m, 6H), 1.05-1.10 (m, 2H), 0.94 (d, J=8.40 Hz, 3H), 0.86-0.90 (m, 2H).

Stage B. Intermediate connection 215V. 1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)ethan-1-one

To a solution of intermediate 215A (1.2 g, 4.57 mmol) in dichloromethane (20 mL) was added Dess-Martin periodinane (4.85 g, 11.43 mmol) at 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM and washed with 10% aqueous NaHCO ₃ followed by brine. The organic layer was concentrated under reduced pressure; the crude product was purified by flash chromatography (Combiflash, 12 g silica gel column) using 0-30% EtOAc in petroleum ether as eluents. Fractions containing the compound were concentrated to give the title compound (1 g, 3.65 mmol, 80% yield) as a white solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.51 (s, 3H), 2.502.51 (m, 1H), 1.89-1.99 (m, 6H), 1.71-1.76 (m, 6H), 1.00- 1.06 (m, 2H), 0.84-0.88 (m, 2H).

Step C. Intermediate 215C. Preparation of N(1-(4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octan-1-yl)ethyl)-3-(2-cyclopropyloxazol-5-yl)aniline

To a stirred solution of intermediate 20B (0.25 g, 0.960 mmol) in methanol (3 ml) was added intermediate 215B (0.192 g, 0.960 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then triethylsilane (0.307 ml, 1.921 mmol) was added, followed by indium(III) chloride (0.021 g, 0.096 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to obtain a residue. The residue was dissolved in EtOAc (50 ml) and the EtOAc solution was washed with water (10 ml) and then with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (12 g silica gel cartridge, gradient 0-40% EtOAc in PE in

- 235 047337 as eluent) to obtain the title compound (0.25 g, 0.534 mmol, 56% yield) as a pale yellow oil. MS (ESI) 445 (M+H).

Step D. Examples 215 and 216. Preparation of N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)ethyl)A-(3 -(2-cyclopropyloxazol-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

To a solution of intermediate 215C (100 mg, 0.225 mmol) in pyridine (4 ml) was added a freshly prepared solution of 3-fluorobicyclo[1.1.1]pentane-1-carbonyl chloride (234 mg, 1.575 mmol) in pyridine (1 ml). DMAP (27.5 mg, 0.225 mmol) was added to the above mixture and the reaction mixture was heated to 90°C and stirred for 12 hours. The reaction mixture was poured into water (10 ml) and extracted with DCM (2x20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (12 g silica gel cartridge, gradient 0-40% EtOAc in PE as eluent) to obtain the desired product as a racemate, which was subjected to chiral SFC to obtain the individual enantiomers. Column: Lux Cellulose-4 (250x4.6) 5.0 µm; isocratic mode, co-solvent: 0.2% NH4OH in MeOH+CAN (1:1); cosolvent percentage: 20%, column temperature: 30°C; overpressure: 100 bar; total flow rate: 4 g/min. Example 215Enantiomer 1 (24 mg, 0.041 mmol, 18% yield): RT = 5.5 min; ¹ H NMR (400 MHz, DMSO-d6): δ 7.70-7.72 (m, 1H), 7.62-7.64 (m, 1H), 7.47-7.56 (m, 2H), 7.22 (d, J=8.00 Hz, 1H ), 4.78 (s, 1H), 2.15-2.21 (m, 1H), 2.032.07 (m, 1H), 1.74-1.83 (m, 12H), 1.55 (s, 6H), 1.01-1.07 (m, 9H ), 0.84-0.86 (m, 2H), FXR EC50 (nM) 269; MS (ESI) 557 (M+H). Example 216-Enantiomer 2 (34 mg, 0.058 mmol, 26% yield): RT=7.5 min; ¹ H NMR (400 MHz, DMSO-d6): δ 7.70-7.72 (m, 1H), 7.62-7.64 (m, 1H), 7.47-7.56 (m, 2H), 7.22 (d, J=8.00 Hz, 1H ), 4.78 (s, 1H), 2.15-2.21 (m, 1H), 2.03-2.07 (m, 1H), 1.74-1.83 (m, 12H), 1.55 (s, 6H), 1.01-1.07 (m, 9H ), 0.84-0.86 (m, 2H), FXR EC ₅₀ (nM) 511; MS (ESI) 557 (M+H).

Examples 217 and 218.

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

O CH ₃ °N

A*n

N'° (217-218)

Step A: Intermediate 217A. Preparation of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)A(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2] octan-1-yl)ethyl)aniline

CH ₃

The compound was synthesized according to the method described for the synthesis of intermediate 215C, replacing intermediate 215B and intermediate 8A where necessary: (0.26 g, 0.584 mmol, 61% yield) as a pale yellow oil. MS (ESI) 446.4 (M+H).

Step B. Examples 217 and 218. Preparation of A(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)ethyl)A-(3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The compound was synthesized according to the method described for the synthesis of Example 215, replacing intermediate 217A and 3-fluorobicyclo[1.1.1]pentane-1carbonyl chloride where necessary: The racemate was purified by chiral SFC to obtain the individual enantiomers. Column: Lux Cellulose-4 (250x4.6) 5.0 µm; isocratic mode, co-solvent: 0.2% NH ₄ OH in MeOH+CAN (1:1); cosolvent percentage: 20%, column temperature: 30°C; overpressure: 100 bar; total flow rate: 4 g/min.

Example 217: Enantiomer 1 (21.6 mg, 0.037 mmol, 17% yield): ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.128.14 (m, 1H), 7.85-7.88 (m, 1H) , 7.62-7.64 (m, 2H), 4.78 (br. s., 1H), 2.18-2.23 (m, 1H), 2.05-2.09 (m, 1H), 1.74-1.83 (m, 12H), 1.53 (br . s., 6H), 1.12-1.15 (m, 2H), 1.01-1.12 (m, 7H), 0.84-0.86 (m, 2H), FXR EC ₅₀ (nM) 1435; MS (ESI) 558 (M+H).

Example 218: Enantiomer 2 (16.8 mg, 0.028 mmol, 12.35% yield): ^1H NMR (400 MHz, DMSO-d6): δ 8.12-8.14 (m, 1H), 7.85-7.88 (m, 1H ), 7.62-7.64 (m, 2H), 4.78 (br. s., 1H), 2.18-2.23 (m, 1H), 2.05-2.09 (m,

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1H), 1.74-1.83 (m, 12H), 1.53 (br. s., 6H), 1.12-1.15 (m, 2H), 1.01-1.12 (m, 7H), 0.84-0.86 (m, 2H), FXR EC ₅₀ (nM) 1116; MS (ESI) 558 (M+H).

Example 219.

¥-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-¥-(3-(4cyclopropyl-III- 1,2,3-triazol-1-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 219A. Preparation of 3-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was synthesized according to the method described for the synthesis of intermediate 1I by substituting 3-bromoaniline and intermediate 4C where necessary: (700 mg, 1.740 mmol, 86% yield) as a brown tarry solid. MS (ESI) 402.2 (M+H); 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.02-6.92 (m, 1H), 6.76 (s, 1H), 6.59 (dd, J=8.0, 2.0 Hz, 2H), 5.80-5.70 (m, 1H) , 2.79 (d, J=6.0 Hz, 2H), 2.05 (m, 1H), 1.89-1.77 (m, 6H), 1.59-1.48 (m, 6H), 1.02 (m, 2H), 0.89-0.80 (m , 2H).

Stage B. Intermediate connection 219V. Preparation of N(3-bromophenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1. 1]pentane-1-carboxamide

The following compounds were synthesized according to the method described for the synthesis of Example 3, replacing intermediate 219A and the corresponding acid where necessary: (320 mg, 0.603 mmol, 36% yield) as a white solid. MS (ESI) 514.0 (M+H); ¹ H NMR (400 MHz, DMSO-de) δ 7.69 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.45-7.39 (m, 2H), 3.56 (br. s., 1H), 3.48 (br. s., 1H), 2.08-2.00 (m, 1H), 1.86 (br. s., 6H), 1.81-1.72 (m, 6H), 1.40 (br. s., 6H), 1.01 ( m, 2H), 0.86-0.79 (m, 2H).

Step C. Intermediate 219C. Preparation of N(3-azidophenyl)-N-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1. 1]pentane-1-carboxamide

To a stirred solution of intermediate 219B (100 mg, 0.194 mmol) in DMF (0.6 mL) at room temperature was added sodium azide (63.2 mg, 0.972 mmol), sodium ascorbate (7.70 mg, 0.039 mmol), trans -N,N-dimethylcyclohexane-1,2-diamine (11.06 mg, 0.078 mmol) and copper(G) iodide (7.40 mg, 0.039 mmol). After stirring for 3 hours at 60°C, the reaction mixture was poured into a biphasic mixture of water (10 ml) and EtOAc (25 ml) and the layers were separated. The aqueous layer was further extracted with EtOAc (2x50 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the title compound (25 mg, 0.052 mmol, 27% yield). MS (ESI) 477 (M+H).

Step D. Example 219. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3 -(4- cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-3 fluorobicyclo[1.1.1]pentane-1-carboxamide

Ethynylcyclopropane (5.55 mg, 0.084 mmol) was added to a stirred solution of intermediate 219C (20 mg, 0.042 mmol) in DMF (2 mL) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure

- 237 047337 NI. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient: 3-minute hold at 19% B, 19-65% B for 25 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (6.0 mg, 0.011 mmol, 26% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 7.99-7.86 (m, 2H), 7.65 (t, J=8.3 Hz, 1H), 7.56-7.46 (m, 1H), 3.61 (d, J=6.4 Hz, 2H), 2.08-2.02 (m, 2H), 1.91 (br. s., 6H), 1.83-1.67 (m, 6H), 1.55-1.33 (m, 6H), 1.080. 93 (m, 4H), 0.89-0.74 (m, 4H). FXR EC ₅₀ (nM) 98.36 MS (ESI) 543.1 (M+H).

Example 220.

3,3-difluoro-N-(3'-methoxy-[1,1'-biphenyl]-3-yl)-N-((4-(3-methyl-1,2,4-oxadiazol-5yl)bicyclo [2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide

To a stirred solution of 1-bromo-3-methoxybenzene (0.5 g, 2.67 mmol) in toluene (5 ml) and ethanol (2 ml) was added (3-nitrophenyl)boronic acid (0.535 g, 3.21 mmol) . The reaction mixture was degassed and filled with argon again. A solution of Na ₂ CO ₃ (0.850 g, 8.02 mmol) in water (0.3 ml) was added to the reaction mass, degassed and again filled with argon. Tetrakis(triphenylphosphine)palladium(0) (0.154 g, 0.134 mmol) was added and the reaction mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature, diluted with water (20 ml) and extracted with EtOAc (3x10 ml). The organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 15% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (0.48 g, 1.885 mmol, 70% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (t, J=2.1 Hz, 1H), 8.23 (dt, J=8.3, 1.1 Hz, 1H), 8.20-8.13 (m, 1H), 7.77 (t , J=7.9 Hz, 1H), 7.49-7.41 (m, 1H), 7.38-7.29 (m, 2H), 7.04 (dd, J=8.1, 2.4 Hz, 1H), 3.85 (s, 3H).

Stage B. Intermediate connection 220V. Preparation of 3'-methoxy-[1,1'-biphenyl]-3-amine

A solution of intermediate 220A (0.48 g, 2.094 mmol) in methanol (10 ml) was purged and washed with nitrogen. Pd-C (0.111 g, 0.105 mmol) was added to the reaction mixture and stirred under hydrogen atmosphere (1 atm, balloon) overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (0.38 g, 1.812 mmol, 87% yield) as an oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.37-7.31 (m, 1H), 7.14-7.05 (m, 3H), 6.90 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 6.84 (t, J=2.0 Hz, 1H), 6.80-6.75 (m, 1H), 6.61-6.53 (m, 1H), 5.13 (s, 2H), 3.81 (s, 3H). MS (ESI) 200 (M+N).

Stage C. Intermediate 220C. Preparation of 3'-methoxy-N-((4-(3-methyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-[1,1'-biphenyl] -3-amine

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The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 220B and intermediate 3C where necessary: compound (0.13 g, 0.29 mmol, 51% yield) as dirty white solid. MS (ESI) 404 (M+N).

Step D. Example 220 5-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3 by replacing intermediate compound 220C and the corresponding acid where necessary: (2 mg, 3.83 μmol, yield 7.74%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.45-7.35 (m, 2H), 7.29 (d, J=7.8 Hz, 1H), 7.25 (s, 1H), 6.97 (dd, J=8.3, 1.7 Hz, 1H), 3.83 (s, 3H), 3.66 (br. s., 2H), 2.98-2.87 (m, 1H), 2.84-2.69 (m, 2H), 2.32 (d, J=1.7 Hz, 2H), 2.26 (s, 3H), 1.92-1.67 (m, 6H), 1.58 -1.31 (m, 6H). FXR EC ₅₀ (nM) 547; MS (ESI) 522 (M+H).

The compound of the following example was prepared in accordance with the method described for the preparation of the compound of example 3, by replacing intermediate 220C and the corresponding acid chlorides.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 221 О fl AU ^CH3 nvA °' ^N 516 506 222 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.78-7.65 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.46-7.36 (m, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 7.8, 2.0 Hz, 1H), 3.85 (s, 3H), 3.65 (br. s., 1H), 3.57 (br. s., 1H), 2.28 (s, 3H), 1.96-1.74 (m, 12H), 1.48 (d, J = 4.9 Hz, 6H).

Example 222.

X-(('1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-X-(3-(2methoxypyridine -4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 222A. Preparation of 3-(2-methoxypyridin-4-yl)aniline

(3-Aminophenyl)boronic acid (4.4 g, 31.9 mmol) was added to a stirred solution of 4-bromo-2-methoxypyridine (5 g, 26.6 mmol) in toluene (50 mL). The reaction mixture was degassed and filled with argon again. A solution of Na ₂ CO ₃ (0.85 g, 8.02 mmol) in water (0.5 ml) was added, degassed and refilled with argon. Tetrakis(triphenylphosphine)palladium(0) (1.536 g, 1.330 mmol) was added and the reaction mixture was stirred at 110°C overnight. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and extracted with EtOAc (3x25 ml). The organic layers were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (6 g, 27 mmol, 100% yield) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=5.5 Hz, 1H), 7.22-7.10 (m, 2H), 6.98-6.83 (m, 3H), 6.66 (ddd,

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J=8.0, 2.0, 1.0 Hz, 1H), 5.23 (s, 2H), 3.88 (s, 3H). MS (ESI) 201 (M+N).

Stage B. Intermediate connection 222V. Preparation of 2-(4-(4-(((3-(2-methoxypyridin-4yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)-2-methylpropanenitrile

The title compound was prepared using the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 47E where necessary. (130 mg, 0.247 mmol, 70% yield) as a brown tarry solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 8.20 (d, J=5.0 Hz, 1H), 7.45 (s, 5H), 7.23 (dd, J=5.0, 1.5 Hz, 1H), 7.18 (t, J =7.8 Hz, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.70-5.65 (m , 2H), 3.92-3.88 (m, 3H), 2.97 (d, J=6.0 Hz, 2H), 2.08 (d, J=9.0 Hz, 2H), 1.89-1.72 (m, 6H), 1.67 (s, 6H). MS (ESI) 468 (M+H).

Step C. Example 222: N((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-4yl)methyl)-3-fluoro-N-(3- (2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 222B and the corresponding acid where necessary: (10 mg, 0.017 mmol, 32% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.67-7.57 (m, 1H ), 7.56-7.50 (m, 1H), 7.47-7.31 (m, 5H), 7.24 (s, 1H), 3.92 (s, 3H), 3.73 (br.s., 2H), 3.64 (d, J= 12.2 Hz, 2H), 2.05-1.95 (m, 2H), 1.86-1.90 (m, 6H), 1.82-1.72 (m, 2H), 1.71-1.51 (m, 10H). FXR EC50 (nM) = 285; MS (ESI) 580 (M+H).

The following examples were prepared according to the method described for the synthesis of Example 3, substituting intermediate 222B and appropriate acids where necessary.

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1.62 (m, 12H), 1.57 (d, J = 11.0 Hz, 2H). 224 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 5.4 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 7.1 Hz, 1H), 7.59 (t, J = 7.9 Hz , 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.39 (q, J = 8.8 Hz, 5H), 7.22 (s, 1H), 3.92 (s, 3H), 3.70 (s, 4H), 2.65 (d, J = 6.1 Hz, 1H), 2.06-1.95 (m, 2H), 1.81-1.70 (m, 3H), 1.65 (s, 8H), 1.62-1.48 (m, 7H), 1.36 (br. s ., 2H).

Example 225.

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

Step A: Intermediate 225A. Preparation of 2-chloro-4-ethoxypyridine

To a stirred solution of 4-bromo-2-chloropyridine (500 mg, 2.60 mmol) in ethanol (5 ml) was added sodium ethoxide in ethanol (1.4 g, 5.20 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was diluted with water (20 ml) and extracted with EtOAc (2x10 ml). The organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (270 mg, 1.45 mmol, 56% yield) as a pale yellow oil. MS (ESI) 158 (M+H).

Stage B. Intermediate connection 225V. Preparation of 4-ethoxy-2-(3-nitrophenyl)pyridine

To a stirred solution of intermediate 225A (270 mg, 1.71 mmol) in toluene (3 ml) and ethanol (3 ml) was added (3-nitrophenyl)boronic acid (286 mg, 1.71 mmol) and Na ₂ CO ₃ ( 545 mg, 5.14 mmol) in water (2 ml). The reaction mixture was degassed and filled with argon again. Tetrakis(triphenylphosphine)-palladium(0) (98 mg, 0.085 mmol) was added and the resulting reaction was heated at 110°C overnight. The reaction mixture was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (2x10 ml). The organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (200 mg, 0.778 mmol, 45% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.96-8.92 (m, 1H), 8.59-8.52 (m, 2H), 8.32-8.26 (m, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.06-7.01 (m, 1H), 4.26 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H). MS (ESI) 245 (M+H).

Stage C. Intermediate 225C. Preparation of 3-(4-ethoxypyridin-2-yl)aniline

A solution of intermediate 225B (200 mg, 0.819 mmol) in methanol (10 ml) was purged and washed with nitrogen. Pd-C (43.6 mg, 0.041 mmol) was added to the reaction mixture and stirred under hydrogen atmosphere (1 atm, balloon) overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give the title compound (150 mg, 0.665 mmol, 81% yield) in

- 241 047337 in the form of pale yellow oil.

1H NMR (400 MHz, DMSO-de) δ 8.41 (d, J=6.0 Hz, 1H), 7.32 (t, J=2.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.12-7.07 (m, 1H), 6.88 (dd, J=5.5, 2.5 Hz, 1H), 6.64-6.59 (m, 1H), 5.13 (s, 2H), 4.19 (q, J =7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H). MS (ESI) 215 (M+H).

Stage D. Intermediate 225D. Preparation of 3-(4-ethoxypyridin-2-yl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 225C and intermediate 4C where necessary. (110 mg, 0.235 mmol, 58% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=6.0 Hz, 1H), 7.36-7.28 (m, 2H), 7.18-7.09 (m, 2H), 6.91-6.86 (m, 1H), 6.67 (dt, J=7.8, 1.6 Hz, 1H), 5.52 (t, J=6.0 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 2.88 (d, J=6.0 Hz, 2H), 2.10-2.02 (m, 1H), 1.90-1.82 (m, 6h), 1.63-1.53 (m, 6H), 1.37 (t, J=7.0 Hz, 3H), 1.06-0.98 (m, 2H), 0.89- 0.82 (m, 2H). MS (ESI) 445 (M+H).

Step E. Example 225. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(3-(4- ethoxypyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 225D and the corresponding acid where necessary. (20 mg, 0.036 mmol, 80% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J=5.6 Hz, 1H), 8.17-8.05 (m, 2H), 7.64 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H), 7.06 (br. s., 1H), 4.27 (q, J=7.3 Hz, 2H), 3.62 (d, J=17.1 Hz, 2H), 2.07 -2.00 (m, 1H), 1.87 (s, 6H), 1.82-1.68 (m, 6H), 1.53-1.34 (m, 9H), 1.05-0.96 (m, 2H), 0.87-0.77 (m, 2H) . FXR EC50 (nM) 241; MS (ESI) 557 (M+H).

Example 226.

A((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(3-(2ethoxypyridin-4-yl)phenyl )-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 226A. Preparation of 2-chloro-4-(3-nitrophenyl)-pyridine

To a stirred solution of 4-bromo-2-chloropyridine (0.25 g, 1.30 mmol) in toluene (5 ml) and ethanol (2 ml) was added (3-nitrophenyl)boronic acid (0.260 g, 1.56 mmol) and Na ₂ CO ₃ (0.413 g, 3.90 mmol) in water (0.2 ml). The reaction mass was degassed and filled with argon again. Tetrakis(triphenylphosphine)-palladium(0) (0.075 g, 0.065 mmol) was added and the reaction mixture was heated at 90°C overnight. The reaction mixture was cooled to room temperature, diluted with water (10 ml) and extracted with EtOAc (2x10 ml). The organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (0.15 g, 0.607 mmol, 47% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (t, J=2.0 Hz, 1H), 8.57-8.54 (m, 1H), 8.38-8.31 (m, 2H), 8.05-8.03 (m, 1H) , 7.90 (dd, J=5.3, 1.8 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H). MS (ESI) 235 (M+H).

Stage B. Intermediate connection 226V. Preparation of 2-ethoxy-4-(3-nitrophenyl)pyridine

To a stirred solution of intermediate 226A (0.15 g, 0.639 mmol) in ethanol (3

- 242 047337 ml) sodium ethoxide in ethanol (0.29 g, 0.639 mmol) was added under an inert atmosphere. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with water (10 ml) and extracted with EtOAc (2x10 ml). The organic layers were combined, washed with brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (110 mg, 0.428 mmol, 67% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (t, J=2.0 Hz, 1H), 8.35-8.21 (m, 3H), 7.80 (t, J=7.8 Hz, 1H), 7.41 (dd, J =5.3, 1.8 Hz, 1H), 7.22 (d, J=1.0 Hz, 1H), 4.37 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H). MS (ESI) 245(M+H).

Step C. Intermediate 226C. Preparation of 3-(2-ethoxypyridin-4-yl)aniline

A solution of intermediate 226B (100 mg, 0.409 mmol) in methanol (5 ml) was purged and washed with nitrogen. Pd-C (21.79 mg, 0.020 mmol) was added to the reaction mixture and stirred under a hydrogen atmosphere (1 atm, balloon) at room temperature overnight. The reaction mixture was filtered through celite and the filtrate was concentrated to give the title compound (80 mg, 0.355 mmol, 87% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19-8.15 (m, 1H), 7.17-7.14 (m, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.93-6.90 (m, 2H) , 6.89-6.85 (m, 1H), 6.65 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 5.22 (s, 2H), 4.34 (q, J=7.0 Hz, 2H), 1.34 (t, J =7.0 Hz, 3H). MS (ESI) 215 (M+H).

Stage D. Intermediate 226D. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-ethoxypyridin-4-yl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 226C and intermediate 4C where necessary (60 mg, 0.121 mmol, 60% yield) as a pale yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (d, J=6.0 Hz, 1H), 7.23-7.11 (m, 2H), 6.98-6.91 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.3, 1.8 Hz, 1H), 5.61 (t, J=6.0 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 2.90 (d, J=6.0 Hz, 2H), 2.12-2.03 (m, 1H), 1.93-1.81 (m, 6H), 1.64-1.51 (m, 6H), 1.34 (t, J=7.0 Hz, 3H), 1.07-0.99 (m, 2H), 0.900.81 (m, 2H). MS (ESI) 445 (M+H).

Step E. Example 226. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(2- ethoxypyridin-4-yl)phenyl)-3-fluorobicyclo[1.E1]pentan-1carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 226D and the corresponding acid where necessary. (12.8 mg, 0.023 mmol, yield 51.1%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J=5.4 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.39 (dd, J=5.4, 1.5 Hz, 1H), 7.21 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.673.54 (m, 2H), 2.11-2.01 (m, 1H), 1.95-1.70 (m, 12H), 1.46 (d, J=5.6 Hz, 6H), 1.36 (t, J =7.1 Hz, 3H) , 1.08-0.96 (m, 2H), 0.88-0.77 (m, 2H). FXR EU ₅₀ (nM) 219; MS (ESI) 557 (M+H).

Example 227.

3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(3-(tetrahydro-2H-pyran-4-yl)-1,2,4oxadiazol-5- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

(227)

Step A: Intermediate 227A. Preparation of methyl 4-(((3-(2-thethoxypyridin-4yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

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The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 88B where necessary. (1.4 g, 3.24 mmol, 71% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (d, J=5.0 Hz, 1H), 7.23-7.10 (m, 2H), 6.97 (d, J=1.0 Hz, 1H), 6.92 (t, J =2.0 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.69 (dd, J=8.0, 1.5 Hz, 1H), 5.56 (t, J=5.8 Hz, 1H), 3.90 (s, 3H ), 3.57 (s, 3H), 2.84 (d, J=6.0 Hz, 2H), 1.77-1.65 (m, 6H), 1.53-1.44 (m, 6H). MS (ESI) 381 (M+H).

Stage B. Intermediate connection 227V. Preparation of methyl 4-((3-fluoro-N-(3-(2-methoxypyridin4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo-[2.2.2]octane-1-carboxylate

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 227A and the corresponding acid where necessary. (220 mg, 0.447 mmol, 85% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.89-7.75 (m, 2H), 7.57 (t, J=8.2 Hz, 1H), 7.47 (d, J =7.6 Hz, 1H), 7.39 (dd, J=5.4, 1.5 Hz, 1H), 7.21 (s, 1H), 3.92 (s, 3H), 3.59 (br. s.,2H), 3.54 (s, 3H ), 1.83 (s, 3H), 1.87 (s, 3H), 1.72-1.53 (m, 6H), 1.44-1.28 (m, 6H). MS (ESI) 493 (M+H).

Step C. Intermediate 227C. Preparation of 4-((3-fluoro-U-(3-(2-methoxypyridin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)bicyclo-[2.2.2]octane-1-carboxylic acid

To a stirred solution of intermediate 227B (330 mg, 0.66 mmol) in methanol (10 ml) was added NaOH (133 mg, 3.3 mmol) in H2O (5 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, acidified with aqueous 1.5 N HCl (pH ~3) and extracted with ethyl acetate (2x20 ml). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the title compound. (8.2 mg, 0.0172 mmol, 52% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.90-7.74 (m, 2H), 7.58 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.39 (dd, J=5.4, 1.7 Hz, 1H), 7.21 (s, 1H), 3.92 (s, 3H), 3.64-3.58 (m, 1H), 3.53(s, 1H )1.941.76 (m, 6H), 1.67-1.54 (m, 6H), 1.35 (d, J=5.1 Hz, 6H). MS (ESI) 479 (M+H).

Stage D. Intermediate 227D. Preparation of N-hydroxytetrahydro-2H-pyran-4carboximidamide

To a stirred solution of tetrahydro-2H-pyran-4-carbonitrile (0.988 mL, 9.00 mmol) in ethanol (12 mL) was added 50% hydroxylamine in water (2.76 mL, 45.0 mmol). The reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (15 ml) and stirred for 10 minutes. The precipitated solid was filtered and dried in vacuo to give the title compound (1.28 g, 6.21 mmol, 69% yield) as a white fluffy solid. MS (ESI) 145 (M+H).

Step E. Example 227. Preparation of 3-fluoro-U-(3-(2-methoxypyridin-4-yl)phenyl)-U-((4-(3(tetrahydro-2H-pyran-4-yl)-1, 2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

- 244 047337

The title compound was prepared according to the method described for the synthesis of intermediate 3A, substituting intermediate 227C and intermediate 227D where necessary. (7.1 mg, 0.012 mmol, 39% yield).

¹ HNMR (400 MHz, DMSO-d6) δ 8.27 (d, J=5.1 Hz, 1H), 7.91-7.77 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.50 (d, J= 7.1 Hz, 1H), 7.41 (dd, J=5.5, 1.6 Hz, 1H), 7.22 (s, 1H), 3.92 (s, 3H), 3.89-3.81 (m, 2H), 3.61 (d, J=15.4 Hz, 2H), 3.43 (td, J=11.4, 2.0 Hz, 2H), 3.06-2.95 (m, 1H), 1.95-1.75 (m, 12H), 1.71-1.58 (m, 2H), 1.48 (d, J=6.4 Hz, 6H), 1.25 (s, 2H). FXR EC50 (nM) = 377; MS (ESI) 587 (M+H).

The title compound was prepared according to the method described for the synthesis of intermediate 3A, substituting intermediate 227C and intermediate 227D where necessary. (7.1 mg, 0.012 mmol, 39% yield).

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 228 ABOUT Il η g /y-snz Ok 517 442 229 o\o with T 543 154 228 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 5.6 Hz, 1H), 7.91-7.73 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.40 (dd,J=5.5, 1.3 Hz, 1H), 7.22 (s, 1H), 3.92 (s, 3H), 3.64 (br. s.,2H), 2.28 (s, 3H) , 1.96-1.71 (m, 12H), 1.46 (br. s., 6H) 229 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J= 5.4 Hz, 1H), 7.91-7.75 (m, 2H), 7.58 (t, J= 7.7 Hz, 1H), 7.53-7.45 (m, 1H), 7.40 (dd,J=5.4, 1.5 Hz, 1H), 7.22 (s, 1H), 3.92 (s, 3H), 3.61 (d, J= 15.4Hz, 2H), 2.05 (ddd, J= 13.4 , 8.5, 5.5 Hz, 1H), 1.95-1.69 (m, 12H), 1.46 (d, J = 8.6 Hz, 6H), 1.06-0.94 (m, 2H), 0.87-0.75 (m, 2H)

Example 230.

-fluoro-X-(3 -(2-methoxypyridin-4-yl)phenyl)-X-((4-(5-methyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Stage A. Intermediate 230A. Preparation of methyl 4-(2-acetylhydrazine-1carbonyl)bicyclo[2.2.2]octane-1-carboxylate

Acetohydrazide (192 mg, 2.59 mmol), DIPEA (1.234 mL, 7.07 mmol) and then HATU (1164 mg, 3.06 mmol). The reaction mixture was stirred at room temperature

- 245 047337 tour during the night. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 30% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (850 mg, 2.313 mmol, 98% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (br. s., 2H), 3.57 (s, 3H), 1.82 (s, 3H), 1.75-1.67 (m, 6H), 1.31-1.20 ( m, 6H). MS (ESI) 269 (M+H).

Stage B. Intermediate connection 230V. Preparation of methyl 4-(5-methyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octane-1-carboxylate

A solution of intermediate 230A (350 mg, 1.304 mmol) in toluene (5 ml) was stirred at 100°C for 20 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (10 ml) and extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 40% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (280 mg, 1.119 mmol, 86% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.61 (s, 3H), 2.45 (s, 3H), 1.85 (m, 12H). MS (ESI) 251 (M+H).

Step C. Intermediate 230C. Preparation of (4-(5-methyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methanol

A stirred solution of intermediate 230B (280 mg, 1.119 mmol) in DCM (6 ml) was cooled to -78°C. Diisobutylaluminum hydride in heptane (2.80 mL, 2.80 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to 0°C and stirred for 1 hour. The reaction was quenched with aqueous 1.5 N HCl, diluted with water (10 ml) and extracted with DCM (2x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 60% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (190 mg, 0.701 mmol, 63% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.40 (br. s., 1H), 3.08 (s, 2H), 2.41 (s, 3H), 1.88-1.77 (m, 6H), 1.49-1.40 ( m, 6H). MS (ESI) 223 (M+H).

Stage D. Intermediate 230D. Preparation of 4-(5-methyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

A stirred solution of oxalyl chloride (0.217 mL, 2.479 mmol) in DCM (4 mL) was cooled to 78°C. DMSO (0.15 mL, 2.02 mmol) in DCM (0.1 mL) was added dropwise to the reaction mixture and stirred for 15 min at the same temperature. Intermediate 230C (180 mg, 0.810 mmol) was added as a solution in DCM (2 mL) followed by TEA (0.79 mL, 5.67 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with DCM (2x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 20 min gradient; 0% B to 20% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (100 mg, 0.454 mmol, 56% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 2.44 (s, 3H), 1.93-1.86 (m, 6H), 1.73-1.65 (m, 6H). MS (ESI) 221 (M+H).

Step E. Intermediate 230E. Preparation of 3-(2-methoxypyridin-4-yl)-N-((4-(5-methyl1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

- 246 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 230D where necessary. (110 mg, 0.245 mmol, 60% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J=5.5 Hz, 1H), 7.24-7.20 (m, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.00 (d, J =1.5 Hz, 1H), 6.96-6.94 (m, 1H), 6.85 (d,J=8.0 Hz, 1H), 6.72 (dd, J=8.0, 1.5 Hz, 1H), 5.65 (t, J=5.8 Hz , 1H), 3.89 (s, 3H), 2.90 (d, J=5.5 Hz, 2H), 2.45 (s, 3H), 1.90-1.82 (m, 6H), 1.63-1.55 (m, 6H). MS (ESI) 405 (M+N).

Step F. Example 230. Preparation of 3-fluoro-X-(3-(2-methoxypyridin-4-yl)phenyl)-X-((4-(5-methyl1,3,4-oxadiazol-2-yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]-pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, substituting intermediate 230E and the corresponding acid where necessary. (0.4 mg, 0.774 µmol, 1.5% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=5.1 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.37 (dd, J=5.5, 1.6 Hz, 1H), 7.19 (s, 1H), 3.91(s, 3H), 3.58 (br. s ., 2H), 2.42 (s, 3H), 1.83-1.71 (m, 6H), 1.42-1.21 (m, 10H), 0.86 (d,J=12.7 Hz, 2H). FXR EC ₅₀ (nM) = 988; MS (ESI) 517 (M+H).

Example 231.

N(3-(2-methoxypyridin-4-yl)phenyl)-X-((4-(5-methyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1yl)methyl )cyclobutanecarboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, substituting intermediate 230E and the corresponding acid where necessary. (7.9 mg, 0.016 mmol, 32% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=5.4 Hz, 1H), 7.82-7.67 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.39 (dd, J=5.4, 1.5 Hz, 1H), 7.20 (s, 1H), 3.91 (s, 3H), 3.65 (s, 2H), 3.12 (d, J=7.3 Hz, 1H), 2.42 (s, 3H), 2.12 (d, J=9.5 Hz, 2H), 2.09 (s, 2H), 1.82-1.69 (m,6H), 1.62 (br. s., 2H), 1.49-1.35 (m, 6H). FXR EC ₅₀ (nM) = 592; MS (ESI) 487 (M+H).

Example 232.

3-fluoro-X-(3-(2-tethoxypyridin-4-yl)phenyl)-X-((4-(5-methyl-1,3,4-thiadiazol-2yl)bicyclo[2.2.2]octane- 1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 232A. Preparation of yl)bicyclo[2.2.2]octane-1-carboxylate methyl 4-(5-methyl-1,3,4-thiadiazol-2-

Lawesson's reagent (2 g, 4.92 mmol) was added to a stirred solution of intermediate 230A (1.2 g, 4.47 mmol) in toluene (12 mL). The reaction mixture was heated at 100°C overnight. The reaction mixture was washed with aqueous sodium bicarbonate (10 ml) and then with water (10 ml). The aqueous layer was extracted with ethyl acetate (2x30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (700 mg, 2.63 mmol, 59% yield) as white

- 247 047337 solid matter.

1H NMR (400 MHz, DMSO-de) δ 3.60 (s, 3H), 2.69 (s, 3H), 1.95-1.80 (m, 12H). MS (ESI) 267 (M+H).

Stage B. Intermediate connection 232V. Preparation of (4-(5-methyl-1,3,4-thiadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was prepared according to the method described for the synthesis of intermediate 230C, replacing intermediate 232A where necessary. (360 mg, 1.510 mmol, 50% yield).

1H NMR (400 MHz, DMSO-de) δ 4.40 (t, J=5.3 Hz, 1H), 3.08 (d, J=5.0 Hz, 2H), 2.63 (s, 3H), 1.90-1.82 (m, 6H) , 1.53-1.41 (m, 6H). MS (ESI) 239 (M+H).

Step C. Intermediate 232C. Preparation of 4-(5-methyl-1,3,4-thiadiazol-2yl)bicyclo[2.2.2]octane-1-carbaldehyde o ^zs Ah ₃

The title compound was prepared according to the method described for the synthesis of intermediate 230D, replacing intermediate 232B where necessary. (240 mg, 1.016 mmol, 69% yield), 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 2.67 (s, 3H), 1.971.89 (m, 6H), 1.76-1.67 (m, 6H). MS (ESI) 237 (M+H).

Stage D. Intermediate 232D. Preparation of 3-(2-methoxypyridin-4-yl)-N-((4-(5methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 232C where necessary. (240 mg, 0.571 mmol, 54% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J=5.5 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.00 ( s, 1H), 6.95 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.65 (s, 1H), 3.89 (s, 3H), 2.90 (d, J=5.5 Hz, 2H), 2.70 (s, 3H), 1.94-1.88 (m, 6H), 1.66-1.58 (m, 6H). MS (ESI) 421 (M+H).

Step E. Example 232 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 232D and the corresponding acid where necessary. (5.6 mg, 0.01051 mmol, yield 22.11%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.53-7.47 (m, 1H), 7.41 (dd, J=5.5, 1.6 Hz, 1H), 7.23 (s, 1H), 3.92 (s, 3H), 3.65 (s, 2H), 2.65 (s, 3H), 1.92-1.77 (m, 12H), 1.49 (br. s., 6H). FXR EC50 (nM) 465; MS (ESI) 533 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 3, replacing intermediate 232D and the existing acid where necessary.

- 248 047337

Etc. No. Structure MS (ESI) FXR ec ₅₀ (M+H) (hM) 233 O Dsu, ί 1 ' /, ^Ν N ₃ C >| '\JJ CH ₃ 517 1102 234 O ^F A D YES. H ₃ C >| '\JJ CH ₃ 539 1756 235 O Ν XX ^F vA J. Pl ' X Act ^ct AY S a JJ CH ₃ 553 895 236 0 AC.CTCT -y 'j ¹ ]D HO' Act <Х<Л \\ 1 T .N „АуД A JU ^CH 3 587 1542 233 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 5.6 Hz, 1H), 7.83 (s, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.62-7.53 (m, 1H) , 7.53-7.45 (m, 1H), 7.39 (d, J = 5.4 Hz, 1H), 7.21 (s, 1H), 3.91 (s, 3H), 3.65 (s, 2H), 2.67- 2.58 (m, 4H ), 1.90-1.73 (m, 6H), 1.72-1.63 (m, 2H), 1.57 (d, J = 6.4 Hz, 4H), 1.52-1.40 (m, 6H), 1.35 (br. s., 2H) 234 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 5.4 Hz, 1H), 7.87 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.58 (t, J = 7.8 Hz , 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 5.6, 1.5 Hz, 1H), 7.23 (s, 1H), 3.91(s, 3H), 3.69 (br. s. , 2H), 2.65 (s, 3H), 1.87-1.71 (m, 6H), 1.55-1.37 (m, 6H), 1.40-1.27 (m, 4H), 1.15-1.04 (m, 1H) 235 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J = 5.4 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.63-7.47 (m, 2H) , 7.39 (dd, J = 5.3, 1.1Hz, 1H), 7.22 (s, 1H), 3.90 (s, 3H), 3.66 (br. s., 2H), 3.01-2.90 (m, 2H), 2.64 ( s, 3H), 2.35-2.25 (m, 1H), 2.18-1.98 (m, 2H), 1.96-1.72 (m, 8H), 1.55-1.37 (m, 6H).

- 249 047337

236 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J = 5.4 Hz, 1H), 7.86 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.60-7.51 (m, 1H) , 7.51-7.40 (m, 1H), 7.38 (dd, J = 5.4, 1.5 Hz, 1H), 7.20 (s, 1H), 6.53 (d, J = 6.8 Hz, 1H), 3.97-3.83 (m, 3H ), 3.68 (br. s., 2H), 2.82 (t, J= 9.2 Hz, 1H), 2.63 (s, 3H), 2.36 -2.31 (m, 2H), 2.03 (br. s., 2H), 1.85-1.68 (m, 6H), 1.52-1.39 (m, 6H)

Example 237.

3,3-difluoro4N-(3 -(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan1 -yl)methyl)cyclobutane -1-carboxamide

Stage A. Intermediate 237A1 & 237A2. Preparation of methyl 4-(6-methylpyridin-24-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1yl)bicyclo[2.2.2]octane-1-carboxylate & methyl carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2 g, 9.42 mmol) and 2-methylpyridine (1.053 g, 11.31 mmol) in DCM (60 ml) and water (60 ml), silver nitrate (0.320 g, 1.885 mmol) was added, followed by potassium persulfate (2.55 g, 9.42 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 ml) and the organic layer was washed with water (2x50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title intermediate 237A1 (200 mg, 0.771 mmol), 1H NMR (400 MHz, DMSO- _d6 ) δ 7.61-7.54 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.43 (s, 3H), 1.901.77 (m, 12H). MS (ESI) 260 (M+H) and intermediate 237A2 (650 mg, 2.506 mmol), 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (d, J=5.5 Hz, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.12 (dd, J=5.3, 1.8 Hz, 1H), 3.60 (s, 3H), 2.43 (s, 3H), 1.87-1.73 (m, 12H). MS (ESI) 260 (M+H).

Stage B. Intermediate connection 237B1 & 237B2. Preparation of 4-(2-methylpyridin-4yl)bicyclo[2.2.2]octan-1-carbaldehyde and (4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1-yl)methanol

^sn z(1-237V1) ^sn z(1-237V2)

A stirred solution of intermediate 237A2 (650 mg, 2.506 mmol) in DCM (20 ml) was cooled to -78°C and stirred for 5 minutes. DIBAL-H in heptane (5.22 ml, 6.27 mmol) was added to the reaction mixture and stirred at -78°C for 20 minutes. The reaction was quenched with ammonium chloride solution and stirred for 2 hours. The organic layer was separated and the aqueous layer was extracted with DCM (2x25 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound 4-(2-methylpyridin-4-yl)bicyclo-[2.2.2]octane-1-carbaldehyde (110 mg, 0.48 mmol, 19% yield ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.21 (s, 1H), 7.15-7.12 (m, 1H), 2.43 ( s, 3H), 1.83-1.77 (m, 6H), 1.73-1.66 (m, 6H). MS (ESI) 230 (M+H). Intermediate 237B1 and (4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1-yl)methanol (250 mg, 1.081 mmol, 43% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.21 (s, 1H), 7.15-7.12 (m, 1H), 2.43 (s , 3H), 1.83-1.77 (m, 6H), 1.73-1.66 (m, 6H). MS (ESI) 230 (M+H) Intermediate 237B2.

Step C. Intermediate 237C. Preparation of 3-(2-methoxypyridin-4-yl)A-((4-(2methylpyridin-4-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

- 250 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I, substituting intermediate 222A and intermediate 237B1 where necessary. (140 mg, 0.33 mmol, 77% yield) as a brown tarry solid.

¹ H NMR (400 MHz, DMSO-de) δ 8.31 (d, J=5.5 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.24-7.11 (m, 4H), 7.00 (d, J =1.5 Hz, 1H), 6.96 (s, 1H), 6.85 (d, J=7.5 Hz, 1H), 6.72 (d, J=9.5 Hz, 1H), 5.77 (s, 1H), 5.63 (t, J =5.5 Hz, 1H), 3.89 (s, 3H), 2.90 (d, J=6.0 Hz, 2H), 2.43 (s, 3H), 1.81-1.74 (m, 6H), 1.65-1.57 (m, 6H) . MS (ESI) 414 (M+H).

Step D. Example 237. Preparation of 3,3-difluoro-N-(3-(2-methoxypyridin-4-yl)-phenyl)-N-((4-(2methylpyridin-4-yl)bicyclo[2.2.2] octan-1-yl)methyl)cyclobutan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 237C and 3,3-difluorocyclobutane-1carboxylic acid where necessary. (2 mg, 3.72 µmol, 8% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32-8.23 (m, 2H), 7.86 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.41 (dd, J=5.5, 1.3 Hz, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 7.05 (d, J=5.4 Hz, 1H), 3.91 (s, 3H), 3.69 (br. s., 2H), 3.01-2.91 (m, 1H), 2.75 (br. s., 2H), 2.40 (s, 3H), 2.34 ( d, J=2.0 Hz, 1H), 1.74-1.56 (m, 6H), 1.52-1.35 (m, 6H). FXR EC ₅₀ (nM) = 541; MS (ESI) 532 (M+n).

Example 238.

3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[ 1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 237C and the corresponding acid where necessary. (2 mg, 3.72 µmol, 8% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (dd, J=5.3, 3.5 Hz, 2H), 7.89-7.78 (m, 2H), 7.59 (t, J=7.7 Hz, 1H), 7.52- 7.44 (m, 1H), 7.41 (dd, J=5.4, 1.5 Hz, 1H), 7.23 (d, J=1.0 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J=5.4 Hz, 1H ), 3.92 (s, 3H), 3.70-3.62 (m, 1H), 3.60-3.51 (m, 1H), 2.41 (s, 3H), 2.09 (s, 1H), 1.96-1.77 (m, 6H), 1.73-1.58 (m, 6H), 1.46 (d, J=5.4 Hz, 6H). FXR EC50 (nM) = 517. MS (ESI) 526 (M+H).

Example 239.

3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(6-methylpyridin-2-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[ 1.1.1]pentane-1-carboxamide

Step A: Intermediate 239A. Preparation of yl)bicyclo[2.2.2]octan-1-yl)methanol (4-(6-methylpyridin-2-

The title compound was prepared according to the method described for the synthesis of intermediate 1G, replacing intermediate 237A1 where necessary. (120 mg, 0.514 mmol, 83% yield) as a brown tarry solid. MS (ESI) 232 (M+H).

Stage B. Intermediate connection 239V. Preparation of 4-(6-methylpyridine-2

- 251 047337 yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was prepared according to the method described for the synthesis of intermediate 3C, replacing intermediate 239A where necessary. (70 mg, yield 59%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 2.40 (s, 3H), 1.92-1.83 (m, 6H), 1.74-1.64 (m, 6H). MS (ESI) 230 (M+H).

Step C. Intermediate 239C. Preparation of methylpyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

3-(2-methoxypyridin-4-yl)-No-((4-(6-

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 239B where necessary. (50 mg, 0.12 mmol, yield 40%).

1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=6.0 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.23 (dd, J=5.5, 1.5 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.04-6.99 (m, 2H), 6.96 (s, 1H), 6.85 (d, J=7.5 Hz, 1H) , 6.73 (d, J=7.5 Hz, 1H), 5.61 (s, 1H), 3.89 (s, 3H), 2.89 (d, J=6.0 Hz, 2H), 2.43 (s, 3H), 1.90-1.81 ( m, 6H), 1.64-1.56 (m, 6H). MS (ESI) 414 (M+H).

Step D. Example 239. Preparation of 3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(6methylpyridin-2-yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 239C and the corresponding acid where necessary. (4.5 mg, 8.56 µmol, 24% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.88-7.78 (m, 2H), 7.63-7.47 (m, 3H), 7.41 (dd, J=5.4 , 1.5 Hz, 1H), 7.23 (s, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.65 (s, 2H ), 2.40 (s, 3H), 1.89 (br. s., 3H), 1.84 (br. s., 3H), 1.75 (t, J=8.1 Hz, 6H), 1.46 (br. s., 6H) . FXR EC ₅₀ (nM) = 1317; MS (ESI) 526 (M+H).

Example 240.

N(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1yl)methyl)cyclobutanecarboxamide

Stage A. Intermediate 240A. Preparation of methyl 4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carboxylate

4-(trifluoromethyl)pyridine (0 .83 g, 5.65 mmol), silver nitrate (0.16 g, 0.94 mmol), and then potassium persulfate (0.160 g, 0.94 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (25 ml) and filtered through celite. The organic layer was separated, washed with brine (25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (600 mg, 1.91 mmol, 40% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J=5.0 Hz, 1H), 7.64 (d, J=1.0 Hz, 1H), 7.59 (d, J=5.0 Hz, 1H), 3.61 (s , 3H), 1.96-1.88 (m, 6H), 1.88-1.81 (m, 6H). MS (ESI) 314 (M+H).

Stage B. Intermediate connection 240V. Preparation of (4-(4-(trifluoromethyl)pyridine-2

- 252 047337 yl)bicyclo[2.2.2]octan-1-yl)methanol

The specified compound was prepared in accordance with the method described for the synthesis of intermediate 1G, replacing intermediate 240A where necessary. (370 mg, 1.27 mmol, 80% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (d, J=5.0 Hz, 1H), 7.62-7.51 (m, 2H), 4.36 (t, J=5.5 Hz, 1H), 3.10 (d, J =5.5 Hz, 2H), 1.93-1.80 (m, 6H), 1.52-1.41 (m, 6H). MS (ESI) 286 (M+H).

Step C. Intermediate 240C. Preparation of 4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 3C, replacing intermediate 240B where necessary. (220 mg, 0.77 mmol, 60% yield) as an oil solution. MS (ESI) 284 (M+H).

1H NMR (300 MHz, DMSO-d ₀ ) δ 9.45 (s, 1H), 78 (d, J=5.0 Hz, 1H), 7.62-7.51 (m, 2H), 1.93-1.80 (m, 6H), 1.52- 1.41 (m, 6H).

Stage D. Intermediate 240D. Preparation of 3-(2-methoxypyridin-4-yl)-N-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 222A and intermediate 240C where necessary (80 mg, 0.17 mmol, 69% yield) as a brown gummy solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (d, J=5.5 Hz, 1H), 8.20-8.16 (m, 1H), 7.61 (s, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.21 (dd, J=5.5, 1.5 Hz, 1H), 7.18-7.10 (m, 1H), 7.00-6.88 (m, 2H), 6.84 (d, J=5.0 Hz, 1H), 6.72 (d , J=7.5 Hz, 1H), 6.64 (d, J=9.0 Hz, 1H), 3.88 (s, 3H), 3.17 (d, J=5.0 Hz, 1H), 2.90 (d, J=5.5 Hz, 1H ), 1.90-1.88 (m, 6H), 1.61-1.59 (m, 6H). MS (ESI) 468 (M+H).

Step E. Example 240. Preparation of N(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1 - yl)methyl)-cyclobutanecarboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 240D and cyclobutanecarboxylic acid where necessary. (10 mg, 0.018 mmol, yield 43%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.81-7.70 (m, 2H), 7.627.48 (m , 3H), 7.42 (d, J=6.8 Hz, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.18 (s, 1H), 3.90 (s, 3H), 3.66 (s, 2H), 3.13 (d, J=6.8 Hz, 1H), 2.21-2.04 (m, 2H), 1.88-1.70 (m, 6H), 1.63 (br. s., 4H), 1.51-1.32 (m, 6H). FXR EC ₅₀ (nM) = 2129; MS (ESI) 550 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 3, substituting intermediate 240D and appropriate acids where necessary.

- 253 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 241 CO o C) g—XX ο=ζ LL /= ² o o 580 1058 241 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J = 5.1 Hz, 1H), 8.27 (d, 7 = 5.4 Hz, 1H), 7.90-7.78 (m, 2H), 7.64-7.53 (m, 3H), 7.50 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 5.5, 1.6 Hz, 1H), 7.23 (s, 1H), 3.92 (s, 3H), 3.72-3.64 (m, 1H ), 3.61 (s, 1H), 1.89- 1.71 (m, 12H), 1.48 (d, J= 5.4 Hz, 6H)

Example 242.

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

Step A: Intermediate 242A. Preparation of 2-chloro-4-(3-nitrophenyl)pyrimidine

To a stirred solution of 2,4-dichloropyrimidine (1 g, 6.71 mmol) in 1,2-dimethoxyethane (15 ml) was added (3-nitrophenyl)boronic acid (1.12 g, 6.71 mmol) and sodium bicarbonate solution (1.13 g, 13.43 mmol) in water (1.5 ml). The reaction mixture was degassed and filled with argon again. Tetrakis(triphenylphosphine)palladium(0) (0.776 g, 0.67 mmol) was added to the reaction mixture and heated at 80°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (15 ml) and extracted with EtOAc (2x15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (1.1 g, 4.43 mmol, 66% yield) as a pale yellow solid. The product has been confirmed by NOE.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.94-8.95 (m, 2H), 8.64 (d, J=7.60 Hz, 1H), 8.44-8.47 (m, 1H), 8.36 (d, J=5.60 Hz , 1H), 7.89 (t, J=8.00 Hz, 1H). MS (ESI) 236 (M+H).

Stage B. Intermediate connection 242V. Preparation of 2-methoxy-4-(3-nitrophenyl)pyrimidine

To a solution of intermediate 242A (500 mg, 2.122 mmol) in methanol (5 mL) was added sodium methoxide in methanol (1.38 g, 6.37 mmol). The reaction mixture was stirred at 80°C overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (20 ml), washed with water (15 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (300 mg, 1.23 mmol, 58% yield) as a solid MS (ESI) 232 (M+H).

Step C. Intermediate 242C. Preparation of 3-(2-methoxypyrimidin-4-yl)aniline

To a stirred solution of intermediate 242B (0.3 g, 1.3 mmol) in tetrahydrogen

- 254 047337 zinc (1.27 g, 19.46 mmol) and an aqueous solution of ammonium chloride (1.0 g, 19.46 mmol) in water (2 ml) were added to the wound (2 ml) and ethanol (2 ml). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (50 ml), filtered through celite. The filtrate was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (230 mg, 1.1 mmol, 84% yield) as a solid. MS (ESI) 202 (M+N).

Stage D. Intermediate 242D. Preparation of M((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-methoxypyrimidin-4-yl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 242C and intermediate 4C where necessary (160 mg, 0.352 mmol, 71% yield) as a yellow solid. MS (ESI) 432 (M+H).

Step E. Example 242. Preparation of M((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(3 -(2-methoxypyrimidin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 242D and the corresponding acid where necessary (17.3 mg, 0.032 mmol, 55% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J=5.4 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.19-8.13 (m, 1H), 7.83 (d, J =5.1 Hz, 1H), 7.68-7.56 (m, 2H), 4.02 (s, 3H), 3.62 (d, J=4.9 Hz, 2H), 2.09-2.02 (m, 1H), 1.88 (br. s. , 6H), 1.82-1.68 (m, 6H), 1.52-1.36 (m, 6H), 1.06-0.95 (m, 2H), 0.87-0.78 (m, 2H). FXR EC ₅₀ (nM) 276; MS (ESI) 544 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 3, replacing intermediate 242D and appropriate acids where necessary.

- 255 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 243 ABOUT A 1 HaC'VyA °'N 550 428 244 ABOUT Duh. kUyA y |G 514 576 245 O ^f UJ 1 DuA and _p ^o_nUL^ y |Г ^N U 564 538 243 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J= 5.1 Hz, 1H), 8.25-8.11 (m, 2H), 7.82 (d, J= 5.1 Hz, 1H), 7.69-7.55 (m, 2H), 4.02 (s, 3H), 3.68 (s, 2H), 2.90 (br. s., 1H), 2.78 (d, J = 10.8 Hz, 2H), 2.41-2.32 (m, 2H), 2.09- 2.01 (m, 1H), 1.851.66 (m, 6H), 1.50-1.32 (m, 6H), 1.07-0.97 (m, 2H), 0.89-0.75 (m, 2H). 244 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (d, J= 5.1 Hz, 1H), 8.14 (d, J= 7.6 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J = 5.1 Hz , 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.53 (d,J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.64 (s, 2H), 3.07 (br. s., 1H ), 2.22-2.07 (m, 2H), 2.06-1.99 (m, 1H), 1.82-1.71 (m, 6H), 1.64 (br. s., 4H), 1.51-1.32 (m, 6H), 1.06-0.94 (m, 2H), 0.87-0.75 (m, 2H). 245 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (d, J = 5.1 Hz, 1H), 8.20 (s, 2H), 7.83 (d, J = 5.4 Hz, 1H), 7.74-7.57 (m, 2H) , 4.09 (s, 3H), 3.67 (d, J = 11.0 Hz, 2H), 2.99-2.88 (m, 1H), 2.17-1.99 (m, 3H), 1.98-1.72 (m, 7H), 1.69 (br . s., 1H), 1.59 (br. s., 1H), 1.53-1.33 (m, 7H), 1.10-0.93 (m, 2H), 0.91-0.76 (m, 2H).

Example 246.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(4'(methylsulfonamido) -[1, G-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

^m (246)

Step A: Intermediate 246A. Preparation of 3-bromo-X-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

- 256 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 4C where necessary (700 mg, 1.74 mmol, 86% yield) as a brown gumy solid. MS (ESI) 402.2 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.02-6.92 (m, 1H), 6.76 (s, 1H), 6.59 (dd, J=8.0, 2.0 Hz, 2H), 5.805.70 (m, 1H ), 2.79 (d, J=6.0 Hz, 2H), 2.05 (m, 1H), 1.89-1.77 (m, 6H), 1.59-1.48 (m, 6H), 1.02 (m, 2H), 0.890.80 ( m, 2H).

Stage B. Intermediate connection 246V. Preparation of A(3-bromophenyl)L-((4-(3-cyclopropyl1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1 ]pentane-1-carboxamide

ABOUT

The indicated compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 246A and 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid where necessary (320 mg, 0.603 mmol, yield 35 %) as a white solid. MS (ESI) 514.0 (M+H); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.45-7.39 (m, 2H), 3.56 (br. s., 1H) , 3.48 (br. s., 1H), 2.08-2.00 (m, 1H), 1.86 (br. s., 6H), 1.81-1.72 (m, 6H), 1.40 (br. s., 6H), 1.01 (m, 2H), 0.86-0.79 (m, 2H).

Step C. Example 246. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(4 '-(methylsulfonamido)-[1,G-biphenyl]-3yl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 246B and the corresponding boronic acid where necessary (16.1 mg, 0.027 mmol, 46% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 7.73 (d, J=8.00 Hz, 2H), 7.66 (t, J=8.00 Hz, 2H), 7.51 (t, J= 7.60 Hz, 1H), 7.30-7.35 (m, 3H), 3.58-3.59 (m, 2H), 3.03 (s, 3H), 2.02-2.06 (m, 1H), 1.75-1.86 (m, 12H), 1.42 -1.46 (m, 6H), 0.98-1.02 (m, 2H), 0.80-0.84 (m, 2H); FXR EC ₅₀ (nM) = 66; MS (ESI) 605 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 246B and the corresponding heteroaryl/arylboronic acids/esters (commercially available).

- 257 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 247 -By AC V /=4 /° P 7 545 341 248 0 Ax AJ\_ zi °'N h ₃ cAM 544 154 249 Caz O=<f ^=4 4 w ^w o / o ΞΕ 543 153 250 0 f^^ Αχ χΑγι_ οχ^ΜΑ °'Ν^ (ΓΎ C.I. 580 778 251 0 /Υ^ν'ΑΑι f^^ /А ΑΑ^ν^_>ι ί τ F ₃ CCT^ 596 277 252 0 F'^ Αχ W^N _ ^F 3Cx^AM Ο'Ν^ ΑΧ 580 833

- 258 047337

253 0 Hga l (GT F ₃ C^^ 580 250 254 0 xT aTa^n yi ^H HI ' ⁿ zS-xAaYaA\A °'N p GT o CHA 569 241 255 ChlA-,^ Oy/AX-X °'N < Ύ J O^aX 556.3 69.80 256 0 ХдХ,. . ^H 3 ^c NJJ n AdАХХ °'N 0 % kJ 605 219 257 0 M o=s=o nh ₂ 591 521 258 0 Ha _and tst 537 479

- 259 047337

259 0 /en XJ 596 268 260 0 Agsi H _!C - ⁰ U °-N F''^ 560 693 261 C'Ux/Ύ °'N Xj H 569 48 247 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.32-8.18 (m, 1H), 7.84-7.65 (m, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.44 ( d, J = 8.1 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 3.52 (d, J = 14.4 Hz, 1H), 2.34 (s, 3H), 2.13-2.00 (m, 1H), 1.89 (br. s., 3H), 1.87-1.61 (m, 9H), 1.45 (d, J= 6.1 Hz, 6H), 1.08 -0.95 (m, 2H), 0.89-0.76 (m, 2H) 248 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.82 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 3.99 (s, 3H), 3.70-3.49 (m, 2H), 2.11-2.00 (m, 1H), 1.97-1.68 (m, 12H), 1.57-1.30 (m , 6H), 1.08-0.91 (m, 2H), 0.90-0.79 (m, 2H) 249 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 8.7, 2.6 Hz, 1H), 7.80 -7.63 (m, 2H), 7.54 (t, J = 8.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.95 (d, J =8.6 Hz, 1H), 3.91 (s,3H), 3.60 (d, J =2.7 Hz, 2H) , 2.12-2.00 (m, 1H), 1.97-1.68 (m, 12H), 1.57-1.35 (m, 6H), 1.08-0.96 (m, 2H), 0.89-0.77 (m, 2H) 250 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 2.0 Hz, 3H), 7.79 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 1.8 Hz, 1H), 7.55 (t , J = 7.8 Hz, 1H), 7.45 (d,J=8.8 Hz, 1H), 3.74 (d,J= 13.7 Hz, 1H), 3.47 (d,J= 14.2 Hz, 1H), 2.10-1.99 (m ,

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1H), 1.93-1.85 (m, 3H), 1.84-1.71 (m, 9H), 1.44 (d, J = 8.8 Hz, 6H), 1.050.96 (m, 2H), 0.86-0.79 (m, 2H) . 251 Ή NMR (400 MHz, DMSO-de) δ 7.91-7.85 (m, 2H), 7.75-7.69 (m, 2H), 7.55 (t, J= 8.2 Hz, 1H), 7.51-7.45 (m, J= 8.1 Hz , 2H), 7.41 (d, J = 7.6 Hz, 1H), 3.68-3.51 (m, 2H), 2.09-1.99 (m, 1H), 1.94-1.69 (m, 12H), 1.50-1.38 (m, 6H ), 1.05-0.97 (m, 2H), 0.82 (dd, J = 4.8, 2.6 Hz, 2H). 252 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.12-8.04 (m, 2H), 7.87-7.70 (m, 4H), 7.58 (t, J =7.8 Hz, 1H), 7.45 (d, J =8.5 Hz, 1H), 3.73 (d, J= 13.1Hz, 1H), 3.50 (d, J= 13.6 Hz, 1H), 2.04 (td, J= 8.7, 4.3 Hz, 1H), 1.90-1.71 (m, 12H), 1.46 (d, J= 7.5 Hz, 6H), 1.05-0.96 (m, 2H), 0.89-0.78 (m, 2H). 253 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 8.0 Hz, 2H), 7.89-7.75 (m, 4H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 3.64 (br. s., 1H), 3.58 (br. s., 1H), 2.04 (td, J = 8.7, 4.3 Hz, 1H), 1.95-1.73 (m, 12H), 1.46 (br. s., 6H), 1.06-0.97 (m, 2H), 0.86-0.80 (m, 2H). 254 Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 7.95 (s, 1H), 7.67-7.51 (m, 4H), 7.44-7.35 (m, 2H), 3.60 (br. s., 2H), 2.11-1.98 (m, 4H), 1.88 (br. s., 6H), 1.82-1.71 (m, 6H), 1.46 (d, J= 8.0 Hz, 6H), 1.06-0.95 (m, 2H ), 0.880.79 (m, 2H). 255 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.60 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.38-7.28 (m, 2H), 7.24 (dd, J = 8.3, 1.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.08 (s, 2H), 3.59 (d, J = 14.6 Hz, 2H), 2.09-2.00 (m, 1H), 1.94-1.71 (m , 12H), 1.51-1.39 (m, 6H), 1.05-0.97 (m, 2H), 0.88-0.79 (m, 2H). 256 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.85 (br. s., 1H), 7.67-7.62 (m, 1H), 7.617.53 (m, 2H), 7.51-7.44 (m, 3H), 7.41 ( d, J = 8.5 Hz, 1H), 7.26 (dt, J= 5.5, 2.8 Hz, 1H), 3.59 (br. s., 2H), 3.05 (s, 3H), 2.09-1.99 (m, 1H), 1.88 (br. s., 6H), 1.84-1.71 (m, 6H), 1.51-1.40 (m, 6H), 1.01 (dd, J = 8.5, 2.5 Hz, 2H), 0.87-0.79 (m, 2H) . 257 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.78-7.67 (m, 3H) , 7.61 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.42 (s, 2H), 3.72 (d, J = 14.1 Hz, 1H), 3.55-3.46 (m, 1H), 2.04 (ddd, J= 13.1, 8.3,4.8 Hz, 1H), 1.90 (br. s., 3H), 1.88-1.73 (m, 9H), 1.46 (d, J = 7.0 Hz, 6H), 1.06-0.97 (m, 2H), 0.86-0.79 (m, 2H). 258 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H),

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7.90-7.77 (m, 3H), 7.70 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 3.75-3.64 (m , 1H), 3.55 (br. s., 1H), 2.04 (ddd, J = 13.2, 8.2,4.8 Hz, 1H), 1.90 (br. s., 3H), 1.87-1.71 (m, 9H), 1.46 (d, J =8.0 Hz, 6H), 1.05-0.97 (m, 2H), 0.87-0.78 (m, 2H). 259 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.84-7.73 (m, 4H), 7.64 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.46-7.39 (m, 2H), 3.70 (d, J= 14.1 Hz, 1H), 3.52 (d, J= 14.1 Hz, 1H), 2.08-2.00 (m, 1H), 1.90 (br. s., 3H), 1.87-1.72 ( m, 9H), 1.46 (d, J = 7.0 Hz, 6H), 1.04-0.98 (m, 2H), 0.86-0.80 (m, 2H). 260 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.69 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.33-7.27 (m, 2H), 3.96 (s, 3H), 3.69 (br. s., 1H), 3.52 (br. s., 1H), 2.09-2.00 (m, 1H) , 1.90 (br. s., 3H), 1.87-1.72 (m, 9H), 1.46 (d, J =7.0 Hz, 6H), 1.01 (dd, J = 8.5, 2.5 Hz, 2H), 0.87-0.78 ( m, 2H). 261 Ή NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (s, 1H), 7.78-7.60 (m, 3H), 7.58-7.47 (m, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.19 ( d, J= 8.1 Hz, 1H), 3.71-3.61 (m, 1H), 3.60-3.49 (m, 1H), 2.11-1.99 (m, 1H), 1.98-1.71 (m, 12H), 1.47 (d, J = 4.9 Hz, 6H), 1.07-0.95 (m, 2H), 0.92 -0.75 (m, 2H)

Example 262.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(3 -(2( trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 262A. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-Na-(3-(5,5-dimethyl-1, 3,2-dioxaborinan-2-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 149C, replacing intermediate 246B where necessary (45 mg, 0.082 mmol, 85% yield) as a brown tarry solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (s, 1H), 7.55-7.53 (m, 1H), 7.49-7.43 (m, 2H), 3.79 (s, 4H), 2.052.00 (m, 1H), 1.84-1.70 (m, 12H), 1.41 (br. s., 6H), 1.01-1.00 (m, 2H), 0.97 (s, 6H), 0.87-0.80 (m, 2H) (2 Protons hidden under the solvent peak).

Step B. Example 262. Preparation of A((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3 -(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 262A and the corresponding heteroaryl halide where necessary (14.6 mg, 0.025 mmol, 69% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 2H), 8.01 (s, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H),

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7.58 (d, J=7.8 Hz, 1H), 3.65-3.59 (m, 2H), 2.11-2.01 (m, 1H), 1.89-1.76 (m, 12H), 1.56-1.35 (m, 6H), 1.09- 0.96 (m, 2H), 0.89-0.76 (m, 2H); FXR EU ₅₀ (nM) = 140; MS (ESI) 582 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 262A and the corresponding heteroaryl/aryl halides (commercially available).

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 263 О ^F j6 °-Ν CF ₃ 621 2708 264 О ^F 15 k °~N H ₃ C'° 583 1505 265 0 MD,, Ν,,χχ/ O-ri Η;Η J D CH ₃ 581 510 266 O ^F 15 °-Ν sn ₃ 567 690.71 267 O G/ iDD MM uchDkM °'N ^F 3 ^C M f J ^u H 659 46

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268 sn ₃ /zhACh on^ A/9 i | ^{НзС υ} H 633 166 269 0 J k/ X ^υ H 631 142 270 ,J._ °' ^u H 606 442 271 0 M F A A A J 554 23 272 Dm a/ Ar^ °' ⁿ /'n't ^u H 607 559 273 0 / Ж ₅ „, Ж A °^AX 556 52

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274 0 AdUZH °'' 557 106 275 °'N H3C—ζ I| J 567.3 58.68 276 0 Xk SAVAS' °-n Ml J 610.2 77.53 277 0 _Dch kxk^N^__>, S-^zhSkh O'N And J N^A 569 35 278 0 /zh _and S^/4/\X °'N H3C—ζ ]| J 584 83 279 0 /Jo, _0 IX NC^jyJ 577 125

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- 266 047337

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292 Lie, 538 148 293 ABOUT /Zhl O'N^ YY 599.2 679.00 294 0 Хгж NC^YLY Ο^ν 1 τ F^^ 555 579 295 0 /ХХ AJ H ₃ C^^ 528 839 296 0 Хгж ₄ NC^^YLY On H ₃ cY J 567 294 297 0 Vrn,._ γ kk ³ Ya NC 538 1253

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298 ^ο Ν Lk 553 1685 299 :.:+ ³ ·-. ^ff 628 660 300 0 XaMv, H ₃ C^yV 528 413 301 0 XaMM _H c-OykU o-rN ^{4 m} z^ η Τ H ₃ C. A to J 0 AA 572 519 302 0 Mf.^ y. L MG ³ AJ 537 861 303 VrOv,^ N^/zhLzh ^ο 'Ν NzSL JI Τ 583 349

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304 Ya <x J H ₃ C 566 248 305 ΝαΛαΌ °~ ⁿ з ^с Н ji T 567 301 306 0 Ha >and NC P G/><1 k'NyV 0-N 578.2 386 307 0 Vra^ NaV/A O'N N 1 I 553 832 308 0 ViA, , AJ A F^O^^J 578 15 309 -JJOvv^ o ⁰ N ^X N N=/ 553 221

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310 0 AM AJ H ₃ CN 528 59 311 o z 588 662 312 °'N CH ₃ 581 916 313 0 ΑχΑνζ and ₃ s ί η g />-<1 mMcM O-D COC CN 592 194 314 -ChMg-vZ _n /u _? jO O-L^ Ϋ-Ν / Ν Ch-D NC 578 504

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315 1 I —X o- _n II Ύ -l 587.2 913 0 Αν O'N O 1 594 138 AdL., . 317 fl J I V x* °~N nAJ F 570 887 Yeah.”= ³¹⁸ Λτθ άΐν tN Aa 553 172 319 _Ν /γΑ\Α °'N VN / N Aa H ₃ C 567 161

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320 0 ХдАА, ..AU ШГ ^{1 НзС} \ А X m^Ч^снз 580 493 321 O- _n From AJ Ύ N^AA CF ₃ 635 1464 322 -Χθν·^ „A A H ₃ C V 1 1 N^AA CH ₃ 580 270 323 ABOUT F^^ аЦ __<Н lSa °' νΑΧ 553 1626 324 O f^^ SU ^ι^ ^Ν \—U N UU A ^m z ⁱ \ L A 567 250 325 O /NyV OM N ₃ C 527 24

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326 °'N N DM N=/ 631 782 327 0 CH ₃ 584 303 328 °A P D. O ^Z \=\ )=o Ί 594 339 329 .Dssi _N /yjO 0-A^ tN Ch-D Cl 587 222 330 0 ^N \_2/ ^N 552 392

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1H), 7.96 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 3.76 (d, J = 13.7 Hz, 1H) , 3.52 (d,J= 13.7 Hz, 1H), 2.11-2.00 (m, 1H), 1.981.89 (m, 3H), 1.89-1.68 (m, 9H), 1.47 (d, J = 8.3 Hz, 6H ), 1.07-0.93 (m, 2H), 0.89-0.69 (m, 2H) 264 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (d, J = 1.2 Hz, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H), 4.13 (s, 3H), 3.76 (d, J = 14.2 Hz, 1H), 3.51 (d,J= 13.7 Hz, 1H), 2.11-2.00 (m, 1H), 2.00-1.89 (m, 3H), 1.89-1.64 (m, 9H), 1.47 (d, J = 8.6 Hz, 6H), 1.08-0.91 (m, 2H), 0.91-0.71 (m, 2H) 265 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 7.87 (s, 1H), 7.89 (s, 1H), 7.83 (d, J =8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.43 (d, J =7.8 Hz, 1H), 3.71 (d, J = 14.2 Hz, 1H), 3.53 (d, J = 14.7 Hz, 1H), 2.59 (s, 3H), 2.5 (s, 3H), 2.12-2.00 (m, 1H), 1.98-1.88 (m, 3H), 1.88-1.65 (m, 9H), 1.46 (d, J =6.8 Hz, 6H), 1.10-0.95 (m , 2H), 0.89-0.75 (m, 2H) 266 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.30 (s, 1H), 8.52 (s, 1H), 7.97 (s, 1H), 7.937.89 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 3.73 (d, J = 13.7 Hz, 1H), 3.54 (d, J = 14.4 Hz, 1H) , 2.64 (s, 3H), 2.102.01 (m, 1H), 1.98-1.88 (m, 3H), 1.88-1.62 (m, 9H), 1.47 (d, J= 7.1 Hz, 6H), 1.10-0.94 (m, 2H), 0.91-0.77 (m, 2H) 267 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J = 8.6 Hz, 2H), 7.75-7.63 (m, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.45-7.29 (m, 3H), 3.60 (q, J= 13.6 Hz, 2H), 2.13-2.00 (m, 1H), 1.96-1.69 (m, 12H), 1.56-1.35 (m, 6H), 1.10-0.96 (m, 2H) , 0.89-0.76 (m, 2H) 268 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 7.79-7.59 (m, 4H), 7.52 (t, J = 7.7 Hz, 1H), 7.41-7.25 (m, 3H), 3.91 ( s, 1H), 3.59 (br. s., 2H), 3.31-3.25 (m, 1H), 2.10-1.99 (m, 1H), 1.87 (d, J = 8.8 Hz, 6H), 1.83-1.65 (m , 6H), 1.55-1.36 (m, 6H), 1.33-1.14 (m, 6H), 1.06-0.95 (m, 2H), 0.88-0.77 (m, 2H) 269 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.80-7.60 (m, 4H), 7.53 (t, J = 7.8 Hz, 1H), 7.46-7.26 (m, 3H), 3.60 ( d, J= 8.1 Hz, 2H), 2.71-2.65 (m, 1H), 2.112.00 (m, 1H), 1.87 (d, J = 9.8 Hz, 6H), 1.83-1.61 (m, 6H), 1.56 -1.34 (m, 6H), 1.12-0.89 (m, 6H), 0.88-0.74 (m, 2H) 270 Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.75 (br. s., 1H), 8.67 (br. s., 1H), 8.14 (dd, J = 8.6, 2.7 Hz, 1H), 7.77-7.66 (m , 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.6

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Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 3.60 (s, 2H), 2.04 (ddd, J = 13.5,8.6,5.3 Hz, 1H), 1.96-1.67 (m, 12H), 1.55 -1.36 (m, 6H), 1.07-0.97 (m, 2H), 0.90-0.76 (m, 2H) 271 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 7.87-7.81 (m, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H) , 7.45 (d, J = 7.8 Hz, 1H), 3.60 (d, J = 7.3 Hz, 2H), 2.32-2.23 (m, 1H), 2.10 -2.00 (m, 1H), 1.97-1.69 (m, 12H ), 1.56-1.31 (m, 6H), 1.16-0.93 (m, 6H), 0.89-0.75 (m, 2H) 272 Ή NMR (400 MHz, DMSO-d ₆ ) δ 11.48 (s, 1H), 9.04 (s, 2H), 7.77-7.82 (m, 2H), 7.55-7.59 (m, 1H), 7.42-7.44 (m, 1H ), 3.58-3.60 (m, 2H), 3.41 (s, 3H), 2.02-2.04 (m, 1H), 1.75-1.87 (m, 12H), 1.43-1.46 (m, 6H), 0.98-1.01 (m , 2H), 0.81-0.84 (m, 2H) 273 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.62 (m, 4H), 7.54 (t, J = 7.8 Hz, 1H), 7.44 (d, J= 8.3 Hz, 2H), 7.38 (d, J= 8.3 Hz, 1H), 4.48 (s, 2H), 3.63-3.49 (m, 2H), 2.10 -2.00 (m, 1H), 1.96-1.71 (m, 12H), 1.47 (d, J= 5.6 Hz, 6H ), 1.07-0.94 (m, 2H), 0.88-0.77 (m, 2H). 3H buried under moisture peak. 274 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (d, J= 2.4 Hz, 1H), 8.19 (dd, J= 8.1, 2.4 Hz, 1H), 7.85-7.70 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.53 (f £ = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.57 (s, 2H), 3.76-3.60 (m, 1H), 3.60-3.48 (m, 1H), 3.41 (s, 3H), 2.11-1.99 (m, 1H), 1.98-1.69 (m, 12H), 1.57-1.32 (m, 6H), 1.100.93 (m, 2H), 0.90 -0.74 (m, 2H) 275 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 7.84-7.69 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H) , 3.64-3.59 (m, 2H), 2.66 (s, 3H), 2.09-2.00 (m, 1H), 1.86 (s, 2H), 1.90 (s, 3H), 1.83-1.67 (m, 7H), 1.48 (d, J= 9.0 Hz, 6H), 1.06-0.94 (m, 2H), 0.89-0.80 (m, 2H). 276 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.837.81 (m, 2H), 7.60 (t, J = 8.2 Hz, 1H) , 7.45 (d, J= 8.1 Hz, 1H), 3.91 (s, 1H), 3.67 (d, J= 13.9 Hz, 1H), 3.57 (d, J= 14.4 Hz, 1H), 2.66-2.58 (m, 1H), 2.ΙΟΙ.99 (m, 1H), 1.86 (s, 2H), 1.91 (s, 3H), 1.83-1.65 (m, 6H), 1.51-1.47 (m, 6H), 1.37-1.17 ( m, 4H), 1.07-0.94 (m, 2H), 0.89-0.73 (m, 2H). 277 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.48 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 10.3 Hz, 1H), 7.87 -7.78 (m, 2H), 7.58 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 3.70-3.58 (m, 2H), 2.10-2.02 (m, 1H), 1.87-1.85 (m, 3H), 1.91-1.88 (m, 3H), 1.84-1.61 (m, 7H), 1.49 (br. s., 6H), 1.01 (dd, J = 7.9, 2.6 Hz,

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2H), 0.88-0.79 (m, 2H). 278 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J = 2.0 Hz, 1H), 8.94 (d, J = 2.4 Hz, 1H), 7.86-7.84 (m, 2H), 7.61 (t, J= 7.9 Hz, 1H), 7.47 (d, J= 7.1 Hz, 1H), 3.343.67 (m, 2H), 2.91 (s, 3H), 2.10-2.00 (m, 1H), 1.91-1.65 (m, 12H ), 1.47 -1.44 (m, 6H), 1.07-0.95 (m, 2H), 0.87-0.78 (m, 2H). 279 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.85-7.75 (m, J = 8.3 Hz, 2H), 7.75-7.62 (m, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.50-7.41 ( m, J = 8.6 Hz, 2H), 7.39 (d, J = 8.8 Hz, 1H), 3.60 (d, J = 4.2 Hz, 2H), 2.04 (td, J = 8.6, 4.2 Hz, 1H), 1.96- 1.66 (m, 14H), 1.60-1.53 (m, 2H), 1.53-1.29 (m, 6H), 1.10-0.96 (m, 2H), 0.89-0.72 (m, 2H) 280 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 8.48 (d, J = 6.8 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 3.65 (br. s., 1H), 3.62-3.52 (m , 1H), 2.08-2.02 (m, 1H), 1.96-1.67 (m, 12H), 1.46 (br. s., 6H), 1.08-0.95 (m, 2H), 0.88-0.77 (m, 2H) 281 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J= 2.4 Hz, 1H), 8.10 (dd, J= 8.9, 2.6 Hz, 1H), 7.82 -7.61 (m, 2H), 7.54 (t, J= 7.9 Hz, 1H), 7.37 (d, J= 7.8 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 3.60 (br. s. , 2H), 2.11-2.00 (m, 1H), 1.97-1.67 (m, 12H), 1.46 (d, J = 8.1 Hz, 6H), 1.35 (t, J = 7.0 Hz, 3H), 1.08-0.94 ( m, 2H), 0.88-0.79 (m, 2H) 282 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.78-7.58 (m, 4H), 7.51 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.68-3.49 (m, 2H), 2.11-1.99 (m, 1H),1.85 (s, 2H), 1.88 (s, 3H), 1.83-1.61 (m , 7H), 1.47 (d, J = 8.1 Hz, 6H), 1.07-0.95 (m, 2H), 0.89-0.74 (m, 2H) 283 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (d, J = 9.3 Hz, 1H), 8.16-8.02 (m, 2H), 7.62 (t, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 9.3 Hz, 1H), 4.56 (q,J=7.ir ₄ , 2H), 3.66(br. s., 1H), 3.56 (d, J = 17.4 Hz , 1H), 2.08-1.99 (m, 1H), 1.89 (br. s., 5H), 1.86-1.60 (m, 7H),1.55-1.26 (m, 9H), 1.01 (dd, J= 8.3, 2.7 Hz, 2H), 0.86-0.79 (m, 2H) 284 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 2.0 Hz, 1H), 7.73-7.69 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.49 (m, 2H), 7.39 (d, J = 7.0 Hz, 1H), 3.62 (br. s., 1H), 3.57 (br. s., 1H), 2.09-1.99 (m, 1H), 1.93-1.72 (m, 12H), 1.45 (d, J =9.5 Hz, 6H), 1.04-0.96 (m, 2H), 0.86-0.79 (m, 2H). 285 Ή NMR (400 MHz, DMSO-de) δ 7.70-7.63 (m, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.37-7.31 (m, 3H), 3.59 (d, J = 8.0 Hz, 2H ), 2.70-2.62 (m, 2H), 2.04 (ddd, J =

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13.3, 8.3, 5.0 Hz, 1H), 1.85 (s, ZN), 1.88 (s, ZN), 1.82-1.74 (m, 6H), 1.47 (d,7 = 7.0 Hz, 6H), 1.22 (t, J = 7.8 Hz, ZN), 1.05-0.97 (m, 2H), 0.87-0.79 (m, 2H). 286 Ή NMR (400 MHz, DMSO-de) δ 8.10-8.03 (m, 1H), 7.83-7.72 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H ), 3.68 (br. s., 1H), 3.53 (br. s., 1H), 2.092.00 (m, 1H), 1.89 (br. s., 3H), 1.86-1.72 (m, 9H), 1.45 (d, J = 6.5 Hz, 6H), 1.050.97 (m, 2H), 0.88-0.80 (m, 2H). 287 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (dd, J = 9.0, 4.5 Hz, 1H), 8.10-8.02 (m, 1H), 7.87 (td, J = 8.7, 3.3 Hz, 1H), 7.83- 7.72 (m, 2H), 7.61-7.53 (m, 1H), 7.497.41 (m, 1H), 3.54 (br. s., 1H), 2.04 (br. s., 1H), 1.95-1.73 (m , 12H), 1.46 (d, J = 8.5 Hz, 6H), 1.01 (d, J = 4.5 Hz, 2H), 0.88-0.80 (m, 2H). 288 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (d, J= 7.0 Hz, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 8.01-7.91 (m, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 3.63 (d, J = 17.6 Hz, 2H) , 2.04 (ddd, J = 13.2, 8.4,5.0 Hz, 1H), 1.89 (d, J =9.0 Hz, 6H), 1.83-1.75 (m, 6H), 1.47 (d, 7=8.0 Hz, 6H), 1.05-0.98 (m, 2H), 0.86-0.79 (m, 2H). 289 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.84-7.74 (m, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H) , 4.42 (q, J = 7.0 Hz, 2H), 3.66-3.53 (m, 2H), 2.09-1.99 (m, 1H), 1.94-1.73 (m, 12H), 1.51-1.41 (m, 6H), 1.38 (t, 7= 7.0 Hz, ZN), 1.05-0.97 (m, 2H), 0.86-0.79 (m, 2H) 290 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.71-7.59 (m, 4H), 7.50 (t, 7 = 7.8 Hz, 1H), 7.31 (d, 7 = 7.5 Hz, 1H), 7.04 (d, 7 = 9.0 Hz, 2H), 4.14-4.04 (m, 2H), 3.59 (d, 7 = 4.5 Hz, 2H), 2.09-2.00 (m, 1H), 1.86 (d, 7 = 9.0 Hz, 6H), 1.83- 1.73 (m, 6H), 1.51-1.41 (m, 6H), 1.36 (t, 7 = 6.8 Hz, ZN), 1.05-0.97 (m, 2H), 0.87-0.79 (m, 2H). 291 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (d, 7 = 5.0 Hz, 1H), 8.44-8.38 (m, 1H), 8.30-8.26 (m, 1H), 8.03 (d, 7 = 5.0 Hz, 1H), 7.74-7.64 (m, 2H), 3.63 (s, 2H), 2.08-2.00 (m, 1H), 1.90 (br. s., 6H), 1.83-1.71 (m, 6H), 1.50-1.39 (m, 6H), 1.060.97 (m, 2H), 0.86-0.78 (m, 2H). 292 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (d, 7 = 8.0 Hz, 1H), 8.19 (t, 7 = 8.0 Hz, 1H), 8.14 (d, 7 = 7.5 Hz, 1H), 8.10-8.07 (m, 1H), 8.05 (d, 7= 8.0 Hz, 1H), 7.63 (t, 7= 7.8 Hz, 1H), 7.56 (d, 7= 8.0 Hz, 1H), 3.65 (br. s., 1H ), 3.60 (br. s., 1H), 2.09-1.99 (m, 1H), 1.88 (br. s., 6H), 1.82-1.73 (m, 6H), 1.46 (d,7= 7.5 Hz, 6H ), 1.05-0.96 (m, 2H), 0.87-0.79 (m, 2H).

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293 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.23-8.15 (m, 1H), 8.10-8.04 (m, 1H), 7.93 (d, J= 7.5 Hz, 1H), 7.86 (s, 1H), 7.70- 7.64 (m, 1H), 7.62-7.58 (m, 1H), 3.67 (br. s., 1H), 3.53 (br. s., 1H), 2.04 (ddd,J = 13.3,8.3,5.0 Hz, 1H ), 1.90-1.93 (m, 6H), 1.81-1.72 (m, 6H), 1.45 (br. s., 6H), 1.05-0.97 (m, 2H), 0.86-0.78 (m, 2H). 294 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (dd, J = 6.3, 2.3 Hz, 1H), 8.22-8.16 (m, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 9.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 3.70 (d, J = 13.6 Hz, 1H) , 3.52 (d, J = 13.1 Hz, 1H), 2.04 (td, J = 8.7, 4.3 Hz, 1H), 1.90 (br. s., 3H), 1.86-1.72 (m, 9H), 1.45 (d, J= 6.5 Hz, 6H), 1.06-0.98 (m, 2H), 0.87-0.79 (m, 2H). 295 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J = 8.5 Hz, 1H), 8.18-8.12 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 3.63 (d, J = 14.1 Hz, 2H), 2.69 (s, 3H), 2.08-2.01 (m, 1H), 1.89 (br. s., 6H), 1.82-1.73 (m, 6H), 1.50-1.41 (m, 6H), 1.04-0.98 (m, 2H), 0.86-0.79 (m, 2H). 296 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 2.5 Hz, 1H), 8.08 (dd, J = 8.8, 2.3 Hz, 1H), 7.80-7.72 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.41-7.34 (m, 2H), 3.98 (s, 3H), 3.68 (d, J= 13.1 Hz, 1H), 3.56-3.49 (m, 1H), 2.09-2.00 (m , 1H), 1.89 (br. s., 3H), 1.86-1.73 (m, 9H), 1.46 (d, J =7.0 Hz, 6H), 1.06-0.97 (m, 2H), 0.870.80 (m, 2H). 297 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (d, J = 2.0 Hz, 1H), 8.45 (dd, J = 8.5, 2.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 3.62 (s, 2H), 2.09 -2.00 (m, 1H), 1.931.81 (m, 6H), 1.81-1.73 (m, 6H), 1.50-1.38 (m, 6H), 1.05-0.97 (m, 2H), 0.860.79 (m, 2H). 298 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (d, J= 7.0 Hz, 1H), 8.56 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.94 (d, J= 7.5 Hz, 1H), 7.68-7.56 (m, 1H), 7.52-7.45 (m, 1H), 7.41-7.32 (m, 1H), 3.66 (br. s., 1H), 3.61 (br. s., 1H), 2.08-1.99 (m, 1H), 1.95-1.83 (m, 6H), 1.83-1.73 (m, 6H), 1.52-1.40 (m, 6H), 1.05-0.98 (m, 2H), 0.86- 0.79 (m, 2H). 299 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.79-7.72 (m, ZN), 7.64-7.60 (m, 1H), 7.607.53 (m, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 6.97 (s, 1H), 6.90-6.71 (m, 1H), 3.68 (br. s., 1H), 3.53 (br. s., 1H), 2.09- 2.00 (m, 1H), 1.90 (br. s., 3H), 1.87-1.73 (m, 9H), 1.46 (d, J= 8.0 Hz, 6H), 1.05-0.98 (m, 2H), 0.87-0.80 (m, 2H).

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300 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.25 (s, 1H), 7.65-7.53 (m, 2H) , 7.39 (d, J= 5.0 Hz, 1H), 3.62 (s, 2H), 2.57 (s, 3H), 2.08-2.00 (m, 1H), 1.88 (br. s., 6H), 1.82-1.73 ( m, 6H), 1.49-1.39 (m, 6H), 1.05-0.97 (m, 2H), 0.86-0.79 (m, 2H). 301 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.73-7.63 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.35-7.25 (m, 3H), 7.06 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.70 (s, 1H), 3.56 (s, 1H), 2.10-1.99 (m, 1H), 1.85-1.89 (m, 6H), 1.78 (t, .7 = 7.8 Hz, 6H), 1.46 (d, J = 6.5 Hz, 6H), 1.05-0.97 (m, 2H), 0.87-0.79 (m, 2H). 302 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.92 (m, 4H), 7.83-7.76 (m, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 3.64 (br. s., 1H), 3.55 (d, J= 15.1 Hz, 1H), 2.08-2.00 (m, 1H), 1.93-1.73 (m, 12H), 1.51-1.39 (m, 6H ), 1.05-0.97 (m, 2H), 0.86-0.79 (m, 2H). 303 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.28 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.83-7.75 (m, 3H), 7.57 (t, J= 8.0 Hz, 1H), 7.40 (d, J= 8.5 Hz, 1H), 3.62 (d, J = 8.0 Hz, 2H), 2.84 (s, 3H), 2.09-1.99 (m, 1H), 1.87-1.90 ( m, 6H), 1.841.75 (m, 6H), 1.48 (d, J = 8.5 Hz, 6H), 1.06-0.97 (m, 2H), 0.86-0.79 (m, 2H). 304 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (d, J = 1.0 Hz, 2H), 7.83-7.70 (m, 4H), 7.54 (t, J= 7.8 Hz, 1H), 7.35 (d, J= 9.0 Hz, 1H), 4.09 (s, 3H), 3.64 (br. s., 1H), 3.59 (br. s., 1H), 2.08-2.00 (m, 1H), 1.87-1.90 (m, 6H) , 1.84-1.73 (m, 6H), 1.48 (d, J= 9.5 Hz, 6H), 1.05-0.97 (m, 2H), 0.87-0.79 (m, 2H). 305 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (d, J = 1.5 Hz, 1H), 7.79-7.69 (m, 4H), 7.55 (t, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 3.64 (br. s., 1H), 3.59 (br. s., 1H), 2.65 (s, 3H), 2.09-2.00 (m, 1H), 1.86-1.90 (m, 6H) , 1.83-1.74 (m, 6H), 1.47 (d, J = 4.0 Hz, 6H), 1.06-0.97 (m, 2H), 0.87-0.79 (m, 2H). 306 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.52 (d, J= 9.5 Hz, 1H), 8.24 (d, J =9.5 Hz, 1H), 8.17-8.09 (m, 2H) , 7.71 (t, J =7.8 Hz, 1H), 7.64 (d, J =8.0 Hz, 1H), 3.69 (br. s., 1H), 3.59 (br. s., 1H), 2.03 (td, J = 8.7, 4.3 Hz, 1H), 1.93 (br. s., 6H), 1.83-1.72 (m, 6H), 1.53-1.38 (m, 6H), 1.06-0.97 (m, 2H), 0.86-0.78 ( m, 2H). 307 'H NMR (400 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 8.69 (d, J= 7.2 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.61 (t, J= 7.7 Hz, 1H), 7.51 (br. s., 2H), 3.72-3.63 (m, 2H), 2.10-2.00 (m, 1H), 1.95-1.72 (m, 12H), 1.53-1.39 (m, 6H), 1.01 (d, J = 6.2 Hz, 2H), 0.83 (br. s., 2H).

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308 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (d, J = 8.4 Hz, 2H), 7.74-7.67 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.31 (t, J = 72.00 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 3.69-3.52 (m, 2H), 2.04 (dq, J = 8.4, 4.2 Hz, 1H), 1.941.72 (m, 12H), 1.52-1.37 (m, 6H), 1.06-0.96 (m, 2H), 0.87-0.77 (m, 2H). 309 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (d, J = 6.6 Hz, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 7.3 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 3.61 (d , J = 11.7 Hz, 2H), 2.11-2.00 (m, 1H), 1.92 (br. s., 6H), 1.84-1.73 (m, 6H), 1.54-1.40 (m, 6H), 1.01 (d, J = 5.9 Hz, 2H), 0.83 (br. s., 2H). 310 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.65 (s, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J =7.6 Hz, 1H), 3.62 (s, 2H), 2.56 (s, 3H), 2.10-2.00 (m, 1H), 1.88 (br. s., 6H) , 1.82-1.72 (m, 6H), 1.52-1.37 (m, 6H), 1.06-0.97 (m, 2H), 0.89-0.78 (m, 2H). 311 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (d, J = 4.0 Hz, 1H), 8.48 (d, J = 7.5 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.81-7.72 (m, 2H), 7.71-7.64 (m, 1H), 7.62-7.53 (m, 3H), 3.64 (br. s., 1H), 3.59 (br. s., 1H), 2.13-2.01 (m, 1H), 1.94 (br. s., 3H), 1.89 (br. s., 3H), 1.84-1.73 (m, 6H), 1.55-1.39 (m, 6H), 1.02 (d, J = 7.9 Hz, 2H), 0.88-0.79 (m, 2H). 312 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.45 (s, 1H), 7.62-7.54 (m, 1H), 7.51-7.39 (m, 3H), 3.60 (d, J = 5.1 Hz, 2H), 2.59 (s, 3H), 2.22 (s, 3H), 2.11-2.01 (m, 1H), 1.88-1.92 (m, 6H), 1.83-1.72 (m, 6H), 1.52-1.36 ( m, 6H), 1.02 (d, J = 8.1 Hz, 2H), 0.88-0.79 (m, 2H). 313 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.41 (s, 1H), 7.95-7.86 (m, 1H), 7.73-7.55 (m, 2H), 7.38 (t, J = 9.0 Hz, 1H), 4.14 (s, 2H), 3.73 (s, 3H), 2.05 (br. s., 1H), 2.00-1.87 (m, 6H), 1.83-1.72 (m, 6H), 1.46 (br . s., 6H), 1.02 (d, J= 6.2 Hz, 2H), 0.83 (br. s., 2H). 314 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (s, 2H), 8.72 (s, 1H), 8.26-8.18 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.50 (d, J =7.8 Hz, 1H), 3.66 (d, J= 12.5 Hz, 1H), 3.56 (d, J= 13.1 Hz, 1H), 2.10-2.00 (m, 1H), 1.91 (br. s., 6H) , 1.83-1.73 (m, 6H), 1.46 (br. s., 6H), 1.01 (d, J= 7.6 Hz, 2H), 0.83 (br. s., 2H). 315 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.33 (s, 1H), 8.16 (d, J= 6.0 Hz, 1H), 8.04 (s, 1H), 7.78-7.68 (m, 2H), 7.42-7.34 ( m, 1H), 7.23 (br. s., 1H), 3.69 (br. s., 1H), 3.58 (br. s., 1H), 2.09-1.99 (m, 1H), 1.91 (br. s. , 6H), 1.77 (d, J= 7.0 Hz, 6H),

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1.46 (br. s., 6H), 1.01 (d, J= 6.2 Hz, 2H), 0.83 (br. s., 2H). 316 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 7.927.84 (m, 2H), 7.78 (d, J = 5.4 Hz, 1H) , 7.70-7.58 (m, 2H), 3.75-3.64 (m, 1H), 3.64-3.52 (m, 1H), 2.11-2.00 (m, 1H), 1.91 (br. s., 6H), 1.85-1.72 (m, 6H), 1.521.38 (m, 6H), 1.01 (d, J = 7.5 Hz, 2H), 0.84 (br. s., 2H). 317 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 8.14 (br. s., 1H), 7.83-7.73 (m, 4H), 7.59 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.7 Hz, 1H), 3.74-3.66 (m, 2H), 2.082.01 (m, 1H), 1.91-1.86 (m, 6H), 1.79 (t, J = 7.6 Hz, 6H), 1.46 (d, J =5.5 Hz, 6H), 1.05-0.98 (m, 2H), 0.86-0.78 (m, 2H). 318 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (d, J = 4.2 Hz, 1H), 8.41 (s, 1H), 8.26 (d, J = 9.3 Hz, 1H), 8.20 (br. s., 2H ), 7.61 (t, J= 8.1 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 7.34 (dd, J = 9.1,4.3 Hz, 1H), 3.70-3.61 (m, 1H), 3.61 -3.52 (m, 1H), 2.102.00 (m, 1H), 1.92 (br. s., 6H), 1.84-1.72 (m, 6H), 1.54-1.40 (m, 6H), 1.06-0.97 (m , 2H), 0.86-0.78 (m, 2H). 319 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.30 (s, 1H), 8.19-8.13 (m, 2H), 8.03 (s, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 3.67 (d, J = 13.3 Hz, 1H), 3.55 (d, J = 13.4 Hz, 1H), 2.44 (s, 3H), 2.09-2.00 ( m, 1H), 1.92 (br. s., 6H), 1.83-1.73 (m, 6H), 1.52-1.41 (m, 6H), 1.01 (d, J = 7.8 Hz, 2H), 0.83 (br. s ., 2H). 320 ΉNMR (400 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 7.63 (s, 1H), 7.59-7.52 (m, 1H), 7.47-7.39 (m, 3H), 7.36 (s, 1H), 3.65 (d, J= 13.7 Hz, 1H), 3.52 (d, J= 13.9 Hz, 1H), 2.33 (s, 3H), 2.22 (s, 3H), 2.10-2.00 (m, 1H), 1.86-1.91 ( m, 6H), 1.82-1.73 (m, 6H), 1.49-1.39 (m, 6H), 1.06-0.97 (m, 2H), 0.87-0.80 (m, 2H). 321 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 8.44 (s, 1H), 8.02 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 3.75 (d, J = 13.7 Hz, 1H), 3.52 (d, J = 14.1 Hz, 1H), 2.58 (s, 3H), 2.09 -2.00 (m, 1H), 1.921.82 (m, 6H), 1.79 (t, J = 7.6 Hz, 6H), 1.47 (d, J = 7.8 Hz, 6H), 1.06-0.98 (m, 2H), 0.83 (br. s., 2H). 322 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (s, 1H), 7.76-7.67 (m, 3H), 7.55 (t, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 3.72 (d, J= 13.8 Hz, 1H), 3.51 (d, J= 14.1 Hz, 1H), 2.37 (s, 3H), 2.10-2.00 (m, 1H), 1.91- 1.82 (m, 6H), 1.79 (t, J = 7.6 Hz, 6H), 1.46 (d, J = 7.3 Hz, 6H), 1.01 (d, J = 7.9 Hz, 2H), 0.83 (br. s., 2H) (3 Protons are buried under solvent peak).

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323 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.29 (s, 1H), 9.02 (s, 1H), 7.92 (d, J = 9.5 Hz, 1H), 7.85 (d, J = 9.8 Hz, 1H), 7.82 -7.75 (m, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 3.69-3.64 (m, 2H), 2.09-2.00 (m, 1H), 1.87-1.90 (m, 6H), 1.82-1.74 (m, 6H), 1.51-1.40 (m, 6H), 1.06-0.97 (m, 2H), 0.86-0.80 (m, 2H). 324 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.83 (t, J = 9.1 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 3.72-3.63 (m, 1H), 3.63-3.53 (m, 1H), 2.09-2.00 (m, 1H), 1.86-1.90 (m, 6H), 1.82-1.74 (m, 6H), 1.52-1.39 (m, 6H), 1.06-0.97 (m, 2H), 0.86-0.78 (m, 2H) (3 Protons hidden under the peak solvent). 325 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.74 (d, J =7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 3.61 (s, 2H), 2.36 (s, 3H), 2.10 -2.00 (m, 1H), 1.87 (br. s., 6H), 1.82-1.72 (m, 6H), 1.50-1.39 (m, 6H), 1.05-0.97 (m, 2H), 0.83 (br. s ., 2H). 326 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.64 (s, 1H), 8.24 (s, 2H), 8.28 (s, 1H), 7.63 (t, J = 7.8 Hz, 1H) , 7.52 (d, J = 7.8 Hz, 1H), 3.62 (d, J = 7.8 Hz, 2H), 2.09-2.02 (m, 1H), 1.92 (br. s., 6H), 1.83-1.74 (m, 6H), 1.52-1.42 (m, 6H), 1.060.97 (m, 2H), 0.84 (br. s., 2H). 327 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.24-8.16 (m, 2H), 8.14 (s, 1H), 7.61 (t, J =7.8 Hz, 1H), 7.51 (d, J =7.9 Hz, 1H), 3.71 (br. s., 1H), 3.58 (br. s., 1H), 2.81 (s, 3H), 2.09-2.00 (m, 1H), 1.89 (br. s. , 6H), 1.78 (t, J= 7.5 Hz, 6H), 1.53-1.39 (m, 6H), 1.01 (d, J = 7.7 Hz, 2H), 0.83 (br. s., 2H). 328 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.85-7.78 (m, 2H), 7.69-7.57 (m, 2H), 4.81 (s, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.71-3.62 (m, 1H), 3.62-3.52 (m, 1H), 3.04 (br. s., 2H), 2.11-1.99 (m, 1H), 1.89 (br. s., 6H ), 1.83-1.72 (m, 6H), 1.511.38 (m, 6H), 1.01 (d, J =7.6 Hz, 2H), 0.87-0.79 (m, 2H). 329 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 8.198.12 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 3.63 (br. s., 1H), 3.60-3.52 (m, 1H), 2.09-2.00 (m, 1H), 1.91 (br. s., 6H), 1.84-1.73 (m, 6H), 1.511.39 (m, 6H), 1.06-0.97 (m, 2H), 0.86-0.79 (m, 2H). 330 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 6.6 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 7.63-7.55 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 7.04 (t, J = 6.9 Hz, 1H), 3.66 (d, J = 13.7 Hz, 1H) , 3.55 (d, 7=13.8

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Hz, 1H), 2.10-2.00 (m, 1H), 1.93 (d, J = 9.0 Hz, 6H), 1.79 (t, J = 7.7 Hz, 6H), 1.48 (d, J = 4.9 Hz, 6H), 1.01 (d, J = 7.6 Hz, 2H), 0.89-0.79 (t, 2H). 331 ^L H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br. s., 1H), 8.09 (s, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.79-7.68 (m, 2H), 7.55 (t, J = ΊΧ Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.56 ( d, J = 9.4 Hz, 1H), 3.713.61 (m, 1H), 3.61-3.50 (m, 1H), 2.11-1.99 (m, 1H), 1.86-1.90 (m, 6H), 1.79 (t, J - 7.5 Hz, 6H), 1.55-1.36 (m, 6H), 1.01 (d, J = 7.7 Hz, 2H), 0.83 (br. s., 2H). 332 ^L H NMR (400 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H), 7.70-7.44 (m, 5H), 7.31 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H ), 3.69-3.51 (m, 4H), 2.13-2.02 (m, 1H), 1.97-1.67 (m, 12H), 1.58-1.30 (m, 6H), 1.02 (dd,J=8.0, 2.0 Hz, 2H ), 0.89-0.74 (m, 2H) 333 ^L H NMR (400 MHz, DMSO-d ₆ ) 8.68 (s, 2H), 8.30 (d, J = 8.1 Hz, 1H), 8.17 (t, J = 1.7 Hz, 1H), 7.59 (t, J = 7.8 Hz , 1H), 7.50 (d, J = 7.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.71-3.61 (m, 2H), 2.12-1.98 (m, 1H), 1.89 (br. s., 6H), 1.84-1.71 (m, 6H),1.53-1.31 (m, 9H), 1.06-0.94 (m, 2H), 0.89-0.71 (m, 2H) 334 ^L H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 2H), 8.31 (d, J = 7.8 Hz, 1H), 8.18 (t, J = 1.8 Hz, 1H), 7.68-7.54 (m, 1H ), 7.53-7.45 (m, 1H), 3.98 (s, 3H), 3.64 (br. s., 1H), 3.56 (d, J= 15.9 Hz, 1H), 2.09-1.99 (m, 1H), 1.97 -1.67 (m, 12H), 1.541.35 (m, 6H), 1.06-0.96 (m, 2H), 0.88-0.77 (m, 2H) 335 ^L H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.36 (d, J= 7.8 Hz, 1H), 8.23 (s, 1H), 7.70-7.50 (m, 2H), 7.5-7.25 (m, 1H), 3.65 (br. s., 1H), 3.59 (br. s., 1H), 2.03 (td, J= 8.6, 4.3 Hz, 1H), 1.89 (br. s., 6H), 1.84-1.59 (m, 6H), 1.55-1.32 (m, 6H), 1.06-0.96 (m, 2H), 0.87-0.78 (m, 2H) 336 1HNMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 8.33 (s, 1H), 8.15-8.00 (m, 3H), 7.88 (d, J= 9.5 Hz, 1H), 7.69-7.59 (m , 1H), 7.59-7.48 (m, 1H), 3.64 (br. s., 2H), 2.13 (s, 3H), 2.09-2.00 (m, 1H), 1.91 (s, 6H), 1.83-1.67 ( m, 6H), 1.56-1.38 (m, 6H), 1.06-0.96 (m, 2H), 0.86-0.78 (m, 2H)

Example 337.

X-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-X-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 337A. Preparation of 2-cyclopropoxy-4-(3nitrophenyl)pyrimidine

To a stirred solution of sodium hydride in mineral oil (138 mg, 3.44 mmol) in tetrahydrofuran (5 ml) was added cyclopropanol (100 mg, 1.722 mmol) at 0°C. The reaction mixture was stirred for 20 minutes and then intermediate 40A (406 mg, 1.722 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour.

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The reaction was quenched with cold water (10 ml) and extracted with EtOAc (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give (0.3 g, 1.108 mmol, 64% yield) as a pale yellow solid. MS (ESI) 258 (M+H).

Stage B. Intermediate 337B. Preparation of 3-(2-cyclopropoxy-pyrimidin-4yl)aniline £Vo NH ₂ |/ \U

Zinc (1.2 g, 18 mmol) was added to a stirred solution of intermediate 337A (300 mg, 1.166 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL). A solution of ammonium chloride (936 mg, 18 mmol) in water (2 ml) was added to the reaction mixture and stirred at room temperature for 3 hours. The reaction mixture was filtered through celite. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give (200 mg, 0.836 mmol, 72% yield) as a pale yellow solid. MS (ESI) 228 (M+H).

Step C. Intermediate 337C. Preparation of 3-(2-cyclopropoxypyrimidin-4-yl)-N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline hnAA

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 337B and intermediate 4C where necessary (130 mg, 0.270 mmol, 53% yield) as a pale yellow solid. MS (ESI) 458 (M+H).

Step D. Example 337. Preparation of N-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-N-((4-(3cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 337C and the corresponding acid where necessary (10.4 mg, 0.018 mmol, 33% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (d, J=5.1 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 7.86 (d, J=5.1 Hz, 1H), 7.69-7.52 (m, 2H), 4.46-4.39 (m, 1H), 3.62 (d, J=16.4 Hz, 2H), 2.09-2.01 (m, 1H), 1.88 (br. s. , 6H), 1.82-1.68 (m, 6H), 1.54-1.36 (m, 6H), 1.08-0.97 (m, 2H), 0.90-0.71 (m, 6H). FXR EC ₅₀ (nM) 380; MS (ESI) 570 (M+H).

The following compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 337C and the corresponding acid where necessary.

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Example 339.

4-(('1-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-4-( 3(2-tethoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 339A. Preparation of N((1-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(2-methoxypyridin-4-yl) aniline

The specified compound was prepared in accordance with the method described for the synthesis of intermediate compound 1I, by replacing intermediate compound 222A and intermediate compound 196K where necessary. (22 mg, 0.046 mmol, 57% yield) as an off-white solid. MS (ESI) 433.4 (M+H).

Step B. Example 339. Preparation of No.((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-No. -(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 339A and the corresponding acid where necessary (9.4 mg, 0.017 mmol, 34% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=5.1 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.42 (dd, J=5.4, 1.5 Hz, 1H), 7.23 (s, 1H), 3.91 (s, 3H), 3.68 (br. s ., 2H), 3.63 (s, 2H), 2.18-2.01 (m, 3H), 1.99-1.76 (m, 8H), 1.70 (br. s., 2H), 1.64-1.47 (m, 2H), 1.12 -0.97 (m, 2H), 0.920.77 (m, 2H). FXR EU ₅₀ (nM) 378; MS (ESI) 545 (m+H).

Example 340.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(2'methoxy-[ 4,4'-bipyridin]-2-yl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 340A. Preparation of 4-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing 4-bromopyridin-2-amine and intermediate 4C where necessary (550 mg, 1.364 mmol, 67% yield) as a gummy liquid. MS (ESI) 404 (M+H).

Stage B. Intermediate connection 340V. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-2'-methoxy-[4,4'-bipyridine]- 2-amine

The indicated compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 340A and (2-methoxypyridin-4-yl)boronic

- 287 047337 acids where needed. (40 mg, 0.093 mmol, 75% yield), as a brown resinous liquid. MS (ESI) 432 (M+H).

Step C. Example 340. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-X-(2 '-methoxy-[4,4'-bipyridin]-2-yl)bicyclo[1.1.1]pentane-1 carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 340B and the corresponding acid where necessary (2 mg, 3.68 μmol, 11% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=5.4 Hz, 1H), 8.35 (d, J=5.9 Hz, 1H), 8.01 (s, 1H), 7.89 (d, J=5.4 Hz, 1H), 7.53 (d, J=4.2 Hz, 1H), 7.40 (s, 1H), 3.94 (s, 3H), 3.72 (s, 2H), 2.07-2.00 (m, 1H), 1.89 (d , J=2.4 Hz, 6H), 1.50-1.30 (m, 6H), 1.17 (t, J=13 Hz, 6H), 1.07-0.95 (m, 2H), 0.82 (dd, J=4.5, 2.6 Hz, 2H); FXR EC ₅₀ (nM) = 398; MS (ESI) 544 (M+H).

Example 341.

¥-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -fluoro-N-(3 -(2methoxypyrimidin- 5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 341A. Preparation of 3-bromo-X-((4-(5-cyclopropyl-1,3,4oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 133D where necessary (120 mg, 0.298 mmol, 74% yield) as a gummy liquid. MS (ESI) 404 (M+N).

Stage B. Intermediate 341B. Preparation of N(3-bromophenyl)-X-((4-(5-cyclopropyl1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1. 1 ]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 341A and the corresponding acid where necessary (120 mg, 0.233 mmol, 85% yield) as a gummy liquid. MS (ESI) 514 (M+H).

Step C. Example 341. Preparation of ¥-((4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-X-( 3-(2-methoxypyrimidin-5yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 341B and (2-methoxypyrimidin-5-yl)boronic acid where necessary (8.9 mg, 0.015 mmol, 39% yield ).

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.83 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 3.99 (s, 3H), 3.63 (br. s., 1H), 3.60-3.49 (m, 1H), 2.19 -2.09 (m, 1H), 1.85 (s, 3H), 1.89 (s, 3H), 1.75 (d, J=7.1 Hz, 6H), 1.45 (br. s., 6H), 1.08 (dd, J=8.1, 2.4 Hz, 2H), 0.99-0.79 ( m, 2H); FXR EC ₅₀ (nM) = 287; MS (ESI) 544 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 341F and the corresponding boronic acids.

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Etc. Name MS FXR No. (ESI) (M+H) ec ₅₀ (hM) 342 ABOUT DD y 543 120 343 and n-s^A/ ¹ )> 543 154 344 About γγΥΜ o-? H ₃ C, '? GT\1> ⁱ n 605 293 342 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 5.4 Hz, 1H), 7.93-7.76 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.41 (dd, J =5.4, 1.5 Hz, 1H), 7.23 (s, 1H), 3.92 (s, 3H), 3.70-3.60(m, 1H), 3.60-3.49 (m, 1H ), 2.18-2.06 (m, 1H), 1.83 (s, 3H), 1.87 (s, 3H), 1.80-1.59 (m, 6H),1.55-1.25 (m, 6H), 1.141.02 (m, 2H ), 0.98-0.82 (m, 2H) 343 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.4, 2.6 Hz, 1H), 7.80 -7.65 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 3.92 (s, 3H), 3.60 (d, J = 7.6 Hz, 2H) , 2.20-2.08 (m, 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.81-1.62 (m, 6H),1.46 (d, J= 8.3 Hz, 6H), 1.14-1.01 (m , 2H), 0.98-0.86 (m, 2H) 344 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.717.63 (m, 2H), 7.53 (t, J = 7.8 Hz, 2H) , 7.39-7.27 (m, 2H), 3.59 (d, J= 10.3 Hz, 2H), 3.04 (s, 3H), 2.19-2.10 (m,lH), 1.85 (s, 3H), 1.88 (s, 3H ), 1.81-1.58 (m, 6H), 1.46 (d, J= 8.1 Hz, 6H), 1.12-1.02 (m, 2H),0.98-0.87 (m, 2H)

Example 345.

c-(('1-(4-('1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-c-(4'(methylsulfonamido)-[ 1,1 '-biphenyl]-3 -yl)bicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 345A. Preparation of 1-(4-(4-(((3-bromophenyl)amino)methyl)-2oxabicyclo[2.2.2]octan-1 -yl)phenyl)cyclopropan-1-carbonitrile

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 141E where necessary (250 mg, 0.57 mmol, 80% yield) as a white solid. MS (ESI) 437 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.40 (d, J=8.1 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 7.02-6.95 (m, 1H), 6.79 (s, 1H), 6.62 (t, J=6.0 Hz, 2H), 5.81 (t, J=5.7 Hz, 1H), 3.85 (s, 2H), 2.86 (d, J=5.9 Hz, 2H), 2.11-2.02 ( m, 2H), 1.86-1.64 (m, 8H), 1.51-1.44 (m, 2H).

Stage B. Intermediate connection 345V. Preparation of Y(3-bromophenyl)-N-((1-(4-(1cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluorobicyclo[1.1.1]pentan- 1carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 345A and the corresponding acid where necessary (190 mg, 0.33 mmol, 73% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 7.76 (t, J=1.8 Hz, 1H), 7.66-7.61 (m, 1H), 7.51-7.40 (m, 2H), 7.36-7.31 (m, 2H) , 7.27-7.21 (m, 2H), 3.68 (s, 2H), 3.59 (br. s., 1H), 3.54 (br. s., 1H), 2.04-1.94 (m, 2H), 1.89 (br. s., 6H), 1.80-1.68 (m, 4H), 1.67-1.50 (m, 4H), 1.49-1.44 (m, 2H). MS (ESI) 549 (M+H).

Step C. Example 345. Preparation of Y((1-(4-(1-cyanocyclopropyl)phenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-N-(4'-(methylsulfonamido )-[1,G-biphenyl]-3yl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 345B and 4(methylsulfonylamino)phenylboronic acid where necessary. (9.3 mg, 0.015 mmol, 40% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 7.82-7.62 (m, 4H), 7.54 (t, J=8.2 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H), 7.36-7.28 (m, 4H), 7.23 (d, J=8.6 Hz, 2H), 3.72 (br. s., 2H), 3.63 (d, J=4.2 Hz, 2H), 3.04 (s, 3H), 2.05-1.95 (m, 2H), 1.89-1.86 (m, 6H), 1.80-1.64 (m, 6H), 1.60 (d, J=11.0 Hz, 2H), 1.49-1.41 (m, 2H) . FXR EC ₅₀ (nM) = 264. MS (ESI) 640 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 345B and the corresponding heteroarylboronates.

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1H), 7.88 (dd, 7= 8.6, 1.7 Hz, 1H), 7.85-7.74 (m, 2H), 7.58 (t, 7= 7.7 Hz,

346

1H), 7.44 (d, 7 = 7.3 Hz, 1H), 7.39-7.28 (m, 7 = 8.3 Hz, 2H), 7.27-7.13 (m, 7 = 8.3 Hz, 2H), 3.80-3.65 (m, 3H ), 3.65 -3.52 (m, 1H), 2.84 (s, 3H), 2.08-1.81 (m, 8H), 1.79-1.64 (m, 6H), 1.59 (br. s., 2H), 1.49-1.38 ( m, 2H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (s, 1H), 7.84-7.78 (m, 2H), 7.78-7.68 (m, 2H), 7.57 (t, 7 = 7.7 Hz, 1H), 7.43 ( d, 7 = 8.6 Hz, 1H), 7.38-7.29 (m, 7 =

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8.6 Hz, 2H), 7.27-7.14 (m, J= 8.6 Hz, 2H), 3.74 (br. s., 2H), 3.65 (d, J= 19.1 Hz, 2H), 2.65 (s, ZN), 2.05 -1.83 (m, 8H), 1.80-1.62 (m, 6H), 1.59 (br. s., 2H), 1.49-1.42 (m, 2H) 348 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 5.4 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz , 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.42 (dd, J = 5.4, 1.5 Hz, 1H), 7.38-7.29 (m, 2H), 7.28-7.14 (m, 3H), 3.97- 3.85 (m, 3H), 3.72 (br. s., 2H), 3.69-3.54 (m, 2H), 2.06-1.94 (m, 2H), 1.89-1.85 (m, 6H), 1.80-1.63 (m, 6H), 1.58 (d, J= 8.6 Hz, 2H), 1.50-1.39 (m, 2H) 349 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.59 (m, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.6 Hz, ZN), 7.23 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 3.73 (br. s., 2H), 3.62 (d, J = 6.1 Hz, 2H), 2.04-1.94 (m, 2H), 1.89 (d, J =9.8 Hz, 6H), 1.80-1.64 (m, 6H), 1.60 (d, J =9.3 Hz, 2H), 1.48-1.37 (m, 2H) 350 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 8.7, 2.6 Hz, 1H), 7.81 -7.67 (m, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.41 (d,J=8.3 Hz, 1H), 7.38-7.28 (m, J= 8.6 Hz, 2H), 7.27-7.14 (m, J= 8.3 Hz, 2H), 6.95 ( d, J = 8.6 Hz, 1H), 3.92 (s, 3H), 3.73 (br. s., 2H), 3.63 (d, J = 5.4 Hz, 2H), 2.041.94 (m, 2H), 1.87 ( s, 3H), 1.90 (s, 3H), 1.79-1.63 (m, 6H), 1.59 (br. s., 2H),1.49-1.41 (m, 2H) 351 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.05 (s, 2H), 7.88 (s, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.39-7.29 (m, J = 8.6 Hz, 2H), 7.29-7.14 (m, J = 8.6 Hz, 2H), 3.99 (s, 3H), 3.78-3.63 ( m, 3H), 3.633.51 (m, 1H), 2.05-1.94 (m, 2H), 1.87 (s, 3H), 1.91 (s, 3H), 1.80-1.62 (m, 6H), 1.58 (br. s., 2H), 1.49-1.38 (m, 2H) 352 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.87 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.38-7.29 (m, J = 8.6 Hz, 2H), 7.28-7.15 (m, J = 8.3 Hz, 2H), 4.43 (q, J = 7.0 Hz, 2H) , 3.73 (br. s., 2H), 3.69-3.53 (m, 2H), 2.07-1.94 (m, 3H), 1.94 -1.79 (m, 6H), 1.79-1.62 (m, 6H), 1.58 (br . s., 2H), 1.50-1.42 (m, 2H), 1.38 (t, J= 7.1 Hz, 2H)

Example 353.

A(('1-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-A(3-(2ethoxypyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 353A. Preparation of 3-romo-N-((l-(3-cyclopropyl-1,2,4oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)aniline

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The compound was prepared according to the method described for the synthesis of intermediate 1I, substituting 3-bromoaniline and intermediate 196K where necessary. (50 mg, 0.124 mmol, 77% yield) as a resinous liquid. MS (ESI) 404 (M+N).

Stage B. Intermediate 353B. Preparation of c-(3-bromophenyl)-A(('1-(3-cyclopropyl1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3- fluorobicyclo[1.G1]pentane-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 353A and the corresponding acid where necessary (50 mg, 0.097 mmol, 78% yield) as a gummy liquid. MS (ESI) 516 (M+H).

Step C. Example 353. Preparation of A((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3- (2-ethoxypyrimidin-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 353B and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (1.5 mg, 2.68 µmol, yield 7%).

¹ H NMR (400 MHz, DMSO-de) δ 9.03 (s, 2H), 7.87 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.69 (s, 2H), 3.63 (s, 2H), 2.18 -2.03 (m, 3H), 2.01-1.77 (m, 8H), 1.76-1.64 (m, 2H), 1.60 (d, J=6.8 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H), 1.08-0.98 (m, 2H), 0.91- 0.78 (m, 2H). FXR EC ₅₀ (nM) = 328. MS (ESI) 560 (M+H).

Example 354.

A(4'-(cyclopropanesulfonamido)-[1,G-biphenyl]-3-yl)-3-fluoro-N-((4-(4-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane- 1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 354A. Preparation of 3-bromo-N-((4-(4-(trifluoromethyl)pyridin2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 240C where necessary (450 mg, 1.01 mmol, 96% yield), as a brown solid. MS (ESI) 439 (M+H).

Stage B. Intermediate 354B. Preparation of A(3-bromophenyl)-3-fluoro-N-((4-(4(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo-[1.1.1] pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 354A and the corresponding acid where necessary (400 mg, 0.73 mmol, 71% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J=5.0 Hz, 1H), 7.72-7.68 (m, 1H), 7.62 (dt, J=6.9, 2.1 Hz, 1H), 7.58- 7.52 (m, 2H), 7.48-7.41 (m, 2H), 3.60 (br. s., 1H), 3.53 (br. s., 1H), 1.93-1.84 (m, 6H), 1.84-1.76 (m , 6H), 1.49-1.38 (m, 6H). MS (ESI) 553 (M+H).

Step C. Example 354. Preparation of A(4'-(cyclopropanesulfonamido)-[1,G-biphenyl]-3-yl)-3-fluoro- 294 047337

X-((4-(4-(triphgormethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1 -yl)methyl)bicyclo[1.1.1]pentan-1 carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 354B and (4(cyclopropanesulfonamido)phenyl)boronic acid where necessary. (18.4 mg, 0.03 mmol, 61% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (br. s., 1H), 8.76 (d, J=4.9 Hz, 1H), 7.80-7.62 (m, 4H), 7.61-7.46 (m, 3H ), 7.44-7.29 (m, 3H), 3.63 (d, J=7.3 Hz, 2H), 2.74-2.63 (m, 1H), 2.00-1.70 (m, 12H), 1.60-1.37 (m, 6H), 1.07-0.87 (m, 4H). FXR EC ₅₀ (nM) = 489. MS (ESl) 668 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 354B and the corresponding boronic acids.

Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (hM) 355 t oj° ΙΖ ° )==U° YES with V---U 642 780 356 o AL 1 j T J AD ⁿ s ^s A JI A £ 620 800 355 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.76 (d, J = 5.1 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 7.8 Hz , 1H), 7.65 (s, 1H), 7.58-7.48 (m, 3H), 7.417.29 (m, 3H), 3.63 (br. s., 2H), 3.04 (s, 3H), 1.99-1.71 ( m, 12H), 1.58-1.40 (m, 6H) 356 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, J = 4.9 Hz, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.86 (dd ,J=8.6, 1.7 Hz, 1H), 7.83-7.73 (m, 2H), 7.64-7.47 (m, 3H), 7.41 (d, J = 8.6 Hz, 1H), 3.71 (d, J = 13.4 Hz, 1H), 3.59 (d, J= 13.2 Hz, 1H), 2.84 (s, 3H), 2.01-1.74 (m, 12H), 1.50 (d, J = 5.6 Hz, 6H)

Example 357.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(3-(2ethoxypyrimidin-5 -yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 357A. Preparation of methyl 4-(((3bromophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

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The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 88B where necessary (6.4 g, 18.17 mmol, 79% yield), as a brown tarry liquid . MS (ESI) 353 (M+H).

Stage B. Intermediate 357B. Preparation of methyl 4-((F(3-bromophenyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylate

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 357A and the corresponding acid where necessary. (2.5 g, 5.38 mmol, 54% yield), as a brown tarry liquid, along with a minor amount of impurities. MS (ESI) 464 (M+H).

Step C. Intermediate 357C. Preparation of 4-((F(3-bromophenyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

The title compound was prepared according to the method described for the synthesis of intermediate 175B, replacing intermediate 357B where necessary (2.1 g, 4.66 mmol, 98% yield), as a brown gum. MS (ESI) 452 (M+H).

Stage D. Intermediate 357D. Preparation of J(3-bromophenyl)-N-((4-(3-(tert-butyl)1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 -fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 3A, by replacing intermediate 357C and (7)-N-hydroxypivalimidamide where necessary (200 mg, 0.377 mmol, 68% yield), as a brown tarry liquid . MS (ESI) 530 (M+H).

Step E. Example 357. Preparation of F((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 357D and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (11.6 mg, 0.020 mmol, 36% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.81 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.61 (d, J=8.6 Hz, 2H), 2.00-1.71 (m, 12H), 1.55-1.41 (m , 6H), 1.38 (t, J=7.1 Hz, 3H), 1.32-1.17 (m, 9H). FXR EC50 (nM) = 83. MS (ESI) 574 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 357D and the corresponding aryl/heteroarylboronates.

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Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (nM) 358 O M CH ₃ jl 1 /~SN ₃ /'Ν N ₃ C 570 154 359 kdk k /CH L J /~CH ₃ n ₃ s o^^ n ₃ s 572 151

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360 0 ^F A0 ab, . 11 J / сн ₃ Н ₃ С 0 N Н ₃ s 573 147 361 0 F А^ \/v4 Π Η λ ^Ν /А/X ^Ν 4 CH u _r ρ ί| dG \/ ^{СНз зА} Ι| I /~CH ₃ '/ N ₃ C ^υ Η 621 843 362 0 F^^ As Χα ^Ν / ^СНз 1ι η ГЯ ^сн · °'N CH ₃ H ₃ cy JJ 599 204 358 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 7.88-7.81 (m, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H) , 7.50-7.31 (m, 1H), 3.61 (d, J = 2.9 Hz, 2H), 2.32 -2.23 (m, 1H), 1.99-1.70 (m, 12H), 1.56-1.33 (m, 6H), 1.30 -1.19 (m, 9H), 1.18-0.97 (m, 4H) 359 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.75-7.63 (m, 3H), 7.63-7.57 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.11-6.97 (m, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.60 (s, 2H), 2.00-1.71 (m, 12H), 1.58-1.39 (m, 6H), 1.36 (t, J= 7.0 Hz, 3H), 1.31-1.18 (m, 9H) 360 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.77 -7.62 (m, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.42-7.31 (m, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.95- 1.72 (m, 12H), 1.57-1.40 (m, 6H), 1.35 (t, J= 7.1 Hz, 3H), 1.30 -1.15 (m, 9H) 361 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.717.59 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H) , 7.42-7.25 (m, 3H),3.60 (s, 2H), 3.04 (s, 3H), 1.98-1.73 (m,12H), 1.58-1.37 (m, 6H), 1.35-1.15 (m, 9H) 362 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.83 -7.70 (m, 2H), 7.57 (t, J= 7.8 Hz, 1H),

7.40 (d, J= 8.1 Hz, 1H), 3.68 (d, J= 13.9 Hz, 1H), 3.58 (d, J= 13.9 Hz, 1H), 2.83 (s, 3H), 2.00-1.71 (m, 12H ), 1.61 -1.45 (m, 6H), 1.33-1.15 (m, 9H)

7.40 (d, J= 8.1 Hz, 1H), 3.68 (d, J= 13.9 Hz, 1H), 3.58 (d, J= 13.9 Hz, 1H), 2.83 (s, 3H), 2.00-1.71 (m, 12H ), 1.61 -1.45 (m, 6H), 1.33-1.15 (m, 9H)

Example 363.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3- (2methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

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Step A: Intermediate 363A. Preparation of D-((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(5, 5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 149C, replacing intermediate 357D where necessary (150 mg, 0.27 mmol, 83% yield), as a white solid. MS (ESI) 496 (M+H) (weight of boronic acid).

Step B. Example 363. Preparation of N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro- N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 363A and 5-bromo-2-methoxypyrimidine where necessary (6.7 mg, 0.012 mmol, 22% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 7.82 (s, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.58 (t, J= 7.8 Hz, 1H) , 7.44 (d, J=9.0 Hz, 1H), 3.99 (s, 3H), 3.61 (d, J=7.8 Hz, 2H), 1.99 -1.69 (m, 12H), 1.59-1.36 (m, 6H), 1.35-1.17 (m, 9H). FXR EC ₅₀ (nM) = 70. MS (ESI) 560 (M+N).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 363A with the corresponding aryl/heteroaryl halides.

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Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (nM) 364 M ^N CH Ш _s ' Ν N Н ₃ s ^m з^ η 622 509 365 0 Mgei \\ I P . N S^/A/xX · Ν-A ri /° Al \ / ^CH 3 ⁿ zSD, II Ί X-cn ₃ ⁿ n n ₃ s 600 84 366 o F^^ Di \D\/O _X \\ I N . N /х LA N-Μ _gn N \/ ^СНз AJ Г~СН ₃ F ₃ CN Н ₃ С 598 454 367 AlM \\ 1 Y ,N DkU N-Μ ri NS/ ⁰ fii \D ^{Nz NzS} b AJ Asn ₃ χ/ NN N ₃ C ° N 623 645

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7.10 (d,J = 8.8 Hz, 1H), 3.91 (s, 3H),3.61 (s, 2H), 1.97-1.69 (m, 12H), 1.57- 1.37 (m, 6H), 1.34-1.22 (m, 9H) 365 Ή NMR (400 MHz, DMSO-de) δ 9.03 (d, J = 2.2 Hz, 1H), 8.94 (d, J = 2.2 Hz, 1H), 7.92-7.81 (m, 2H), 7.61 (t, J = 8.2 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 3.64 (d, J = 19.3 Hz, 2H), 2.91(s, 3H), 2.00-1.71 (m, 12H), 1.49 (d, J = 7.3 Hz, 6H), 1.33-1.22 (m, 9H) 366 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 2H), 8.05-7.99 (m, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.73-7.63 (m, 1H), 7.58 ( d, J = 8.8 Hz, 1H), 3.63 (d, J= 14.9 Hz, 2H), 2.02-1.72 (m, 12H), 1.57-1.37 (m, 6H), 1.35-1.18 (m, 9H) 367 ΉNMR (400 MHz, DMSO-d ₆ ) δ 11.49 (br. s., 1H), 9.05 (s, 2H), 7.83 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.45 (d, J =7.8 Hz, 1H), 3.62 (br. s., 2H), 3.42 (s, 3H), 1.99-1.73 (m, 12H), 1.58-1.38 ( m, 6H), 1.33-1.21 (m, 9H) 368 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.89-7.77 (m, 2H), 7.76-7.64 (m, 2H), 7.55 (t, J = 7.7 Hz, 1H), 7.44-7.34 (m, 1H), 7.34-7.20 (m, 3H), 3.61 (d, J= 10.5 Hz, 2H), 2.01-1.71 (m, 12H),1.57-1.35 (m, 6H), 1.33-1.16 (m, 9H) 369 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (s, 2H), 8.31 (dt, J = 7.8, 1.3 Hz, 1H), 8.19 (t, J = 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (ddd, J = 7.8, 2.2, 1.2 Hz, 1H), 3.98 (s, 3H), 3.66(br. s., 1H), 3.58 (br. s., 1H), 1.88 (d, J= 9.5 Hz, 6H), 1.84-1.62 (m, 6H), 1.59-1.34 (m, 6H),1.33-1.18 (m, 9H) 370 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 2H), 8.40-8.24 (m, 1H), 8.18 (t, J= 1.8 Hz, 1H), 7.65- 7.56 (m, 1H), 7.53- 7.43 (m, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.65 (br. s., 1H), 3.58 (br. s., 1H), 1.88 (d, J = 8.8 Hz, 6H) , 1.84-1.60 (m, 6H), 1.571.32 (m, 9H), 1.31-1.12 (m, 9H) 371 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.36 (dt, J = 7.6, 1.4 Hz, 1H), 8.24 (t, J = 1.7 Hz, 1H), 7.69-7.50 (m, 2H), 7.43 (s, 1H), 3.66 (br. s., 1H), 3.59 (br. s., 1H), 1.89 (br. s., 6H), 1.86 -1.61 (m, 6H), 1.57 -1.36 (m, 6H), 1.32-1.17 (m, 9H) 372 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J = 8.8 Hz, 2H), 7.75-7.64 (m, 2H), 7.54 (t, J = 7.8 Hz, 2H), 7.44-7.30 (m, 3H), 3.60 (d, J= 8.8 Hz, 2H), 1.96-1.72 (m, 12H), 1.55-1.39(m, 6H), 1.31-1.19 (m, 9H) 373 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J= 2.7 Hz, 1H), 8.17 (d, J= 8.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.05 (t , J = 1.8 Hz, 1H), 7.80 (dd, J = 8.8, 2.9 Hz, 1H), 7.65-7.52 (m, 1H), 7.52-7.42(m, 1H), 7.38 (s, 1H), 3.62 (br. s., 2H), 1.88 (br. s., 6H), 1.85- 1.59 (m, 6H), 1.56 -1.33 (m, 6H), 1.32-1.17 (m, 9H)

Example 374.

X-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-X-((4-(3-isopropyl-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 374A. Preparation of D-(3-bromophenyl)-3-ph'gor-D-((4-(3isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl) bicyclo-[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 3A, replacing intermediate 357C and (Z)-N'hydroxyisobutyrimidamide where necessary (160 mg, 0.310 mmol, 70% yield), as a gray tarry liquid along with a small amount of impurities. MS (ESI) 518 (M+H).

Step B. Example 374. Preparation of D-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-D-((4-(3isopropyl-1,2,4-oxadiazol-5-yl)bicyclo [2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 374A and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (11 mg, 0.020 mmol, 34% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.82 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 4.43 (q, J=6.9 Hz, 2H), 3.61 (d, J=13.7 Hz, 2H), 2.99 (dt, J=13.8, 7.0 Hz, 1H), 1.99-1.71 (m, 12H), 1.56-1.40 (m, 6H),

1.38 (t, J=7.0 Hz, 3H), 1.22 (d, J=6.8 Hz, 6H). FXR EC ₅₀ (nM) = 44. MS (ESI) 560 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 374A and the corresponding aryl/heteroarylboronates/boronic acids.

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Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (hM) 375 CO X o z A o' Vu s to AZ Ο=ζ ^Ш o < o co X 558 61 376 /zh, \\ I T .Ν ^Ν ~4 ⁿ ₃ Сж° ί Т /~~СН ₃ 4Н ₃ s ^υ n 607.3 32 377 with X o ;ζ o' Υ% A °=ζ ^w o / o with X 544 52 378 0 Dx kkY-N_СИз S^^i^xJM θΊΜ ⁴ сн ₃ ^Η 3^Υ II] 585 53

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379 Vzp gA °' ^СНз s. BP ^and n 633 132 380 o N __СНз 0-Ν^СН ₃ JJ 582 283 381 О ^f> ^ A ^^Α ^ν Α ^Η3 ^уАД ON CH ₃ НзС^СГ IT 559 40 382 0 A ^v ⁿ A ^H3 ON CH ₃ ^НзС \АХ 545 98 375 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.72-7.59 (m, 4H), 7.50 (t, 7=7.8 Hz, 1H), 7.31 (d, 7=7.8 Hz, 1H), 7.04 (d, 7= 8.8 Hz, 2H), 4.09 (q, 7=6.9 Hz, 2H), 3.60 (d, 7=4.4 Hz, 2H), 2.99 (dt, 7=13.9, 6.9 Hz, 1H), 1.93-1.75 (m, 12H), 1.54-1.42 (m, 6H), 1.36 (t, 7=7.0 Hz, 3H), 1.27-1.18 (m, 6H) 376 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.90 (br. s., 1H), 7.74 (d, 7=8.7 Hz, 2H), 7.717.63 (m, 2H), 7.53 (t, 7=7.8 Hz , 1H), 7.39-7.29 (m, 3H), 3.60 (d, 7=4.0 Hz, 2H), 3.04 (s, 3H), 3.02-2.94 (m, 1H), 1.94-1.74 (m, 12H), 1.53-1.41 (m, 6H), 1.271.17 (m, 6H) 377 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.74-7.60 (m, 4H), 7.51 (t, 7=7.8 Hz, 1H), 7.32 (d, 7=8.2 Hz, 1H), 7.06 (d, 7= 8.7 Hz, 2H), 3.81 (s, 3H), 3.60 (d, 7=5.7 Hz, 2H), 2.99 (dt, 7=13.8, 7.0 Hz, 1H), 1.94-1.73 (m, 12H), 1.55- 1.42 (m, 6H), 1.28-1.17 (m, 6H)

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, 7=1.5 Hz, 1H), 8.00 (d, 7=8.4 Hz, 1H), 7.86 (dd, 7=8.6, 1.8 Hz, 1H), 7.83 -7.75 (m, 2H), 7.57 (t, 7=7.8 Hz, 1H), 7.41 (d, 378 7=8.1 Hz, 1H), 3.68 (d, 7=13.2 Hz, 1H), 3.57 (d, 7 =13.7 Hz, 1H), 2.99 (dt, 7=13.8, 7.0 Hz, 1H), 2.84 (s, 3H), 1.97-1.76 (m, 12H), 1.56-1.40 (m, 6H), 1.271.18 ( m, 6H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (br. s., 1H), 7.77-7.63 (m, 4H), 7.53 (t, 7=7.8 Hz, 1H), 7.35 (d, 7=8.6 Hz , 3H), 3.68-3.52 (m, 2H), 2.99 (dt, 7=13.8, 7.0 379

Hz, 1H), 2.71-2.64 (m, 1H), 1.95-1.74 (m, 12H), 1.55-1.39 (m, 6H), 1.27-1.17 (m, 6H), 1.02-0.92 (m, 4H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (d, 7=8.1 Hz, 2H), 7.90-7.76 (m, 4H), 7.60 (t, 7=8.1 Hz, 1H), 7.48 (d, 7= 7.6 Hz, 1H), 3.71-3.62 (m, 1H), 3.62-3.53 (m, 1H), 380

2.99 (dt, 7=13.8, 7.0 Hz, 1H), 1.96-1.75 (m, 12H), 1.56-1.40 (m, 6H), 1.28-1.17 (m, 6H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, 7=2.0 Hz, 1H), 8.10 (dd, 7=8.8, 2.8 Hz, 1H), 7.75-7.67 (m, 2H), 7.54 (t, 7=8.0 Hz, 1H), 7.37 (d, 7=7.0 Hz, 1H), 6.91 (d, 381 7=8.5 Hz, 1H), 4.37 (q, 7=7.0 Hz, 2H), 3.61 (s, 2H ), 2.99 (dt, 7=13.7, 7.0 Hz, 1H), 1.94-1.75 (m, 12H), 1.52-1.42 (m, 6H), 1.35 (t, 7=7.3 Hz, 3H), 1.26-1.18 ( m, 6H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (d, 7=2.5 Hz, 1H), 8.11 (dd, 7=8.5, 2.5 Hz, 1H), 7.74-7.68 (m, 2H), 7.54 (t, 7=8.3 Hz, 1H), 7.38 (d, 7=8.0 Hz, 1H), 6.95 (d, 382

7=8.5 Hz, 1H), 3.91 (s, 3H), 3.63-3.58 (m, 2H), 2.99 (dt, 7=13.7, 7.0 Hz, 1H), 1.93-1.76 (m, 12H), 1.53-1.42 (m, 6H), 1.26-1.19 (m, 6H)

Example 383.

3-fluoro-U-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)4U-(3-(2methoxypyrimidin-5 -yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Ay _/ ^СНз _n ^AaA СНз ^НзС mАы ( ₃₈ 3)

Step A: Intermediate 383A. Preparation of Y-(3-(5,5-dimethyl-'1,3,2-dioxaborinan-2yl)phenyl)-3-fluoro-U-((4-(3-isopropyl-1,2,4-oxadiazol- 5-yl)bicyclo[2.2.2]octan-1 yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 262A, replacing intermediate 374A where necessary (90 mg, 0.164 mmol, 70% yield), as a white solid. MS (ESI) 482 (M+H) (weight of boronic acid).

Step B. Example 383. Preparation of 3-fluoro-U-((4-(3-isopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-( 3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo-[1.1.1]pentan-1- 306 047337 carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 383A and 5-bromo-2-methoxypyrimidine where necessary (3.7 mg, 6.78 μmol, 12% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.87-7.80 (m, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.58(t, J=7.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 3.99 (s, 3H), 3.61 (d, J=13.0 Hz, 2H), 2.99 (quin, J=7.0 Hz, 1H), 1.98-1.69 ( m, 12H), 1.57-1.36 (m, 6H), 1.28-1.15 (m, 6H). FXR EC ₅₀ (nM) = 47. MS (ESI) 545 (M+N).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 383A and the corresponding aryl/heteroaryl halides.

Etc. No. Name MS (ESI) (M+N) FXR ec ₅₀ (nM) 384 O хЦ Υ^Υγ^ ^Ν \__/ ^0Η3 Ο'Ν^ЗН ₃ II \ Ε ₃ (7Ίν 584 184 385 O xC ^^^A ^m \--7 ^СНз Ο'Ν^СНз II \ γχΧ 556 35 386 o xA HaAah/ ^СНз Р OyyAz °'Ν СНз 594 274 387 o /DH^^DAk Hu ΧΧΧαΙ__CH _{3 F} O'/'CH ₃ 580 47 388 XX about LL? 583 906 389 O F^^ Hu __/ ^СНз ON^СНз n ₃ s—I |T ^N ^l< 586 61

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2.99 (quin, J= 7.0Hz, 1H), 2.00-1.71 (m, 12H), 1.59-1.37 (m, 6H), 1.31-1.12 (m, 6H) 385 Ή NMR (400 MHz, DMSO-de) δ 9.04 (s, 2H), 7.84 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 3.61 (d, J = 7.1Hz, 2H), 2.99 (dt,7 = 13.9, 6.9 Hz, 1H), 2.31-2.20 (m, 1H), 1.97-1.74 (m, 12H), 1.57-1.38 (m, 6H), 1.27-1.17 (m, 6H), 1.14 -0.99 (m, 4H) 386 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, 7=2.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.61 (dd, 7=8.3, 1.8 Hz, 1H), 7.57-7.49 ( m, 2H), 7.43-7.37 (m, 1H), 3.64 (d, 7=13.6 Hz, 1H), 3.56 (d, 7=13.6 Hz, 1H), 2.98 (dt, 7=13.9, 6.8 Hz, 1H ), 1.88 (br. s., 4H), 1.85-1.77 (m, 8H), 1.51-1.40 (m, 6H), 1.26-1.18 (m, 6H) 387 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.83-7.77 (m, 2H), 7.72-7.66 (m, 2H), 7.53 (t, 7=8.0 Hz, 1H), 7.48-7.11 (m, 4H), 3.66-3.53 (m, 2H), 2.97 (dt, 7=13.7, 7.0 Hz, 1H), 1.91-1.75 (m, 12H), 1.45-1.47 (m, 6H), 1.25-1.17 (m, 6H) 388 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (d, 7=2.0 Hz, 1H), 8.45 (dd, 7=8.3, 2.3 Hz, 1H), 8.00 (d, 7=8.5 Hz, 1H), 7.92 -7.83 (m, 2H), 7.61 (t, 7=7.8 Hz, 1H), 7.51 (d, 7=8.0 Hz, 1H), 3.68-3.61 (m, 1H), 3.59-3.52 (m, 1H), 2.96 (dt, 7=13.7, 7.0 Hz, 1H), 1.91-1.74 (m, 12H), 1.49-1.40 (m, 6H), 1.23-1.16 (m, 6H) 389 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (d, 7=2.5 Hz, 1H), 8.93 (d, 7=2.0 Hz, 1H), 7.87-7.83 (m, 2H), 7.60 (t, 7= 8.0 Hz, 1H), 7.48-7.43 (m, 1H), 3.67 (d, 7=13.6 Hz, 1H), 3.58 (d, 7=13.1 Hz, 1H), 2.98 (dt, 7=13.7, 7.0 Hz, 1H), 2.90 (s, 3H), 1.951.76 (m, 12H), 1.46 (d, 7=10.5 Hz, ZN), 1.48 (d, 7=9.5 Hz, ZN), 1.25-1.18 (m, 6H ) 390 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, 7=8.0 Hz, 2H), 7.72-7.66 (m, 2H), 7.54 (t, 7=7.5 Hz, 1H), 7.40-7.33 (w, ZN), 3.59 (d, 7=12.5 Hz, 2H), 2.98 (dt, 7=13.9, 6.8 Hz, 1H), 1.93-1.75 (m, 12H), 1.46 (d, 7=8.0 Hz, 6H), 1.25-1.18 (m, 6H) 391 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (d, 7=2.5 Hz, 1H), 8.19 (dd, 7=8.0, 2.5 Hz, 1H), 7.81-7.74 (m, 2H), 7.57 (t, 7=7.8 Hz, 1H), 7.52 (d, 7=8.0 Hz, 1H), 7.44 (d, 7=7.5 Hz, 1H), 4.55 (s, 2H), 3.66 (d, 7=13.1 Hz, 1H) , 3.56 (d, 7=13.6 Hz, 1H), 3.40 (s, 3H), 2.98 (dt, 7=13.7, 7.0 Hz, 1H), 1.93-1.77 (m, 12H), 1.51-1.42 (m, 6H ), 1.25-1.18 (m, 6H) 392 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (d, 7=8.0 Hz, ZN), 7.69 (d, 7=5.5 Hz, 1H), 7.53 (t, 7=7.8 Hz, 1H), 7.43 (d , 7=8.0 Hz, 2H), 7.37 (d, 7=9.0 Hz, 1H), 4.46 (s, 2H), 3.65 (d, 7=14.1 Hz, 1H), 3.55 (d, 7=14.1 Hz, 1H ), 2.98 (dt, 7=13.7, 7.0 Hz,

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1H), 1.93-1.76 (m, 12H), 1.51-1.42 (m, 6H), 1.25-1.17 (m, 6H) (3 protons hidden under the solvent) 393 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.80 (s, 2H), 8.37 (d, 7=7.5 Hz, 1H), 8.26-8.22 (m, 1H), 7.64-7.58 (m, 1H), 7.57 -7.52 (m, 1H), 3.61 (d, 7=15.6 Hz, 2H), 2.97 (dt, 7=13.7, 7.0 Hz, 1H), 2.33 (s, 3H), 1.88 (br. s., 5H) , 1.85-1.75 (m, 7H), 1.491.41 (m, 6H), 1.25-1.17 (m, 6H) 394 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 2H), 8.37 (d, 7=8.0 Hz, 1H), 8.25 (s, 1H), 7.64-7.59 (m, 1H), 7.57-7.52 ( m, 1H), 3.65 (d, 7=15.6 Hz, 2H), 2.97 (dt, 7=13.7, 7.0 Hz, 1H), 2.72-2.65 (m, 2H), 1.93-1.76 (m, 12H), 1.49 -1.41 (m, 6H), 1.28-1.18 (m, 9H) 395 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 2H), 8.30 (d, 7=8.0 Hz, 1H), 8.17 (t, 7=1.8 Hz, 1H), 7.59 (t, 7=7.8 Hz , 1H), 7.50 (d, 7=7.5 Hz, 1H), 4.27 (q, 7=7.0 Hz, 2H), 3.64 (br. s., 1H), 3.57 (br. s., 1H), 2.97 ( dt, 7=13.9, 6.8 Hz, 1H), 1.93-1.75 (m, 12H), 1.49-1.43 (m, 6H), 1.39 (t, 7=7.0 Hz, ZN), 1.26-1.18 (m, 6H)

Example 396.

X-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3yl)bicyclo [2.2. 2] octan-1 -yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 396A. Preparation of 4-((X-(3-bromophenyl)-3fluorobicyclo[1.1.1]pentan-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

To a stirred solution of intermediate 357C (1.65 g, 3.66 mmol) in DMF (15 ml) was added ammonium chloride (235 mg, 4.40 mmol), TEA (1.5 ml, 10.99 mmol) and BOP (1.78 g, 4.03 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, diluted with water (50 ml) and extracted with ethyl acetate (2x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give the title compound (1.6 g, 3.56 mmol, 97% yield). MS (ESI) 450 (M+H).

Stage B. Intermediate 396V. Preparation of X-(3-bromophenyl)-N-((4cyanobicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

A stirred solution of intermediate 396A (1.6 g, 3.56 mmol) in pyridine (15 ml) was cooled to 0°C. TFAA (2.51 mL, 17.80 mmol) was added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ice water (50 ml) and extracted with ethyl acetate (2x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (850 mg, 1.97 mmol, 55% yield) as a pale brown resinous liquid. MS (ESI) 431 (M+H).

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Step C. Intermediate 396C. Preparation of (E)-Na-(3-bromophenyl)-3-fluoro-Na-((4-(Nahydroxycarbamidoyl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1 -carboxamide

ABOUT

The title compound was prepared according to the method described for the synthesis of intermediate 227F, replacing intermediate 396B where necessary (820 mg, 1.766 mmol, 92% yield) as a white solid. MS (ESI) 464 (M+H).

Stage D. Intermediate 396D. Preparation of D-(3-bromophenyl)-3-fluoro-D-((4-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)bicyclo[1.1.1]pentane-1carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 3A, replacing intermediate 396C and the corresponding acid where necessary (850 mg, 1.608 mmol, 91% yield), as a brown solid. MS (ESI) 528 (M+H).

Step E. Example 396. Preparation of N(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1methylcyclopropyl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 396D and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (20.7 mg, 0.035 mmol, 62% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.63 (br. s., 1H), 3.57 (br. s., 1H), 1.85 (s, 3H), 1.89 (s, 3H), 1.78-1.58 (m, 6H), 1.53-1.30 (m, 12H), 1.29 -1.18 (m, 2H), 1.11-0.96 (m, 2H). FXR EC50 (nM) = 46. MS (ESI) 572 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 396D and the corresponding boronic acids/esters.

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Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (hM) 397 h ί'ί ^{υ υ} Η 645 183 398 Μ °=ζ ο. / ^ζτ J ⁰ CO □Ξ 619 93 399 ο A, ΜΥΥ /1 sp ₃ [ιη^ 570 58 400 1¾ ο / ο CO τ 558 51 401 ^Ν ~·ο ί τ HgC^O^N^ 571 42 402 -lsk-Ч Sx/ΧχΜΜΜ Ν-Ο НзС ^- у ]l J 597 35

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403 Aku _n AJ n^o CH ₃ Y ⁿ 568 100 404 0 x<s. N—d) NY +/ ^u AJ F ₃ C^N 596 221 405 0 VaOvA /%/U ^N ~o P ₂ NSSU+D 592 53 397 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 7.80-7.60 (m, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.6 Hz, 3H) , 3.59 (d, J= 17.9 Hz, 2H), 2.73-2.65 (m, 1H), 1.85 (s, 3H), 1.88(s, 3H), 1.77-1.63 (m, 6H), 1.45 (s, 8H ), 1.27-1.18 (m, 3H), 1.08-1.01 (m, 2H), 1.01-0.90(m, 4H) 398 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.717.62 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H) , 7.39-7.24 (m, 3H), 3.59 (d, J = 12.5 Hz, 2H), 3.04 (s, 3H), 1.86(s, 3H), 1.88 (s, 3H), 1.78-1.57 (m, 6H ), 1.53-1.33 (m, 9H), 1.27-1.19 (m, 2H), 1.08-0.99 (m, 2H) 399 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.73-7.56 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.8,1.0 Hz, 1H), 7.10-6.94 ( m, 2H), 4.09 (q, J= 7.0 Hz, 2H), 3.693.47 (m, 2H), 1.86(d, J= 9.5 Hz, 6H), 1.78-1.57 (m, 6H), 1.57-1.38 (m, 9H), 1.36 (t, J= 7.0 Hz, 3H), 1.28-1.19(m, 2H), 1.08-1.00 (m, 2H). 400 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.82 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 3.99 (s, 3H), 3.62 (br. s., 1H), 3.57 (br. s., lH), 1.85 (s, 3H), 1.88 (s, 3H ), 1.77-1.57 (m, 6H), 1.45 (s, 9H), 1.26-1.18 (m, 2H), 1.07-0.98(m, 2H) 401 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.6, 2.7

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Hz, 1H), 7.77 -7.62 (m, 2H), 7.53 (t, J= 7.9 Hz, 1H), 7.36 (dd, J= 7.1, 1.2 Hz, 1H), 6.91 (dd, J = 8.7, 0.6 Hz , 1H), 4.37 (q, J = 7.0 Hz, 2H), 3.59 (d, J = 7.6 Hz, 2H), 1.85 (s, ZN), 1.88 (s, ZN), 1.78 -1.57 (m, 6H) , 1.57-1.38 (m, 9H), 1.35 (t, J = 7.0 Hz, ZN), 1.27-1.18 (m, 2H), 1.09-0.96 (t, 2H) 402 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 -7.71 (m, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 3.76-3.62 (m, 1H), 3.61-3.47 (m, 1H), 2.83 (s, 3H), 1.86 (s, 3H), 1.90 (s, 3H), 1.79-1.59(m, 6H), 1.57-1.30 (m, 9H), 1.27-1.16 (m, 2H), 1.08- 0.95 (m, 2H) 403 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.87-7.81 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H) , 7.45 (d, J= 8.8 Hz, 1H), 3.68-3.51 (m, 2H), 2.32-2.23 (m, 1H),1.84 (s, 3H), 1.88 (s, 3H), 1.78-1.60 (m , 6H), 1.54-1.31 (m, 9H), 1.27-1.19 (m, 2H), 1.16 -0.93 (m, 6H) 404 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.04-7.98 (m, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.70- 7.63 (m, 1H), 7.62- 7.55 (m, 1H),3.66 (br. s., 1H), 3.58 (br. s., 1H), 1.86 (s, 3H),1.90 (s, 3H), 1.77-1.57 (m, 6H), 1.56-1.31 (m, 9H), 1.26-1.20 (m, 2H), 1.08-1.02 (m, 2H) 405 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.88-7.77 (m, 2H), 7.76-7.65 (m, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H), 7.34-7.20 (m, 3H), 3.69-3.59 (m, 1H), 3.59-3.48(m, 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.56 (m, 6H), 1.56-1.29 (m, 9H), 1.27-1.17 (m, 2H),1.07-0.98 (m, 2H)

Example 406.

N((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4'(methylsulfonamido)- [1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 406A. Preparation of 3-bromo-N-((4-(5-cyclopropyl-1-methyl-Spirazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing: 3-bromoaniline and intermediate 124E where necessary (130 mg, 0.298 mmol, 59% yield) as an off-white solid. MS (ESI) 416 (M+H).

Stage B. Intermediate 406B. Preparation of P-(3-bromophenyl)-P-((4-(5-cyclopropyl-1methyl-N-pyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1 .1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, by replacing: intermediate 406A and the corresponding acid where necessary (100 mg, 0.180 mmol, 57% yield), as an off-white solid. MS (ESI) 526

- 314 047337 (M+N).

Step C. Example 406. Preparation of X-((4-(5-cyclopropyl-1-methyl-III-pyrazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-X-( 4'-(methylsulfonamido)-[1,G-biphenyl]-3yl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 406B and (4(methylsulfonamido)phenyl)boronic acid where necessary (203 mg, 0.032 mmol, 68% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (br. s., 1H), 7.78-7.71 (m, 2H), 7.67 (d, J=8.1 Hz, 1H), 7.64-7.60 (m, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.33 (d, J=8.6 Hz, 3H), 5.59 (s, 1H), 3.69 (s, 3H), 3.57 (d, J=11.5 Hz, 2H), 3.04 (s, 3H), 1.88-1.85 (m, 6H), 1.78-1.71 (m, 1H), 1.68-1.50 (m, 6H), 1.40-1.38 (m, 6H), 0.88-0.85 ( m, 2H), 0.550.50 (m, 2H). FXR EC ₅₀ (nM) 203. MS (ESI) 618 (M+N).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 406B and the corresponding boronic acids/esters.

Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (hM) 407 О /Ах, ΑΑΑ/Χχ /И vj ν JJ ^СНз Н ₃ С О Ν 570 209 408 O n ₃ sDi Λ ^{3 x} o 554 160 409 O F ^/t '~' ⁷ dA ZDuAh ⁿ 'N H ₃ cV J| J sn ₃ 595 73 410 o f^ ⁷ dA АААд\_/н Д^ДдЧ^ Nn ΙΑ—У Ji J CH ₃ 622 465 411 o f^ ⁷ /Ax, AAA/X. /1 i | P U<1 Ν- _ν Jl J CH ₃ n 581 144 407 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.79 (d, J = 1.7 Hz, 1H), 7.76 (d,

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J= 8.1 Hz, 1H), 7.56 (t, J= 7.8 Hz, 1H), 7.40 (d, J= 7.8 Hz, 1H), 5.59 (s, 1H), 4.43 (q, J= 7.1 Hz, 2H) , 3.69 (s, ZN), 3.62-3.52 (m, 1H), 1.98-1.78 (m, 7H), 1.78-1.70 (m, 1H), 1.67-1.51 (m, 6H), 1.38-1.35 (m, 9H), 0.87-0.85 (m, 2H), 0.53-0.51 (m, 2H). 408 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.72-7.62 (w, ZH), 7.61-7.57 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 5.59 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.69-3.57 (m, 2H), 1.87-1.85 (m , 6H), 1.79-1.71 (m, 1H), 1.68-1.52 (m, 6H), 1.40-1.38 (m, 6H), 0.88-0.85 (m, 2H), 0.55-0.52 (m, 2H). 409 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.6, 1.7 Hz, 1H), 7.81 -7.68 (m, 2H), 7.56 (t, J= 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 5.59 (s, 1H), 3.73-3.60 (m, 5H), 2.83 ( s, 3H), 1.91-1.86 (m, 6H), 1.78-1.71 (m, 1H), 1.68-1.51 (m, 6H), 1.40 (d, J = 5.9 Hz, 6H), 0.870.83 (m, 2H), 0.54 -0.51 (m, 2H). 410 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (d, J = 2.2 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.90-7.73 (m, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 5.59 (s, 1H), 3.78 (s, 3H) 3.57 -3.52 (m, 2H), 2.65-2.57 (m, 1H), 1.91 -1.86 (m, 6H), 1.78-1.71 (m, 1H), 1.70-1.49 (m, 6H), 1.48-1.28 (m, 8H), 1.28-1.19 (m, 2H), 0.93-0.80 (m, 2H), 0.57-0.46 (m, 2H). 411 'NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 7.73 (d, J = 1.5 Hz, 1H), 7.717.61 (m, 2H), 7.59-7.45 (m, 2H), 7.33 ( d, J= 8.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 5.59 (s, 1H), 3.69 (s, 3H), 3.63-3.51 (m, 2H), 1.99-1.78 (m , 6H), 1.78-1.71 (m, 1H), 1.69-1.50 (m, 6H), 1.39 (d, J= 6.1 Hz, 6H), 0.94-0.81 (m, 2H), 0.580.48 (m, 2H ).

Example 412.

X-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4'(methylsulfonamido) -[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 412A. Preparation of 3-bromo-N-((4-(3-cyclopropyl-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 126B where necessary (140 mg, 0.321 mmol, 64% yield) as an off-white solid. MS (ESI) 414 (M+H).

Stage B. Intermediate 412B. Preparation of X-(3-bromophenyl)-N-((4-(3-cyclopropyl-1methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1 .1]pentane-1-carboxamide

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The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 412A and the corresponding acid where necessary (100 mg, 0.180 mmol, 57% yield) as an off-white solid. MS (ESI) 528 (M+H).

Step C. Example 412. Preparation of D-((4-(3-cyclopropyl-1-me'gyl-1I-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro -N-(4'-(methylsulfonamido)-[1,G-biphenyl]-3yl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 412B and (4(methylsulfonamido)phenyl)boronic acid where necessary (5.3 mg, 8.59 µmol, 18% yield ).

¹ I NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1I), 7.73 (d, J=8.6 Hz, 2H), 7.68 (d, J=8.1 Hz, 1I), 7.66-7.60 (m, 1I), 7.53 (t, J=7.8 Hz, 1I), 7.41-7.26 (m, 3H), 5.62 (s, 1I), 3.72 (s, 3H), 3.58-5.56 (m, 2I), 3.04 (s , 3H), 1.88-1.86 (m, 6H), 1.77-1.60 (m, 7I), 1.45-1.42 (m, 6H), 0.76-0.72 (m, 2I), 0.54-0.52 (m, 2I). FXR EC ₅₀ (nM) 105. MS (ESI) 617 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 412B and the corresponding boronic acids/esters.

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414 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.64 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 7.8, 1.0 Hz, 1H), 7.07-7.01 ( m, 2H), 5.62 (s, 1H), 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.64-3.47 (m, 2H), 1.87-1.81 (s, 6H), 1.76-1.59 (m, 7H), 1.45-1.41 (m, 6H), 0.76-0.73 (m, 2H), 0.54-0.52 (m, 2H). 415 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.85 (dd, J = 8.6, 2.0 Hz, 1H), 7.81 -7.76 (m, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.45-7.40 (m, 1H), 5.60 (s, 1H), 3.71 (s, 3H), 3.63-3.61 (m, 1H ), 3.53-3.51 (m, 1H), 2.84 (s, 3H), 1.91-1.73 (m, 6H), 1.73-1.65 (m, 7H), 1.50-1.44 (m, 6H), 0.74-0.72 (m , 2H), 0.54-0.52 (m, 2H).

Example 416.

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

ABOUT

To a stirred solution of intermediate 246B (20 mg, 0.039 mmol) in 1,4dioxane (2 ml) was added 1-methylpiperazine (7.79 mg, 0.078 mmol), sodium tert-butoxide (11 mg, 0.117 mmol) and Xantphos (4 .5 mg, 7.78 µmol). The reaction mixture was degassed and filled with argon again. Pd ₂ (dba) ₃ (3.56 mg, 3.89 µmol) was added to the reaction mixture and the vial (pressure release bottle) was sealed under argon. The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 ml) and extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative LC/MS using the following conditions (column. Waters XBridge C18, 150 mmx19 mm, 5 μm particles; mobile phase A. 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B. 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient 5-minute hold at 20% B, 20-58% B for 25 minutes, then 5-minute hold at 100% B;

flow rate 15 ml/min; column temperature 25°C). Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3 mg, 5.62 μmol, 14% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.26 (t, J=8.1 Hz, 1H), 6.95-6.93 (m, 1H), 6.89 (s, 1H), 6.76 (d, J=8.3 Hz, 1H ), 3.58-3.44 (m, 2H), 3.27-3.05 (m, 4H), 2.57-2.53 (m, 3H), 2.33-2.29 (m, 4H), 2.11-1.99 (m, 1H), 1.86-1.44 (m, 12H), 1.43-1.40 (m, 6H), 1.03-0.99 (m, 2H), 0.85-0.82 (m, 2H). FXR EC50 (nM) = 1058. MS (ESI) 534 (M+H).

The following compound was prepared in accordance with the method described for the synthesis of example 416, by replacing intermediate 246B and the corresponding amines.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 417 O°-N ^Z 520 207 417 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.28 (t, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.2, 2.1 Hz, 1H), 6.90 (t, J = 2.0 Hz, 1H), 6.78 (d, J = 7.3 Hz, 1H), 3.75 (t, J = 4.8 Hz, 4H), 3.58-3.45 (m, 2H), 3.21-3.07 (m, 4H), 2.08-2.03 (m, 1H), 1.86-1.70 (m, 12H), 1.49-1.38 (m, 6H), 1.09-0.96 (m, 2H), 0.90-0.82 (m, 2H).

Example 418.

A-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-A-(('1-(2-(trifluoromethyl)pyrimidin-5-yl)-2oxabicyclo[2.2.2]octane-4 -yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 418A. Preparation of (trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)aniline

3-bromo-X-((1-(2-

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 181E where necessary (130 mg, 0.270 mmol, 77% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-de) δ 9.07 (s, 2H), 7.00 (t, J=8.0 Hz, 1H), 6.80 (t, J=2.0 Hz, 1H), 6.67-6.61 (m, 2H ), 5.83 (t, J=5.8 Hz, 1H), 3.90 (s, 2H), 2.91 (d, J=6.0 Hz, 2H), 2.28-2.17 (m, 2H), 1.99-1.89 (m, 2H) , 1.821.69 (m, 4H). MS (ESI) 443 (M+H).

Stage B. Intermediate connection 418V. Preparation of F(3-bromophenyl)-3-fluoro-X-((1-(2(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)bicyclo[1.1. 1]pentane-1carboxamide

ABOUT

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 418A and the corresponding acid where necessary (130 mg, 0.234 mmol, 80% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 2H), 7.77-7.74 (m, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.51-7.41 (m, 2H), 3.74 (s, 2H), 3.59 (d, J=14.1 Hz, 2H), 2.20-2.10 (m, 2H), 1.89 (br. s., 8H), 1.68 (br. s., 2H), 1.58 (br .s., 2H). MS (ESI) 556 (M+H).

Step C. Example 418. Preparation of F(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((1-(2(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2 .2]octan-4-yl)methyl)bicyclo[1.1.1]pentan-1carboxamide

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The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 418B and the corresponding halide where necessary (17 mg, 0.028 mmol, 62% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J=7.3 Hz, 4H), 7.88 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 4.43 (q, J=7.0 Hz, 2H), 3.78 (br. s., 2H), 3.66 (d, J=13.2 Hz, 2H) , 2.232.06 (m, 2H), 1.91-1.87 (m, 8H), 1.77-1.67 (m, 2H), 1.63 (d, J=9.3 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H ). FXR EC ₅₀ (nM) = 2038. MS (ESI) 598 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 418B and the corresponding boronates/boronic acids.

Etc. No. Name MS (ESI) (M+H) FXR ec ₅₀ (nM) 419 O ^F х5 хгх Н,сА Г) ^{N CFs} /'Ν' ^{44 υ} Η 645 523 420 0 ^F Λ /VS/ Xcf ₃ ND z O ΑΑ 582 802 421 CO o 0 οχ ζ—АА °=/ o co X 623 2172

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422 O ^F /5 n^cf ₃ НзС^СГ^ 596 1517 419 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (br. s., 1H), 9.01 (s, 2H), 7.84-7.61 (m, 4H), 7.59-7.48 (m, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 3.78 (br. s., 2H), 3.65 (s, 2H), 3.10 -2.96 (m, 3H), 2.24-2.07 ( m, 2H), 2.03-1.79 (m, 8H), 1.79-1.67 (m, 2H), 1.67-1.51 (m, 2H) 420 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.79-7.62 (m, 4H), 7.53 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H) , 7.15-7.01 (m, 2H), 3.87-3.74 (m, 5H), 3.65 (s, 2H), 2.23-2.07 (m, 2H), 1.89 (d, J = 8.6 Hz, 8H), 1.73 (br .s., 2H), 1.64 (d, J = 13 Hz, 2H) 421 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 8.48 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.88 (dd, J = 8.4, 1.8 Hz, 1H), 7.85-7.76 (m, 2H), 7.59 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 3.80 (br. s., 2H), 3.74 -3.68 (m, 1H), 3.683.60 (m, 1H), 2.84 (s, 3H), 2.24-2.07 (m, 2H), 1.93-1.89 (m, 4H), 1.74 (br. s., 2H ), 1.63 (br. s., 2H) 422 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.79-7.58 (m, 4H), 7.52 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H) , 7.10-6.97 (m, 2H), 4.09 (q, J= 7.1 Hz, 2H), 3.78 (br. s., 2H), 3.65 (s, 2H), 2.23-2.08 (m, 2H), 1.89 ( d, J = 8.6 Hz, 8H), 1.72 (br. s., 2H), 1.67-1.53 (m, 2H), 1.36 (t, J = 7.0Hz, 3H)

Example 423.

M((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-M(5-(2ethoxypyrimidin-5-yl) pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 423A. Preparation of 5-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-3-amine

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 5-bromopyridin-3-amine and intermediate 4C where necessary (300 mg, 0.744 mmol, 43% yield). MS (ESI) 405 (M+N).

Stage B. Intermediate 423B. Preparation of i(5-bromopyridin-3-yl)-N-((4-(3cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3- fluorobicyclo[1.1.1]pentane-1carboxamide

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To a stirred solution of intermediate 423A (300 mg, 0.744 mmol) in DCM (20 mL) was added 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (116 mg, 0.893 mmol) followed by pyridine (0.301 mL, 3 .72 mmol) and POCl ₃ (0.139 ml, 1.488 mmol) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with DCM (20 ml), washed with water (30 ml) and extracted with EtOAc (2x30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (200 mg, 0.361 mmol, 48% yield). MS (ESI) 515 (M+H).

Step C. Example 423. Preparation of Y-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(5-(2 -ethoxypyrimidin-5-yl)pyridin-3-yl)-3fluorobicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 423B and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (9.3 mg, 0.017 mmol, 43% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 2H), 8.99 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.32 (t, J=2.2 Hz, 1H), 4.44 (q, J=7.0 Hz, 2H), 3.71 (br. s., 1H), 3.54 (br. s., 1H), 2.08-2.02 (m, 1H), 1.90 (br. s., 6H), 1.85-1.66 (m, 6H), 1.53-1.41 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.06-0.96 (m, 2H), 0.87-0.79 (m , 2H). FXR EC ₅₀ (nM) 238. MS (ESI) 559 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 423B and the corresponding boronates.

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427 O ChlZH \\ 1 T , N nd/ ί T V ι> ⁰ n 606 671 428 0 /f fl » D N-? N\JlJ K F ₃ C^N^ V 583 3549 424 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.15 (t, J = 2.2 Hz, 1H), 7.83-7.69 (m, 2H), 7.16-7.01 (m, 2H), 4.18-4.00 (m, 2H), 3.70 (br. s., 1H), 3.54 (br. s., 1H), 2.09-2.00 (m, 1H), 1.99-1.84 (m, 6H), 1.84-1.58 (m, 6H), 1.46 (d, J =5.1 Hz, 6H), 1.38-1.29 (m, 3H), 1.09-0.96 (m, 2H) , 0.90-0.76 (m, 2H) 425 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.30 (t , J = 2.2 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.94 (dd, J= 8.6, 2.0 Hz, 1H), 3.76 (d, J= 13.7 Hz, 1H), 3.55 (br . s., 1H), 2.942.78 (m, 3H), 2.08-2.02 (m, 1H), 1.89 (s, 3H), 1.93 (s, 3H), 1.85-1.66 (m, 6H), 1.59- 1.31 (m, 6H), 1.09-0.96 (m, 2H), 0.87-0.76 (m, 2H) 426 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 8.24 (t , 7 = 2.1 Hz, 1H), 8.18 (dd, J = 8.7, 2.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.38 (q, J = 6.9 Hz, 2H), 3.70 (br . s., 1H), 3.55 (br. s., 1H), 2.09-2.01 (m, 1H), 1.90 (br. s., 6H), 1.85-1.57 (m, 6H), 1.55-1.38 (m , 6H), 1.36 (t, J= 7.1 Hz, 3H), 1.07-0.95 (m, 2H), 0.91-0.77 (m, 2H) 427 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.18 (t, J = 2.1 Hz , 1H), 7.90-7.75 (m, J = 8.8 Hz, 2H), 7.457.27 (m, J = 8.8 Hz, 2H), 3.70 (br. s., 1H), 3.54 (br. s., 1H ), 3.06 (s, 3H), 2.092.02 (m, 1H), 1.90 (br. s., 5H), 1.85 -1.58 (m, 7H), 1.45 (d, J = 8.6 Hz, 6H), 1.07 -0.95 (m, 2H), 0.88-0.79 (m, 2H) 428 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.57 (s, 2H), 9.15 (d, J = 2.2 Hz, 1H), 8.82 (d, J = 2.2 Hz, 1H), 8.50 (t, J = 2.2 Hz , 1H), 3.74 (br. s., 1H), 3.56 (br. s., 1H), 2.09-

2.01 (m, 1H), 1.92 (br. s., 6H), 1.87-1.60 (m, 6H), 1.60-1.32 (m, 6H), 1.09-0.95 (m, 2H), 0.89 -0.78 (m, 2H)

2.01 (m, 1H), 1.92 (br. s., 6H), 1.87-1.60 (m, 6H), 1.60-1.32 (m, 6H), 1.09-0.95 (m, 2H), 0.89 -0.78 (m, 2H)

Example 429.

\-(3-(2-ethoxy11irimidin-5-yl)(])enyl)-3-(])tor-\-((4-(5-iso11ro11yl-1,2,4-oxadiazol-3yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

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Step A: Intermediate 429A. Preparation of X-(3-bromophenyl)-3-fluoro-X-((4-(5 isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo -[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 1A, replacing intermediate 396C and the corresponding acid where necessary (190 mg, 0.368 mmol, 85% yield). MS (ESI) 516 (M+H).

Step B. Example 429. Preparation of N(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 429A and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (10.5 mg, 0.019 mmol, 39% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.88-7.79 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.57(t, J=7.8 Hz, 1H ), 7.48-7.37 (m, 1H), 4.43 (q, J=7.0 Hz, 2H), 3.63 (br. s., 1H),3.60-3.46 (m, 1H), 3.20 (dt, J=13.9, 7.0 Hz, 1H), 1.85 (s, 3H), 1.89 (s, 3H), 1.79-1.61 (m, 6H), 1.56-1.40 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.32-1.24 (m, 6H). FXR EC ₅₀ (nM) = 46. MS (ESI) 560 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 429A and the corresponding boronic acids/esters.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 430 0 Αχ \A/N , ^sn z III Y y-\ _n zvV ^N 'O CH ₃ ^H 3 ^C AJJ ^u H 607 40 431 0 Ε^3ΓΟγΝ CH ₃ ch ₃ pJU N-Zhsnz 558 25 432 0 Yw CH ₃ ^N '° ^СНз 559 51 433 0 As , ^CH 3 \\ 1 Y γ\ 5^%/J ^N 'O CH ₃ H3C—ji j 585 37

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434 0 I ch ₃ n~c) zn ₃ 556 57 435 0 Ay AAn / ^СНз II T _n ^A^A N'O CH ₃ AJ F ₃ C^I\F 584 240 436 0 CH ₃ N-0 ⁷ ^CH ₃ AJ F ₂ HCCy^ 580 46 430 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.707.61 (m, 2H), 7.53 (t, J = 7.8 Hz, 2H) , 7.40-7.23 (m, 2H), 3.60 (d, J = 11.5 Hz, 2H), 3.20 (dt, 7 = 13.9,7.0 Hz, 1H), 3.04 (s, 3H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.58 (m, 6H), 1.56-1.31 (m, 6H), 1.31-1.20 (m, 6H) 431 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.74-7.58 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.12-6.98 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.59 (d, J = 9.3 Hz, 2H), 3.23-3.17 (m, 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.64 (m, 6H), 1.57-1.39 (m, 6H), 1.36 (t, J = 7.0 Hz, 3H), 1.31 -1.23 (m, 6H) 432 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J= 2.4 Hz, 1H), 8.10 (dd, 7= 8.7, 2.6 Hz, 1H), 7.83 -7.62 (m, 2H), 7.53 (t , 7= 8.1 Hz, 1H), 7.37 (d, 7= 8.1 Hz, 1H), 6.91 (d, 7= 8.6 Hz, 1H), 4.37 (q, 7= 7.1 Hz, 2H), 3.60 (d, 7 = 7.8 Hz, 2H), 3.20 (dt, 7 = 13.9, 7.0 Hz, 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.80-1.61 (m, 6H), 1.46 (d, 7 = 8.3 Hz, 6H), 1.35 (t, 7= 7.0 Hz, 3H), 1.31-1.20 (m, 6H) 433 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, 7 = 1.5 Hz, 1H), 8.00 (d, 7 = 8.3 Hz, 1H), 7.85 (dd, 7 = 8.6, 2.0 Hz, 1H), 7.82 -7.71 (m, 2H), 7.57 (t, 7 = 7.7 Hz, 1H), 7.40 (d, 7 = 8.3 Hz, 1H), 3.68 (d,7= 13.0 Hz, 1H), 3.55 (d,7= 13.2 Hz, 1H), 3.19 (dt, 7= 14.0, 7.1 Hz, 1H), 2.83 (s, 3H), 1.86 (s, 3H), 1.91 (s, 3H), 1.75 (t, 7

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= 7.7 Hz, 6H), 1.47 (d, J= 5.1 Hz, 6H), 1.27 (d, J= 7.1 Hz, 6H) 434 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.84 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 3.70-3.47 (m, 3H), 2.322.22 (m, 1H), 2.01-1.80 (m, 6H), 1.80-1.61 (m, 6H), 1.56- 1.36 (m, 6H), 1.331.23 (m, 6H), 1.18-0.89 (m, 4H) 435 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.01 (t, J = 1.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.73-7.62 (m, 1H) , 7.61-7.52 (m, 1H), 3.66 (br. s., 1H), 3.58 (br. s., 1H), 3.23-3.15 (m, 1H), 1.86 (s, 3H), 1.90 (s, 3H), 1.80-1.61 (m, 6H), 1.45 (d, J = 4.6 Hz, 3H), 1.47 (d, J = 4.6 Hz, 3H), 1.32-1.24 (m, 6H) 436 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.88-7.77 (m, 2H), 7.75-7.63 (m, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.34-7.20 (m, 3H), 3.63 (br. s., 1H), 3.57 (br. s., 1H), 3.20 (dt, J= 13.9, 7.0 Hz, 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.81-1.61 (m, 6H), 1.46 (d, J =9.5 Hz, 6H), 1.33-1.21 (m, 6H)

Example 437.

¥-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-¥-(3-( 2ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 194G and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (12.9 mg, 0.022 mmol, 47% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.82 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 4.43 (q, J=7.0 Hz, 2H), 3.60 (d, J=18.8 Hz, 2H), 1.85 (s, 3H), 1.89 (s, 3H), 1.79-1.63 (m, 6H), 1.57-1.40 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.33 (s, 9H). FXR EC ₅₀ (nM) = 39. MS (ESI) 574 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 194G and the corresponding boronic acids/esters.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 438 0 Dk M/A^N Р ^Нз ί Ί Ύ VV ^CH 3 _ ^N '° ^СНз h ₃ cJ j Τ LA/ ^ϋ Η 621 46 439 0 Yw _СНз AfA ^N ~° ^СНз 572 70 440 0 Ύα ch ₃ ^Ν '° ^СНз 573 103 441 co T°=ζ O^Z ABOUT co T 599 68 442 Ax _N kZ\/ NY CH ₃ II J v/^In 570 71

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443 0 Τα χ/Ά P ^h 3 fl Ί Ύ D-DSНз No ^Z CH ₃ II J F ₃ C^I\F 598 357 444 0 'CsAw'. /AV ^N 'O ch ₃ P RgNSSG^ 594 61 445 0 'HdHook™. /AV nq ^z ch ₃ AJ F ₃ C^^ 596 719 438 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.717.61 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H) , 7.40-7.27 (m, 3H), 3.60 (d, J = 8.3 Hz, 2H), 3.04 (s, 3H), 1.85 (s, 3H), 1.88 (s, 3H), 1.81-1.63 (m, 6H ), 1.53-1.37 (m, 6H), 1.37-1.26 (m, 9H) 439 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.56 (m, 4H), 7.50 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.59 (d, J = 6.8 Hz, 2H), 1.86(d, J = 9.3 Hz, 6H), 1.79-1.58 (m, 6H) , 1.57-1.39 (m, 6H), 1.39-1.26 (m, 12H) 440 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.7, 2.6 Hz, 1H), 7.79 -7.63 (m, 2H), 7.53 (t, J= 8.2 Hz, 1H), 7.42-7.32 (m, 1H), 6.97-6.85 (m, 1H), 4.37 (q, J= 7.1 Hz, 2H), 3.60 (d, J = 5.4 Hz, 2H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.59 (m, 6H), 1.57-1.38 (m, 6H),1.38-1.25 (m, 12H) 441 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.81 -7.69 (m, 2H), 7.57 (t, J= 7.7 Hz, 1H), 7.40 (d, 7=7.3 Hz, 1H), 3.68 (d, J= 13.9 Hz, 1H), 3.56 (d, J = 13.4 Hz, 1H), 2.83 (s, 3H), 1.86 (s, 3H), 1.91 (s, 3H),1.75 (t, 7= 7.8 Hz, 6H), 1.47 (d, 7 = 5.6 Hz, 6H) , 1.33 (s, 9H)

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442 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.88-7.82 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H) , 7.46 (d, J = 8.1 Hz, 1H), 3.60 (d, J = 12.0 Hz, 2H), 2.31-2.22 (m, 1H), 1.84 (s, 3H), 1.88 (s, 3H), 1.80- 1.69 (m, 6H), 1.55-1.36 (m, 6H),1.33 (s, 9H), 1.14-1.01 (m, 4H) 443 DNMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.06-7.99 (m, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.67(t, J = 7.8 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 3.66 (br. s., 1H), 3.59 (br. s., 1H), 1.86(s, 3H), 1.90 (s, 3H), 1.82-1.66 ( m, 6H), 1.57-1.37 (m, 6H), 1.33 (s, 9H) 444 DNMR (400 MHz, DMSO-d ₆ ) δ 7.88-7.76 (m, 2H), 7.75-7.62 (m, 2H), 7.54 (t, J= 7.8 Hz, 1H), 7.39 (dd, J= 7.1, 1.2 Hz , 1H), 7.34-7.20 (m, 3H), 3.68-3.60 (m, 1H), 3.60-3.51 (m, 1H),1.85 (s, 3H), 1.88 (s, 3H), 1.81-1.60 (m , 6H), 1.46 (d, J = 9.5 Hz, 6H), 1.33 (s, 9H) 445 DNMR (400 MHz, DMSO-d ₆ ) δ 8.07-7.93 (m, J = 8.3 Hz, 2H), 7.91-7.82 (m, J = 8.3 Hz, 2H), 7.82-7.71 (m, 2H), 7.60 (t , J = 8.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 3.73-3.61 (m, 1H), 3.61-3.52 (m, 1H), 1.85 (s, 3H), 1.89 (s, 3H), 1.80-1.60 (m, 6H), 1.56-1.37 (m, 6H), 1.33 (s, 9H)

Example 346.

A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4' ((trifluoromethyl)sulfonamido)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 446A. Preparation of A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(5,5- dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 149C, replacing intermediate 194G where necessary (270 mg, 0.480 mmol, 91% yield) as an off-white solid. MS (ESI) 496 (M+H) (weight of boronic acid).

Step B. Example 446. Preparation of A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1 -yl)methyl)-3-fluoro- N-(4'-((trifluoromethyl)sulfonamido)-[1,1'-biphenyl]-3 -yl)bicyclo[1.1.1]pentane-1 carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 446A and the corresponding halide where necessary (4.7 mg, 7.64 μmol, 17% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J=8.8 Hz, 2H), 7.74-7.63 (m, 2H), 7.54 (t, J=7.8 Hz, 1H), 7.447.29 (m , 3H), 3.62 (s, 1H), 3.57 (br. s., 1H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.62 (m, 6H), 1.46 (d, J= 5.6 Hz, 6H), 1.33 (s, 9H). FXR EC ₅₀ (nM) = 225. MS (ESI) 675 (M+H).

The following compounds were prepared according to the method described for the synthesis of the compound

- 330 047337 according to example 149, by replacing intermediate 446A and the corresponding aryl/heteroaryl halides.

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454 -Aw No ^Z CH ₃ H3C 544 31 455 An _F ^N 'O CH ₃ 595 17 456 ΛλΌγΐ·l£ ^h = JL J И Υ nq ch ₃ n ₃ s^1D 556 106 457 0 P OnJ/V ^N ~0 CH ₃ >A 608 144 458 ^N O CH ₃ ^N ^bT 626 251 447 Ή NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (br. s., 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.72-7.63 (m, 2H), 7.61-7.43 (m, 2H) , 7.36 (d, J= 8.1 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 3.65 (d, J= 13.7 Hz, 1H), 3.55 (d, J= 13.9 Hz, 1H), 2.01 -1.79 (m, 6H), 1.78-1.67 (m, 6H), 1.45 (d, J = 4.4 Hz, 6H), 1.33(s, 9H) 448 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 7.77-7.58 (m, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 3H) , 3.68-3.50 (m, 2H), 3.28 (dt, J= 13.6, 6.8 Hz, 1H), 1.85 (s, 3H), 1.87 (s, 3H), 1.80-1.59 (m, 6H), 1.57-1.37 (m, 6H), 1.33 (s,

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9Н), 1.29-1.20 (m, 6Н) 449 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (d, J = 2.2 Hz, 1H), 8.94 (d, J = 2.2 Hz, 1H), 7.97-7.75 (m,2H), 7.61 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 3.733.61 (m, 1H), 3.61-3.50 (m, 1H), 2.9O (s, 3H), 2.05-1.80 (m, 6H), 1.80-1.57 (m, 6H), 1.56-1.37 (m, 6H), 1.33 (s, 9H) 450 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (s, 2H), 8.31 (d, J = 7.8 Hz, 1H), 8.18 (t, J = 1.7 Hz, 1H), 7.65-7.56 (m, 1H) , 7.51 (d, J =9.0 Hz, 1H), 3.98 (s, 3H), 3.65 (br. s., 1H), 3.57 (br. s., 1H), 1.86(s, 3H), 1.89 (s , 3H), 1.79-1.59 (m, 6H), 1.55-1.36 (m, 6H), 1.36-1.28 (m, 9H) 451 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.69 (s, 2H), 8.30 (d, J = 7.8 Hz, 1H), 8.238.13 (m, 1H), 7.60 (t, J = 7.7 Hz, 1H) , 7.51 (d, J= 8.1 Hz, 1H), 4.27 (q, J= 7.0 Hz, 2H), 3.65 (br. s., 1H), 3.57 (br. s., 1H), 1.86 (s, 3H ), 1.89 (s, 3H), 1.79-1.59 (m, 6H), 1.54-1.34 (m, 9H), 1.33 (s, 9H) 452 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.36 (d, J = 7.8 Hz, 1H), 8.24 (t, J = 1.7 Hz, 1H), 7.69-7.51 (m, 3H) , 3.65 (br. s., 1H), 3.58 (br. s., 1H), 1.87 (s, 3H),1.89 (s, 3H), 1.79-1.61 (m, 6H), 1.56-1.35 (m, 6H), 1.33 (s, 9H) 453 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 2H), 8.38 (d, J = 7.6 Hz, 1H), 8.26 (t, J = 1.8 Hz, lH), 7.62 (t, J = 7.8 Hz , 1H), 7.55 (d, J = 8.1 Hz, 1H), 3.65 (br. s., 1H), 3.58 (br. s., 1H), 2.69 (q, J = 7.4 Hz, 2H), 1.86 ( s, 3H), 1.89 (s, 3H), 1.79-1.56 (m, 6H), 1.55-1.36 (m, 6H), 1.36-1.28 (m, 9H), 1.28-1.22 (m, 3H) 454 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (s, 2H), 8.37 (d, J = 7.8 Hz, 1H), 8.25 (t, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz , 1H), 7.55 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 17.9 Hz, 2H), 2.34 (s, 3H), 1.87 (d, J = 9.0 Hz, 6H), 1.78-1.57 (m, 6H), 1.551.36 (m, 6H), 1.36-1.28 (m, 9H) 455 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J= 2.7 Hz, 1H), 8.18 (d, J= 8.8 Hz, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.05 (s , 1H), 7.80 (dd, J= 8.7, 2.8 Hz, 1H), 7.637. 20 (m, 3H), 3.61 (s, 2H), 1.88 (br. s., 6H), 1.79-1.65 (m, 6H), 1.55-1.37 (m, 6H), 1.33 (s, 9H). 456 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.58 (m, 4H), 7.53 (t, J = 7.8 Hz, 1H), 7.42-7.30 (m, 3H), 3.60 (d, J = 11.2 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 1.88-1.85 (m, 6H), 1.79-1.62 (m, 6H), 1.56-1.38 (m, 6H), 1.33 (s, 9H), 1.22 (t, J = 7.6 Hz, 3H). 457 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 1.7 Hz, 1H), 7.77-7.69 (m, 2H),

7.61 (dd, J= 8.6, 2.0 Hz, 1H), 7.58-7.48 (m, 2H), 7.46-7.37 (m, 1H), 3.63 (br. s., 1H), 3.57 (br. s., lH ), 1.89-1.84 (m, 6H), 1.79-1.64 (m, 6H), 1.56-1.38 (m, 6H), 1.33 (s, 9H). 458 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J = 2.4 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.93-7.79 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 3.673.57 (m, 2H), 2.62 -2.58 (m, 1H), 1.90-1.86 (m, 6H), 1.80-1.62 (m , 6H), 1.561.37 (m, 6H), 1.37-1.28 (m, 11H), 1.25 (dt, J = 7.5, 2.8 Hz, 2H).

Example 459.

N((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-and (3-(2ethoxypyrimidin-5-yl) phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

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Step A: Intermediate 459A. Preparation of Na(3-bromophenyl)-N-((4-(5-(difluoromethyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo [1.1.1]pentane-1-carboxamide

ABOUT

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1A, by replacing intermediate 396C and the corresponding acid where necessary (160 mg, 0.305 mmol, 71% yield). MS (ESI) 524 (M+H).

Step B. Example 459. Preparation of N((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-( 2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 459A and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (8.7 mg, 0.014 mmol, 29% yield ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.82 (t, J=1.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.62-7.50 (m, 1H), 7.50-7.33 (m, 2H), 4.43 (q, J=7.0 Hz, 2H), 3.71-3.62 (m, 1H), 3.60-3.52 (m, 1H), 2.00-1.71 (m, 12H) , 1.581.42 (m, 6H), 1.38 (t, J=7.0 Hz, 3H). FXR EC ₅₀ (nM) = 192. MS (ESI) 568 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 459A and the corresponding boronic acids/esters.

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.70460

7.60 (m, 2H), 7.57-7.46 (m, 2H), 7.42 (s, 1H), 7.39-7.24 (m, 2H), 3.61 (d, J =

13.2 Hz, 2H), 3.04 (s, 3H), 1.95-1.70 (m, 12H), 1.49 (d, J =8.3 Hz, 6H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.78-7.59 (m, 4H), 7.56-7.45 (m, 1H), 7.45-

461 7.35 (m, 1H), 7.34-7.27 (m, 1H), 7.10-6.97 (m, 2H), 4.17-3.99 (m, 2H), 3.61 (d, J - 11.0 Hz, 2H), 1.96 -1.70 ( m, 12H), 1.49 (fU~8.6Hz, 6H), 1.39-1.29 (m, ZH) Ή NMR (400MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 462 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.83-7.74 (m, 2H), 7.63-7.48 (m, 1H), 7.487.35 (m, 2H), 3.70 (d, J = 13.9 Hz, 1H), 3.57 (d, J = 14.2 Hz, 1H), 2.83 (s, 3H), 1.98-1.70 (m, 12H), 1.50 (d, J = 5.4 Hz, 6H) Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2Η), 7.89-7.82 (m, 1H), 7.80 (d, J = 463 7.6 Hz, 1H), 7.63-7.51 (m, 1H), 7.51-7.34 (m, 2H), 3.74-3.51 (m, 2H), 2.32 - 2.20 (m, 1H), 1.96-1.69 (m, 12H) , 1.57-1.33 (m, 6H), 1.21-0.96 (m, 4H) Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.02 (s, 1H), 7.96 (d, J = 7.6 Hz, 464 1H), 7.67(1, J =7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.51-7.33 (m, 1H), 3.68 (br. s., 1H), 3.62 -3.54 ( m, 1H), 1.97-1.71 (m, 12H), 1.58-1.34 (m, 6H) 465 'H NMR (400 MHz, DMSO-d ₆ ) δ 7.87-7.78 (m, 2H), 7.76-7.65 (m, 2H), 7.59-7.51 (m, 1H), 7.46-7.35 (m, 2H), 7.30 ( dd, J= 6.8, 1.7 Hz, 3H), 3.69-3.62 (m, 1H), 3.60-3.51 (m, 1H), 1.98 -1.70 (m, 12H), 1.57-1.37 (m, 6H)

Example 466.

D-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)A-((4-(3-(difluoromethyl)-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octane-1 - yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

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Step A: Intermediate 466A. Preparation of A-(3-bromophenyl)-A-((4-(3-(difluoromethyl)1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3- fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

The title compound was prepared according to the method described for the synthesis of intermediate 1A by replacing intermediate 357C and (E)-2,2-difluoro-Nhydroxyacetimidamide where necessary (200 mg, 0.381 mmol, 57% yield) to in the form of a white resinous liquid. MS (ESI) 524 (M+H).

Step B. Example 466. Preparation of F(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-N-((4-(3(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2 .2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 466A and 2-cyclopropyl-5-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)pyrimidine where it required (4.1 mg, 6.55 µmol, 14% yield).

1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 2H), 7.84 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.53 -7.35 (m, 2H), 3.70-3.50 (m, 2H),2.32-2.23 (m, 1H), 1.97-1.69 (m, 12H), 1.60-1.37 (m, 6H), 1.21-0.96 (m, 4H).

FXR EC ₅₀ (nM) = 349. MS (ESI) 564 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 466A and the corresponding aryl/heteroarylboronates.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 467 О F^ ⁷ А=У ί I Η - Ν ДчУ N-Д' AJ / ^F F ₃ CNF 592 2110 468 Xw P A . n AyXyX n-Д jf A /~ ^F F ₂ HCCr''^ F 588 184 469 0 Ay XAXy ^N _T Y'N f °y/° f A h ₃ c [j 615 654 470 0 f^ ⁴ ^ Ay XA ⁿ _ϊ _n AU <Tn f A J Η ₃ (ΑΑ> N 568 164

- 337 047337

471 O Yes _х °'NF НзС ^- у 1! J 593 135 467 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.02 (t, J = 1.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.73-7.64 (m, 1H) , 7.63-7.53 (m, 1H), 7.32 (s, 1H), 3.68 (br. s., 1H), 3.61 (br. s., 1H), 1.99-1.76 (m, 12H), 1.58-1.36 ( m, 6H) 468 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.90-7.77 (m, 2H), 7.76-7.65 (m, 2H), 7.55 (t, J = 8.1 Hz, 1H), 7.50-7.35 (m, 2H), 7.35-7.24 (m, 3H), 3.62 (d, J= 16.9 Hz, 2H), 2.02-1.75 (m, 12H), 1.50 (d, J= 9.3 Hz, 6H) 469 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.78-7.71 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H) , 7.53 (t, J= 7.8 Hz, 1H), 7.41-7.25 (m, 4H), 3.61 (d, J =7.1 Hz, 2H), 3.04 (s, 3H), 1.87 (d, J =9.5 Hz, 12H), 1.62-1.39 (m, 6H) 470 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.82 (t, J = 1.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz , 1H), 7.47-7.32 (m, 2H), 4.43 (q, J= 7.0 Hz, 2H), 3.73-3.48 (m, 2H), 2.04-1.76 (m, 12H), 1.60-1.40 (m, 6H ), 1.38 (t, J= 7.0 Hz, 3H) 471 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 -7.70 (m, 2H), 7.57 (t, J= 8.1 Hz, 1H), 7.48-7.19 (m, 2H), 3.75-3.65 (m, 1H), 3.63-3.54 (m, 1H), 2.84 (s , 3H), 2.04-1.78 (m, 12H), 1.51 (d, J = 5.4 Hz, 6H)

Example 472.

M((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-M(5-(2ethoxypyrimidin- 5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 472A. Preparation of methyl 4-(((5-bromopyridin-3yl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 5-bromopyridin-3-amine and intermediate 88B where necessary (800 mg, 2.061 mmol, 36% yield). MS (ESI) 353 (M+H).

Stage B. Intermediate 472B. Preparation of 4-(((5-bromopyridin-3yl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

- 338 047337

To a stirred solution of intermediate 472A (1 g, 2.83 mmol) in THF was added methanol (5 mL), water (2.5 mL), and then LiOH (0.40 g, 16.98 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was concentrated, diluted with water (10 ml), acidified with aqueous 1.5 N HCl and extracted with ethyl acetate (3x20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give the title compound (700 mg, 2.04 mmol, 72% yield). MS (ESI) 339 (M+H).

Step C. Intermediate 472C. Preparation of 5-bromo-N-((4-(3-(tert-butyl)-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-3-amine

The specified compound was prepared in accordance with the method described for the synthesis of intermediate compound 1A, by replacing intermediate compound 472B and (E)-N-hydroxypivalimidamide where necessary. (600 mg, 1.431 mmol, 69% yield). MS (ESI) 419 (M+N).

Stage D. Intermediate 472D. Preparation of J(5-bromopyridin-3-yl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of example 323B, by replacing intermediate 472C and the corresponding acid where necessary (300 mg, 0.564 mmol, 53% yield). MS (ESI) 531. (M+N).

Step E. Example 472. Preparation of F((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(5 -(2-ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 472D and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (19.1 mg, 0.033 mmol, 70% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (s, 2H), 8.99 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.32 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 3.72 (br. s., 1H), 3.55 (br. s., 1H), 1.91 (br. s., 5H), 1.87-1.68 (m, 7H) , 1.54-1.33 (m, 9H), 1.33-1.09 (m, 9H). FXR EC ₅₀ (nM) 758. MS (ESI) 575 (m+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 472D and the corresponding boronates.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 473 0 Siz ί|Ί G/U-6 ^c w W- ₄ ON CH ₃ JL J 571 501 474 0 xC AxL SPz Ο v /)-Ch- ^sn z °-N CH ₃ H3C—J] J 600 541 475 О A An /СНз О Y/)—F ^ch = _η /%/*\+ ^N Ο'Ν СНз ^НзС '/ 1 J /'N-« ^υ Η 622 1596 476 As d ο=ζ \=/ ^Ш о < о с ΞΕ 573 560 477 ΞΕ co > O S l /=4 /=° k □What about? A 574 485 473 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 2H), 9.01 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.35 (t, J = 2.0 Hz , 1H), 3.71 (br. s., 1H), 3.56 (br. s., 1H), 2.33-2.23 (m, 1H), 1.90 (br. s., 5H), 1.87-1.57 (m, 7H ), 1.55-1.36 (m, 6H), 1.341.19 (m, 9H), 1.16-1.03 (m, 4H) 474 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.30 (t , J = 2.1 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 3.75 (br. s., 1H), 3.56 (br. s ., 1H), 2.85 (s, 3H),

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1.90 (s, ZN), 1.93 (s, ZN), 1.87-1.59 (m, 6N), 1.57-1.45 (m, 5N), 1.42 (br. s., 1H), 1.35-1.17 (m, 9H) 475 'H NMR (400 MHz, DMSO-de) δ 9.96 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.18 (t, J = 2.1 Hz , 1H), 7.91-7.76 (m, J= 8.6 Hz, 2H), 7.447.28 (m, J= 8.8 Hz, 2H), 3.70 (br. s., 1H), 3.56 (br. s., 1H ), 3.06 (s, 3H), 1.90 (br. s., 5H), 1.87-1.59 (m, 7H), 1.57-1.35 (m, 6H), 1.34-1.15 (m, 9H) 476 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.20-8.13 (m, 1H), 7.87-7.72 (m, J = 8.8 Hz, 2H), 7.15-7.00 (m, J = 8.8 Hz, 2H), 4.11 (q, J = 6.8 Hz, 2H), 3.70 (br. s., 1H), 3.55 (br. s. , 1H), 1.90 (br. s., 6H), 1.87-1.64 (m, 6H), 1.47 (br. s., 6H), 1.36 (t, J = 7.0 Hz, ZN), 1.30-1.10 (m , 9H) 477 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.29-8.21 (m, 1H), 8.19 (dd, J = 8.8, 2.7 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.70 (br. s. , 1H), 3.57 (br. s., 1H), 1.90 (br. s., 5H), 1.87-1.59 (m, 7H), 1.59-1.39 (m, 6H), 1.36 (t, J = 7.1 Hz , ZN), 1.31-1.11 (m, 9H)

Example 478.

D-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-D-(5-( 2ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A. Il)amino)methyl)bicyclo[2.2.2]octane-1-carboxamide intermediate

478A. Preparation of 4-(((5-bromopyridine-3-

The title compound was prepared according to the method described for the synthesis of Example 144A, replacing intermediate 472B with ammonium chloride where necessary (199 mg, 0.59 mmol, 100% yield). MS (ESI) 338 (M+H).

Stage B. Intermediate 478V. Preparation of 4-(((5-bromopyridin-3-yl)amino)methyl) bicyclo[2.2.2]octane-1-carbonitrile

To a stirred solution of intermediate 478A (200 mg, 0.591 mmol) in pyridine (4 mL) was added imidazole (403 mg, 5.91 mmol) followed by POCl ₃ (0.331 mL, 3.55 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was cooled to room temperature and poured into crushed ice. The aqueous solution was extracted with EtOAc (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (100 mg, 0.31 mmol, 52% yield). MS (ESI) 320 (M+H).

Step C. Intermediate 478C. Preparation of (7)-4-(((5-bromopyridine-3

- 341 047337 yl)amino)methyl)-U-hydroxybicyclo[2.2.2]octane-'1-carboximidamide νη ₂

The title compound was prepared according to the method described for the synthesis of intermediate 88F, replacing intermediate 478B where necessary (100 mg, 0.275 mmol, 88% yield). MS (ESI) 353 (M+H).

Stage D. Intermediate 478D. Preparation of 5-bromo-U-((4-(5-(tert-butyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-3-amine

CH ₃ (-CH ₃ Sh ₃

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1A, by replacing intermediate 478C and the corresponding acid where necessary (90 mg, 0.22 mmol, 76% yield). MS (ESI) 419 (M+H).

Step E. Intermediate 478E. Preparation of J(5-bromopyridin-3-yl)-U-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-3-fluorobicyclo[1.1.1]pentane-1carboxamide

CH ₃ £-CH ₃ CH ₃

The specified compound was prepared in accordance with the method described for the synthesis of example 423B, by replacing intermediate 478D and the corresponding acid where necessary (80 mg, 0.104 mmol, 48% yield). MS (ESI) 531 (M+H).

Step F. Example 478. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-U-(5 -(2-ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 478E and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (19.3 mg, 0.034 mmol, 59% yield ).

¹ H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 2H), 8.99 (d, J=2.0 Hz, 1H), 8.68 (d, J=2.2 Hz, 1H), 8.34 (t, J=2.1 Hz, 1H), 4.44 (q, J=6.9 Hz, 2H), 3.72 (br. s., 1H), 3.52 (d, J=12.7 Hz, 1H), 1.90 (d, J=9.0 Hz, 6H) , 1.811.64 (m, 6H), 1.56-1.40 (m, 6H), 1.38 (t, J=7.1 Hz, 3H), 1.33 (s, 9H). FXR EC ₅₀ (nM) 1095. MS (ESI) 575 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 478E and the corresponding boronates.

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Etc. No. Structure MS (ESI) FXR EC ₅ o (M+H) (hM) 479 0 YES Dk \A/ ^N / ^СНз ί| η if —(-СНз Ν-ο СНз °Ν Ύ J Ν^ΑΧ Η 586 367 480 0 //^νΥΙί f^ Mx ΜΑ A ί| Ί ιΓ -(CH ₃ Ν-ο CH ₃ >-h Ύ Τ Ν' ⁴ !/ 627 988 481 0 °γθjO-i^ ^{ν0 СНз} НзС й 622 580 482 O F^^ Mx, aMa^NP” ³ ί| 1 |T —(СНз /χΛγ ^{Ν n} ~o CH ₃ Ji TH ₃ C^O^^ 573 322 483 0 \Mv/NP ^H 3 π Ί if —(CH _{3 F} /hD/N N'O ^CH 3 _F YqAM 595.1 255 484 O F^^ Ma aAk^n ^{P n} z ί|Ί ιΓ —(CH ₃ S^/1 ^N No ^Z CH ₃ H ₃ C—( JI J 600 344 479 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.60 (d,

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J =2.2 Hz, 1H), 8.22 (s, 1H), 7.85 (d,J= 1.5 Hz, 1H), 7.68-7.60 (m, 1H), 7.23 (d, J= 8.1 Hz, 1H), 3.73 ( br. s., 1H), 3.54 (br. s., 1H), 1.88 (s, 3H), 1.91 (s, 3H), 1.81-1.65 (m, 6H), 1.46 (br. s., 6H) , 1.33 (s, 9H) 480 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (d, J = 2.2 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.70 (d , J = 2.2 Hz, 1H), 8.38 (t, J = 2.2 Hz, 1H), 3.74 (br. s., 1H), 3.56 (br. s., 1H), 2.64 (td, J = 8.4, 3.9 Hz, 1H), 1.93 (br. s., 6H), 1.82-1.61 (m, 6H), 1.54-1.39 (m, 6H), 1.39-1.29 (m, 11H), 1.29-1.22 (m, 2H) 481 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 7.92 -7.72 (m, J = 8.6 Hz, 2H), 7.43-7.27 (m, J = 8.8 Hz, 2H), 3.71 (br. s., 1H), 3.54 (br. s., 1H), 3.06 (s , 3H), 1.90 (br. s., 6H), 1.81-1.58 (m, 6H), 1.57-1.37 (m, 6H), 1.33 (s, 9H) 482 NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.23-8.08 (m, 1H), 7.89-7.66 (m, 2H ), 7.17-7.00 (m, J = 8.8 Hz, 2H), 4.10 (q, J = 6.8 Hz, 2H), 3.70 (br. s., 1H), 3.54 (br. s., 1H), 1.90 ( br. s., 6H), 1.801.60 (m, 6H), 1.57-1.39 (m, 6H), 1.39-1.29 (m, 12H) 483 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 2.2 Hz, 1H), 8.31-8.17 (m, 1H), 8.01-7.82 (m, 2H), 7.44-7.15 (m, 3H), 3.72 (br. s., 1H), 3.54 (br. s., 1H), 1.91 (br. s., 6H), 1.81-1.61 (m, 6H) , 1.58-1.38 (m, 6H), 1.33 (s, 9H) 484 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 1.7 Hz, 1H), 8.30 (t , J = 2.2 Hz, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.95 (dd, J = 8.6, 2.0 Hz, 1H), 3.75 (br. s., 1H), 3.55 (br. s ., 1H), 2.85 (s, 3H), 1.90 (s, 3H), 1.93 (s, 3H), 1.81-1.59 (m, 6H), 1.46 (br. s., 6H), 1.33 (s, 9H )

Example 485.

D-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-D-(5-( 5(difluoromethoxy)pyrimidin-2-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

ABOUT

To a stirred solution of intermediate 478E (20 mg, 0.038 mmol) in toluene (1 ml) was added 5-(difluoromethoxy)-2-(trimethylstannyl)pyrimidine (12 mg, 0.038 mmol). The reaction mixture was degassed and filled with argon again. Tetrakis (4.35 mg, 3.76 μmol) was added to the reaction mixture and the reaction vessel was sealed (pressure release vessel). The reaction mixture was heated at 110°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient : hold 0 minutes at 20% B, 20-80% B for 25 minutes, then hold for 5 minutes at 100% B; flow rate 15 ml/min; column temperature 25°C). Collection of fractions was initiated by signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (1.2 mg, 1.97 μmol, 5% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.98 (s, 2H), 8.84 (d, J=2.2 Hz, 1H), 8.58 (t, J=2.1 Hz, 1H),

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7.64 (s, 1H), 7.46-7.28 (m, 1H), 3.66 (br. s., 2H), 1.91 (br. s., 6H), 1.80-1.59 (m, 6H), 1.55-1.37 (m , 6H), 1.33 (s, 9H). FXR EC ₅₀ (nM) 41. MS (ESI) 597 (M+H).

Example 486.

Y-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(5(difluoromethoxy)- [2,3'-bipyridin]-5'-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 486A. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(5-( trimethylstannyl)-pyridin-3yl)bicyclo[1.1.1]pentane-1-carboxamide

Hexamethyldithine (0.016 mL, 0.075 mmol) was added to a stirred solution of intermediate 478E (20 mg, 0.038 mmol) in toluene (1 mL). The reaction mixture was degassed and filled with argon again. 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (2.45 mg, 3.76 μmol) was added to the reaction mixture and the reaction vessel was sealed. The reaction mixture was heated at 110°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (25 mg, 93% yield). 1H NMR (400 MHz, DMSO- _d6 ) δ 8.54 (d, J=20.00 Hz, 2H), 7.94 ( s, 1H), 3.54 (d, J=12.00 Hz, 2H), 1.71-1.81 (m, 12H), 1.40-1.43 (m, 6H), 1.33 (s, 9H), 0.42 (s, 9H).

Step B. Example 386. Preparation of No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-No-(5 -(difluoromethoxy)-[2,3'-bipyridin]-5'-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

To a stirred solution of intermediate 486A (25 mg, 0.041 mmol) in toluene (1 ml) was added 2-bromo-5-(difluoromethoxy)pyridine (18.2 mg, 0.081 mmol). The reaction mixture was degassed and filled with argon again. Tetrakis (4.69 mg, 4.06 µmol) was added to the reaction mixture and the reaction vessel was sealed (pressure release vessel). The reaction mixture was heated at 110°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative LC/MS under the following conditions. (Column. Waters XBridge C18, 150 mmx19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient : 0-minute hold at 15% B, 15-65% B for 25 minutes, then 5-minute hold at 100% B; flow rate 15 ml/min; column temperature 25°C). Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.5 mg, 5.88 μmol, 14% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (d, J=1.7 Hz, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.9 Hz, 1H), 8.48 (t, J=2.2 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H), 7.86 (dd, J=8.7, 3.1 Hz, 1H), 7.4 (t, J =72 Hz, 1H), 3.70 (br. s., 2H), 3.58 (br. s., 1H), 1.90 (br. s., 6H), 1.81-1.64 (m, 6H), 1.56-1.37 (m, 6H), 1.33 (s , 9H). FXR EC50 (nM) 89. MS (ESI) 596 (M+H).

Example 487.

N(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl) bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

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Step A: Intermediate 487A. Preparation of 3-bromo-N-((4-(5-(trifluoromethyl)pyridin2-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 185C where necessary (430 mg, 0.959 mmol, 91% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91-8.85 (m, 1H), 8.10 (dd, J=8.5, 2.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.01- 6.94 (m, 1H), 6.78 (t, J=2.3 Hz, 1H), 6.64-6.58 (m, 2H), 5.79-5.73 (m, 1H), 2.82 (d, J=5.5 Hz, 2H), 1.931 .84 (m, 6H), 1.63-1.54 (m, 6H). MS (ESI) 439.2 (M+H).

Stage B. Intermediate 487B. Preparation of A(3-bromophenyl)-3-fluoro-N-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo-[1.1.1] pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 487A and the corresponding acid where necessary (300 mg, 0.539 mmol, 55% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.88-8.82 (m, 1H), 8.08 (dd, J=8.5, 2.5 Hz, 1H), 7.72-7.68 (m, 1H), 7.61 (dt, J =7.4, 1.8 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.47-7.39 (m, 2H), 3.61 (br. s., 1H), 3.53 (br. s., 1H), 1.88 (br. s., 6H), 1.84-1.75 (m, 6H), 1.50-1.39 (m, 6H). MS (ESI) 553 (M+H).

Step C. Example 487. Preparation of A(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2] octan-1-yl)methyl)bicyclo-[1.1.1]pentan-1-carboxamide

The indicated compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 487B and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-2-ethoxypyrimidine where necessary (18.3 mg, 0.031 mmol, 68% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 8.84 (s, 1H), 8.07 (dd, J=8.6, 2.4 Hz, 1H), 7.83 (s, 1H), 7.78 ( d, J=7.8 Hz, 1H), 7.63-7.47 (m, 2H), 7.43 (d, J=7.6 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.76-3.59 (m, 2H ), 1.991.71 (m, 12H), 1.49 (d, J=4.4 Hz, 6H), 1.38 (t, J=7.1 Hz, 3H). FXR EC50 (nM) = 418. MS (ESI) 595 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 487B and the corresponding boronates/boronic acids.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 488 0 Α> Αν Ο 1A °γΡ J0A ^CF3 H ₃ C Η 642 876 489 0 Α+ Α^Αμ-, ί J ¥ Ί Py ^^CF ₃ H ₃ C^O^A 593 1636 490 O 591 334 491 0 f^^ A> A^A ⁿ a l j TA _N yyxA x _x a _CF3 F ₃ cA^ 619 1632 492 0 /y^N'PX'l i H ₃ cWN 594 567 493 CO o ^z— n °y \=/ ^w o A 615 552

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494 CO o o/o with I 581 516 488 'H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.84 (s, 1H), 8.07 (dd, J = 8.6, 2.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H ), 7.71-7.61 (m, 2H), 7.59-7.48 (m, 2H), 7.43-7.26 (m, 3H), 3.62 (d, J= 11.2 Hz, 2H), 3.04 (s, 3H), 2.00- 1.70 (m, 12H), 1.58-1.35 (m, 6H) 489 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.6, 2.4 Hz, 1H), 7.75-7.58 (m, 4H), 7.56-7.45 ( m, 2H), 7.37-7.26 (m, 1H), 7.04 (d, J = 9.0 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.62 (d, J = 10.8 Hz, 2H), 1.99-1.70 (m, 12H), 1.50 (d, J= 8.3 Hz, 6H), 1.36 (t, J = 7.0 Hz, 3H) 490 'H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.85 (s, 1H), 8.08 (d, J= 8.3 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.46 (d, 7.8 Hz, 1H), 3.66 (br. s., 1H) , 3.60 (br. s., 1H), 2.31-2.23 (m, 1H), 2.00-1.73 (m, 12H), 1.49 (br. s., 6H), 1.19-0.95 (m, 4H) 491 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.49 (s, 2H), 8.93-8.79 (m, 1H), 8.08 (dd, J = 8.6,2.0 Hz, 1H), 8.05-8.00 (m, 1H), 7.96 (d, J =8.1 Hz, 1H), 7.67 (t, J =7.8 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 3.71- 3.50 (m, 2H), 2.00-1.73 (m, 12H), 1.49 (d, J = 4.6 Hz, 6H) 492 'H NMR (400 MHz, DMSO-d ₆ ) δ 8.89-8.80 (m, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.16-8.00 (m, 2H), 7.77-7.63 (m, 2H) , 7.60-7.45 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 6.98-6.86 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.62 (d, J = 12.5 Hz, 2H), 1.98-1.71 (m, 12H), 1.50 (d, J = 8.8 Hz, 6H), 1.35 (t, J = 7.0 Hz, 3H) 493 'H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.07 (dd, J = 8.4, 2.1 Hz, 1H), 7.90-7.77 (m, 2H), 7.77-7.63 (m, 2H) , 7.60-7.50 (m, 2H), 7.39 (d, J = 8.6 Hz, 1H), 7.35-7.14 (m, 2H), 3.66 (br. s., 1H), 3.60 (br. s., 1H) , 1.98-1.70 (m, 12H), 1.59-1.30 (m, 6H) 494 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.84 (s, 1H), 8.08 (dd, J= 8.3, 2.4 Hz, 1H), 7.83 (d, J= 1.7 Hz, 1H) , 7.78 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.47-7.40 (m, 1H), 3.99 (s, 3H), 3.68 (br. s., 1H), 3.59 (br. s., 1H), 2.05-1.76 (m, 12H), 1.49 (br. s., 6H)

Example 495.

X-(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluoro-X-((4-(5-(trifluoromethyl)pyridin-2yl)bicyclo[2.2.2]octane-1- yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

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Step A: Intermediate 495A. Preparation of X-(3-(5,5-dimethyl-'1,3,2-dioxaborinan-2yl)phenyl)-3-fluoro-U-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo [2.2.2]octan-1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 149C, replacing intermediate 487B where necessary (200 mg, 0.311 mmol, 69% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.56-7.50 (m, 2H), 7.49 -7.44 (m, 2H), 3.78 (s, 4H), 3.65-3.49 (m, 2H), 1.85-1.74 (m, 12H), 1.45 (d, J=7.5 Hz, 6H), 0.96 (s, 6H ).

Step B. Example 495. Preparation of N(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluoro-U-((4-(5(trifluoromethyl)pyridin-2-yl)bicyclo[2.2 .2]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 495A and 2-bromo-5-(difluoromethoxy)pyridine where necessary (4.6 mg, 7.17 µmol, yield 17 %).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J=2.7 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 8.13 -7.98 (m, 3H), 7.80 (dd, J=8.8, 2.9 Hz, 1H), 7.65-7.20 (m, 4H), 3.65 (br. s., 2H), 1.89 (br. s., 6H) , 1.85-1.62 (m, 6H), 1.58-1.35 (m, 6H). FXR EC ₅₀ (nM) = 271. MS (ESI) 616 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 495A and the corresponding aryl/heteroaryl halides.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 496 0 F^^ Y+ _y nYQ ly if ^^CF ₃ ^h 3 ^c \Au ⁿ 579 539 497 0 /''/AYfY f^' A 1J TY /Аж ^^CF ₃ 577 989 498 co about O O co=E 595 524 499 0 ΛΥ^ ^ΝΧ Υ\/\Ι F^^ Y> kYY% nJO XX r γ - ⁷ '//f, AY f ₂ hco 617 135

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500 О nJO ul if ^^CF ₃ h ₃ c _Xo A^n 581 810 496 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, ZN), 8.38 (d, J= 7.6 Hz, 1H), 8.30-8.23 (m, 1H), 8.07 (dd, J= 8.2, 2.3 Hz, 1H), 7.69-7.58 (m, 1H), 7.587.45 (m, 2H), 3.69 (br. s., 1H), 3.59 (br. s., 1H), 2.74-2.66 (m, 2H), 1.90 (br. s., 6H), 1.86-1.61 (m, 6H), 1.58-1.36 (m, 6H), 1.30-1.19 (m, 3H) 497 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 8.07 (dd, J = 8.3, 2.2 Hz, 1H), 7.77-7.61 (m, 4H), 7.59-7.47 (m, 2H), 7.40-7.28 (m, 3H), 3.62 (d, J = 14.7 Hz, 2H), 2.66 (q, J = 7.6 Hz, 2H), 2.00-1.70 (m, 12H), 1.50 (d, J = 8.3 Hz , 6H), 1.22 (t, J = 7.6 Hz, ZN) 498 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.84 (d, J = 2.4 Hz, 1H), 8.69 (s, 2H), 8.31 (d, J = 7.8 Hz, lH), 8.19 (t, J = 1.7 Hz , 1H), 8.07 (dd, J = 8.3, 2.2 Hz, 1H), 7.64-7.57 (m, 1H), 7.56-7.41 (m, 2H), 4.28 (q, J = 6.9 Hz, 2H), 3.69 ( br. s., 1H), 3.58 (br. s., 1H), 1.87 (s, 3H), 1.90 (s, ZN), 1.84-1.62(m, 6H), 1.591.42 (m, 6H), 1.40 (t, J = 7.0 Hz, ZN) 499 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.84 (d, J = 2.4 Hz, 1H), 8.43-8.33 (m, 1H), 8.25 (t, J = 1.8 Hz, 1H) , 8.07 (dd, J= 8.7,2.3 Hz, 1H), 7.72-7.55 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.43(s, 1H), 3.70 (br. s., 1H), 3.59 (br. s., 1H), 1.90 (br. s., 5H), 1.86-1.57 (m, 7H), 1.57-1.31 (m, 6H) 500 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.88-8.81 (m, 1H), 8.71 (s, 2H), 8.36-8.28 (m, 1H), 8.20 (t, J= 1.8 Hz, 1H), 8.07 ( dd, J = 8.9, 2.6 Hz, 1H), 7.65-7.57 (m, 1H), 7.56-7.46 (m, 2H), 3.98 (s, 3H), 3.70 (br. s., 1H), 3.58 (br . s., 1H), 1.88 (s, 3H), 1.90 (s, 3H), 1.84-1.60 (m, 6H), 1.58 -1.39 (m, 6H)

Example 501.

A((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-A(3-(2ethoxypyrimidin- 5-yl)phenyl)-3-hydroxycyclobutane-1-carboxamide

Step A: Intermediate 501A. Preparation of oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

3-bromo-H-((4-(3-(tert-butyl)-1,2,4-

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 191C where necessary (1.1 g, 2.445 mmol, 64% yield) as a brown solid. MS (ESI) 418 (M+H).

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Stage B. Intermediate 501B. Preparation of Ch-((4-(3-(tert-butyl)-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 -(2-ethoxypyrimidin-5 -yl)aniline

The title compound was prepared according to the method described for the synthesis of Example 149 by replacing intermediate 501A and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (70 mg, 0.144 mmol, 60% yield) to as a brown solid. MS (ESI) 462 (M+H).

Step C. Example 501. Preparation of F((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-U-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxycyclobutane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 501B and the corresponding acid where necessary (6.6 mg, 0.012 mmol, 17.87% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J=3.2 Hz, 2H), 7.83-7.61 (m, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.397.26 (m , 1H), 4.96 (br. s., 1H), 4.42 (q, J=7.1 Hz, 2H), 3.71 (br. s., 1H), 3.65 (d, J=4.2 Hz, 2H), 2.45 ( d, J=7.8 Hz, 1H), 2.36 (dd, J=10.5, 5.9 Hz, 1H), 1.93 (t, J=8.3 Hz, 2H), 1.86-1.74 (m, 6H), 1.71 (br. s ., 1H), 1.53-1.32 (m, 9H), 1.32-1.16 (m, 9H).

The following compounds were prepared in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 501B and the corresponding acids.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 502 O A /Х/Х /к ^Ν Γν1 ^НзС Ж^ A ЦА СН ₃ II 1 Г/УЧ-снз _{СНз N|} yU °'N СНз Агг 574 689 503 H ₃ C j? o- ⁷ A Ιλ.ν р ⁿ з СН ₃ N^АА O-Ν CH ₃ ^сАлг 560 1577 504 O X /X/X ^NzS xk7' 7 G\1 NSG' Ax kAx^N P ⁿ z CH ₃ Ν γν °'N ^CH 3 574 288 505 О BocHN^^ As kAxM\ / ^C J ³ u Π v />А ^СНз CH ₃ Ο-Ν СН ₃ ί Λ J 671 621

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506 0 СНз -4% °-N СНз 571 2372 507 A ^РзС xГ7' ΐ^ΓλΙ HO''^ ⁷ Ау \A\ctN СИз Р] ^Г/Д-СНз СНз well» O-Ν СНз 628 188 502 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.11-8.92 (m, 2H), 7.76 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H) , 7.38 (d, J = 9.0 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.65 (s, 2H), 3.52 (t, J = 7.3 Hz, 1H), 3.12-2.92 (m, 3H), 2.60 (t, J= 8.9 Hz, 1H), 1.94 (t, J = 7.8 Hz, 4H), 1.87-1.65(m, 6H), 1.551.30 (m, 9H), 1.30-1.16 (m , 9H) 503 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.85 (s, 1H), 7.73 (d, 7=8.1 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.66 (s, 2H), 3.54 (br. s., 2H ), 1.90-1.67 (m, 6H), 1.60 (s, 3H), 1.51-1.31 (m, 9H), 1.31 -1.16 (m, 9H) 504 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.76 (s, 1H), 7.70 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 4.42 (q,7=7.1 Hz, 2H), 3.66 (s, 2H), 2.66-2.55 (m, 1H), 2.12 (t, J = 10.3 Hz, 2H) , 1.941.68 (m, 6H), 1.62 (br. s., 2H), 1.51-1.31 (m, 9H), 1.30-1.19 (m, 9H), 0.99 (s, 3H) 505 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.80 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.43 -7.38 (m, 1H), 7.28 (br. s., 1H), 4.43 (q, J= 7.1 Hz, 2H), 3.58 (br. s., 2H), 1.88-1.74 (m, 6H), 1.69 (d, J= 6.4 Hz, 6H), 1.53-1.40 (m, 6H), 1.38 (t, J = 7.1 Hz, ZN), 1.33-1.07 (m, 18H) 506 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 8.35 (br. s., 2H), 7.85 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.59 (t , J = 7.8 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 4.43 (q, 7=7.2 Hz, 2H), 3.65 -3.51 (m, 2H), 1.93-1.69 (m, 12H) , 1.56-1.40 (m, 6H), 1.38 (t, J= 7.2 Hz, ZN), 1.31-1.19 (m, 9H). 507 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.83 (s, 1H), 7.72 (d, 7=8.1 Hz, 1H), 7.55 (t, J= 7.8 Hz, 1H), 7.42 (d, J = 7.1Hz, 1H), 4.42 (q, 7=7.0 Hz, 2H), 3.68 (br. s., 2H), 2.85 (quin, 7 = 9.0 Hz, 1H), 2.34 (t, 7 = 10.8 Hz, 2H), 2.06 (d, 7 = 11.7 Hz, 2H), 1.90-1.69 (m, 6H), 1.55-1.40 (m, 6H), 1.37 (t, 7 = 7.0 Hz, ZN), 1.31 -1.16 (m, 9H)

Example 508.

(cis)<H-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)<H-(3 -(2ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methylcyclobutan-1-carboxamide

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Step A: Intermediate 508A. Preparation of oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

3-bromo-No-((4-(5-(tert-butyl)-1,2,4-

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 206F where necessary (650 mg, 1.55 mmol, 84% yield) as a white solid. MS (ESI) 418 (M+H).

Stage B: 508B Intermediate. Preparation of D-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 -(2-ethoxypyrimidin-5 -yl)aniline

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 508A and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (110 mg, 0.236 mmol, 66% yield) to as a brown solid. MS (ESI) 462 (M+H).

Step C. Example 508. Preparation of (cis)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) -N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3methylcyclobutan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 508B and the corresponding acid where necessary (12.2 mg, 0.021 mmol, 49% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.77 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H) , 7.36 (d, J=8.8 Hz, 1H), 4.90 (s, 1H), 4.42 (q, J=7.1 Hz, 2H), 3.65 (br. s., 2H), 2.60 (t, J=8.4 Hz , 1H), 2.21-2.01 (m, 2H), 1.84-1.65 (m, 6H), 1.61 (br. s., 2H), 1.45-1.28 (m, 18H), 0.99 (s, 3H). FXR EC50 (nM) = 210. MS (ESI) 574 (M+H).

The following compounds were prepared in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 508B and the corresponding acids.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 509 O ^RzS xG7' Υ Γν HO''^ ⁷ /A AAn / ^CH z || Ί Ύ U-Dsnz sn, YES ^N -° ^sn z 628 230 510 H ₃ C ? °·- ⁷ A LAn SIZ Η Ί and U-Dsnz SNz Ν-γΧ-Χ ^Ν '° ^SNz 560 974 511 O A Gu ^ν γνί Нз%х</ J. LA^N , ^СН з ίΐ Ί and У-Д ^СН 3 _СНз ^Ν Α снз 574 411 509 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.84 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.53 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.68 (br. s., 2H), 2.85 (t, J = 9.0 Hz, 1H ), 2.34 (t, J= 10.4 Hz, 2H), 2.05 (br. s., 2H), 1.86-1.58 (m, 6H), 1.58-1.28 (m, 18H). 510 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.87 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 4.54 (d, J = 5.4 Hz, 2H), 4.42 (q, J = 7.0 Hz, 2H), 3.66 (br. s., 2H), 3.53 (br. s ., 2H), 1.89-1.63 (m, 6H), 1.60 (s, 3H), 1.49-1.28 (m, 18H). 511 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.07-8.96 (m, 2H), 7.77 (s, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H) , 7.38 (d, J= 8.8 Hz, 1H), 4.42 (q, J= 6.9 Hz, 2H), 3.64 (s, 2H), 3.56-3.47 (m, 1H), 3.09-2.97 (m, 3H), 2.65-2.55 (m, 1H), 1.94 (t, J= 7.8 Hz, 4H), 1.83-1.60 (m, 6H), 1.46-1.28 (m, 18H).

Example 512.

(cis)-M((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-3-hydroxy -3methyl-X-(4'-(methylsulfonamido)-[1,1'-biphenyl]-3-yl)cyclobutan-1-carboxamide

ABOUT

Step A: Intermediate 512A. Preparation of M(3'-(((4-(5-(tert-butyl)-'1,2,4-oxadiazol3-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)-[1 ,1'-biphenyl]-4-yl)methanesulfonamide

- 355 047337

The title compound was prepared according to the method described for the synthesis of Example 149 by replacing intermediate 508A and (4(methylsulfonamido)phenyl)boronic acid where necessary (130 mg, 0.253 mmol, 71% yield) as white solid matter. MS (ESI) 509 (M+H).

Step B Example 512 Preparation of (cis)-X-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-hydroxy-3-methyl-N-(4'-(methylsulfonamido)-[1,G-biphenyl]-3yl)cyclobutane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 512A and the corresponding acid where necessary (5 mg, 7.72 μmol, 19% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.65-7.53 (m, 2H), 7.49 (t, J=8.1 Hz, 1H ), 7.39-7.23 (m, 3H), 4.90 (s, 1H), 3.64 (br. s., 2H), 3.03 (s, 3H), 2.64-2.54 (m, 1H), 2.12 (t, J= 10.5 Hz, 2H), 1.83-1.66 (m, 6H), 1.62 (br. s., 2H), 1.49-1.35 (m, 6H), 1.33 (s, 9H). FXR EC50 (nM) = 909. MS (ESI) 621 (M+H).

The following compounds were prepared in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 512A and the corresponding acids.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 513 O ^H0 ' A pH ₃ H | —£СН ₃ О ZNzV ^N 'O сн ₃ Н ₃ С U 675 922 514 O A /x/. A kA^N СНз Η Ί Ύ у-к-снз О ZN/AZ No ^Z СН ₃ Н ₃ С U 621 2257 513 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.67 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.42-7.26 (m, 3H), 6.53 (s, 1H), 3.66 (br. s., 2H), 3.03 (s, 3H), 2.90-2.78 (m, 1H), 2.39-2.24 (m, 2H), 2.06 (d,J= 14.4 Hz, 2H), 1.83 -1.54 (m, 6H), 1.52-1.35 (m, 6H), 1.33 (s, 9H). 514 DNMR (400 MHz, DMSO-d ₆ ) δ 9.86 (br. s., 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.61 (s, 2H), 7.49 (t, J = 8.2 Hz, 1H) , 7.36-7.21 (m, 3H), 3.63-3.49 (m, 3H), 3.09-2.96 (m, 6H), 2.05-1.87 (m, 4H), 1.81-1.67 (m, 6H), 1.42 (d, J = 7.6 Hz, 6H), 1.33 (s, 9H).

Example 515.

A((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-X-(4'- 356 047337 ( difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-methyloxetane-3-carboxamide

Step A: Intermediate 515A. Preparation of X-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-4'-(difluoromethoxy)-[ 1 ,1'-biphenyl]-3-amine

The title compound was prepared according to the method described for the synthesis of Example 149 by replacing intermediate 508A and (4-(difluoromethoxy)phenyl)boronic acid where necessary (130 mg, 0.267 mmol, 74% yield) as brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.60 (m, 2H), 7.28-7.20 (m, 3H), 7.16-7.07 (m, 1H), 6.87-6.83 (m, 1H), 6.74 ( d, J=8.5 Hz, 1H), 6.63 (dd, J=7.8, 1.8 Hz, 1H), 5.53 (t, J=6.3 Hz, 1H), 2.88 (d, J=6.0 Hz, 2H), 1.891. 80 (m, 6H), 1.63-1.54 (m, 6H), 1.36 (s, 9H). MS (ESI) 482 (M+H).

Step B. Example 515. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1 -yl)methyl)-X-(4 '-(difluoromethoxy)-[1,1 '-biphenyl]-3-yl)-3-methyloxetane-3-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 515A and the corresponding acid where necessary (4.7 mg, 8.11 μmol, 19% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.87-7.77 (m, 2H), 7.74 (s, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.53 -7.12 (m, 5H), 4.55 (d, J=5.4 Hz, 2H), 3.65 (br. s., 2H), 3.53 (br. s., 2H), 1.88-1.65 (m, 6H), 1.60 (s, 3H), 1.51-1.36 (m, 6H), 1.33 (s, 9H). FXR EC ₅₀ (nM) = 357. MS (ESI) 580 (M+H).

The following compounds were prepared in accordance with the method described for the synthesis of the compound of Example 3, by replacing intermediate 515A and the corresponding acids.

Etc. No. Structure MS (ESI) (M+N) FXR ec ₅₀ (nM) 516 O A ^Rz ChL7' Ϊ ΓΊ NO''' /Ah, AAAzN / ^CH z || Ί n уАг ^с з /хАА N- _O ^z СН ₃ J t f ₂ hco^^^ 648 94

- 357 047337

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.87-7.76 (m, 2H), 7.71 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.57-7.44 (m, 1H), 7.38 ( d, J = 8.6 Hz, 1H), 7.34-7.20 (m, 3H), 6.53 (s, 1H), 3.67 (br. s., 2H), 2.84 (t, J = 8.9 Hz, 1H), 2.39- 2.27 (m, 2H), 2.04 (br. s., 2H), 1.80-1.64 (m, 6H), 1.55-1.35 (m, 6H),1.33 (s, 9H)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d, J = 8.8 Hz, 2H), 7.70-7.56 (m, 2H), 7.55-7.20 (m, 5H), 3.65 (br. s., 2H) , 2.65-2.54 (m, 1H), 2.19-2.05 (m, 2H), 1.82-1.65 (m, 6H), 1.61 (br. s., 2H), 1.46-1.37 (m, 6H), 1.37-1.26 (m, 9H), 0.98 (s, 3H)

Example 518.

(cis)-D-(3 -(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxy-D-((4-(5-(3-methyloxetan-3-yl)-1,2,4oxadiazol- 3-yl)bicyclo[2.2.2]octan-1-yl)methyl)cyclobutan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, substituting 3-bromoaniline and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (850 mg, 3.75 mmol, 64% yield ) as a white solid. MS (ESI) 216 (M+H).

Stage B: 518V Intermediate. Preparation of methyl 4-(((3-(2-ethoxypyrimidin-5yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 518A and intermediate 88B where necessary (1.3 g, 3.12 mmol, 79% yield) as a white solid. MS (ESI) 396 (M+H).

Step C. Intermediate 518C. Preparation of 4-(((3-(2-ethoxypyrimidin-5yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

To a solution of intermediate 518B (1.3 g, 3.29 mmol) in tetrahydrofuran (20 ml) add

- 358 047337 poured a solution of sodium hydroxide (0.39 g, 9.86 mmol) in water (20 ml). The reaction mixture was stirred at 50°C overnight. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water (20 ml), acidified (pH ~2) with 1.5 ml aqueous HCl solution and extracted with EtOAc (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give the title compound (1.05 g, 2.61 mmol, 80% yield). MS (ESI) 382 (M+H).

Stage D. Intermediate 518D. yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxamide

Preparation of 4-(((3-(2-ethoxypyrimidine-5-

To a stirred solution of intermediate 518C (850 mg, 2.228 mmol) in dichloromethane (15 ml) was added ammonium chloride (596 mg, 11.14 mmol), BOP (985 mg, 2.228 mmol), followed by TEA (0.95 ml, 6.68 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml) and extracted with DCM (2x50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give the title compound (1 g, 2.103 mmol, 94% yield) as an off-white solid. MS (ESI) 381 (M+H).

Step E. Intermediate 518E.

yl)phenyl)amino)methyl)bicyclo[2.2.2]octane-1-carbonitrile

Preparation of 4-(((3-(2-ethoxypyrimidine-5-

The title compound was prepared according to the method described for the synthesis of intermediate 194D, replacing intermediate 516D where necessary (110 mg, 0.288 mmol, 18% yield) as an off-white solid. MS (ESI) 363 (M+H).

Step F: Intermediate 518F. Preparation of (7)-4-(((3-(2-ethoxypyrimidin-5yl)phenyl)amino)methyl)-N-hydroxybicyclo[2.2.2]octane-1-carboximidamide

The title compound was prepared according to the method described for the synthesis of intermediate 88F, replacing intermediate 518E where necessary (120 mg, 0.288 mmol, 95% yield) as an off-white solid. MS (ESI) 396 (M+H).

Stage G. Intermediate 518G. Preparation of 3-(2-ethoxypyrimidin-5-yl)-N-((4-(5-(3methyloxetan-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan- 1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1A, replacing intermediate 518F and the corresponding acid where necessary (130 mg, 0.260 mmol, 86% yield) as an off-white solid. MS (ESI) 476 (M+H).

Step H. Example 518. Preparation of (cis)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxy-N-((4-(5(3-methyloxetan-3-yl)- 1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)cyclobutan-1 carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 518G and the corresponding acid where it

- 359 047337 required (7 mg, 0.011 mmol, yield 22%).

1H NMR (400 MHz, DMSO-de) δ 9.09-8.91 (m, 2H), 7.77 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H) , 7.38 (d, J=8.3 Hz, 1H), 4.83 (d, J=5.9 Hz, 2H), 4.51 (d, J=5.9 Hz, 2H), 4.42 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 3.56-3.46 (m, 1H), 3.08-2.96 (m, 3H), 2.66-2.53 (m, 1H), 1.94 (t, J=7.9 Hz, 4H), 1.84-1.58 (m , 9H), 1.54-1.29 (m, 9H). FXR EC ₅₀ (nM) 1294. MS (ESI) 588 (M+N).

The following compounds were prepared in accordance with the method described for the synthesis of the compound of example 3, by replacing intermediate 518G and the corresponding acids.

Etc. No. Structure MS (ESI) (M+H) FXR EC ₅₀ (hM) 519 O NOR DOUCTS CH ₃ O |ί Χ\η Nn VO CH ₃ Ν ^υ CHA^LG 588 504 520 Ο ω ΞΕ >=+ Μ ΜΌ + M cr 642 449 519 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.77 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 4.87 (s, 1H), 4.83 (d, J = 6.1 Hz, 2H), 4.52 (d, J = 6.1 Hz, 2H), 4.42 (q, J = 7.1 Hz , 2H), 3.67 (br. s., 2H), 2.65-2.57 (m, 1H), 2.19-2.06 (m, 2H), 1.84-1.67 (m, 9H), 1.62 (br. s., 2H) , 1.53-1.30 (m, 9H), 0.99 (s, 2H). 520 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 2H), 7.83 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.55 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 6.51 (s, 1H), 4.83 (d, J = 5.9 Hz, 2H), 4.52 (d, J = 6.1 Hz, 2H), 4.42 (q, J = 7.0 Hz , 2H), 3.69 (br. s., 2H), 2.91-2.78 (m, 1H), 2.39-2.26 (m, 2H), 2.06 (d, J= 10.3 Hz, 2H), 1.851.72 (m, 6H), 1.71 (s, 3H), 1.54-1.40 (m, 6H), 1.37 (t, J= 7.0 Hz, 3H).

Example 521.

N(4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluoro-X-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 521A. Preparation of 3-bromo-X-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

- 360 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1A, replacing intermediate 194E and the corresponding acid where necessary (450 mg, 0.957 mmol, 96% yield) as a yellow solid. MS (ESI) 470 (M+H).

Stage B. Intermediate 521B. Preparation of D-(3-bromophenyl)-3-fluoro-D-((4-(5-(1(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane- 1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 521A and the corresponding acid where necessary (400 mg, 0.687 mmol, 77% yield) in the form of a gummy mass. MS (ESI) 582 (M+H).

Step C. Example 521. Preparation of N(4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1(trifluoromethyl)cyclopropyl)-1, 2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 521B and 2-(4-ethoxyphenyl)-5,5-dimethyl-1,3,2dioxaborinan where necessary (8,2 mg, 0.013 mmol, yield 25%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.55 (m, 4H), 7.50 (t, J=7.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.04 (d, J =8.8 Hz, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.59 (d, J=10.0 Hz, 2H), 1.85 (s, 3H), 1.88(s, 3H), 1.79-1.55 (m , 10H), 1.55-1.39 (m, 6H), 1.36 (t, J=7.0 Hz, 3H). FXR EC ₅₀ (nM) = 112. MS (ESI) 624 (M+H).

The following compounds were prepared according to the method described for the synthesis of compound 149 by replacing intermediate 521B and the corresponding aryl/heteroarylboronic acids/esters.

- 361 047337

- 362 047337

522 ΉNMR (400 MHz, DMSO-d ₆ ) δ 7.89-7.77 (m, 2H), 7.76-7.64 (m, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H ), 7.34-7.20 (m, 2H), 7.12 (s, 1H), 3.63 (br. s., 1H),3.60-3.50 (m, 1H), 1.85 (s, 3H), 1.88 (s, 3H) , 1.79-1.59 (m, 10H), 1.47 (d, J =9.5 Hz, 6H) 523 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.88 (s, 1H), 7.74 (d, J= 8.6 Hz, 2H), 7.717.62 (m, 2H), 7.52(t, J= 7.8 Hz, 1H) , 7.41-7.24 (m, 3H), 3.60 (d, J= 11.5 Hz, 2H), 3.04 (s, 3H), 1.85 (s, 3H), 1.88 (s, 3H), 1.79-1.54 (m, 10H ), 1.47 (d, J = 8.1 Hz, 6H) 524 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.86 (dd, J =8.4, 1.8 Hz, 1H), 7.83 -7.71 (m, 2H), 7.56 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 3.73-3.63 (m, 1H), 3.61-3.49 (m, 1H), 2.83 (s, 3H), 1.86 (s, 3H), 1.91 (s, 3H), 1.79-1.57(m, 10H), 1.47 (d, J = 4.9 Hz, 6H) 525 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 7.82 (s, 1H), 7.77 (d, J - 8.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 4.43 (q, J = 6.9 Hz, 2H), 3.66-3.52 (m, 2H), 1.85 (s, 3H),1.88 (s, 3H), 1.79-1.56 ( m, 10H), 1.46 (d, J = 9.0 Hz, 6H), 1.38 (t, J = 7.0 Hz, 3H) 526 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 7.94-7.70 (m,2H), 7.60 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 12.2 Hz, 1H), 2.66-2.58 (m, 1H) , 1.86 (s, 3H), 1.91 (s, 3H), 1.80-1.58 (m, 10H), 1.58 -1.38 (m, 6H), 1.36-1.30 (m, 2H), 1.28-1.16 (m, 2H)

Example 527.

\D(4-(5-(1,1-di(])to].ptyl)-1,2,4-oxadiazol-3-yl)bi11iclo[2.2.2]octan-1-yl)methyl)- \-(4'-ethoxy-[1,1'biphenyl]-3 -yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 527A. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of Intermediate 1A, substituting the compound of Example 194E and the corresponding acid where necessary (380 mg, 0.882 mmol, 89% yield) as a brown gummy mass. MS (ESI) 426 (M+H).

Stage B. 527V intermediate connection. Preparation of X-(3-bromophenyl)-X-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-fluorobicyclo[1.1.1]pentane-1carboxamide

- 363 047337

The said compound was prepared according to the method described for the synthesis of Example 3, by replacing intermediate 527A and the corresponding acid where necessary (400 mg, 0.687 mmol, 77% yield) as a gum mass MS (ESI) 538 ( M+N).

Step C. Example 527. Preparation of F((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-No- (4'-ethoxy-[1,G-biphenyl]-3-yl)-3-fluorobicyclo-[1.1.1]pentane-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 527B and the corresponding boronic acid where necessary (16.6 mg, 0.028 mmol, 50% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.76-7.58 (m, 4H), 7.50 (t, J=7.8 Hz, 1H), 7.37-7.27 (m, 1H), 7.13-6.95 (m, 2H ), 4.09 (q, J=6.8 Hz, 2H), 3.60 (d, J=8.3 Hz, 2H), 2.14 (t, J=19.7 Hz, 3H), 1.98-1.69 (m, 12H), 1.59-1.38 (m, 6H), 1.38-1.28 (m, 3H). FXR EC ₅₀ (nM) = 103. MS (ESI) 580 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 527B and the corresponding aryl/heteroarylboronic acids/esters

- 364 047337

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 528 О Ах CA^N Г Г 1 » ZvA ^N O ^CH 3 П F ₂ HCC7^ 602 73 529 0 F^^ Ax nA-Ν g [Μ Ύ yA ^F _n Aa no ch ₃ II \ 582 106 530 0 f^^ At, AA g P » A s^/vA ^N O CH ₃ ΑΛΊΓ J ^N A 634 145 528 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.87-7.77 (m, 2H), 7.76-7.64 (m, 2H), 7.55 (t, J= 8.1 Hz, 1H), 7.40 (d, J= 8.3 Hz, 1H), 7.35-7.21 (m, 3H), 3.71-3.61 (m, 1H), 3.61-3.51 (m, 1H), 2.14(t, J= 19.6 Hz, 3H), 1.98-1.70 (m, 12H) , 1.49 (d, J =9.5 Hz, 6H) 529 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 2H), 7.87-7.80 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H) , 7.44 (d, J= 7.8 Hz, 1H), 4.43 (q, J= 7.1 Hz, 2H), 3.71-3.51 (m, 2H), 2.14 (t, J= 19.6 Hz, 3H), 2.00-1.70 ( m, 12H), 1.47 (d, J= 5.9 Hz, 3H), 1.49 (d, J= 4.9 Hz, ZN), 1.38 (t, J = 7.0 Hz, 3H) 530 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (d, J = 2.2 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 7.94-7.77 (m,2H), 7.60 (t, J= 7.8 Hz, 1H), 7.52-7.41 (m, 1H), 3.743.63(m, 1H), 3.62-3.51 (m, 1H), 2.66-2.59 (m, 1H), 2.22-2.05 (m, 3H) , 1.991.70 (m, 12H), 1.59-1.37 (m, 6H), 1.37-1.17 (m, 4H)

Example 531.

¥-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-c-(4-( 2ethoxypyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 531A. Preparation of oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

4-bromo-X-((4-(5-(tert-butyl)-1,2,4- 365 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing 4-bromopyridin-2-amine and intermediate 206F where necessary (250 mg, 0.596 mmol, 41% yield) as an oily liquid. MS (ESI) 419 (M+N).

Stage B. Intermediate 531B. Preparation of D-(4-bromopyridin-2-yl)-D-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

ABOUT

As kJVxN, ^sn z

Ιίι π V-Д ^СНз _Β AM ^Ν 'Ο СНз

To a stirred solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (84 mg, 0.644 mmol) in acetonitrile (2 ml), 1-chloro-N,^2-trimethylpropenylamine (0.086 ml, 0.644 mmol) was added dropwise. at 0°C. The reaction mixture was stirred at 0°C for 1 hour until a clear solution was obtained. The reaction mixture was cooled to -10°C. A solution of intermediate 531A (180 mg, 0.429 mmol) in acetonitrile (1 mL) was added to the reaction mixture, followed by a solution of 4-methylmorpholine (0.094 mL, 0.858 mmol) in acetonitrile (1 mL). The resulting reaction mixture was stirred at 0°C for 30 minutes, then allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was diluted with 10% aqueous citric acid (10 ml) and extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (130 mg, 0.245 mmol, 57% yield) as an oily liquid. MS (ESI) 531 (M+H).

Step C. Example 531. Preparation of No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-No-(4 -(2-ethoxypyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 531B and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (4.8 mg, 8.35 µmol, yield 15%).

¹ HNMR (400 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.63 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J=5.3, 1.6 Hz, 1H) , 4.45 (q, J =7.1 Hz, 2H), 3.71 (s, 2H), 1.91 (d, J=2.4 Hz, 6H), 1.81-1.59 (m, 6H), 1.58-1.29 (m, 16H), 1.24 (s, 2H). FXR EC ₅₀ (nM) = 159. MS (ESI) 575 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 531B and the corresponding aryl/heteroarylboronic acids/esters.

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533 0 /AAA NY СНз Jf t F^CCT^ 595 26 534 0 Xw? n 7 Ύ uChdsnz _ γγΧΧ ^ν ό ^СНз Η ₃ Χ ί J ^u H 622 77 535 0 ^ρ ΑΑθγΝ СНз Hi П YJCH ₃ S^/αΛα No ^Z CH ₃ [>4 Ύ J 627 202 536 0 -Vw /hour ^ν ~Ό CH ₃ H ₃ C^C> NT 574 29 537 0 /Ά^Ν^ΥΧ] pAU aU \A\^N , ^CH 3 Hl I W ^CH 3 ν-ό сн ₃ Н ₃ С—JJ Т naa 600 67 538 0 F^AXTOyN CH' Hi and -\ ^СНз _N yV NY СН ₃ ^Η 3°Ό ^Λ ν^ 561 121

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539 sn, Hi u zhusn _{3 Ν} γΛζ ^N -0 СН ₃ II J already 571 119 540 J-n 7 Ύ u-D-snz OAH/F ^ν ~Ό СНз Ά t t N 586 71 532 ^X H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J= 5.1 Hz, 1H), 7.96-7.85 (m, 2H), 7.82 (s, 1H), 7.73(dd, J= 5.3, 1.6 Hz , 1H), 7.15-7.01 (m, J =9.0 Hz, 2H), 4.12 (q, J= 7.0 Hz, 2H), 3.70 (s, 2H), 1.90(d, J = 2.4 Hz, 6H), 1.79 -1.54 (m, 6H), 1.52-1.28 (m, 18H) 533 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J = 5.4 Hz, 1H), 8.09-7.94 (m, 2H), 7.89 (s, 1H), 7.79 (dd, J = 5.3, 1.6 Hz, 1H),7.45-7.26 (m, 3H), 3.71 (s, 2H), 1.90 (d, J= 2.4 Hz, 6H),1.80-1.58 (m, 6H), 1.51-1.36 (m, 6H), 1.36 -1.26 (m, 9H) 534 Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.007.86 (m, J = 8.6 Hz, 2H), 7.83 (s, 1H) , 7.75 (dd,7=5.3, 1.6 Hz, 1H), 7.43-7.29 (m, J = 8.8 Hz, 2H), 3.70 (s, 2H), 3.07 (s, 3H), 1.90 (d, J = 2.4 Hz, 6H), 1.801.58 (m, 6H), 1.49-1.35 (m, 6H), 1.35- 1.25 (m, 9H) 535 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (d, J = 2.2 Hz, 1H), 9.07 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 5.4 Hz, 1H), 8.02 (d , J= 1.2 Hz, 1H), 7.92 (dd, 7=5.3, 1.6 Hz, 1H), 3.73 (s, 2H), 2.69-2.63 (m, 1H), 1.92 (d, 7= 2.4 Hz, 6H) ,1.79-1.62 (m, 6H),1.48-1.38 (m, 6H), 1.38-1.30 (m, 10H), 1.30-1.19 (m, 3H) 536 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (d, 7 = 2.2 Hz, 1H), 8.58 (d, 7 = 5.4 Hz, 1H), 8.27 (dd, 7 = 8.7, 2.6 Hz, 1H), 7.90 (s, 1H), 7.80 (dd,7=5.3, 1.6 Hz, 1H), 6.97 (d, 7= 8.8 Hz, 1H), 4.39 (q, 7= 7.1 Hz, 2H), 3.70 (s, 2H) , 1.90 (d, 7= 2.7 Hz, 6H), 1.81-1.57 (m, 6H), 1.49 (s, 1H), 1.45 -1.28 (m, 17H) 537 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, 7 = 1.2 Hz, 1H), 8.62 (d, 7 = 5.4 Hz, 1H), 8.11-7.98 (m,2H), 7.96 (d,7= 1.0 Hz, 1H), 7.86 (dd,7=5.3, 1.6 Hz, 1H), 3.73 (s, 2H), 2.86 (s, 3H), 1.92 (d, 7 = 2.4 Hz, 6H), 1.82-1.59 ( m, 6H), 1.50-1.35

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(m, 6H), 1.33 (s, 9H) 538 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 2H), 8.63 (d, J= 5.1 Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J= 5.4, 1.5 Hz, 1H) , 4.01 (s, 3H), 3.71 (s, 2H), 1.91 (d,J=2.7 Hz, 6H), 1.78-1.59 (m, 6H), 1.49 -1.35 (m, 6H), 1.33 (s, 9H ) 539 Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 2H), 8.65 (d, J= 5.4 Hz, 1H), 8.00 (d, J= 1.0 Hz, 1H), 7.89 (dd, J= 5.3, 1.6 Hz, 1H), 3.71 (s, 2H), 2.36-2.25 (m, 1H), 1.90 (d,/=2.4 Hz, 6H), 1.81 -1.56 (m, 6H), 1.53-1.28 (m, 15H ), 1.17-1.01 (m, 4H) 540 Ή NMR (400 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 8.57 (d, J= 5.4 Hz, 1H), 7.96 (d, / = 1.5 Hz, 1H), 7.88 (d, J= 1.2 Hz , 1H), 7.83-7.70 (m, 2H), 7.24 (d,/= 8.1 Hz, 1H), 3.71 (s, 2H), 1.96-1.82 (m, 6H), 1.81-1.59 (m, 6H), 1.52-1.34 (m,6H), 1.33 (s, 7H), 1.30-1.19 (m, 2H)

Example 541.

D-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-D-(4-( 5(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 541A. Preparation of D-((4-(5-(tert-butyl)-'1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(4-(5, 5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of intermediate 149c, by replacing intermediate 531B where necessary MS (ESI) 497 (M+H) (boronic acid weight).

Step B. Example 541. Preparation of No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-No-(4 -(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 541A and 2-chloro-5-(difluoromethoxy)pyrimidine where necessary (3.7 mg, 6.20 µmol, yield 12 %).

¹ H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 2H), 8.75 (d, J=5.20 Hz, 1H), 8.25 (d, J=6.80 Hz, 1H), 8.23 (d, J=12.40 Hz, 1H),7.49 (s, 1H), 3.73 (s, 2H), 1.93 (s, 6H), 1.73-1.69 (m, 6H), 1.41-1.39 (m, 6H), 1.37 (s, 9H) . FXR EC ₅₀ (nM) = 18. MS (ESI) 597 (m+N).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 541A and the corresponding aryl/heteroaryl halides.

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Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 542 O /L aTa^N , ^CH z ίίι uChg ^sn z A CHz λ AD N ₃ C 0 575 22 543 0 аС Х/Cn , ^СН з i| 7 hW ^ch 3 / ^Ν <ΑαΤ ν-O СНз h ₃ c,Aaa ⁿ 559 14 544 O Am UAn СНз n 7 ТуА ^сн з /AVaV No ^Z СНз g ₂ nssu^ 596 20 542 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.76 (s, 2H), 8.70 (d, J = 5.1 Hz, 1H), 8.20 (dd, J = 5.1, 1.5 Hz, 1H), 8.15 (s, 1H) , 4.32 (q, J= 6.8 Hz, 2H), 3.72 (s, 2H), 2.00-1.86 (m, 6H), 1.79-1.64 (m, 6H), 1.48-1.34 (m, 9H), 1.32 (s , 9H) 543 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (s, 2H), 8.73 (dd, J = 5.1, 0.5 Hz, 1H), 8.26 (dd, J = 5.1, 1.5 Hz, 1H), 8.22 (dd, J= 1.5, 0.7 Hz, 1H), 3.73 (s, 2H), 2.73 (q, J =7.6 Hz, 2H), 1.93 (d, J = 2.4 Hz, 6H), 1.82-1.56 (m, 6H), 1.53-1.36 (m, 6H), 1.35-1.18 (m, 12H) 544 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.75-8.60 (m, 2H), 8.35 (d, J= 8.8 Hz, 1H), 8.13 (s, 1H), 8.09 (dd, J= 5.1, 1.5 Hz, 1H), 7.88 (dd, J = 8.8, 2.9 Hz, 1H), 7.44 (s, 1H), 3.72 (s, 2H), 1.92 (d, J = 2.4Hz, 6H), 1.80-1.56 (m, 6H ), 1.49-1.34 (m, 6H), 1.34-1.28 (m, 9H)

Example 545.

A((4-(3-cyclopropyl-'1-methyl-'1H-pyrazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)A-(4-(4(difluoromethoxy)phenyl )pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

ABOUT

Step A: Intermediate 545A. Preparation of 4-bromo-X-((4-(3-cyclopropyl-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

- 370 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 4-bromopyridin-2-amine and intermediate 126B where necessary (320 mg, 0.770 mmol, 66% yield) as a gummy liquid. MS (ESI) 415 (M+H).

Stage B. 545V intermediate connection. Preparation of L(4-bromopyridin-2-yl)L-((4-(3cyclopropyl-1 -methyl-1 H-pyrazol-5 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 - fluorobicyclo[1.1.1]pentane-1 carboxamide

ABOUT

The title compound was prepared according to the method described for the synthesis of intermediate 531B, replacing intermediate 545A and the corresponding acid where necessary (200 mg, 0.379 mmol, 52% yield) as a colorless liquid. MS (ESI) 527 (M+H).

Step C. Example 545. Preparation of N((4-(3-cyclopropyl-1-methyl-III-pyrazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-U-(4-(4- (difluoromethoxy)phenyl)pyridin-2-yl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate 545B and 2-(4-(difluoromethoxy)phenyl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane there, where needed (12 mg, 0.020 mmol, 43% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J=5.4 Hz, 1H), 8.10-7.92 (m, 2H), 7.91-7.83 (m, 1H), 7.78 (dd, J=5.4, 1.7 Hz, 1H), 7.45-7.26 (m, 3H), 5.62 (s, 1H), 3.80-3.63 (m, 5H), 1.91 (d, J=2.4 Hz, 6H), 1.78-1.55 (m, 6H ), 1.49-1.26 (m, 6H), 0.80-0.68 (m, 2H), 0.58-0.45 (m, 2H) One proton is hidden under the moisture peak at approximately 2.5 ppm. FXR EC ₅₀ (nM) = 115. MS (ESI) 591 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 149 by replacing intermediate 545B and the corresponding aryl/heteroarylboronic acids/esters.

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Etc. No. Structure MS (ESI) FXR EC ₅₀ (M+N) (nM) 546 M 'o/.z-'A CO Y about co T 596 48 547 co /\ T z jLS Y CX ck° CO I 618 251 546 ^NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, 7 = 1.5 Hz, 1H), 8.62 (d, 7 = 5.4 Hz, 1H), 8.09-8.03 (m,lH), 8.03-7.98 (m, 1H), 7.95 (s, 1H), 7.86 (dd,7 = 5.3, 1.6 Hz, 1H), 5.62 (s, 1H), 3.71 (s, 5H), 2.86 (s, 3H), 1.92 (d, 7 = 2.4 Hz, 6H), 1.791.61 (m, 6H), 1.51-1.29 (m, 6H), 0.80-0.70 (m, 2H), 0.58-0.46 (m, 2H) (One proton hidden under the humidity peak) . 547 Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.57 (d, 7 = 5.4 Hz, 1H), 7.92 (d, 7 =8.8 Hz, 2H), 7.83 (s, 1H), 7.75 (dd,7=5.4, 1.7 Hz, 1H), 7.36 (d, 7 =8.8 Hz, 2H), 5.62 (s, 1H), 3.77-3.67 (m, 5H), 3.07 (s, 3H), 1.91 ( d, 7= 2.7 Hz, 6H), 1.69 (dd, 7= 9.3, 4.4 Hz, 6H), 1.54 -1.26 (m, 6H), 0.81-0.68 (m, 2H), 0.60-0.47 (m, 2H) . (One proton is hidden under the moisture peak).

Example 548.

A-((4-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-'1-yl)methyl)-A-(4-(2ethoxypyrimidin-5- yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

ABOUT

Step A: Intermediate 548A. Preparation of oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

4-bromo-X-((4-(3-cyclopropyl-1,2,4-

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing 4-bromopyridin-2-amine and intermediate 4C where necessary (400 mg, 0.992 mmol, 49% yield) as a brown solid. MS (ESI) 404.0 (M+N).

¹ H NMR (400 MHz, DMSO-d6) δ 7.81 (d, J=5.5 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 6.67 (t, J=6.3 Hz, 1H), 6.61 ( dd, J=5.5, 1.5 Hz, 1H), 3.10 (dd, J=16.8, 5.8 Hz, 2H), 2.11-2.02 (m, 1H), 1.93-1.75 (m, 6H), 1.54-1.40 (m, 6H), 1.08-0.99 (m, 2H), 0.89-0.82 (m, 2H).

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Stage B: 548V Intermediate. Preparation of U(4-bromopyridin-2-yl)U-((4-(3cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo [1.1.1]pentane-1carboxamide

To a stirred solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (206 mg, 1.587 mmol) in DCM (6 mL) was added intermediate 548A (320 mg, 0.793 mmol) followed by 4methylmorpholine (0.446 mL, 3 .97 mmol). The reaction mixture was cooled to 0°C. POCl ₃ (0.185 ml, 1.984 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with DCM (30 ml), washed with 10% aqueous citric acid (25 ml), 10% aqueous sodium bicarbonate (25 ml) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (50 mg, 0.097 mmol, 12% yield) as a brown gummy mass. MS (ESI) 515 (M+H).

Step C. Example 548. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(4-(2- ethoxypyrimidin-5-yl)pyridin-2-yl)-3fluorobicyclo[1.1.1]pentan-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 548B and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (3.5 mg, 6.14 µmol, yield 16%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 2H), 8.62 (d, J=5.4 Hz, 1H), 7.98 (s, 1H), 7.87 (dd, J=5.4, 1.5 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 2.09-2.00 (m, 1H), 1.90 (d, J=2.7 Hz, 6H), 1.82-1.63 (m, 6H ), 1.491.29 (m, 9H), 1.06-0.96 (m, 2H), 0.87-0.77 (m, 2H). FXR EC50 (nM) = 111. MS (ESI) 559 (M+H).

Example 549.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-fluoro-N-(4-(2methylbenzo^ ]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 549A. Preparation of Y((4-(3-cyclopropyl-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-(2-methylbenzo^]thiazol-6-yl )pyridine-2-amine

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 548A and 6-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-2-methylbenzo^]thiazole there, where required (90 mg, 0.191 mmol, 77% yield) as a brown solid. MS (ESI) 472 (M+H).

Step B. Example 549. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4 -(2-methylbenzo^]thiazol-6-yl)pyridin-2yl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 549A and the corresponding acid where necessary (0.9 mg, 1.459 μmol, 5% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (s, 1H), 8.61 (d, J=5.4 Hz, 1H), 8.11-7.98 (m, 2H), 7.95(s, 1H), 7.86 ( d, J=5.1 Hz, 1H), 3.72 (s, 2H), 2.85 (s, 3H),2.10-1.99 (m, 1H), 1.91 (d, J=2.2 Hz, 6H), 1.83-1.66 (m , 6H), 1.581.28 (m, 6H), 1.06-0.95 (m, 2H), 0.89-0.74 (m, 2H). FXR EC ₅₀ (nM) = 36. MS (ESI) 584 (M+H).

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Example 550.

N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4-(2methylbenzo^ ]oxazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentan-1-carboxamide

Stage A. Intermediate 550A. Preparation of 4-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-(2-methylbenzo^]oxazol-6-yl )pyridine-2-amine

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 548A and 6-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-2-methylbenzo^]oxazole there, where needed (70 mg, 0.154 mmol, 62% yield) as a brown resinous mass. MS (ESI) 456 (M+H).

Step B. Example 550. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(4 -(2-methylbenzo^]oxazol-6-yl)pyridin-2yl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 550A and the corresponding acid where necessary (1.3 mg, 2.290 μmol, 3% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.94-7.89 (m, 1H), 7.87 (d, J=5.4 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 3.73 (s, 2H), 2.68 (s, 3H), 2.10-1.99 (m, 1H), 1.92 (d, J=2.4 Hz, 6H), 1.83-1.67 (m, 6H), 1.50-1.35 (m, 6H), 1.07-0.98 (m, 2H), 0.89-0.80 (m, 2H). FXR EC ₅₀ (nM) = 70. MS (ESI) 568 (M+H).

Example 551.

N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro<N-(4- (2methylbenzo^]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide

connection 551A. Receipt

Stage A. Intermediate

4-bromo-N-((4-(3-(tert-butyl)-1,2,4 oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing 4-bromopyridin-2-amine and intermediate 191C where necessary (700 mg, 1.669 mmol, 73% yield) as a gummy liquid. MS (ESI) 420 (M+N).

Stage B. Intermediate 551B. Preparation of N(4-bromopyridin-2-yl)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl )-3-fluorobicyclo[1.1.1]pentane-1carboxamide

- 374 047337

The title compound was prepared according to the method described for the synthesis of intermediate 531B, replacing intermediate 551A and the corresponding acid where necessary (70 mg, 0.132 mmol, 34% yield) as a colorless liquid. MS (ESI) 531 (M+H).

Step C. Example 551. Preparation of N((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)-3-fluoro- Y-(4-(2-methylbenzo^]thiazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 551B and 6-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)-2-methylbenzo^]thiazole there, where needed (13 mg, 0.021 mmol, 38% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J=1.2 Hz, 1H), 8.62 (d, J=5.1 Hz, 1H), 8.11-8.00 (m,2H), 7.97 (d, J =1.0 Hz, 1H), 7.87 (dd, J=5.4, 1.7 Hz, 1H), 3.74 (s, 2H), 2.86 (s, 3H), 1.92 (d, J=2.4 Hz, 6H), 1.86-1.66 (m, 6H), 1.56-1.36 (m, 6H), 1.25 (s, 9H). FXR EC ₅₀ (nM) = 55. MS (ESI) 600 (M+H).

Example 552.

N(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-U-((4-(5-methoxypyrimidin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[ 1.1 .1 ]pentane-1-carboxamide

Step A: Intermediate 552A. Preparation of methyl 4-(5-bromopyrimidin-2yl)bicyclo[2.2.2]octane-1-carboxylate |H ₃ C-O /—y N=\ ^Br

O '' Ν— ⁷

To a stirred solution of 5-bromopyrimidine (1 g, 6.29 mmol) in DCM (55 ml) and water (55 ml) was added 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.07 g , 5.03 mmol), potassium persulfate (1.70 g, 6.29 mmol) and silver nitrate (0.21 g, 1.258 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered through celite. The organic layer was separated, washed with water (30 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 10% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (250 mg, 0.769 mmol, 12% yield) and methyl 4-(5-bromopyrimidin-4-yl)bicyclo[2.2.2]octane-1carboxylate ( 750 mg, 2.306 mmol, yield 37%). MS (ESI) 325 (M+H).

Stage B. Intermediate 552B. Preparation of (4-(5-bromopyrimidin-2yl)bicyclo[2.2.2]octan-1-yl)methanol

IHO /—у N=\ ^λ —(\ J— ^Br \—f N— ⁷

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1G by replacing intermediate 552A where necessary (150 mg, 0.505 mmol, 82% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 2H), 4.35 (t, J=5.5 Hz, 1H), 3.09 (d, J=5.0 Hz, 2H), 1.91-1.82 (m, 6H), 1.50-1.40 (m, 6H).

Step C. Intermediate 552C. Preparation of 4-(5-bromopyrimidin-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

IO ,—, N=\

CHZCH /~ ^Vg

Ν' No. ⁷

The title compound was prepared according to the method described for the synthesis of intermediate 3C, replacing intermediate 552B where necessary (130 mg, 0.440 mmol, 87% yield). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.93 (s, 2H), 1.90-1.95 (m, 6H), 1.66-1.71 (m, 6H).

Stage D. Intermediate 552D. Preparation of N((4-(5-bromopyrimidin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-ethoxypyrimidin-5-yl)aniline

- 375 047337

The indicated compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 518A and intermediate 552C where necessary (70 mg, 0.142 mmol, 40% yield). MS (ESI) 494 (M+H).

Step E. Intermediate 552E. Preparation of A((4-(5-bromopyrimidin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1 .1]pentane1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 552D and the corresponding acid where necessary (80 mg, 0.070 mmol, 33% yield). MS (ESI) 606 (M+H).

Step F. Example 552. Preparation of A(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5methoxypyrimidin-2-yl)bicyclo[2.2.2]octane-1 - yl)methyl)bicyclo-[1.1.1]pentane-1-carboxamide

To a stirred solution of intermediate 552E (20 mg, 0.033 mmol) in 1,4dioxane (3 ml) was added methanol (0.027 ml, 0.659 mmol), Cs2CO ₃ (16 mg, 0.049 mmol) and 2-di-tert-butylphosphino-2', 4',6'-triisopropylbiphenyl (2.8 mg, 6.59 µmol). The reaction mixture was degassed and filled with argon again. Pd ₂ (dba) ₃ (3.0 mg, 3.30 µmol) was added to the reaction mixture and the reaction vessel was sealed. The reaction mixture was stirred at 75°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient : 0-minute hold at 25% B, 25-65% B for 25 minutes, then 5-minute hold at 100% B; flow rate 15 ml/min; column temperature 25°C). Collection of fractions was initiated by signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (5.6 mg, 9.14 μmol, 28% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 2H), 8.43 (s, 2H), 7.87-7.79 (m, 2H), 7.77 (d, J=7.6 Hz, 1H), 7.57 (t , J=7.8 Hz, 1H), 4.43 (q, J=6.9 Hz, 2H), 3.85 (s, 3H), 3.67 (br. s., 1H), 3.55 (d, J=7.6 Hz, 1H), 2.00-1.71 (m, 12H), 1.59-1.40 (m, 6H), 1.38 (t, J=7.1 Hz, 3H). FXR EC ₅₀ (nM) 359. MS (ESI) 558 (M+H).

Example 553.

N-((4-(3 -(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1 -yl)methyl)-N-(3 - (2ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 553A. Preparation of (1-(hydroxymethyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate °L

HO ⁷ 'M/ ^X ₀ Ts

The title compound was prepared according to the method described for the synthesis of intermediate 88A, replacing intermediate 196F where necessary (900 mg, 2.76 mmol, 52% yield) as a white solid. MS (ESI) 344 (M+H). NH3 adduct.

Stage B. Intermediate 553B. Preparation of (1-formyl-2-oxabicyclo-[2.2.2]octan-4yl)methyl 4-methylbenzenesulfonate

- 376 047337 °k (U '--' OTs

The title compound was prepared according to the method described for the synthesis of intermediate 208B, replacing intermediate 553A where necessary (430 mg, 1.326 mmol, 72% yield) as a white solid. MS (ESI) 342 (M+H). NH3 adduct.

Step C. Intermediate 553C. Preparation of (1-(((3-bromophenyl)amino)-methyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzenesulfonate

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 3-bromoaniline and intermediate 553B where necessary (440 mg, 0.916 mmol, 79% yield) as a brown gummy mass. MS (ESI) 480 (M+H).

Stage D. Intermediate 553D. Preparation of (1-((U-(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl methylbenzenesulfonate

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 553C and the corresponding acid where necessary (330 mg, 0.557 mmol, 61% yield) as a brown gummy mass. MS (ESI) 592 (M+H).

Step E. Intermediate 553E. Preparation of (1-((U-(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl acetate

The title compound was prepared according to the method described for the synthesis of intermediate 141C, replacing intermediate 553D where necessary (230 mg, 0.479 mmol, 92% yield) as a white solid. MS (ESI) 480 (M+H).

Step F: Intermediate 553F. Preparation of N(3-bromophenyl)-3-fluoro-U-((4(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 141D, replacing intermediate 553E where necessary (180 mg, 0.411 mmol, 86% yield). MS (ESI) 438 (M+H).

Stage G. Intermediate 553G. Preparation of 1-((No(3-bromophenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid

A stirred solution of intermediate 553F (160 mg, 0.365 mmol) in acetone (2 ml) was cooled to 0°C. Chromium trioxide (0.36 mL, 0.730 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 15 minutes. The reaction was quenched with isopropanol (5 ml) and concentrated under reduced pressure. The residue was diluted with water (10 ml), extracted with ethyl acetate (2x10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried

- 377 047337 sewn in vacuum to obtain the title compound (160 mg, 0.354 mmol, 97% yield). MS (ESI) 452 (M+H).

Stage H. Intermediate 553H. Preparation of X-(3-bromophenyl)-X-((4-(3-(tert-butyl)1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-1-yl) methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 1A by replacing intermediate 553G and (7)-N-hydroxypivalimidamide where necessary (130 mg, 0.244 mmol, 69% yield) as a brown solid. MS (ESI) 532 (M+H).

Stage I. Example 553. Preparation of No. ((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-1-yl)methyl)-No. -(3-(2-ethoxypyrimidin-5-yl)phenyl)-3fluorobicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of Example 149, replacing intermediate 553H and (2-ethoxypyrimidin-5-yl)boronic acid where necessary (10.8 mg, 0.018 mmol, 38% yield ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 2H), 7.82-7.68 (m, 2H), 7.53 (t, J=8.1 Hz, 1H), 7.42-7.35 (m, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.86 (s, 2H), 3.72 (s, 2H), 2.09-1.98 (m,4H), 1.85 (s, 3H), 1.87 (s, 4H), 1.82 -1.70 (m, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.32-1.20 (m, 9H). FXR EC ₅₀ (nM) = 1594. MS (ESI) 576 (M+H).

Example 554.

N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3,3-difluoro-N-(3-(2methylbenzo ^]thiazol-6-yl)phenyl)cyclobutane-1-carboxamide

Step A: Intermediate 554A. Preparation of 3-(2-methylbenzo^]thiazol-6-yl)aniline

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing 6-bromo-2-methylbenzo^]thiazole and (3-aminophenyl)boronic acid where necessary (60 mg, 0.250 mmol, yield 57 %), as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.21 (d, J=1.5 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.157.09 ( m, 1H), 6.90 (t, J=2.0 Hz, 1H), 6.87-6.83 (m, 1H), 6.59 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 5.19 (s, 2H), 2.82 (s, 3H). MS (ESI) 241 (M+H).

Stage B. Intermediate 554B. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-methylbenzo^]thiazol-6-yl) aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing intermediate 554A and intermediate 4C where necessary (90 mg, 0.182 mmol, 87% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (d, J=1.5 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 2.0 Hz, 1H) , 7.15 (t, J=7.8 Hz, 1H), 6.94 (s, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 5.57 (t, J= 6.0 Hz, 1H), 2.90 (d, J=6.0 Hz, 2H), 2.82 (s, 3H), 2.11-2.03 (m, 1H), 1.91-1.83 (m, 6H), 1.64-1.56 (m, 6H ), 1.07-1.00 (m, 2H), 0.88-0.83 (m, 2H). MS (ESI) 471 (M+H).

Step C. Example 554. Preparation of N((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl) bicyc

- 378 047337 lo[2.2.2]octan-1-yl)methyl)-3,3-difluoro-X-(3-(2-methylbenzo^]thiazol-6-yl)-phenyl)cyclobutan-1carboxamide

The title compounds were prepared according to the method described for the synthesis of Example 3, replacing intermediate 554B and the corresponding acids where necessary (13.4 mg, 0.023 mmol, 53.6% yield).

¹ H NMR (400 MHz, DMSO-de) δ 8.46 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.86 (dd, J=8.4, 1.8 Hz, 1H), 7.81 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 3.69 (br. s., 2H), 2.98 (d, J=5.4 Hz, 1H), 2.84 (s, 3H), 2.78 (d, J=12.0 Hz, 2H), 2.39-2.26 (m, 2H), 2.09-1.98 (m, 1H ), 1.84-1.70 (m, 6H), 1.54-1.36 (m, 6H), 1.05-0.96 (m, 2H), 0.85-0.77 (m, 2H). FXR EC ₅₀ (nM) 232; MS (ESI) 589 (M+H).

The following compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 554B and the corresponding acid where necessary.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 555 ΞΕ ω About ζ^ω / ° R ί 583 55 555 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 8.4, 1.8 Hz, 1H), 7.81 -7.71 (m, 2H), 7.57 (t, J= 7.9 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 3.68 (d, J= 14.7 Hz, 1H), 3.56 (d, J= 14.4 Hz, 1H), 2.84 (s, 3H), 2.07-2.00 (m, 1H), 1.98-1.69 (m, 12H), 1.56-1.36 (m, 6H), 1.06-0.94 (m, 2H), 0.90 -0.77 (m, 2H).

Example 556.

-fluoro-X-(( 1 -(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3 -(2methylbenzo^]thiazol-6-yl)phenyl)bicyclo [1.1.1]pentane-1-carboxamide

Step A: Intermediate 556A. Preparation of D-(('1-(4-methoxyphenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(2-methylbenzo^]thiazol-6-yl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing intermediate 554A and intermediate 128E where necessary (70 mg, 0.112 mmol, 69% yield) as a brown gum solid. MS (ESI) 471 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=1.5 Hz, 1H), 7.98-7.92 (m, 1H), 7.74-7.63 (m, 1H), 7.33-7.27 (m, 2H) , 7.20-7.09 (m, 1H), 6.95 (s, 1H), 6.89-6.82 (m, 3H), 6.66 (d, J=8.5 Hz, 1H), 5.63-5.58 (m, 1H), 3.89 (s , 2H), 3.73 (s, 3H), 2.96 (d, J=6.0 Hz, 2H), 2.82 (s, 3H), 2.42-2.41 (m, 2H), 2.09-1.99 (m, 2H), 1.83 ( d, J=11.5 Hz, 2H), 1.76 (br. s., 2H).

Step B. Example 556. Preparation of 3-fluoro-X-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4yl)methyl)-N-(3 -(2-methylbenzo^]thiazole -6-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

- 379 047337

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 556A and the corresponding acid where necessary (14 mg, 0.024 mmol, 37% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.88 (dd, J=8.6, 2.0 Hz, 1H), 7.85-7.74 (m, 2H), 7.58 (t, J=7.9 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.30-7.16 (m, 2H), 6.90-6.73 (m, 2H) , 3.81-3.65 (m, 6H), 3.64-3.55 (m, 1H), 2.84 (s, 3H), 2.03 -1.83 (m, 8H), 1.75 (d, J=11.0 Hz, 2H), 1.67 (br . s., 2H), 1.57 (br. s., 2H). FXR EC50 (nM) = 815.84. MS (ESI) 583 (M+H).

Example 557.

3,3-difluoro<N-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(2methylbenzo^]thiazol-6-yl) phenyl)cyclobutane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 556A and the corresponding acid where necessary (16 mg, 0.027 mmol, 42% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.87 (dd, J=8.4, 1.8 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30-7.11 (m, J =9.0 Hz, 2H), 6.89-6.71 (m, 2H), 3.70 (s, 7H), 3.01 (dd, J=11.7, 8.3 Hz, 1H), 2.84 (s, 3H), 2.77 (br. s. , 1H), 2.34 (br. s., 2H), 2.01-1.89 (m, 2H), 1.76 (d, J=5.4 Hz, 2H), 1.70-1.60 (m, 2H), 1.57 (d, J= 12.0 Hz, 2H). FXR EC ₅₀ (nM) = 1579. MS (ESI) 589 (M+H).

Example 558.

3-fluoro-N-((1-(2-methoxypyrimidin-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(2methylbenzo^]thiazol-6- yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 558A. Preparation of i((1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(2-methylbenzo-^]thiazol-6-yl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 554A and intermediate 140E where necessary (20 mg, 0.042 mmol, 35% yield) as a brown gummy mass. MS (ESI) 473 (M+H).

Step B. Example 558. Preparation of 3-fluoro<N-((1-(2-methoxypyrimidin-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-N-(3-(2- methylbenzo^]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 558A and the corresponding acid where necessary (4 mg, 6.50 μmol, 15% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 2H), 8.48 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.88 (dd, J= 8.4, 1.8 Hz, 1H), 7.85-7.75 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.44 (d, J =7.1 Hz, 1H), 3.88 (s, 3H), 3.80- 3.66 (m, 3H), 3.66-3.57 (m, 1H), 2.84 (s, 3H), 2.09-1.98 (m, 2H), 1.97-1.77 (m, 8H), 1.76-1.63 (m, 2H), 1.59 (br. s., 2H). FXR EC ₅₀ (nM) = 561. MS (ESI) 585 (M+H).

Example 559.

i((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-N-(3-(5fluorobenzo^] Oxazol-2-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

- 380 047337

Step A: Intermediate 559A. Preparation of D-(5-fluoro-2-hydroxyphenyl)-3nitrobenzamide

To a stirred solution of 3-nitrobenzoyl chloride (2 g, 10.78 mmol) in THF (40 mL) was added TEA (4.51 mL, 32.3 mmol) followed by 2-amino-4-fluorophenol (1.37 g, 10.78 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 ml), washed with 10% aqueous sodium bicarbonate (2x25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried in vacuo to give the title compound (1.7 g, 5.48 mmol, 51% yield) as a brown solid. MS (ESI) 277 (M+H).

Stage B. Intermediate 559B. Preparation of 5-fluoro-2-(3-nitrophenyl)benzo^]oxazole

To a stirred solution of intermediate 559A (1.6 g, 5.79 mmol) in xylene (35 ml) was added p-toluenesulfonic acid monohydrate (0.220 g, 1.158 mmol). The reaction mixture was refluxed in a Dean-Stark condenser overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with water (25 ml) and extracted with ethyl acetate (2x30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (1.25 g, 4.70 mmol, 81% yield) as a brown solid. MS (ESI) 259 (M+H).

Step C. Intermediate 559C. Preparation of 3-(5-fluorobenzo^]oxazol-2-yl)aniline

To a stirred solution of intermediate 559B (1.2 g, 4.65 mmol) in ethanol (30 ml) and tetrahydrofuran (30 ml) was added zinc (4.56 g, 69.7 mmol), followed by a solution of ammonium chloride (3 .73 g, 69.7 mmol) in water (10 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (50 ml) and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (0.5 g, 2.059 mmol, 44% yield) as a brown solid. MS (ESI) 229 (M+H).

Stage D. Intermediate 559D. Preparation of D-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(5-fluorobenzo^]oxazol-2-yl )aniline

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1I, by replacing intermediate 559C and intermediate 4C

- 381 047337 where needed (180 mg, 0.377 mmol, 77% yield) as a brown solid.

¹ H NMR (400 MHz, DMSO-de) δ 7.82 (dd, J=9.0, 4.5 Hz, 1H), 7.68 (dd, J=9.0, 2.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.35 -7.25 (m, 3H), 6.90 (dd, J=8.0, 1.0 Hz, 1H), 5.94 (t, J=6.0 Hz, 1H), 2.91 (d, J=6.0 Hz, 2H), 2.12-2.03 ( m, 1H), 1.93-1.84 (m, 6H), 1.65-1.55 (m, 6H), 1.08-1.00 (m, 2H), 0.89-0.84 (m, 2H).

Step E. Example 559. Preparation of N((4-(3-Cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(3 -(5-fluorobenzo^]oxazol-2yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 559D and the corresponding acid where necessary (15.2 mg, 0.027 mmol, 41% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.26-8.16 (m, 1H), 8.12 (s, 1H), 7.88 (dd, J=9.0, 4.4 Hz, 1H), 7.80-7.66 (m, 3H), 7.35 (td, J=9.3, 2.7 Hz, 1H), 3.63 (s, 2H), 2.09-2.01 (m, 1H), 1.91 (br. s.,6H), 1.82-1.65 (m, 6H), 1.551 .36 (m, 6H), 1.06-0.95 (m, 2H), 0.88-0.74 (m, 2H). FXR EC50 (nM) = 217. MS (ESI) 571 (M+H).

The following compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 559D and appropriate acids where necessary.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 560 ABOUT F A F— 577 1508 560 ¹ NMR (400 MHz, DMSO-d ₆ ) δ 8.24-8.09 (m, 2H), 7.87 (dd 1H), 7.79-7.63 (m, 3H), 7.34 (td, J = 9.3, 2.7 Hz, 1H), 3.69 ( 2.87 (m, 1H), 2.86-2.70 (m, 2H), 2.41-2.32 (m, 2H), 2.10-2.C 1.67 (m, 6H), 1.56-1.31 (m, 6H), 1.07-0.95 (m, 2H), 0.87-0.1 I, J = 9.0, 4.4 Hz, br. s., 2H), 2.97)0 (m, 1H), 1.86 ^r 7 (m, 2H)

Example 561.

Ch-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -φτορ-Ν-(3 -(2methylbenzo^ ]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 561A. Preparation of F((4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(2-methylbenzo^]thiazol-6-yl) aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 554A and intermediate 133D where necessary (90 mg, 0.191 mmol, 67% yield) as a gummy liquid. MS (ESI) 471 (M+H).

Step B. Example 561. Preparation of N((4-(5-cyclopropyl-1,3,4-oxadiazol-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-(3 -(2-methylbenzo^]thiazol-6yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound according to

- 382 047337 example 3, by replacing intermediate 561A and the corresponding acid where necessary (4.2 mg, 7.21 µmol, 11% yield).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.86 (dd, J=8.4, 1.8 Hz, 1H), 7.82-7.74 (m, 2H), 7.57 (t, J=8.1 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 3.74-3.62 (m, 1H), 3.61-3.49 (m, 1H) , 2.84 (s, 3H), 2.18-2.10 (m, 1H), 1.92 (d, J=8.1 Hz, 3H), 1.85 (d, J=8.8 Hz, 3H), 1.80-1.67 (m, 6H), 1.46 (d, J=4.6 Hz, 6H), 1.11-1.03 (m,2H), 0.97-0.89 (m, 2H). FXR EC ₅₀ (nM) = 58. MS (ESI) 583 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 3, substituting intermediate 561A and appropriate acids where necessary.

Etc. No. Structure MS (ESI) (M+H) FXR EU so (nM)

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (dd, J= 7.1, 1.7 Hz, 1H), 8.00 (d, J= 8.3 Hz, 1H), 7.85 (ddd, J = 8.4, 4.8, 2.0 Hz, 1H), 7.80-7.65 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.45-7.29 (m, 1H), 6.O3 (dd, 7= 10.4, 4.5 Hz, 1H), 5.96 -5.81 (m, 1H), 3.67 (br. s., 2H), 2.84 (s, 3H), 2.29 (d,7= 9.5 Hz, 1H), 2.18-2.00 (m, 3H), 1.851.56 ( m, 8H), 1.52-1.32 (m, 6H), 1.11-1.02 (m, 2H), 0.96-0.85 (m, 2H) 5.965.81 (m, 1H),

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 7.99 (d, J = 8.40 Hz, 1H), 7.827.86 (m, 2H), 7.75 (d, J = 8.00 Hz, 1H) , 7.56 (t, J = 15.60 Hz, 1H), 7.44 (d, J = 7.60 Hz, 1H), 3.81 (s, 2H), 3.02-3.04 (m, 1H), 2.83 (s, 3H), 2.14- 2.15 (m, 1H), 2.10-2.15 (m, 3H), 1.83-1.87 (m, 2H), 1.74 (d, J = 15.20 Hz, 7H), 1.43 (s, 6H), 1.06 (d, J = 14.40 Hz, 2H), 0.92 (d, J = 15.60 Hz, 2H)

Example 564.

F((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro<X-(3(2 -methylbenzo^]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

ABOUT

Step A: Intermediate 564A. Preparation of F((1-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-(2-methylbenzo^]thiazol-6 -yl)aniline

- 383 047337

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 554A and intermediate 196K where necessary (32 mg, 0.061 mmol, 76% yield) as an off-white solid. MS (ESI) 473 (M+H).

Step B. Example 564. Preparation of 4-(('1-(3-cyclopropyl-'1,2,4-oxadiazol-5-yl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3- fluoro-N-(3-(2-methylbenzo^]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 564A and the corresponding acid where necessary (11.8 mg, 0.020 mmol, 32% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.87 (dd, J=8.6, 2.0 Hz, 1H) , 7.85-7.76 (m, 2H), 7.58 (t, J=7.8 Hz, 1H), 7.44 (d, J=7.8 Hz, 1h), 3.75-3.57 (m, 4H), 2.84 (s, 3H), 2.172.02 (m, 3H), 2.02-1.79 (m, 8H), 1.72 (br. s., 2H), 1.61 (d, J=9.3 Hz, 2H), 1.10-0.99 (m, 2H), 0.91 -0.77 (m, 2H). FXR EC ₅₀ (nM) 207. MS (ESI) 585 (M+H).

The following compounds were prepared according to the method described for the synthesis of Example 3, substituting intermediate 564A and appropriate acids where necessary.

- 384 047337

566 XlZ O with T 605 922 567 O ^F y ^A l ^N/ Y\0 ^F mJ 1 III » D SaJ\Z N-D NzS~Jj JV 605 432 565 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.93-7.81 (m, 2H), 7.77 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.84-3.57 (m, 4H), 2.99 (td, J = 8.6, 2.8 Hz, 1H), 2.91-2.69 (m, 5H), 2.34 (br. s., 2H), 2.17-2.03 (m, 3H), 2.02 -1.86 (m, 2H), 1.76-1.63 (m, 2H), 1.63 -1.50 (m, 2H), 1.10-0.98 (m, 2H), 0.90-0.78 (m, 2H) 566 Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (dd, J = 7.3, 1.7 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.91-7.66 (m, 3H), 7.55 (t, J = 7.9 Hz, 1H), 7.47-7.33 (m, 1H), 3.81-3.58 (m, 4H), 3.22-3.08 (m, 1H), 2.84 (s, 3H), 2.47 (br. s., 1H ), 2.342.24 (m, 1H), 2.20-1.99 (m, 4H), 1.99-1.83 (m, 2H), 1.81-1.62 (m, 4H), 1.58 (d, J= 10.0 Hz, 2H), 1.11-0.98 (m, 2H), 0.92-0.72 (m, 2H). 1H buried under DMSO peak. 567 'H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.87 (d, J =2.7 Hz, 1H), 7.78 (d, J =8.1 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 3.91 (s, 1H), 3.68 (s, 4H), 3.08-2.96 (m, 1H ), 2.84 (s, 3H), 2.31 (m, 1H), 2.20-2.00 (m, 5H), 2.00-1.89 (m, 3H), 1.85 (d, J = 8.6 Hz, 1H), 1.69 (m. , 3H), 1.57 (m, 2H), 1.11-0.96 (m, 2H), 0.92-0.70 (m, 2H)

Example 568 and 569.

D-(('1-(4-cyanophenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-D-(3-(2-methylbenzo^]thiazol6-yl)phenyl )bicyclo[1.1.1]pentane-1-carboxamide (568)

D-(('1-(4-(dimethylcarbamoyl)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-D-(3-(2methylbenzo^]thiazol-6- yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (569)

Step A: Intermediate 568A. Preparation of methyl 4-(1-hydroxy-4,4bis((tosiloxy)methyl)cyclohexyl)benzoate

- 385 047337

A stirred solution of methyl 4-iodobenzoate (1.755 g, 6.70 mmol) in THF (10 ml) was cooled to 0°C. Isopropyl magnesium chloride (5.36 mL, 6.97 mmol) was added dropwise to the reaction mixture and stirred for 10 minutes. A solution of (4-oxocyclohexane-1,1diyl)bis(methylene)bis(4-methylbenzenesulfonate) (2.5 g, 5.36 mmol) was added dropwise to the reaction mixture (see ACS Medicinal Chemistry Letters, 5 (5), 609-614; 2014) in THF (5 ml). The reaction mixture was stirred at 5°C for 1 hour. The reaction mixture was quenched with ammonium chloride solution (10 ml), allowed to warm to room temperature and extracted with ethyl acetate (2x25 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (2.7 g, 2.78 mmol, 52% yield) as a yellow solid. MS (ESI) 620 (M+H+17).

Stage B. Intermediate 568B. Preparation of 4-(4-((tosiloxy)methyl)-2oxabicyclo[2.2.2]octan-1-yl)benzoic acid /—Q /=\ OH

Tso^At/

The specified compound was prepared in accordance with the method described for the synthesis of intermediate 141B, replacing intermediate 568A where necessary. MS (ESI) 434 (M+H) (NH3 adduct).

Step C. Intermediate 568C. Preparation of methyl 4-(4-((tosiloxy)methyl)-2oxabicyclo[2.2.2]octan-1-yl)benzoate /=\O-CH3

TsO^ At/ VJ ⁷ X

K2CO3 (1.19 g, 8.64 mmol) was added to a stirred solution of intermediate 568B (1.8 g, 4.32 mmol) in DMF (20 mL). The reaction mixture was stirred for 10 minutes. MeI (0.540 mL, 8.64 mmol) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 100% B; flow rate = 30 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (1 g, 2.044 mmol, 47% yield) as a white solid. MS (ESI) 448 (M + H) (NH3 adduct).

Stage D. Intermediate 568D. Preparation of methyl 4-(4-(acetoxymethyl)-2oxabicyclo[2.2.2]octan-1-yl)benzoate /=\O-CH3

At/ V+7 X

The title compound was prepared according to the method described for the synthesis of intermediate 141C, replacing intermediate 568C where necessary (660 mg, 1.638 mmol, 78% yield) as a brown gumy solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (dd, J=1.60, 6.80 Hz, 2H), 7.53 (dd, J=1.60, 6.80 Hz, 2H), 3.84 (s, 3H), 3.82 (s , 2H), 2.84 (s, 2H), 2.14-2.08 (m, 2H), 2.04 (s, 3H), 1.85-1.68 (m, 6H). MS (ESI) 319 (M+H).

Step E. Intermediate 568E. Preparation of methyl 4-(4-(hydroxymethyl)-2oxabicyclo[2.2.2]octan-1-yl)benzoate >^O /=\O-CH3

Ns/ xTT/ V+7 X

The title compound was prepared according to the method described for the synthesis of intermediate 141D, replacing intermediate 568D where necessary (550 mg, 1.831 mmol, 88% yield), as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (dd, J=2.00, 5.20 Hz, 2H), 7.53 (dd, J=4.80, 5.20 Hz, 2H), 4.55-4.52 (m, 1H), 3.83 (s, 3H), 3.80 (s, 2H), 3.17 (s, 1H), 3.15 (s, 1H), 2.11-2.05 (m, 2H), 1.82-1.54 (m, 6H). MS (ESI) 277 (M+H).

Step F: Intermediate 568F. Preparation of methyl 4-(4-formyl-2-oxabicyclo[2.2.2]octan-1-yl)benzoate

- 386 047337

The title compound was prepared according to the method described for the synthesis of intermediate 3C, replacing intermediate 568E where necessary (170 mg, 0.471 mmol, 65% yield) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 7.92 (d, J=8.40 Hz, 2H), 7.55 (d, J=8.00 Hz, 2H), 4.02 (s, 2H) , 3.85 (s, 3H), 2.18-2.15 (m, 2H), 1.92-1.90 (m, 6H). MS (ESI) 275 (M+H).

Stage G. Intermediate 568G. Preparation of methyl 4-(4-(((3-(2-methylbenzo^]thiazol-6yl)phenyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-1-yl)benzoate

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 554A and intermediate 568F where necessary (40 mg, 0.080 mmol, 73% yield), as a brown gummy mass. MS (ESI) 499 (M+N).

Stage H. Intermediate 568H. Preparation of methyl 4-(4-((3-fluoro-N-(3-(2methylbenzo^]thiazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)-2oxabicyclo[2.2.2 ]octan-1-yl)benzoate

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 568G and the corresponding acid where necessary (30 mg, 0.049 mmol, 64% yield) as a brown gummy mass. MS (ESI) 611 (M+H).

Stage I. Intermediate 568I. Preparation of 4-(4-((3-fluoro-N-(3-(2-methylbenzo^]thiazol6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamido)methyl)-2-oxabicyclo[2.2. 2]octan-1-yl)benzoic acid

The title compound was prepared according to the method described for the synthesis of intermediate 175E, replacing intermediate 568H where necessary (25 mg, 0.036 mmol, 73% yield) as a brown gummy mass. MS (ESI) 597 (M+H).

Step J. Intermediate 568J. Preparation of D-((1-(4-carbamoylphenyl)-2oxabicyclo[2.2.2]octan-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo^]thiazol-6-yl)phenyl )bicyclo[1.1.1]pentane-1-carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 114A, replacing intermediate 568I where necessary (35 mg, crude) as a brown gummy mass. MS (ESI) 596 (M+H).

Step K. Examples 568 and 569. Preparation of N((1-(4-cyanophenyl)-2-oxabicyclo[2.2.2]octan-4yl)methyl)-3-fluoro-N-(3-(2-methylbenzo^] thiazol-6-yl)-phenyl)bicyclo[1.1.1]pentane-1-carboxamide and N- 387 047337 (('1-(4-(dimethylcarbamoyl)phenyl)-2-oxabicyclo[2.2.2]octane-4 -yl)methyl)-3-fluoro-c-(3-(2methylbenzo^]thiazol-6-yl)-phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of intermediate 114B, replacing intermediate 568J where necessary.

Example 568: (2.3 mg, 3.98 µmol, 7% yield).

¹ H NMR (400 MHz, DMSO-d ₀ ) δ 8.00 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.62-7.49 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 3.80-3.65 (m, 3H), 3.65-3.56 (m, 1H), 2.83 (s , 3H), 2.10-1.99 (m, 2H), 1.97-1.82 (m, 6H), 1.80-1.65 (m, 4H), 1.65-1.54 (m, 2H). FXR EC ₅₀ (nM) = 2445. MS (ESI) 578 (M+H).

Example 569: (5.4 mg, 8.66 µmol, 15% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=1.7 Hz, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.88 (dd, J=8.4, 1.8 Hz, 1H), 7.85-7.79 (m, 2H), 7.59 (t, J=7.7 Hz, 1H), 7.44 (d, J=7.3 Hz, 1H), 7.41-7.35 (m, J=8.3 Hz, 2H), 7.33-7.27 (m, J=8.3 Hz, 2H), 3.80-3.66 (m, 3H), 3.66-3.57 (m, 1H), 2.96 (br. s., 3H), 2.89 (br. s., 3H), 2.84 (s, 3H), 2.081.97 (m, 2H), 1.97-1.85 (m, 6H), 1.77 (d, J=11.7 Hz, 2H), 1.69 (br. s., 2H), 1.61 (br. s., 2H). FXR EC ₅₀ (nM) = 2222. MS (ESI) 624 (M+H).

Example 570.

Acyclopropyl-4-((3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.E1]pentane-1carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of intermediate 114A by replacing intermediate 227C and cyclopropylamine where necessary (7.2 mg, 0.014 mmol, 33.0% yield): ¹ H NMR (400 MHz , DMSO-d ₆ ) δ 8.27 (d, J=5.4 Hz, 1H), 7.87-7.75 (m, 2H), 7.57 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H ), 7.39 (dd, J=5.4, 1.5 Hz, 1H), 7.26-7.11 (m, 2H), 3.92 (s, 3H), 3.56(d, J=16.6 Hz, 2H), 2.59-2.55 (m, 1H), 1.94-1.74 (m, 6H), 1.62-1.46 (m, 6H), 1.32 (br. s., 6H), 0.60-0.46 (m, 2H), 0.45-0.29 (m, 2H). FXR EC50 (nM) = 926. MS (ESI) 518 (M+H).

Example 571.

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

Step A: Intermediate 571A. Preparation of A(3-bromophenyl)-N-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- 3-fluorobicyclo[1.1.1]pentane-1carboxamide

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1A, by replacing intermediate 396C and the corresponding acid where necessary (9.6 mg, 0.017 mmol, 55% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74-7.68 (m, 1H), 7.61 (dt, J=7.3, 1.7 Hz, 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 ).

Step B. Example 571. Preparation of A(3-cyclopropylphenyl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 571A and cyclopropylboronic acid where necessary (7.7 mg, 0.015 mmol, 27% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38-7.25 (m, 1H), 7.19-7.07 (m, 2H), 7.04 (s, 1H), 3.62 -3.44 (m, 2H), 2.14 (t , J=19.7 Hz, 3H), 2.04-1.94 (m, 1H), 1.77 (d, J=8.3 Hz, 6H), 1.81 (d, J=7.3 Hz, 6H), 1.45 (d, J=9.0 Hz ,

- 388 047337

6H), 1.07-0.93 (m, 2H), 0.72 (d, J=4.6 Hz, 2H). FXR EC50 (nM) = 47. MS (ESI) 500 (M+H).

Example 572.

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

Step A: Intermediate 572A. Preparation of A(3-bromophenyl)-3-fluoro-A((4-(5(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo [1.1.1]pentane-1 carboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 1A, substituting intermediate 396C and the corresponding acid where necessary: (1.2 g, 2.186 mmol, 78% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (t, J=1.8 Hz, 1H), 7.61 (dt, J=7.6, 1.7 Hz, 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). MS (ESI) 543 (M+H).

Step B. Example 572. Preparation of N(3-cyclopropylphenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1 -yl)methyl)bicyclo-[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 572A and cyclopropylboronic acid where necessary (4.5 mg, 8.04 μmol, 15% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.35-7.27 (m, 1H), 7.12 (t, J=7.2 Hz, 2H), 7.04 (s, 1H), 3.61-3.52 (m, 1H), 3.52 -3.45 (m, 1H), 2.03-1.96 (m, 1H), 1.85-1.60 (m, 12H),1.56-1.34 (m, 6H), 1.00 (dd, J=8.2, 2.1 Hz, 2H), 0.72 (d, J=4.2 Hz, 2H). FXR EC50 (nM) = 146. MS (ESI) 504 (M+H).

Example 573.

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

Step A: Intermediate 573A. Preparation of D-(3-bromophenyl)-3-fluoro-A((4-(5-(1fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )bicyclo[1.1.1]pentane-1carboxamide

The indicated compound was prepared in accordance with the method described for the synthesis of intermediate 1A, by replacing intermediate 396C and the corresponding acid where necessary (450 mg, 0.845 mmol, 65% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.75-7.67 (m, 1H), 7.61 (dt, J=7.3, 1.7 Hz, 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). MS (ESI) 533 (M+H).

Step B. Example 573. Preparation of N(3-cyclopropylphenyl)-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]pentan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 573A and cyclopropylboronic acid where necessary (5.3 mg, 10.74 μmol, 19% yield).

- 389 047337 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.38-7.24 (m, 1H), 7.18-7.06 (m, 2H), 7.06-6.96 (m, 1H), 3.63-3.41 (m, 2H ), 2.04-1.93 (m, 1H), 1.93-1.67 (m, 14H), 1.55-1.25 (m, 8H), 1.08-0.91 (m, 2H), 0.72 (d, J=4.4 Hz, 2H). FXR EC ₅₀ (nM) = 44. MS (ESI) 494 (M+H).

Example 574.

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

Step A: Intermediate 574A. Oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

Preparation of methyl 4-(5-(1,1-difluoroethyl)-1,2,4-

The title compound was prepared according to the method described for the synthesis of intermediate 1A by replacing intermediate 206C and the corresponding acid where necessary (4.2 g, 11.75 mmol, 53.2% yield), as a colorless gum solid matter. MS (ESI) 301 (M+H).

Stage B. Intermediate 574B. Preparation of (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was prepared according to the method described for the synthesis of intermediate 1G, replacing intermediate 574A where necessary (3000 mg, 10.58 mmol, 76% yield), as a colorless liquid. MS (ESI) 273 (M+H).

Step C. Intermediate 574C. Preparation of 4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was prepared according to the method described for the synthesis of intermediate 3C, replacing intermediate 574B where necessary (2000 mg, 7.40 mmol, 67.2% yield), as a colorless white resinous solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.46 (br. s., 1H), 2.16 (t, J=19.6 Hz, 3H), 1.94-1.76 (m, 12H).

Stage D. Intermediate 574D. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-fluoroaniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing intermediate 574C and 3-bromo-4-fluoroaniline where needed (500 mg, 0.416 mmol, 28% yield) as a brown gum. MS (ESI) 444 (M+H).

Step E. Intermediate 574E. Preparation of Y(3-bromo-4-fluorophenyl)U-((4-(5-('1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl )methyl)-3-fluorobicyclo[1.1.1]pentane-1carboxamide

- 390 047337

The title compound was prepared according to the method described for the synthesis of Example 3, replacing intermediate 574D where necessary (160 mg, 0.288 mmol, 85% yield) as a brown gum. MS (ESI) 556 (M+H).

Step F. Example 574. Preparation of N(3-cyclopropyl-4-fluorophenyl)-X-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2 ] octan-1 -yl)methyl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 574E and cyclopropylboronic acid where necessary (13 mg, 0.024 mmol, 45% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.20 (d, J=8.3 Hz, 2H), 6.99 (d, J=7.3 Hz, 1H), 3.56 (d, J=13.2 Hz, 1H), 3.41 ( d, J=13.9 Hz, 1H), 2.22-2.02 (m, 4H), 1.96-1.68 (m, 12H), 1.43 (d, J=7.8 Hz, 6H), 1.02 (d, J=8.6 Hz, 2H ), 0.85-0.72 (m, 2H). FXR EC ₅₀ (nM) = 244. MS (ESI) 518 (M+H).

Example 575.

N-(3 -(azetidin-1 -yl)-4-fluorophenyl)-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]pentan-1-carboxamide

To a stirred solution of intermediate 574E (30 mg, 0.054 mmol) in 1,4dioxane (2 ml) was added azetidine (9.24 mg, 0.162 mmol), sodium tert-butoxide (15.55 mg, 0.162 mmol) and XantPhos (6 .24 mg, 10.78 µmol). The resulting mixture was evacuated and again filled with argon for 5 min, and then Pd ₂ (dba) ₃ (4.94 mg, 5.39 μmol) was added under argon. After stirring at 110°C overnight, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative LC/MS under the following conditions: column: Waters XBridge C18, 150 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile: water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 35% B, 35-85% B for 20 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (0.9 mg, 1.690 μmol, 3% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.07 (dd, J=8.4, 12.3 Hz, 1H), 6.71-6.60 (m, 1H), 6.45 (dd, J=2.6, 8.2 Hz, 1H), 4.00 -3.84 (m, 4H), 3.65-3.55 (m, 1H), 3.37 (br s, 1H), 2.32-2.24 (m, 2H), 2.14 (t, J=19.6 Hz, 3H), 1.99-1.82 ( m, 6H), 1.82-1.70 (m, 6H), 1.55-1.36 (m, 6H). FXR EC50 (nM) = 410. MS (ESI) 533 (M+H).

Example 576.

(cis)-X-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- 3hydroxy<X-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-(trifluoromethyl)cyclobutan-1carboxamide

Step A: Carboxylate intermediate 576A. Preparation of methyl 4-cyanobicyclo-[2.2.2]octane-1-

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (15

- 391 047337 g, 70.7 mmol) ammonium chloride (9.45 g, 177 mmol), BOP (37.5 g, 85 mmol) and Et ₃ N (39.4 ml, 283 mmol). After stirring the reaction mixture for 1 hour at room temperature, the reaction mixture was poured into cold water (100 ml) and extracted with DCM (2x150 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude compound. The crude product was taken up in pyridine (150 ml) at 0° C. and 2,2,2-trifluoroacetic anhydride (50.1 ml, 353 mmol) was added. The reaction mixture was stirred for 30 min at 0°C. The reaction mixture was poured into cold water (100 ml) and extracted with EtOAc (2x500 ml). The combined organic layers were washed with brine (250 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 30% B). The pure fractions were combined, concentrated and dried in vacuo to give methyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate (12 g, 62.1 mmol, 88% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ = 3.58 (s, 3H), 1.93-1.83 (m, 6H), 1.78-1.68 (m, 6H).

Stage B. Intermediate 576B. Preparation of methyl (E)-4-(N'hydroxycarbamidoyl)bicyclo[2.2.2]octane-1-carboxylate

H ₃ C-O y-y NH ₂

O ⁷ '--' ⁴ N

BUT

To a solution of methyl 4-cyanobicyclo[2.2.2]octane-1-carboxylate (12 g, 62.1 mmol) in ethanol (120 mL) was added 50% aqueous hydroxylamine (19.17 mL, 310 mmol). The reaction mixture was boiled at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure and water (30 ml) was added. The reaction mixture was stirred for 10 minutes. The solids were filtered and dried in vacuo to give methyl (E)-4-(N-hydroxycarbamidoyl)bicyclo-[2.2.2]octane-1-carboxylate (10 g, 44.2 mmol, 71% yield) as a white solid substances.

1H NMR (400 MHz, CDCl3-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).

Step C. Intermediate 576C. Preparation of methyl 4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

Н ₃ С _F °а /ΣΣΧ ^N <Z^CH ₃ / \ / о Н ₃ с-О '—' Ν ^υ

2-Fluoro-2-methylpropanoic acid (5 .02 ml, 53.0 mmol) and Et3N (18.48 ml, 133 mmol), followed by BOP (23.46 g, 53.0 mmol). The reaction mixture was stirred at room temperature for 1 hour and then overnight at 110°C. The reaction mixture was concentrated, diluted with water (100 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude product was purified by flash chromatography (120 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 30% B). The pure fractions were combined, concentrated and dried in vacuo to give methyl 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2.2]octane 1-carboxylate ( 8.2 g, 27.7 mmol, 63% yield as colorless gummy solid 1H NMR (400 MHz, DMSO- _d6 ) δ = 3.60 (s, 3H), 1.92-1.79 (m, 15H), 1.76 (s, 3H). MS (ESI) 297 (M+H).

Stage D. Intermediate 576D. Preparation of (4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol

To a stirred solution of methyl 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1-carboxylate (7.5 g, 25.3 mmol ) in THF (75 ml) was added dropwise DIBAL-H (63.3 ml, 76 mmol) at -78°C. The reaction mixture was allowed to warm to room temperature and continued stirring at room temperature for 2 hours. The reaction mixture was quenched with aqueous 1.5 N HCl (50 ml), and the aqueous solution was extracted with EtOAc (2x100 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 40% B). The pure fractions were combined, concentrated and dried in vacuo to give (4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methanol (6.5 g, 24.22 mmol, 96% yield) as a colorless liquid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ = 4.43 (t, J=5.4 Hz, 1H), 3.08 (d, J=5.4 Hz, 2H), 1.88-1.71 (m, 12H),

- 392 047337

1.50-1.36 (m, 6H). MS (ESI) 269 (M+H).

Step E. Intermediate 576E. Preparation of 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol3 -yl)bicyclo[2.2.2]octan-1-carbaldehyde

To a stirred solution of (4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol (3.00 g, 11. 18 mmol) in DCM (30 ml) at 0°C was added Dess-Martin periodinane (5.69 g, 13.42 mmol). The reaction mixture was stirred at 0°C for 30 minutes and then diluted with DCM (50 ml). The organic solution was washed with 10% aqueous sodium bicarbonate (3x20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 25% B). The pure fractions were combined, concentrated and dried in vacuo to give 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1carbaldehyde (1, 9 g, 7.13 mmol, 64% yield) as a colorless white resinous solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ = 9.50-9.40 (m, 1H), 1.97-1.50 (m, 18H)

Step F: Intermediate 576F. Preparation of 3-bromo-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

To a stirred solution of 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane1-carbaldehyde (1.9 g, 7.13 mmol) 3-bromoaniline (1.227 g, 7.13 mmol) and AcOH (0.817 mL, 14.27 mmol) were added to MeOH (20 mL), followed by 4 A molecular sieves (100 mg). The reaction mixture was heated overnight at 60°C. The reaction mixture was then cooled to 0°C and sodium cyanoborohydride (1.345 g, 21.40 mmol) was added thereto, and the reaction mixture was gradually warmed to room temperature over 1 hour. The reaction mixture was concentrated and the residue was dissolved in cold water (50 ml ). The aqueous solution was extracted with EtOAc (2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B). The pure fractions were combined, concentrated and dried in vacuo to give 3-bromo-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2] octan-1-yl)methyl)aniline (2.3 g, 5.45 mmol, 76% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ =7.01-6.92 (m, 1H), 6.76 (s, 1H), 6.59 (d, J=8.3 Hz, 2H), 5.79 (t, J=5.9 Hz, 1H), 2.80 (d, J=5.8 Hz, 2H), 1.90-1.79 (m, 9H), 1.75 (s, 3H), 1.62-1.48 (m, 6H). MS (ESI) 422 (M+H).

Stage G. Intermediate 576G. Preparation of (cis)4N-(3-bromophenyl)-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane- 1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamide

To a stirred solution of 3-bromo-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) aniline (1.8 g, 4.26 mmol) in DCM (20 ml), (cis)-3hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxylic acid (0.942 g, 5.11 mmol) was added, followed by pyridine ( 1.724 ml, 21.31 mmol). The reaction mixture was cooled to 0°C and POC13 (0.993 ml, 10.65 mmol) was added. After stirring the reaction mixture for 1 hour at 0°C, DCM (250 ml) was added. The organic solution was washed with cold water (2x30 ml) and then with saline (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 50% B). The pure fractions were combined, concentrated and dried in vacuo to give (cis)-Ni-(3-bromophenyl)-Ni-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-trifluoromethyl)-cyclobutane-1carboxamide: (1.65 g, 2.80 mmol, 66% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ = 7.71 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.48-7.35 (m, 2H), 6.57 (s, 1H), 3.59 ( br. s., 2H), 2.80-2.64 (m, 1H), 2.39-2.24 (m, 2H), 2.12-1.96 (m, 2H), 1.80 (s, 3H), 1.79-1.67 (m, 9H) , 1.45-

- 393 047337

1.33 (m, 6H). MS (ESI) 588 (M+H).

Step H. Example 576. Preparation of (cis)4N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-31)bicyclo[2.2.2]octane-1- yl)methyl)-3-hydroxy-N-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3(trifluoromethyl)cyclobutan-1-carboxamide

To a stirred solution of (cis)-N-(3-bromophenyl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2] octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1 carboxamide (20 mg, 0.034 mmol) and (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (6.12 mg, 0.034 mmol) in 1,4-dioxane (1 ml)/H ₂ O (0.1 ml) was added K2CO3 (9.39 mg, 0.068 mmol) at room temperature. Argon gas was bubbled through the solution for 5 min and then Pd(dppf)Cl ₂ (2.5 mg, 0.340 µmol) was added. The reaction mixture was heated to 100°C and stirred for 1 hour. The reaction mixture was concentrated and the crude product 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: 40-80% B for 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 ml/min. Fractions containing the product were combined and dried by centrifugal evaporation to give (cis)-N-((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3-1)-bicyclo[2.2 .2]octan-1-yl)methyl)-3-hydroxy-N-(4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl) cyclobutane-1-carboxamide (12.9 mg, 0.019 mmol, 56% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.71-7.60 (m, 4H), 7.59-7.54 (m, 2H), 7.51 (t, J=7.8 Hz, 1H), 7.38-7.31 (m, 1H), 6.53 (s, 1H), 5.08 (s, 1H), 3.73-3.62 (m, 2H), 2.85 (quin, J=9.0 Hz, 1H), 2.39-2.27 (m, 2H), 2.10-1.97 (m, 2H), 1.85-1.67 (m, 12H), 1.55-1.35 (m, 12H); FXR EC ₅₀ (nM) = 19; MS (ESI) 644 (M+H).

Example 577.

(cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- 3hydroxy4N-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-methylcyclobutan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 576E and the corresponding boronic acid where necessary: (14.2 mg, 0.024 mmol, 51% yield); 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.657.55 (m, 6H), 7.49 (t, J=15.60 Hz, 1H), 7.30 (d, J=8.00 Hz, 1H), 5.05 (s, 1H ), 4.88 (s, 1H), 3.65 (s, 2H), 2.622.57 (m, 1H), 2.15-2.10 (m, 2H), 1.79-1.73 (m, 12H), 1.65-1.62 (m, 2H ), 1.46-1.44 (m, 12h), 0.98 (s, 3H); FXR EC ₅₀ (nM) = 23; MS (ESI) 590 (M+H).

Example 578.

(cis)-No-(4'-(1-cyanocyclopropyl)-3'-fluoro-[1,G-biphenyl]-3-yl)-No-((4-(5-(1-fluorocyclopropyl)-1 ,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1 carboxamide

Step A: Intermediate 578A. Preparation of 3-bromo-N-((4-(5-(1-fluorocyclopropyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 194E and the corresponding acid where necessary: (1.1 g, 2.62 mmol, 77% yield). MS (ESI) 420 (M+2).

Stage B. Intermediate 578B. Preparation of (cis)-No-(3-bromophenyl)-No-((4-(5-(1

- 394 047337 fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1-carboxamide

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 578A and the corresponding acid where necessary: (420 mg, 0.594 mmol, 50% yield), as a brown solid. MS (ESI) 586 (M+H).

Step C. Example 578. Preparation of (cis)-X-(4'-(1-cyanocyclopropyl)-3'-fluoro-[1,G-biphenyl]-3-yl)N-((4-(5-( 1 -fluorocyclopropyl)-1,2,4-oxadiazol-3 -yl)bicyclo-[2.2.2]octan-1 -yl)methyl)-3-hydroxy-3 (trifluoromethyl)cyclobutan-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 578B and the corresponding boronate ester where necessary: (9.8 mg, 0.015 mmol, 43% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (s, 1H), 7.72 (t, J=19.60 Hz, 2H), 7.61 (d, J=9.60 Hz, 1H), 7.54 (q, J=22.00 Hz, 2H), 7.43 (d, J=8.00 Hz, 1H), 6.51 (s, 1H), 3.68 (s, 2H), 2.88-2.83 (m, 1H), 2.50-2.30 (m, 2H), 2.082 .03 (m, 2H), 1.80-1.72 (m, 10H), 1.52-1.44 (m, 10H). FXR EC ₅₀ (nM) = 92; MS (ESI) 667 (M+H).

Example 579.

N(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-X-((4-(5-(1-fluorocyclopropyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

ABOUT

F xL· YES/ Ν f

III V\7

No ^{z V}

JL J r/V

V (579)

This compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 573A and the corresponding boronate ester where necessary: (9.8 mg, 0.017 mmol, 30% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.88-7.81 (m, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H ), 7.46 (d, J=9.0 Hz, 1H), 3.60 (d, J=15.7 Hz, 2H), 2.32-2.23 (m, 1H), 1.95-1.80 (m, 6H), 1.79-1.67 (m, 8H), 1.54-1.36 (m, 8H), 1.11-1.05 (m, 4H). FXR EC ₅₀ (nM) = 45; MS (ESI) 572 (M+H).

Example 580.

N(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate compound 572A and the corresponding boronate ester where necessary: (2.2 mg, 3.48 μmol, 8% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 2H), 7.84 (s, 1H), 7.79 (d, J=7.60 Hz, 1H), 7.58 (t, J=15.60 Hz, 1H), 7.46 (d, J=8.00 Hz, 1H), 3.60 (m, 2H), 2.33-2.32 (m, 1H), 1.88-1.78 (m, 12H), 1.50-1.47 (m, 6H), 1.10-1.04 ( m, 4H). FXR EU ₅₀ (nM) = 160; MS (ESI) 582 (M+H).

Example 581.

(cis)-X-(6-fluoro-4'-isopropoxy-[1,G-biphenyl]-3-yl)-X-((4-(5-(1-fluorocyclopropyl)-1,2,4oxadiazol- 3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -hydroxy-3 -(trifluoromethyl)cyclobutan-1 carboxamide

- 395 047337

Step A: Intermediate 581A. Preparation of methyl 4-(((3-bromo-4fluorophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing 3-bromo-4-fluoroaniline and intermediate 88B where necessary: (1.5 g, 4.05 mmol, 77% yield). MS (ESI) 370 (M+H).

Stage B. Intermediate 581B. Preparation of 4-(((3-bromo-4fluorophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

The indicated compound was synthesized according to the method described for the synthesis of intermediate 175B, replacing intermediate 581A where necessary: (1.2 g, 3.37 mmol, 83% yield) as a white solid. MS (ESI) 356 (M+H).

Step C. Intermediate 581C. Preparation of 4-(((3-bromo-4fluorophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxamide

The compound was synthesized according to the method described for the synthesis of intermediate 184A, replacing intermediate 581B where necessary: (2 g crude) as a brown wax, which was used as such in the next step. MS (ESI) 355 (M+H).

Stage D. Intermediate 581D. Preparation of 4-(((3-bromo-4fluorophenyl)amino)methyl)bicyclo[2.2.2]octane-1-carbonitrile

The specified compound was synthesized in accordance with the method described for the synthesis of intermediate compound 194D, by replacing intermediate compound 581C where necessary; (1.6 g, 4.74 mmol, 84% yield) as a white solid. MS (ESI) 339 (M+H).

Step E. Intermediate 581E. Preparation of 4-(((6-fluoro-4'-isopropoxy-[1,1'-biphenyl]3 -yl)amino)methyl)bicyclo[2.2.2]octane-1-carbonitrile

The compound was synthesized according to the method described for the synthesis of Example 149, replacing intermediate 581D where necessary: (500 mg, 1.274 mmol, 86% yield) as a brown wax. MS (ESI) 393 (M+H).

- 396 047337

Step F: Intermediate 581F. Preparation of (cis)-Na-((4-cyanobicyclo[2.2.2]octan-1yl)methyl)-Na-(6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3-yl)- 3-hydroxy-3-(trifluoromethyl)cyclobutane-1carboxamide

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 581E and the corresponding acid where necessary: (300 mg, 0.537 mmol, 56% yield) as a brown wax. MS (ESI) 559 (M+H).

Stage G. Intermediate 581G. Preparation of (cis)-N-(6-fluoro-4'-isopropoxy-[1,1'biphenyl]-3-yl)-3-hydroxy-N-((4-((7)-N-hydroxycarbamidoyl)bicyclo [2.2.2]octan-1-yl)methyl)-3(trifluoromethyl)cyclobutan-1-carboxamide

The title compound was synthesized according to the method described for the synthesis of intermediate 88F, replacing intermediate 581F where necessary: (240 mg, 0.406 mmol, 60% yield) as a white solid. MS (ESI) 592 (M+H).

Step H. Example 581. Preparation of (cis)-No-(6-fluoro-4'-isopropoxy-[1,G-biphenyl]-3-yl)-No((4-(5-(1fluorocyclopropyl)-1, 2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of intermediate 3A, by replacing intermediate 581G and the corresponding acid where necessary: (16.4 mg, 0.025 mmol, 49% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.56 (dd, J=7.09, 2.45 Hz, 1H), 7.50 (d, J=7.58 Hz, 2H), 7.42-7.29 (m, 2H), 7.04 ( d, J=8.80 Hz, 2H), 6.52 (s, 1H), 4.69 (dt, J=12.10, 6.17 Hz, 1H), 3.74-3.50 (m, 2H), 2.84 (t, J=8.93 Hz, 1H ), 2.39-2.28 (m, 2H), 2.15-2.00 (m, 2H), 1.83-1.68 (m, 8H), 1.52-1.35 (m, 8H), 1.30 (d, J=6.11 Hz, 6H). FXR EU ₅₀ (nM) = 74; MS (ESI) 660 (M+H).

Example 582.

(cis)F-(4'-((2-cyanopropan-2-yl)oxy)-6-fluoro-[1,G-biphenyl]-3-yl)-N-((4-(5-(2 -fluoropropan-2-yl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1carboxamide

Step A: Intermediate 582A. Preparation of 3-bromo-4-fluoroJ-((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) aniline

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing 3-bromo-4-fluoroaniline and intermediate 576C where necessary: (590 mg, 1.340 mmol, 85% yield) as a brown wax. MS (ESI) 440 (M+H).

Stage B. Intermediate 582B. Preparation of (cis)-N-(3-bromo-4-fluorophenyl)-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-hydroxy-3-397 047337 (trifluoromethyl)cyclobutan-1-carboxamide

The compound was synthesized according to the method described for the synthesis of Example 3, replacing intermediate 582A and the corresponding acid where necessary: (240 mg, 0.396 mmol, 58% yield) as a brown wax. MS (ESI) 608 (M+H).

Step C. Intermediate 582C. Preparation of 2-(4-bromophenoxy)-2-methylpropanenitrile

BOP ( 5.12 g, 11.58 mmol). The reaction mixture was cooled to 0°C and TEA (3.23 mL, 23.16 mmol) was added dropwise. After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (20 ml) and extracted with DCM (3x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in pyridine (20 ml) and cooled to 0°C. Trifluoroacetic anhydride (2.432 g, 11.58 mmol) was added to this reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3x20 ml).

The combined organic layers were washed with 1.5 N aqueous HCl (2x50 ml) and then brine (2x20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 80% B; flow rate = 30 mL/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (750 mg, 3.12 mmol, 41% yield) as a brown oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.57 (m, 2H), 7.15-7.13 (m, 2H), 1.69 (s, 6H).

Stage D. Intermediate 582D. Preparation of 2-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2yl)phenoxy)-2-methylpropanenitrile

The title compound was synthesized according to the method described for the synthesis of intermediate 149C, replacing intermediate 582C and the corresponding acid where necessary: (1.0 g, 3.66 mmol, 63% yield) as a white fluffy solid .

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (d, J=8.00 Hz, 2H), 7.14 (d, J=8.00 Hz, 2H), 3.75 (s, 4H), 1.71 (s, 6H), 0.96 (s, 6H).

Step E. Example 582. Preparation of (cis)-N-(4'-((2-cyanopropan-2-yl)oxy)-6-fluoro-[1,G-biphenyl]-3yl)-N-((4 -(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl) cyclobutane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 582B and intermediate compound 582D where necessary: (12.4 mg, 0.018 mmol, 54% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.71-7.59 (m, 3H), 7.51-7.42 (m, 1H), 7.42-7.35 (m, 1H), 7.30 (d, J=8.6 Hz, 2H) , 6.53 (s, 1H), 3.80-3.49 (m, 2H),2.91-2.80 (m, 1H), 2.39-2.28 (m, 2H), 2.16-2.00 (m, 2H), 1.84-1.66 (m, 18H), 1.54-1.37 (m, 6H). FXR EU ₅₀ (nM) = 48; MS (ESI) 687 (M+H).

Example 583.

(cis)-N-(4'-((2-cyanopropan-2-yl)oxy)-[1,1'-biphenyl]-3-yl)-\-((4-(5-( 1-fluorocyclopropyl )-1,2,4oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1 carboxamide

- 398 047337

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 578B and intermediate compound 582D where necessary: (5.8 mg, 8.03 μmol, 24% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (d, J=8.8 Hz, 2H), 7.71 (s, 1H), 7.65 (br d, J=7.8 Hz, 1H), 7.51 (t, J =7.9 Hz, 1H), 7.40-7.33 (m, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.52 (s, 1H), 3.76-3.56 (m, 2H), 2.90-2.81 (m, 1H), 2.38-2.28 (m, 2H), 2.10-1.97 (m, 2H), 1.81-1.62 (m, 14H), 1.51-1.33 (m, 8H). FXR EC ₅₀ (nM) = 49; MS (ESI) 667 (M+H).

Example 584.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane -1-yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

Step A: Intermediate 584A. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(3bromophenyl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1-yl)methyl)carbamate

To a stirred solution of intermediate 576D (200 mg, 0.474 mmol) in tetrahydrofuran (10 ml) at -50°C was added LiHMDS in THF (1.184 ml, 1.184 mmol). The reaction mixture was stirred at -50°C for 10 minutes. A solution of pyridin-2-yl (1,1,1trifluoro-2-methylpropan-2-yl)carbonate (236 mg, 0.947 mmol) in 0.5 ml of dry THF was added to the reaction mixture at -50°C and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (25 ml) and extracted with EtOAc (2x25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 35% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (150 mg, 0.247 mmol, 52% yield) as an off-white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (s, 1H), 7.46-7.28 (m, 3H), 3.57 (s, 2H), 1.83-1.68 (m, 12H), 1.64 (s, 6H ), 1.51-1.17 (m, 6H). MS (ESI) 576 (M+H).

Step B Example 584 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 584A and the corresponding boronic acid where necessary: (13 mg, 0.020 mmol, 47% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68-7.52 (m, 3H), 7.50-7.44 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.27 (br d, J= 6.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.67 (td, J=5.9, 12.1 Hz, 1H), 3.63 (s, 2H), 1.85-1.70 (m, 12H), 1.65 ( s, 6H), 1.50-1.36 (m, 6H), 1.29 (d, J=6.1 Hz, 6H). FXR EC ₅₀ (nM) = 31; MS (ESI) 632 (M+H).

Example 585.

3-cyano-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N- (4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)bicyclo[1.1.1]pentan-1-carboxamide

- 399 047337

Step A: Intermediate 585A. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 574C and 3-bromoaniline where necessary (150 mg, 0.334 mmol, 68% yield), as an off-white solid. MS (ESI) 426 (M+H).

Stage B. Intermediate connection 585V. Preparation of methyl 3-((3-bromophenyl)((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )bicyclo[1.1.1]pentane-1carboxylate

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 585A and 3(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid where necessary (120 mg, 0.197 mmol, yield 84%) as an off-white solid. MS (ESI) 578 (M+H).

Step C. Intermediate 585C. Preparation of 3-((3-bromophenyl)((4-(5-(1,1-difluoroethyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )bicyclo[1.1.1]pentane-1-carboxylic acid

The title compound was prepared according to the method described for the synthesis of intermediate 145B, replacing intermediate 585B where necessary (110 mg, 0.195 mmol, 94% yield) as a brown gumy solid. MS (ESI) 564 (M+H).

Stage D. Intermediate 585D. Preparation of Y1-(3-bromophenyl)-Y1-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) bicyclo[1.1.1]pentane-1,3dicarboxamide

The title compound was prepared according to the method described for the synthesis of intermediate 114A, replacing intermediate 585C where necessary (100 mg, 0.169 mmol, 87% yield) as an off-white solid. MS (ESI) 563 (M+H).

Step E. Intermediate 585E. Preparation of N(3-bromophenyl)-3-cyano-N-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl )methyl)bicyclo[1.1.1]pentane-1carboxamide

- 400 047337

The title compound was prepared according to the method described for the synthesis of intermediate 114B, replacing intermediate 585D where necessary (80 mg, 0.139 mmol, 79% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.77-7.72 (m, 1H), 7.62 (br d, J=7.3 Hz, 1H), 7.49-7.39 (m, 2H), 3.663.47 (m, 2H ), 2.23-1.97 (m, 9H), 1.82-1.72 (m, 6H), 1.46-1.35 (m, 6H). MS (ESI) 545 (M+H).

Step F. Example 585. Preparation of 3-cyano<N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl) methyl)-N-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3yl)bicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 585E and the corresponding boronic acid where necessary: (13 mg, 0.021 mmol, 58% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.75-7.63 (m, 4H), 7.62-7.51 (m, 3H), 7.38 (br d, J=7.3 Hz, 1H), 5.07 (s, 1H), 3.65-3.49 (m, 2H), 2.20-1.93 (m, 9H), 1.86-1.72 (m, 6H), 1.58-1.28 (m, 12H). FXR EC ₅₀ (nM) = 18; MS (ESI) 601 (M+H).

Example 586.

-(tert-butyl)-1-(6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3 -yl)-1 -((4-(5-(1-fluorocyclopropyl)-1, 2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

Step A: Intermediate 586A. Preparation of 6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3 amine

The specified compound was prepared in accordance with the method described for the synthesis of the compound of example 149, by replacing 3-bromo-4-fluoroaniline and the corresponding boronic acid where necessary: (1.0 g, 4.08 mmol, 86% yield) . MS (ESI) 246 (M+H).

Stage B. Intermediate 586B. Preparation of methyl 4-(5-(1-fluorocyclopropyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

The title compound was prepared according to the method described for the synthesis of intermediate 3A, replacing intermediate 206C and the corresponding acid where necessary: (2.4 g, 8.07 mmol, 91% yield). MS (ESI) 295 (M+H).

Step C. Intermediate 586C. Preparation of (4-(5-(1-fluorocyclopropyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was prepared according to the method described for the synthesis of intermediate 1G, replacing intermediate 586B where necessary: (1.6 g, 6.01 mmol, 80% yield). MS (ESI) 267 (M+H).

Stage D. Intermediate 586D. Preparation of 4-(5-(1-fluorocyclopropyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carbaldehyde

- 401 047337

The title compound was prepared according to the method described for the synthesis of intermediate 3C, replacing intermediate 586C where necessary: (1.6 g, 6.05 mmol, 77% yield). MS (ESI) 265 (M+H).

Step E. Intermediate 586E. Preparation of 6-fluoro-N-((4-(5-(1-fluorocyclopropyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4'-isopropoxy -[1,1'-biphenyl]-3-amine

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing intermediate 586D and intermediate 586A where necessary: (1.6 g, 3.24 mmol, 88% yield) as a brown wax. MS (ESI) 494 (M+H).

Step F. Example 586. Preparation of 3-(tert-butyl)-1-(6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3-yl)-1((4-(5-( 1 -fluorocyclopropyl)-1,2,4-oxadiazol-3 -yl)bicyclo-[2.2.2]octan-1-yl)methyl)urea

To a stirred and cooled solution of intermediate 586E (30 mg, 0.061 mmol) in DCM (1 ml) at 0°C was added triphosgene (27.1 mg, 0.091 mmol) followed by TEA (0.051 ml, 0.365 mmol). After stirring the reaction mixture overnight at room temperature, 2-methylpropan-2-amine (4.45 mg, 0.061 mmol) in THF (2 mL) was added followed by TEA (0.051 mL, 0.365 mmol). The reaction mixture was heated to 50°C and stirred overnight. The reaction mixture was concentrated under reduced pressure. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 2 minute hold at 15% B, 15-57% B for 25 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (21 mg, 0.034 mmol, 56% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.49 (d, J=7.3 Hz, 2H), 7.42 (br d, J=6.8 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 4.75 (s, 1H), 4.68 (td, J=6.0, 12.0 Hz, 1H), 3.54 (s, 2H), 1.87-1.65 (m, 8H), 1.49- 1.35 (m, 8H), 1.30 (d, J=5.9 Hz, 6H), 1.21 (s, 9H). FXR EC50 (nM) = 36; MS (ESI) 593 (M+H).

Example 587.

(cis)-N((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 hydroxy-N-(4'-(2-hydroxypropan-2-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3 -yl)-3 (trifluoromethyl) cyclobutane-1-carboxamide

Step A: Intermediate 587A. Preparation of ethyl 3'-((cis)-N-((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl )methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1carboxamido)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate

OEt

The specified compound was synthesized in accordance with the method described for the synthesis of the compound

- 402 047337 research according to example 149, by replacing intermediate 576E and the corresponding boronic acid where necessary: (44 mg, 0.066 mmol, 78% yield); MS (ESI) 662 (M+H).

Step B. Example 587. Preparation of (cis)-Y-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-hydroxy<U-(4'-(2-hydroxypropan-2-yl)-2',3',4',5'-tetrahydro-[1,Hbiphenyl]-3 -yl)- 3-(trifluoromethyl)cyclobutane-1-carboxamide

A solution of intermediate 587A (40 mg, 0.060 mmol) in THF (2 ml) was cooled to 0°C and methylmagnesium bromide (0.201 ml, 0.604 mmol) was added. The reaction mixture was allowed to warm to room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride (5 ml). The aqueous mixture was extracted with EtOAc (15 ml), and the organic layer was washed with brine (5 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 15% B, 15-65% B for 25 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (12.5 mg, 0.019 mmol, 32% yield); ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.44-7.29 (m, 3H), 7.26-7.15 (m, 1H), 6.52 (s, 1H), 6.31-6.17 (m, 1H), 4.23-3.99 (m, 1H), 3.76-3.50 (m, 2H), 2.80 -2.64 (m, 1H), 2.47-2.22 (m, 4H), 2.12-1.87 (m, 5H), 1.83-1.64 (m, 12H) , 1.54-1.33 (m, 6H), 1.31-1.16 (m, 2H), 1.09 (d, J=3.7 Hz, 6H). FXR EC ₅₀ (nM) = 42; MS (ESI) 648 (M+H).

Example 588.

(cis)-N-(3-(3,6-dihydro-2H-pyran-4-yl)phenyl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2, 4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)-cyclobutane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate 576E and the corresponding boronic acid where necessary: (4.1 mg, 0.007 mmol, 16% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.71-7.33 (m, 4H), 7.30-7.16 (m, 1H), 6.57-6.46 (m, 1H), 6.39-6.29 (m, 1H), 4.50- 4.43 (m, 1H), 4.24 (br d, J=2.45 Hz, 1H), 3.83 (t, J=5.50 Hz, 1H), 3.71-3.49 (m, 2H), 3.01-2.83 (m, 1h), 2.79-2.71 (m, 1H), 2.48-2.41 (m, 1H), 2.36-2.27 (m, 2H), 2.10-1.94 (m, 2H), 1.84-1.68 (m, 12H), 1.52-1.31 (m , 6H). FXR EU ₅₀ (nM) = 395; MS (ESI) 592 (M+H).

Example 589.

N((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluoro-U-( 3-(4hydroxypiperidin-1-yl)phenyl)bicyclo[1.1.1]pentan-1-carboxamide

A solution containing intermediate 527B (70 mg, 0.130 mmol), piperidin-4-ol (15.78 mg, 0.156 mmol), cesium carbonate (127 mg, 0.390 mmol) and (R)-(+)-BINAP (16 .19 mg, 0.026 mmol) in 1,4dioxane (2 ml) was degassed and refilled with argon three times and Pd ₂ (dba) ₃ (11.91 mg, 0.013 mmol) was added. The reaction mixture was heated to 110°C and stirred for 18 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0-minute hold at 15% B, 15-50% B for 20 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min. Collection of fractions was initiated by signals. Fractions containing the product were combined and dried by centrifugal evaporation to give Ch-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-fluoro-U-(3-(4-hydroxypiperidine-1

- 403 047337 yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (1.0 mg, 1.679 µmol, 1% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.23 (t, J=7.9 Hz, 1H), 6.92 (dd, J=1.7, 8.6 Hz, 1H), 6.86 (s, 1H), 6.736.65 ( m, 1H), 4.68 (d, J=4.2 Hz, 1H), 3.69-3.62 (m, 1H), 3.62-3.52 (m, 3H), 3.47-3.42 (m, 1H), 2.93-2.84 (m, 2H), 2.13 (t, J=19.7 Hz, 3H), 1.95-1.72 (m, 14H), 1.54-1.37 (m, 8H). FXR EC50 (nM) = 436; MS (ESI) 559 (M+H).

Example 590.

(cis)A-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 hydroxy-N-(3-(6-(2-hydroxypropan-2-yl)spiro[3.3]hept-1-en-2-yl)phenyl)-3 (trifluoromethyl)cyclobutan-1-carboxamide

Stage A. Intermediate 590A. (((trifluoromethyl)sulfonyl)oxy)spiro[3.3]hept-5-ene-2-carboxylate

Preparation of methyl 6-

To a stirred solution of LiHMDS (8.92 ml, 8.92 mmol) in THF (2 ml) at -78°C, a solution of methyl 6-oxospiro[3.3]heptane-2-carboxylate (500 mg, 2.97 mmol) was added dropwise ) in THF (2 ml) at 78°C and stirred for 45 minutes. A solution of A(5-chloropyridin-2-yl)1,1,1-trifluoro-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (2.34 g, 5.95 mmol) in THF (5 ml) was then added dropwise. at 78°C, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with water (10 ml) and extracted with ethyl acetate (2x20 ml). The combined organic layers were washed with water (10 ml) and then brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Gexane, B = EtOAc; gradient 30 min; 0% B to 50% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.3]hept-5-ene2-carboxylate (500 mg, 1.665 mmol, 56% yield) as yellow oil. MS (ESI) 318 (M+18).

Stage B. Intermediate connection 590V. Preparation of methyl 6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)spiro[3.3] hept-5-ene-2-carboxylate

To a stirred solution of intermediate 590A (300 mg, 0.999 mmol) in 1,4dioxane (5 ml) at room temperature was added 4,4,4',4',5,5,5',5'-octamethyl-2,2 '-bi(1,3,2dioxaborolane) (507 mg, 1.998 mmol) and potassium acetate (441 mg, 4.50 mmol). The resulting reaction mixture was purged with argon for 5 min and Pd(dppf)Cl ₂ (36.6 mg, 0.050 mmol) was added. The reaction mixture was heated to 110°C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (20 ml). The resulting solution was washed with water (10 ml) and then with saline (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 80% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[3.3]hept-5-ene -2carboxylate (150 mg, 0.539 mmol, 54% yield) as a brown oil. MS (ESI) 214 (N-64, adduct of boronic acid and water).

Step C. Example 590. Preparation of (cis)-No-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-hydroxyA-(3-(6-(2-hydroxypropan-2-yl)spiro[3.3]hept-1-en-2yl)phenyl)-3-(trifluoromethyl)cyclobutan-1-carboxamide

This compound was synthesized according to the method described for the synthesis of Example 149, replacing intermediate 576E and intermediate 590B where necessary: (7.1 mg, 10.76 µmol, 24% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.43-7.32 (m, 2H), 7.30-7.19 (m, 2H), 6.75 (s, 1H), 6.54 (s, 1H), 6.45 (s,

- 404 047337

1H), 4.10 (d, J=1.5 Hz, 1H), 3.81-3.43 (m, 2H), 2.78 (s, 1H), 2.74-2.65 (m, 1H), 2.61 (s, 1H), 2.32 (br t, J=10.9 Hz, 2H), 2.26-2.12 (m, 2H), 2.09-1.99 (m, 2H), 1.97-1.90 (m, 2H), 1.84-1.65 (m, 12H), 1.50-1.30 ( m, 6H), 1.070.98 (m, 6H). FXR EC ₅₀ (nM) = 11; MS (ESI) 660 (M+H).

Example 591.

1,1,1-trifluoro-2-methylpropan-2-yl (4'-(1-cyanocyclopropyl)-3'-fluoro-[1,1'-biphenyl]-3 -yl)((4-(5- (2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-carbamate

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 584A and the corresponding boronic acid where necessary: (20 mg, 0.030 mmol, 70% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.78-7.64 (m, 2H), 7.62-7.51 (m, 3H), 7.49-7.42 (m, 1H), 7.41-7.32 (m, 1H), 3.65 (s, 2H), 1.82-1.71 (m, 14H), 1.69-1.60 (m, 6H), 1.53-1.47 (m, 2H), 1.41 (br dd, J=7.1, 7.8 Hz, 6H). FXR EC ₅₀ (nM) = 77; MS (ESI) 657 (M+H).

Example 592.

(cis)-U-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-U-((4-(5-(2-fluoropropan-2-yl)-1, 2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1 carboxamide

Solution containing intermediate 576E (25 mg, 0.042 mmol), 2-oxa-6azaspiro[3,3]heptane hemioxalate (12.25 mg, 0.042 mmol), X-PHOS (4.05 mg, 8.50 μmol) and Cs ₂ CO ₃ (27.7 mg, 0.085 mmol) in 1,4-dioxane (2 ml) were degassed and refilled with argon three times and Pd ₂ (dba) ₃ (3.89 mg, 4.25 µmol) was added . The reaction mixture was heated to 110°C and stirred for 18 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The crude product 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 with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient: 0 minute hold at 35% B, 35-85% B for 20 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (14.9 mg, 0.025 mmol, 58% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.24-7.14 (m, 1H), 6.62 (d, J=7.6 Hz, 1H), 6.54 (s, 1H), 6.41-6.31 (m, 2H), 4.72 (s, 3H), 3.97 (s, 3H),3.69-3.43 (m, 4H), 2.82-2.69 (m, 1H), 2.38-2.25 (m, 2H), 2.19-1.98 (m, 2H), 1.83 -1.67 (m, 12H), 1.53-1.27 (m, 6H). FXR EU ₅₀ (nM) = 970; MS (ESI) 607 (M+H).

Example 593.

(cis)-U-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- 3hydroxyJ-(3 -(6-(2-hydroxypropan-2-yl)pyridazin-3 -yl)phenyl)-3 -(trifluoromethyl)cyclobutan-1 carboxamide

ABOUT

^sn z (593)

Step A: Intermediate 593A. Preparation of (cis)F-((4-(5-(2-fluoropropan-2-yl)-1,2,4

- 405 047337 oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-N-(3-(4,4,5,5-tetramethyl-1,3,2dioxaborolane- 2-yl)phenyl)-3-(trifluoromethyl)-cyclobutane-1-carboxamide

A solution of intermediate 576E (100 mg, 0.170 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi(1,3,2-dioxaborolane) (51 .8 mg, 0.204 mmol) and potassium acetate (41.7 mg, 0.425 mmol) in 1,4-dioxane (5 ml) were degassed and refilled with argon for 5 min and PdCl ₂ (dppf) (9.95 mg) was added , 0.014 mmol). The reaction mixture was heated to 90°C and stirred for 12 hours. The reaction mixture was filtered through a pad of celite, and the celite layer was washed with ethyl acetate (20 ml). The filtrate was concentrated under reduced pressure to obtain a residue. The crude product was purified by flash chromatography (12 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 50% B; flow rate = 24 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (75 mg, 0.118 mmol, 69% yield). MS (ESI) 636 (M+H).

Stage B. Intermediate 593B. Preparation of 2-(6-chloropyridazin-3-yl)propan-2-ol

To a stirred solution of methylmagnesium bromide (5.79 mL, 17.38 mmol) in THF (2.5 mL) and toluene (10 mL) at -20°C under N2, a solution of tert-butanol (0.554 mL, 5.0 mL) was added dropwise. 79 mmol) in THF (7 ml). The reaction mixture was stirred for 30 minutes and then methyl 6chloropyridazine-3-carboxylate (1 g, 5.79 mmol) was added in portions. The solution was left to warm to 0°C and stirred for 30 minutes. The reaction was quenched with aqueous 1N HCl and the resulting solution was extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (20 ml) and then with brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated under reduced pressure to give the title compound 2-(6-chloropyridazin-3-yl)propan-2-ol (800 mg, 4.63 mmol, 80% yield). MS (ESI) 173 (M+H)

Step C. Example 593. Preparation of (cis)-No-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-hydroxy<N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

The title compound was prepared according to the general method described for the synthesis of Example 149, replacing intermediate 593 A and intermediate 593 B where necessary: (20.5 mg, 0.032 mmol, 58% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.34-8.28 (m, 1H), 8.18-8.09 (m, 2H), 8.02-7.96 (m, 1H), 7.67-7.60 (m, 1H), 7.58- 7.52 (m, 1H), 6.58 -6.53 (m, 1H), 5.59-5.54 (m, 1H), 3.80-3.61 (m, 2H), 2.85-2.77 (m, 1H), 2.37-2.31 (m, 2H ), 2.15-2.03 (m, 2H), 1.82-1.70 (m, 12H), 1.61 -1.53 (m, 6H), 1.48-1.39 (m, 6H). FXR EC50 (nM) = 566. MS (ESI) 646 (M+H).

Example 594.

3-fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- N-(3(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

Step A: Intermediate 594A. Preparation of 5-(3-aminophenyl)-pyridazin-3(2H)-one

- 406 047337

The title compound was prepared according to the method described for the synthesis of Example 149 by substituting 5-chloropyridazin-3(2H)-one and (3-aminophenyl)boronic acid where necessary: (450 mg, 2.404 mmol, yield 66%) as a white solid. MS (ESI) 188 (M+H).

Stage B. Intermediate 594B. Preparation of 5-(3-(((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino) phenyl)pyridazin-3(2H)-one

The title compound was prepared according to the method described for the synthesis of intermediate 1F, replacing intermediate 594A and intermediate 576C where necessary: (110 mg, 0.250 mmol, 47% yield) as an off-white solid. MS (ESI) 438 (M+H).

Step C. Example 594. Preparation of 3-fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1- yl)methyl)-N-(3-(6-oxo-1,6-dihydropyridazin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 594B and the corresponding acid where necessary: (10.2 mg, 0.018 mmol, 39% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.29-13.04 (m, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.65-7.49 (m, 2H), 7.28 (d, J=2.0 Hz, 1H), 3.69-3.63 (m, 1H), 3.59-3.53 (m, 1H), 2.29 (d, J=2.7 Hz , 1H), 1.93-1.86 (m, 3H), 1.85-1.67 (m, 14H), 1.54-1.37 (m, 6h). FXR EC ₅₀ (nM) = 1838. MS (ESI) 567 (M+NH4).

Example 595.

(cis)-N((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)-3 hydroxy-N-(6-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-3 -(trifluoromethyl)cyclobutane-1 carboxamide

Step A: Intermediate 595A. Preparation of 6-bromo-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin- 2-amine

The indicated compound was synthesized according to the method described for the synthesis of intermediate 1I, by replacing intermediate 576C and 6-bromopyridin-2-amine where necessary: (170 mg, 0.402 mmol, 41% yield). MS (ESI) 423 (M+H).

Stage B. Intermediate connection 595V. Preparation of (cis)-N-(6-bromopyridin-2-yl)-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 3, by replacing intermediate 595A and the corresponding acid where necessary: (200 mg, 0.339 mmol, 72% yield). MS (ESI) 589 (M+H).

Step C. Example 595. Preparation of (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3

- 407 047337 yl)bicyclo[2.2.2]octan-'1-yl)methyl)-3-hydroxyU-(6-(4-(2-hydroxypropan-2-yl)f)enyl)pyridin-2-yl) -3(trifluoromethyl)cyclobutane-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound of example 149, by replacing intermediate compound 595B and the corresponding boronic acid where necessary: (12.9 mg, 0.019 mmol, 56% yield); 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.94-8.06 (m, 3H) 7.89 (d, J=7.83 Hz, 1H) 7.60 (d, J=8.56 Hz, 2H) 7.44 (d, J=7.83 Hz , 1H) 6.53 (s, 1H) 5.10 (s, 1H) 3.82 (s, 2H) 2.95-3.08 (m, 1H) 2.25-2.38 (m, 2H) 2.02-2.21 (m, 2H) 1.78 (s, 3H ) 1.63-1.77 (m, 9H) 1.46 (s, 6H) 1.31-1.44 (m, 6H). FXR EC ₅₀ (nM) = 64; MS (ESI) 645 (M+H).

Example 596.

No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-No.-(2-(2ethoxypyrimidin-5 -yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

Step A: Intermediate 596A. Preparation of 2-bromo-N-((4-(5-(tert-butyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-4-amine

The title compound was prepared according to the method described for the synthesis of intermediate 1I, replacing 2-bromopyridin-4-amine and intermediate 206F where necessary: (350 mg, 0.793 mmol, 62% yield). MS (ESI) 421 (M+2H).

Stage B. Intermediate 596B. N(2-bromopyridin-4-yl)-N-((4-(5-(tert-butyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-fluorobicyclo-[1.1.1]pentane-1-carboxamide

The indicated compound was synthesized according to the method described for the synthesis of the compound in Example 3, by replacing intermediate 596B and the corresponding acid where necessary: (50 mg, 0.085 mmol, 36% yield). MS (ESI) 533 (M+2H).

Step C. Example 596. Preparation of N((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan1-yl)methyl)-N-(2 -(2-ethoxypyrimidin-5-yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 596B and the corresponding boronic acid where necessary: (9.1 mg, 0.015 mmol, 32% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 2H), 8.74 (d, J=5.4 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 7.51 (dd, J= 5.3, 1.8 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.98 (d, J=2.4 Hz, 6H), 1.84-1.65 (m, 6H), 1.54- 1.34 (m, 9H), 1.33 (s, 9H). FXR EC ₅₀ (nM) = 321; MS (ESI) 575 (M+H).

Example 597.

No.((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-No.-(2-(2cyclopropylpyrimidin-5 -yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentan-1-carboxamide

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 149, by replacing intermediate compound 596B and the corresponding boronic acid where necessary: (12.2 mg, 0.021 mmol, 45% yield).

- 408 047337

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.35 (s, 2H), 8.77 (d, J=5.4 Hz, 1H), 8.21 (d, J=1.5 Hz, 1H), 7.54 (dd, J=5.3 , 1.8 Hz, 1H), 3.65 (s, 2H), 2.30 (ddd, J=12.8, 7.9, 5.4 Hz, 1H), 1.97 (d, J=2.4 Hz, 6H), 1.83-1.59 (m, 6H) , 1.53-1.36 (m, 6H), 1.33 (s, 9H), 1.20-1.00 (m, 4H). FXR EU ₅₀ (nM) = 226; MS (ESI) 571 (M+H).

Example 598.

2-cyanopropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)(4 '-(2-hydroxypropan-2-yl)-[1,1 '-biphenyl]-3-yl)-carbamate

Step A: Intermediate 598A. Preparation of 2-cyanopropan-2-yl carbonochloridate n ₃ sec.

NC.CL XI

CH ₃ O

To a stirred solution of phosgene (3.09 ml, 5.88 mmol) under a nitrogen atmosphere at -15°C was added a solution of 2-hydroxy-2-methylpropanenitrile (500 mg, 5.88 mmol) in pyridine (1 ml). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give 2-cyanopropan-2ylcarbonochloridate (300 mg, 2.040 mmol, 34% yield), which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) δ 1.48 (s, 6H).

Stage B. Intermediate 598B. Preparation of 2-(3'-(((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino )-[1,1'-biphenyl]-4-yl)propan-2-ol

The title compound was synthesized according to the method described for the synthesis of Example 149 by replacing intermediate 576D and the corresponding boronic acid where needed: (160 mg, 0.301 mmol, 64% yield), MS (ESI) 478 (M +H).

Step C. Example 598. Preparation of 2-cyanopropan-2-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3yl)carbamate

To a stirred solution of intermediate 598B (30 mg, 0.063 mmol) in DCM (1 mL) at room temperature was added intermediate 598A (9.27 mg, 0.063 mmol), followed by pyridine (5.08 μL, 0.063 mmol). After stirring for 2 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The crude product 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 with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0-minute hold at 20% B, 20-70% B for 20 minutes, then 5-minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (5.7 mg, 9.68 μmol, 15% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.60 (m, 3H), 7.60-7.51 (m, 3H), 7.46 (t, J=7.8 Hz, 1H), 7.40-7.29 (m, 1H) , 5.05 (s, 1H), 3.68 (s, 2H), 1.87-1.57 (m, 18H), 1.50-1.35 (m, 12H). FXR EC ₅₀ (nM) = 29. MS (ESI) 589 (M+H).

Example 599.

1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(( trans)-4hydroxy-4-methylcyclohexyl)-1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)urea

- 409 047337

BUT

This compound was synthesized according to the method described for the synthesis of Example 586, by replacing intermediate 598B and (trans)-4-amino-1methylcyclohexan-1-ol where necessary: (22.1 mg, 0.035 mmol, yield 38%).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.63-7.60 (m, 2H), 7.60-7.56 (m, 2H), 7.55 (s, 1H), 7.52 (d, J=11.00 Hz, 1H), 7.49 -7.46 (m, 1H), 7.30 (d, J=7.58 Hz, 1H), 5.20-5.15 (m, 1H), 5.06 (s, 1H), 4.17 (s, 1H), 3.60 (s, 2H), 3.53-3.46 (m, 1H), 1.79 (s, 3H), 1.78-1.70 (m, 9H), 1.66-1.59 (m, 2H), 1.46 (s, 6H), 1.45-1.37 (m, 6H), 1.371.23 (m, 6H), 0.99 (s, 3H). FXR EC ₅₀ (nM) = 30; MS (ESI) 633 (M+H).

Example 600.

1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(4 -hydroxy4-(trifluoromethyl)cyclohexyl)-1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)urea (Isomer-1)

BUT

^sn z (600)

Stage A. 600A intermediate. Preparation of 8-(trifluoromethyl)-1,4dioxaspiro[4.5]decan-8-ol

(Trifluoromethyl)trimethylsilane (5.46 g, 38 .4 mmol) followed by TBAF (1M solution in THF) (38.4 ml, 38.4 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 4 hours. An aqueous saturated ammonium chloride solution (30 ml) was added to the reaction mixture and the mixture was stirred for 10 minutes. The resulting solution was extracted with diethyl ether (3x50 ml). The combined ethereal extracts were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (3.6 g, 15.92 mmol, 83% yield) as a brown oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 5.83 (s, 1H), 3.87 (s, 4H), 1.71-1.80 (m, 4H), 1.56-1.67 (m, 4H). MS (ESI) 227 (M+H).

Stage B. Intermediate connection 600V. Preparation of 4-hydroxy-4-(trifluoromethyl)cyclohexan1-one

To a stirred solution of intermediate 600A (3 g, 13.26 mmol) in THF (80 mL) was added an aqueous 1.5N HCl solution (44.2 mL, 66.3 mmol) at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was diluted with EtOAc (50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x30 ml). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (2.2 g, 12.08 mmol, 91% yield) as an off-white semi-solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.30 (s, 1H), 2.63-2.50 (m, 2H), 2.19-2.15 (m, 2H), 2.00-1.91 (m, 4H).

Stage C. Intermediate compound 600С1 and 600С2. Preparation of 4-((4-methoxybenzyl)amino)-1(trifluoromethyl)cyclohexan-1-ol

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To a solution of intermediate 600B (1.5 g, 8.24 mmol) in 1,2-dichloroethane (30 ml) was added (4-methoxyphenyl)methanamine (1.356 g, 9.88 mmol), sodium triacetoxyborohydride (5.24 g , 24.71 mmol) and AcOH. (0.943 ml, 16.47 mmol). The reaction mixture was heated to 80°C and stirred for 6 hours. The reaction mixture was allowed to cool to room temperature and neutralized by adding 10% aqueous NaOH (20 ml). The resulting solution was extracted with DCM (3x20 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude product was purified by flash chromatography (40 g silica gel cartridge; A = Hexane, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give intermediate 600C1 (800 mg, 2.64 mmol, 64% yield), MS (ESI) 304 (M + H) and intermediate 600C2 (900 mg, 2 .97 mmol, yield 72%) MS (ESI) 304 (M + H) as a brown oil.

Stage D. Intermediate 600D. Preparation of 4-amino-1-(trifluoromethyl)-cyclohexan-1ol η ₂ ν· •CF ₃ ΌΗ

A stirred solution of intermediate 600C1 (0.8 g, 2.64 mmol) in ethanol (20 ml) was degassed and replenished with nitrogen three times, and 10% Pd/C (0.281 g, 0.264 mmol) was added. The resulting mixture was stirred at room temperature under a hydrogen cylinder (1 atm) for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound (0.4 g, 2.184 mmol, 83% yield). as an off-white solid. MS (ESI) 184 (M+H).

Step E. Example 600. Preparation of 1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-(4-hydroxy-4-(trifluoromethyl)cyclohexyl)-1-(4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)urea

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 586, by replacing intermediates 598B and 600D where necessary: (9.9 mg, 0.014 mmol, 15% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.52 (m, 6H), 7.48 (t, J=7.8 Hz, 1H), 7.33 (br d, J=8.3 Hz, 1H), 5.68 (s, 1H), 5.05 (s, 1H), 5.01-4.91 (m, 1H), 3.78-3.70 (m, 1H), 3.62 (s, 2H), 1.82-1.65 (m, 14H), 1.63-1.56 (m, 2H), 1.51-1.39 (m, 14H), 1.37-1.25 (m, 2H). FXR EC ₅₀ (nM) = 16; MS (ESI) 687 (M+H).

Example 601.

-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 -yl)methyl)-3 -(4- Hydroxy4-(trifluoromethyl)cyclohexyl)-1 -(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)urea (Isomer-2)

Step A: Intermediate 601A. Preparation of 4-amino-1-(trifluoromethyl)-cyclohexan-1ol η ₂ ν· •CF ₃ ΌΗ

The specified compound was prepared in accordance with the method described for the synthesis of intermediate 600D, using intermediate 600C2 where necessary. (0.42 g, 2.293 mmol, 87% yield). MS (ESI) 184 (M+H).

Step G Example 601 Preparation of 1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) -3-(4-hydroxy-4-(trifluoromethyl)cyclohexyl)-1-(4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)urea

The specified compound was synthesized in accordance with the method described for the synthesis of the compound in example 586, by replacing intermediate compound 598B and intermediate compound 601A where necessary: (5.2 mg, 7.27 μmol, 8% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.68-7.59 (m, 2H), 7.59-7.50 (m, 4H), 7.50-7.39 (m, 1H), 7.29 (br d,

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J=7.6 Hz, 1H), 5.62 (s, 1H), 5.42 (d, J=8.3 Hz, 1H), 5.05 (s, 1H), 3.91 (s, 1H), 3.61 (s, 2H), 3.51- 3.42 (m, 1H), 1.84-1.58 (m, 17H), 1.55-1.32 (m, 14H). FXR EC ₅₀ (nM) = 246; MS (ESl) 687 (M+h).

Example 602.

Isopropyl (4-(((cis)-3 -hydroxy-N-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3 -yl)-3 (trifluoromethyl)cyclobutan- 1-carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

ABOUT

X

GE N O CH ₃ f ₃ cV ϊ ίΐ ϊ I

BUT' [|I ABOUT CH ₃

II J n

NzSuTA ^but Υ ^CH 3 (602)

Step A: Intermediate 602A. Preparation of methyl 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylate

O _ch /—u N ₃ C CH ₃

1^—(C ΝΗ )^CH ₃

H ₃ C-O ' ^—ζ Yao

ABOUT

To a solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5 g, 9.42 mmol) in toluene (50 ml) at 0°C was added diphenylphosphoryl azide (5.06 ml, 23.56 mmol ), followed by TEA (3.28 ml, 23.56 mmol). The reaction mixture was stirred at room temperature for 1 hour and then heated to 110°C for 1 hour. Tert-butanol (11.27 ml, 118 mmol) was added and the reaction mixture was stirred overnight at 110°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The residue was reconstituted in a mixture of ethyl acetate (50 ml) and water (30 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash chromatography (80 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 25% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (5.2 g, 11.74 mmol, 50% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.42 (br s, 1H), 3.58-3.38 (m, 3H), 1.83-1.60 (m, 12H), 1.41-1.27 (m, 9H).

Stage B. Intermediate 602B. Preparation of tert-butyl (4-formylbicyclo[2.2.2]octan1-yl)carbamate

ABOUT

LAH (5.26 mL, 5.26 mmol) was added to a solution of intermediate 602A (1.0 g, 3.50 mmol) in tetrahydrofuran (20 mL) at 78°C. The reaction mixture was stirred at -78°C for 20 minutes and quenched with aqueous saturated ammonium chloride solution (10 ml). The mixture was diluted with ethyl acetate (30 ml) and the resulting solution was filtered through a pad of celite. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash chromatography (24 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 40% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (0.41 g, 1.618 mmol, 46% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.40 (s, 1H), 6.51-6.43 (m, 1H), 1.79-1.74 (m, 6H), 1.63-1.57 (m, 6H), 1.36 (s, 9H).

Step C. Intermediate 602C. Preparation of tert-butyl (4-(((3bromophenyl)amino)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

IBr /—\ H ₃ C CH ₃ /—\ / ^NH / ^CH3

I A—NH ' ' λ-Ο \=/ o

The title compound was prepared according to the method described for the synthesis of intermediate 1I using intermediate 602B and 3-bromoaniline where required: (0.32 g, 0.782 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.96-6.89 (m, 1H), 6.74-6.69 (m, 1H), 6.63-6.50 (m, 2H), 6.32 (br s, 1H), 5.67 (t , J=5.5 Hz, 1H), 2.71 (d, J=6.0 Hz, 2H), 1.80-1.67 (m, 6H), 1.50-1.43 (m, 6H), 1.36 (s, 9H). MS (ESI) 409

- 412 047337 (M+H).

Stage D. Intermediate 602D. Preparation of tert-butyl(4-(((cis)A-(3-bromophenyl)-3hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

ABOUT

The title compound was prepared according to the method described for the synthesis of Example 3 using intermediate 602C and the appropriate acid where needed: (0.32 g, 0.528 mmol, 72% yield) as an off-white solid .

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.61 (m, 1H), 7.53 (br d, J=6.5 Hz, 1H), 7.41-7.34 (m, 2H), 6.52 (s, 1H), 6.29-6.18 (m, 1H), 3.54-3.53 (m, 1H), 3.61-3.47 (m, 1H), 2.74-2.66 (m, 1H), 2.35-2.22 (m, 2H), 2.10-1.99 (m , 2H), 1.70-1.57 (m, 12H), 1.45-1.14 (m, 9H). MS (ESI) 575 (M+H).

Step E: Intermediate 602E. Preparation of tert-butyl (4-(((cis)-3-hydroxy-N(4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-3-(trifluoromethyl)- cyclobutan-1carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

The title compound was prepared according to the method described for the synthesis of Example 149 using intermediate 602D and the corresponding boronic acid where needed: (0.21 g, 0.306 mmol, 59% yield) as an off-white solid substances. MS (ESI) 631 (M+H).

Step F: Intermediate 606F. Preparation of (cis)-N((4-aminobicyclo[2.2.2]octan-1yl)methyl)-3-hydroxy-N(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]- 3-yl)-3-(trifluoromethyl)cyclobutane1-carboxamide

A solution of 4M HCl in 1,4-dioxane (0.198 mL, 0.793 mmol) was added to a stirred solution of intermediate 602E (100 mg, 0.159 mmol) in 1,4-dioxane (5 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (80 mg, 0.053 mmol, 33% yield) as an off-white solid MS (ESI) 531 ( M+N).

Step G: Example 602. Preparation of isopropyl (4-(((cis)-3-hydroxy-N(4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3 -yl)-3 -(trifluoromethyl)cyclobutan-1-carboxamido)methyl)bicyclo[2.2.2]octan-1 yl)carbamate

DIPEA (0.016 mL, 0.094 mmol) was added to a stirred solution of intermediate 602F (50 mg, 0.094 mmol) in dichloromethane (2 mL) at room temperature. The reaction mixture was cooled to 0°C and isopropyl chloroformate (11.55 mg, 0.094 mmol) was added. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was diluted with DCM (10 ml), and the organic solution was washed with water (10 ml) and then brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude compound was purified by preparative HPLC using the following conditions: (column: Waters XBridge BEH C18 XP (50x2.1 mm) 2.5 μm; mobile phase A: acetonitrile 5:95: water with 10 mM NH4OAc; mobile phase B: 95: 5 acetonitrile: water with 10 mM NH4OAc; temperature: 50°C; gradient: 0100% B for 3 minutes; flow rate: 1.1 ml/min). Fractions containing the product were combined and dried by centrifugal evaporation to give isopropyl (4-(((cis)-3-hydroxy-N(4'-(2hydroxypropan-2-yl)-[1,1'-biphenyl)]- 3-yl)-3-(trifluoromethyl)cyclobutan-1- 413 047337 carboxamido)methyl)bicyclo[2.2.2]-octan-1-yl)carbamate (9.6 mg, 0.016 mmol, 17% yield).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.60 (m, 4H), 7.53-7.46 (m, 1H), 7.35-7.27 (m, 1H), 6.58-6.46 (m, 2H), 5.06 ( s, 1H), 4.69-4.57 (m, 2H), 3.65-3.51 (m, 2H), 2.91-2.72 (m, 1H), 2.39-2.28 (m, 2H), 2.10-1.97 (m, 2H), 1.70-1.58 (m, 6H), 1.56-1.46 (m, 7H), 1.40-1.31 (m, 6H), 1.11 (d, J=6.11 Hz, 6H). FXR EC50 (nM) = 142; MS (ESI) 617 (M+H).

Example 603.

(cis)F-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)-F((4((trifluoromethyl)sulfonamido)bicyclo[2.2. 2]octan-1-yl)methyl)cyclobutan-1-carboxamide

Step A: Intermediate 603A. Preparation of tert-butyl (difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1 carboxamido)methyl)bicyclo[2.2.2]octan-1-yl) carbamate (4-(((cis)-\-(4'-

The title compound was prepared according to the general method described for the synthesis of Example 149 using intermediate 602D and the corresponding boronic acid where needed: (350 mg, 0.449 mmol, 53% yield) as an off-white solid . MS (ESI) 639 (M+H).

Stage B. Intermediate 603B. Preparation of (cis)J-((4-aminobicyclo[2.2.2]octan-1yl)methyl)J-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3 -yl)-3-hydroxy- 3-(trifluoromethyl)cyclobutane-1 carboxamide

The title compound was prepared according to the general method described for the synthesis of intermediate 606F, using intermediate 603A and the corresponding boronic acid as needed: (200 mg, 0.260 mmol, 55% yield) as an off-white solid substances. MS (ESI) 539 (M+H).

Step C. Example 603. Preparation of (cis)-No-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3-hydroxy-3(trifluoromethyl)-F((4-(( trifluoromethyl)sulfonamido)bicyclo[2.2.2]-octan-1-yl)methyl)cyclobutan-1carboxamide

Sodium bicarbonate (3.12 mg, 0.037 mmol) was added to a stirred solution of intermediate 603B (20 mg, 0.037 mmol) in dichloromethane (2 mL) at room temperature. The reaction mixture was cooled to 0°C and trifluoromethanesulfonic acid anhydride (11.52 mg, 0.041 mmol) was added. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with DCM (10 ml) and the organic solution was washed with water (10 ml) and then brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude compound was purified by preparative HPLC using the following conditions: (column: Waters XBridge BEH C18 XP (50x2.1 mm), 2.5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM NH ₄ OAc; mobile phase B : 95:5 acetonitrile:water with 10 mM NH ₄ OAc; temperature: 50°C; gradient: 0-100% B for 3 min; flow rate: 1.1 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain the title compound (8.2 mg, 0.012 mmol, 33% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 7.79 (d, J=8.3 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.54-7.09 (m, 5H), 6.50 (s, 1H), 3.72-3.50 (m, 2H), 2.87-2.74 (m, 1H), 2.38-2.25 (m, 2H), 2.11-1.97 (m, 2H ),

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1.81-1.61 (m, 6H), 1.51-1.32 (m, 6H). FXR EC ₅₀ (nM) = 1821; MS (ESI) 671 (M+H).

Example 604.

(cis)-3-hydroxy-N-(4'-isopropoxy-[1,G-biphenyl]-3-yl)-N-((4-(3-isopropylureido)bicyclo[2.2.2]octane-1- yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide

ABOUT

Step A: Intermediate 604A. Preparation of (cis)-N-((4-aminobicyclo[2.2.2]octan-1yl)methyl)-N-(3-bromophenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide

To a stirred solution of intermediate 602D (100 mg, 0.174 mmol) in dichloromethane (5 mL) at 0° C. was added TFA (0.013 mL, 0.174 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (75 mg, 0.121 mmol, 70% yield) as a pale brown solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.89-7.68 (m, 4H), 7.61-7.50 (m, 1H), 7.49-7.28 (m, 2H), 2.80-2.62 (m, 1H), 2.40 -2.22 (m, 2H), 2.12-1.94 (m, 2H), 1.65-1.51 (m, 6H), 1.47-1.29 (m, 6H). MS (ESI) 475 (M+H).

Stage B. Intermediate 604B. Preparation of (cis)-N-(3-bromophenyl)-3-hydroxy-N-((4(3-isopropylureido)bicyclo[2.2.2]octan-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1 -carboxamide

TEA (0.106 mL, 0.757 mmol) was added to a stirred solution of intermediate 604A (0.12 g, 0.252 mmol) in dichloromethane (3 mL) at room temperature. The reaction mixture was cooled to 0°C and 2-isocyanatopropane (0.032 g, 0.379 mmol) was added. The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was diluted with DCM (20 ml), and the organic solution was washed with water (10 ml) and then with brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by flash chromatography (4 g silica gel cartridge; A = Hexane, B = EtOAc; gradient 30 min; 0% B to 35% B). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (0.12 g, 0.111 mmol, 44% yield) as a white solid. MS (ESI) 560 (M+H).

Step C. Example 604. Preparation of (cis)-3-hydroxy-N-(4'-isopropoxy-[1,G-biphenyl]-3-yl)-N-((4(3-isopropylureido)bicyclo[2.2. 2] octan-1 -yl)methyl)-3 -(trifluoromethyl)cyclobutan-1-carboxamide

The specified compound was prepared in accordance with the method described for the synthesis of the compound in example 149, using intermediate compound 604B and the corresponding boronic acid where necessary: (9 mg, 0.015 mmol, 16% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.56 (m, 4H), 7.46 (t, J=7.8 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.01 (d, J =8.8 Hz, 2H), 6.50 (s, 1H), 5.41 (d, J=7.6 Hz, 1H), 5.27 (s, 1H), 4.68 (td, J=6.0, 12.2 Hz, 1H), 3.64-3.49 (m, 3H), 2.82 (t, J=8.9 Hz, 1H), 2.36-2.27 (m, 2H), 2.11-1.99 (m, 2H), 1.67-1.58 (m, 6H), 1.40-1.27 (m , 12H), 0.96 (d, J=6.6 Hz, 6H). FXR EU ₅₀ (nM) = 968; MS (ESI) 616 (M+H).

Example 605.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-( 1,1-difluoroethyl)pyridin-2-1)bicyclo[2.2.2]-octan-1 yl)methyl)( 4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate

- 415 047337

Step A: Intermediate 605A. Preparation of 3-(1,1-difluoroethyl)-pyridine

To a stirred solution of 1-(pyridin-3-yl)ethan-1-one (10.00 g, 83 mmol) in DCM (100 mL) in a screw cap reaction vessel was added diethylaminosulfur trifluoride (32.7 mL, 248 mmol) . The reaction vessel was sealed with a screw cap under a nitrogen atmosphere. The reaction mixture was heated overnight at 50°C. The reaction mixture was cooled to room temperature and added dropwise to a cooled aqueous 2N NaOH solution and extracted with DCM (2x300 ml). The combined organic extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was purified by flash column chromatography (120 g silica gel cartridge; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate = 120 ml/min). The pure fractions were combined and concentrated under reduced pressure to give the title compound (7 g, 48.9 mmol, 59% yield) as a pale yellow liquid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.81 (dd, J=1.0, 2.2 Hz, 1H), 8.72 (td, J=0.7, 4.9 Hz, 1H), 8.05-7.96 (m, 1H), 7.58-7.51 (m, 1H), 2.08-1.98 (m, 3H).

Stage B. 605V Intermediate. Preparation of methyl 4-(5-(1,1-difluoroethyl)pyridin-2yl)bicyclo[2.2.2]octane-1-carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (2.224 g, 10.48 mmol), N-hydroxyphthalimide (1.710 g, 10.48 mmol) and DMAP (0.043 g, 0.349 mmol ) in DMSO (40 ml) was added 4N-diisopropylcarbodiimide (1.633 ml, 10.48 mmol). The reaction mixture was stirred at room temperature for 24 hours. In another vessel, intermediate 605A (1.00 g, 6.99 mmol) was dissolved in DMSO (20 mL) and TFA (1.076 mL, 13.97 mmol) was added. This mixture was added to the above reaction mixture, followed by 2,4,5,6-tetra(9H-carbazol-9yl)isophthalonitrile (4CZIPN) (0.055 g, 0.070 mmol). The entire stirred reaction mixture was degassed and refilled with nitrogen, and irradiated with two blue LEDs (34 W) for 3 hours. The reaction mixture was quenched with 10% aqueous NaHCO ₃ solution, diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography (40 g silica gel cartridge; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 10% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (1.45 g, 4.69 mmol, 67% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (dd, J=0.9, 2.5 Hz, 1H), 7.94-7.88 (m, 1H), 7.46 (dd, J=0.8, 8.3 Hz, 1H), 3.60 (s, 3H), 2.10-1.94 (m, 3H), 1.92-1.78 (m, 12H). MS (ESI) 310 (M+H).

Step C. Intermediate 605C. Preparation of (4-(5-(1,1-difluoroethyl)-pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methanol

To a stirred solution of intermediate 605B (4.4 g, 14.22 mmol) in THF (44 mL), diisobutylaluminum hydride in THF (1.0 M) (35.6 mL, 35.6 mmol). The reaction mixture was stirred at -78°C for 30 minutes. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate (2x75 ml), the organic layer was washed with aqueous 1.5N HCl solution (50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (80 g silica gel cartridge; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 30% B; flow rate

- 416 047337 = 80 ml/min).

The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (3.2 g, 11.37 mmol, 80% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 (br s, 1H), 7.88 (dd, J=2.5, 8.0 Hz, 1H), 7.47-7.40 (m, 1H), 4.38 (t, J=5.5 Hz, 1H), 3.09 (d, J=5.5 Hz, 2H), 2.00 (t, J=19.1 Hz, 3H), 1.87-1.78 (m, 6H), 1.51-1.41 (m, 6H). MS (ESI) 282 (M+H).

Stage D. Intermediate 605D. Preparation of 4-(5-(1,1-difluoroethyl)-pyridin-2yl)bicyclo[2.2.2]octane-1-carbaldehyde

To a stirred solution of intermediate 605C (3.20 g, 11.37 mmol) in DCM (64 ml) was added Dess-Martin periodinane (4.2 g, 11.37 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was allowed to warm to room temperature, diluted with DCM (50 ml), washed with 10% aqueous sodium bicarbonate solution (2x50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (24 g silica gel cartridge; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 20% B; flow rate = 24 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (2.25 g, 8.05 mmol, 71% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.51-9.45 (m, 1H), 8.73-8.68 (m, 1H), 7.91 (dd, J=2.5, 8.5 Hz, 1H), 7.48 (d, J= 7.5 Hz, 1H), 2.01 (t, J=18.8 Hz, 3H), 1.92-1.87 (m, 6H), 1.75-1.67 (m, 6H).

Step E: Intermediate 605E. 4-bromo-N-((4-(5-(1,1-difluoroethyl)-pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

To a solution of intermediate 605D (1.0 g, 3.58 mmol) and 4-bromopyridin-2-amine (563 mg, 3.25 mmol) in MeOH (20 mL) was added acetic acid (0.373 mL, 6.51 mmol ), and then molecular sieves 4A. (100 mg). The reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was cooled to 0°C and sodium cyanoborohydride (409 mg, 6.51 mmol) was added. The reaction mixture was stirred for 1 hour and poured into water (20 ml). The aqueous layer was extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (800 mg, 1.833 mmol, 56% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (dd, J=1.0, 2.5 Hz, 1H), 7.88 (dd, J=2.5, 8.0 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H ), 7.45 (d, J=7.5 Hz, 1H), 6.78 (d, J=1.5 Hz, 1H), 6.66 (t, J=6.0 Hz, 1H), 6.61-6.55 (m, 1H), 3.15 (dd , J=5.8, 18.3 Hz, 2H), 2.08-1.93 (m, 3H), 1.88-1.80 (m, 6H), 1.55-1.47 (m, 6H). MS (ESI) 436 (M+H).

Stage F: Intermediate 605F. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4bromopyridin-2-yl)((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo-[2.2.2] octan-1-yl)methyl)carbamate

To a stirred solution of intermediate 605E (0.25 g, 0.573 mmol) in THF (2 ml), cooled to -50°C, was added dropwise lithium hexamethyldisilazane in THF (1.0 M) (1.432 ml, 1.432 mmol) in within 2 minutes. The reaction mixture was stirred at -50°C for 10 minutes. To this reaction mixture was added a solution of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl)carbonate (0.214 g, 0.859 mmol) in THF (0.5 ml) and the reaction mixture was stirred at - 50°C for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride (10 ml). The reaction mixture was diluted with water (15 ml) and extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with brine

- 417 047337 (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (0.23 g, 0.390 mmol, 68.0% yield) as a brown solid. MS (ESI) 590 (M+H).

Step G Example 605 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1- yl)methyl)(4-(4-(2-hydroxypropan-2yl)phenyl)pyridin-2-yl)carbamate

A mixture of intermediate 605F (30 mg, 0.051 mmol), (4-(2-hydroxypropan-2yl)phenyl)boronic acid (9.15 mg, 0.051 mmol) and K ₂ CO ₃ (14.04 mg, 0.102 mmol) in 1,4-dioxane (1 ml) and H2O (0.25 ml) were stirred at room temperature. Argon gas was bubbled through the mixture for 5 min. PdCl ₂ (dppf) (1.859 mg, 2.54 µmol) was added and argon gas was bubbled through the mixture for an additional 5 min. The reaction mixture was heated at 110°C for 1 hour. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 ml). The organic layer was washed with water (5 ml), brine (5 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The crude product 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: 28-85% B for 20 minutes, then hold for 5 minutes at 100% B; flow rate: 15 ml/min. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (18.7 mg, 0.029 mmol, 56% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J=1.0 Hz, 1H), 8.45 (d, J=5.1 Hz, 1H), 7.84 (dd, J=2.2, 8.6 Hz, 1H), 7.76 (d, J=8.6 Hz, 3H), 7.62 (d, J=8.3 Hz, 2H), 7.57 (dd, J=1.3, 5.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 5.14 (s, 1H), 3.89 (d, J=11.0 Hz, 2H), 1.97 (t, J=19.0 Hz, 3H), 1.80-1.68 (m, 12H), 1.46 (s, 6H), 1.44-1.33 (m, 6H). FXR EC50 (nM) = 52. MS (ESI) 646 (M+H).

Example 606.

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-((2-cyanopropan-2-yl)oxy)phenyl)pyridin-2-yl)((4-(5(1, 1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

CH ₃ O ^RzS AX NzOJUD

NC O'

The title compound was synthesized according to the general method described for the synthesis of Example 149 by replacing intermediate 605F and the corresponding boronic acid where necessary: (15.9 mg, 0.024 mmol, 47% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 7.93-7.82 (m, 3H), 7.81 (s, 1H), 7.58 (dd , J=1.5, 5.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 3.88 (s, 2H), 1.97 (t, J=19.0 Hz , 3H), 1.83-1.68 (m, 18H), 1.45-1.34 (m, 6H). FXR EC ₅₀ (nM) = 95. MS (ESI) 671 (M+H).

Example 607.

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1yl)methyl)(5 -(2-hydroxypropan-2-yl)-[2,4'-bipyridin]-2'-yl)carbamate

CH ₃ O

H ₃ C O N

Step A: Intermediate 607A. Preparation of 2-(6-bromopyridin-3-yl)-propan-2-ol

To a stirred solution of methyl 6-bromonicotinate (1 g, 4.63 mmol) in THF (10 ml), cooled to -30°C, was added dropwise methylmagnesium bromide in diethyl ether (3M) (6.17 ml, 18.52 mmol) for 3 minutes. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x50

- 418 047337 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel column, 120 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (brown solid, 0.9 g, 4.17 mmol, 90% yield).

¹ H NMR (300 MHz, DMSO-d ₀ ) δ 8.48 (dd, J=0.7, 2.6 Hz, 1H), 7.80 (dd, J=2.6, 8.3 Hz, 1H), 7.57 (dd, J=0.7, 8.3 Hz, 1H), 5.33-5.30 (m, 1H), 1.44 (s, 6H).

Stage B. Intermediate 607B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridin-2-yl)carbamate

Mixture of intermediate 605F (150 mg, 0.254 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi(1,3,2-dioxaborolane) (129 mg, 0.508 mmol) and potassium acetate (112 mg, 1.143 mmol) in dioxane (3 ml) were stirred at room temperature. Argon gas was bubbled through the mixture for 5 min. PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (9.29 mg, 0.013 mmol) was added and argon gas was bubbled through the mixture for 5 minutes. The reaction mixture was heated at 100°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 ml). The organic layer was washed with water (15 ml), brine (15 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel column, 4 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (100 mg, 0.180 mmol, 71% yield) as a brown gum. MS (ESI) 556 (M+H).

Step C Example 607 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1- yl)methyl)(5-(2-hydroxypropan-2-yl)-[2,4'-bipyridin]2'-yl)carbamate

The title compound was synthesized according to the general method described for the synthesis of Example 149, replacing intermediate 607A and intermediate 607B where necessary: (10.1 mg, 0.015 mmol, 31% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.16 (s, 1H) , 8.11-8.05 (m, 1H), 8.04-7.98 (m, 1H), 7.91(d, J=4.4 Hz, 1H), 7.84 (dd, J=2.0, 8.6 Hz, 1H), 7.38 (d, J =8.3 Hz, 1H), 5.34 (s, 1H), 3.91 (s, 2H), 1.97 (t, J=19.1 Hz, 3H), 1.83-1.66 (m, 12H), 1.50 (s, 6H), 1.44 -1.32 (m, 6H). FXR EU ₅₀ (nM) = 96. MS (ESI) 647 (M+H).

Example 608.

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1yl)methyl)(4 -(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)pyridin-2-yl) carbamate

Step A: Intermediate 608A. Preparation of 2-(2-chloropyrimidin-5-yl)propan-2-ol

H ₃ C but-)—/ ^C|

H ₃ C \=N

To a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (1 g, 5.79 mmol) in THF (20 mL), methylmagnesium bromide in diethyl ether (3 M) (5.79 mL, 17.38 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0°C for 15 minutes. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Unrefined ochi product

- 419 047337 flash silica gel column chromatography (silica gel column, 24 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (brown solid, 750 mg, 4.35 mmol, 75% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 2H), 5.33-5.30 (s, 1H), 1.47 (s, 6H).

Step B Example 608 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1- yl)methyl)(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2yl)pyridin-2-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 608A and intermediate 607B where necessary: (7.3 mg, 0.011 mmol, 24% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (s, 2H), 8.65 (d, J=1.2 Hz, 1H), 8.59 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 8.11 (dd, J=1.3, 5.3 Hz, 1H), 7.84 (dd, J =2.2, 8.6 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 5.53 (s, 1H), 3.94 (s , 2H),1.97 (t, J=19.1 Hz, 3H), 1.84-1.66 (m, 12H), 1.53 (s, 6H), 1.45-1.33 (m, 6H). FXR EC ₅₀ (nM) = 301. MS (ESI) 648 (M+H).

Example 609.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane- 1-yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate

CH ₃ O

A

NzSMt ⁴ N

A kJ P ^H 3 li 7 xi Hf

LJ ^N -0 F

NzS^ACh

NoD ^sn z (609)

Step A: Intermediate 609A. Preparation of methyl 4-cyanobicyclo[2.2.2]octane-1carboxylate

Ammonium chloride (2.52 g, 47.1 mmol) was added to a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (5.0 g, 23.56 mmol) in EtOAc (75 mL). ), DIPEA (20.57 ml, 118 mmol) and 50% propylphosphonic anhydride in EtOAc (45 g, 70.7 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was heated at 75°C overnight. The reaction mixture was concentrated under reduced pressure. Residual water (100 ml) was added and the reaction mixture was stirred for 30 minutes at room temperature. The solids were filtered, dried in vacuo to give the title compound (4.4 g, 22.77 mmol, 97% yield) as a brown solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.60-3.55 (m, 3H), 1.93-1.82 (m, 6H), 1.75-1.68 (m, 6H).

Stage B. Intermediate 609B. Preparation of methyl (E)-4-(N'hydroxycarbamidoyl)bicyclo[2.2.2]octane-1-carboxylate

O /—y NH ₂

НзС-О ⁷ '— ^{7 X} N

BUT

Hydroxylamine (50% aqueous solution, 12.05 mL, 197 mmol) was added to a stirred solution of intermediate 609A (7.6 g, 39.3 mmol) in ethanol (160 mL). The reaction mixture was refluxed at 80°C for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was diluted with water (100 ml). The solids were filtered and dried in vacuo to give the title compound (8.3 g, 36.7 mmol, 93% yield) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.89 (s, 1H), 5.19-5.10 (m, 2H), 3.60-3.54 (m, 3H), 1.73-1.63 (m, 12H).

- 420 047337

MS (ESI) 227 (M+H).

Step C. Intermediate 609C. Preparation of methyl 4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

H ₃ C _F

O /\Ν^γΑ-F/\/o

N ₃ s-O '—' Ν ^U

To a stirred solution of intermediate 609B (2 g, 8.84 mmol) in DMF (40 mL) was added 2,2-difluoropropanoic acid (1.459 g, 13.26 mmol), benzotriazol-1-yl oxytris(dimethylamino)phosphonium hexafluorophosphate ( 4.3 g, 9.72 mmol) followed by TEA (4.93 mL, 35.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then heated at 110°C for 4 hours. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The aqueous layer was extracted with EtOAc (2x75 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 40 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (2.1 g, 6.99 mmol, 79% yield) as a brown gummy mass.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.61 (s, 3H), 2.16 (t, J=19.6 Hz, 3H), 1.94-1.78 (m, 12H).

Stage D. Intermediate 609D. Preparation of (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol n ₃ with _F gm / \ / V 0 but ^λ ' Ι\Γ ^υ

To a stirred solution of intermediate 609C (2.1 g, 6.99 mmol) in THF (20 mL), diisobutylaluminum hydride (1.0 M) (17.48 mL, 17 .48 mmol). The reaction mixture was stirred at -78°C for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate (2x50 ml). The organic layer was washed with an aqueous 1.5 N HCl solution (50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 40 g; A = hexanes, B = EtOAc; gradient 30 min; 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 (1.7 g, 6.24 mmol, 89% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 4.41 (t, J=5.3 Hz, 1H), 3.09 (d, J=5.0 Hz, 2H), 2.15 (t, J=19.6 Hz, 3H), 1.90- 1.80 (m, 6H), 1.50-1.41 (m, 6H).

Step E. Intermediate 609E. Preparation of 4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

H ₃ C _F

Ί' ⁰

To a stirred solution of intermediate 609D (1.7 g, 6.24 mmol) in DCM (35 mL) was added Dess-Martin periodinane (3.178 g, 7.49 mmol) at 0°C. The reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was diluted with DCM (50 ml), washed with 10% aqueous sodium bicarbonate solution (3x 50 ml). The organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 24 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 25% B; flow rate = 24 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (1.3 g, 4.76 mmol, 76% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 2.25-2.05 (m, 3H), 1.95-1.83 (m, 6H), 1.74-1.63 (m, 6H).

Step F: Intermediate 609F. Preparation of 4-bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2- amine

- 421 047337

Acetic acid (3.85 mL, 67.3 mmol) was added to a stirred solution of intermediate 609E (10 g, 37 mmol) and 4-bromopyridin2-amine (5.82 g, 33.6 mmol) in MeOH (200 mL). , and then molecular sieves. 4A (500 mg).

The reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was cooled to 0°C and sodium cyanoborohydride (4.23 g, 67.3 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water (100 ml) and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (silica gel column, 120 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (9.0 g, 21.06 mmol, 63% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.79-7.83 (m, 1H), 6.70 (t, J=5.48 Hz, 1H), 6.76 (d, J=1.51 Hz, 1H), 6.60 (dd, J =5.48, 1.70 Hz, 1H), 3.12-3.19 (m, 2H), 2.08-2.24 (m, 3H), 1.82-1.87 (m, 6H), 1.48-1.56 (m, 6H). MS (ESI) 427 (M+H).

Stage G. Intermediate 609G. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4bromopyridin-2-yl)((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1yl)methyl)carbamate

To a stirred solution of intermediate 609F (6.0 g, 14.04 mmol) in THF (60 mL), LiHMDS in THF (1.0 M) (35.1 mL, 35.1 mmol) was added dropwise at -50° C for 5 minutes. The reaction mixture was stirred at -50°C for 10 minutes. To this reaction mixture was added a solution of pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (3.5 g, 14.04 mmol) in THF (10 ml). The reaction mixture was stirred at -50°C for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water (50 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel column, 120 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (5.8 g, 9.98 mmol, 71% yield) as pale yellow resinous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.32-8.28 (m, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.50 (dd, J=1.8, 5.3 Hz, 1H),

3.86-3.82 (m, 2H), 2.19-2.05 (m, 3H), 1.81-1.72 (m, 6H), 1.68 (s, 6H), 1.41-1.30 (m, 6H). MS (ESI) 581 (M+H).

Step H. Example 609. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2 .2]octan-1-yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2yl)carbamate

A mixture of intermediate 609G (25 mg, 0.043 mmol), (4-(2-hydroxypropan-2-yl)phenyl)boronic acid (7.74 mg, 0.043 mmol) and K2CO3 (11.89 mg, 0.086 mmol) in 1 ,4-dioxane (1 ml) and H2O (0.25 ml) were stirred at room temperature. Argon gas was bubbled through the mixture for 5 minutes. PdCl ₂ (dppf) (1.573 mg, 2.150 µmol) was added and argon gas was bubbled through the mixture for an additional 5 min. The reaction mixture was heated at 110°C for 90 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc (5 ml). The organic layer was washed with water (5 ml), brine (5 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative LC/MS following

- 422 047337 blowing conditions: column: Waters XBridge C18, 150 mmx19 mm, particles 5 microns; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 28% B, 28-80% B for 20 minutes, then 5 minute hold at 100% B; flow rate: 15 ml/min; Column temperature: 25°C. Collection of fractions was initiated by signals. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (11.3 mg, 0.018 mmol, 43% yield).

1H NMR (400 MHz DMSO-d ₆ ) δ 8.44 (d, J=5.1 Hz, 1H), 7.76 (d, J=8.8 Hz, 3H), 7.62 (d, J=8.3 Hz, 2H), 7.57 (dd , J=1.5, 5.1 Hz, 1H), 5.13 (s, 1H), 3.86 (s, 2H), 2.12 (t, J=19.7 Hz, 3H), 1.80-1.57 (m, 12H), 1.46 (s, 6h), 1.44-1.26 (m, 6H). FXR EC ₅₀ (nM) = 30. MS (ESI) 637 (M+H).

Example 610.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3 yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 609B and the corresponding boronic acid where necessary: (8.0 mg, 0.013 mmol, 29.2% yield).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J=5.4 Hz, 1H), 7.86-7.68 (m, 3H), 7.53 (dd, J=1.5, 5.4 Hz, 1H), 7.06 (d , J=8.8 Hz, 2H), 4.72 (td, J=6.0,12.0 Hz, 1H), 3.85 (s, 2H), 2.12 (t, J=19.7 Hz, 3H), 1.84-1.72 (m, 6H) , 1.70 (m, 6H), 1.46-1.34 (m, 6H), 1.30 (d, J=6.1 Hz, 6H). FXR EC ₅₀ (nM) = 47. MS (ESI) 637 (M+H).

Example 611.

3-(tert-butyl)-1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-1-((4-(5-(trifluoromethyl) -1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

^Sn z (611)

Step A: Intermediate 611A. Preparation of methyl 4-(5-(trifluoromethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate

O /—y N^y ^CF 3 / \ / o n ₃ s-o ⁴

Pyridine (5 mL, 61.9 mmol) was added to a stirred solution of intermediate 206C (7 g, 30.9 mmol) in DMF (70 mL). The reaction mixture was cooled to 0°C and trifluoroacetic anhydride (6.55 ml, 46.4 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice water (50 ml) and extracted with ethyl acetate (2x75 ml). The combined organic layers were washed with aqueous 1N HC1 (2x25 ml) and then brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel flash column chromatography (silica gel cartridge, 80 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 30% B; flow rate = 80 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (colorless liquid, 8 g, 26.3 mmol, 85% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.61 (s, 3H), 1.92-1.81 (m, 12H).

Stage B. Intermediate 611B. Preparation of (4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol

ΖΣΣΧ Ny ^CF 3 / \ / Q but ⁴ —' i\r ^u

- 423 047337

The title compound was prepared according to the general method described for the synthesis of intermediate 1G, replacing intermediate 611A where necessary: (colorless liquid, 4 g, 14.48 mmol, 55% yield).

¹ H NMR (400 MHz, DMSO-d ₀ ) δ 4.44 (t, J=5.3 Hz, 1H), 3.09 (d, J=5.5 Hz, 2H), 1.88-1.82 (m, 6H), 1.501.42 ( m, 6H). MS (ESI) 279 (M+H).

Step C. Intermediate 611C. Preparation of 4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was prepared according to the general method described for the synthesis of intermediate 3C, replacing intermediate 611B where necessary: (colorless liquid, 1.6 g, 5.83 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 1.94-1.88 (m, 6H), 1.74-1.67 (m, 6H).

Stage D. Intermediate 611D. Preparation of 3-bromo-N-((4-(5-(trifluoromethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the general method described for the synthesis of intermediate 1I by replacing intermediate 611C and 3-bromoaniline where necessary: (off-white solid, 650 mg, 1.511 mmol, 75% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.00-6.93 (m, 1H), 6.80-6.74 (m, 1H), 6.63-6.57 (m, 2H), 5.81-5.74 (m, 1H), 2.81 ( d, J=5.9 Hz, 2H), 1.91-1.82 (m, 6H), 1.62-1.48 (m, 6H). MS (ESI) 430 (M+H).

Step E: Intermediate 611E. Preparation of 1-(4-bromopyridin-2-yl)-3-(tert-butyl)-1((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2 ] octan-1-yl)methyl)urea

The title compound was prepared according to the general method described for the synthesis of Example 586, replacing intermediate 611D and the corresponding amine where necessary: (brown gum, 600 mg, 1.134 mmol, 69% yield). MS (ESI) 529 (M+H).

Step F Example 611 Preparation of 3-(tert-butyl)-1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3yl)-1-((4-( 5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2.2]octan-1-yl)methyl)urea

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 611E and the corresponding boronic acid where necessary: (7.1 mg, 10.81 μmol, 23% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.43 (m, 7H), 7.31 (d, J=7.8 Hz, 1H), 5.18-4.98 (m, 1H), 4.74 (s, 1H), 3.60 (s, 2H), 1.83-1.72 (m, 6H), 1.52-1.39 (m, 12H), 1.21 (s, 9H). FXR EC ₅₀ (nM) = 41. MS (ESI) 585 (M+H).

Example 612.

3-(tert-butyl)-1-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-1-((4-(5-(trifluoromethyl)-1,2,4oxadiazole -3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

- 424 047337

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 611E and the corresponding boronic acid where necessary: (10 mg, 0.016 mmol, 35% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.80-7.72 (m, 2H), 7.62 (s, 1H), 7.58-7.46 (m, 2H), 7.37-7.10 (m, 4H), 4.75 (s, 1H), 3.60 (s, 2H), 1.84-1.68 (m, 6H), 1.51-1.36 (m, 6H), 1.20 (s, 9H). FXR EC ₅₀ (nM) = 65. MS (ESI) 593 (M+H).

Example 613.

3-(tert-butyl)-1-(4'-(2-(difluoromethoxy)propan-2-yl)-[1,1'-biphenyl]-3-yl)-1-((4-(5- (trifluoromethyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

Step A: Intermediate 613A. Preparation of 2-(4-bromophenyl)propan-2-ol

To a stirred solution of methyl 4-bromobenzoate (3 g, 13.95 mmol) in THF (30 ml) at -10°C, methyl magnesium bromide in THF (3M) (13.95 ml, 4.19 mmol) was added dropwise. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water (30 ml) and extracted with ethyl acetate (2x50 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (silica gel column, 40 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (yellow liquid, 2.5 g, 11.62 mmol, 83% yield) .

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.29-7.55 (m, 4H), 5.11 (s, 1H), 1.32-1.51 (m, 6H).

Stage B. Intermediate 613B. Preparation of 1-bromo-4-(2-(difluoromethoxy)propan-2yl)benzene

Potassium hydrogen fluoride (2905 mg, 37.2 mmol) and ( bromodifluoromethyl)trimethylsilane (2.179 ml, 13.95 mmol) under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 ml) and extracted with DCM (2x30 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (silica gel column, 24 g, conditions: 25% ethyl acetate in petroleum ether) to give the title compound (350 mg, 1.320 mmol, 28% yield) as a colorless liquid.

¹ HNMR (300 MHz, DMSO-d ₆ ) δ 7.60 (d, J=8.59 Hz, 2 H), 7.13-7.33 (m, 3H), 1.63 (s, 6H).

Step C. Intermediate 613C. Preparation of 2-(4-(2-(difluoromethoxy)propan-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

- 425 047337

The indicated compound was prepared according to the general method described for the synthesis of intermediate 607B, replacing intermediate 613B where necessary: (0.3 g, 0.961 mmol, 51% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.65-7.73 (m, 2H), 7.47 (d, J=8.26 Hz, 2H), 6.27-6.83 (m, 1H), 1.59-1.68 (m, 6H), 1.29 (s, 12H).

Step D Example 613 Preparation of 3-(tert-butyl)-1-(4'-(2-(difluoromethoxy)propan-2-yl)-[1,1'biphenyl]-3 -yl)-1 -( (4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3 -yl)bicyclo-[2.2.2]octan-1 yl)methyl)urea

This compound was synthesized according to the general method described for the synthesis of Example 149 by replacing intermediate 611E and intermediate 613C where necessary: (5.2 mg, 7.87 µmol, 17% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (d, J=8.3 Hz, 2H), 7.63 (s, 1H), 7.56 (d, J=8.3 Hz, 3H), 7.54-7.44 (m, 1H ), 7.34 (br d, J=7.8 Hz, 1H), 6.80-6.39 (m, 1H), 4.76 (s, 1H), 3.60 (s, 2H), 1.83-1.72 (m, 6H), 1.68 (s , 6H), 1.50-1.36 (m, 6H), 1.21 (s, 9H). FXR EC ₅₀ (nM) = 79. MS (ESI) 635 (M+H).

Example 614.

1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-3-(spiro[2.3]hexan-5-ylmethyl)-1-((4- (5(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

Step A: Intermediate 614A. Preparation of 1-(3-bromophenyl)-3-(spiro[2.3]hexan-5ylmethyl)-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2 .2]octan-1-yl)methyl) urea

The title compound was prepared according to the general method described for the synthesis of Example 586, replacing intermediate 611D and the corresponding amine where necessary: (gum solid, 80 mg, 0.141 mmol, 76% yield). MS (ESI) 567 (M+H).

Step B. Example 614. Preparation of 1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-3(spiro[2.3]hexan-5-ylmethyl)- 1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)urea

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 614A and the corresponding boronic acid where necessary: (5.6 mg, 8.99 μmol, 20.41% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.58 (m, 2H), 7.57-7.50 (m, 4H), 7.50-7.42 (m, 1H), 7.28 (br d, J=7.6 Hz, 1H), 5.66 (t, J=5.6 Hz, 1H), 5.04 (s, 1H), 3.61 (s, 2H), 3.14 (m, 2H), 2.48-2.37 (m, 1H), 2.03-1.94 (m , 2H), 1.84-1.68 (m, 8H), 1.48-1.39 (m, 12H), 0.40-0.17 (m, 4H). FXR EC ₅₀ (nM) = 171. MS (ESI) 623(M+H).

Example 615.

1,1,1-trifluoro-2-methylpropan-2-yl(4-(4-(chlorodifluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1,1difluoroethyl)-1,2,4 -oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

- 426 047337

Step A: Intermediate 615A. Preparation of 2-(4-(chlorodifluoromethoxy)-phenyl)-5,5dimethyl-1,3,2-dioxaborinan

The title compound was prepared according to the general method described for the synthesis of intermediate 607B by replacing 1-bromo-4-(chlorodifluoromethoxy)benzene where necessary: (0.3 g, 1.033 mmol, 53% yield) as white loose solid.

¹ H NMR (300 MHz, DMSO-d6) δ 7.81 (d, J=8.6 Hz, 2H), 7.33 (dd, J=0.8, 7.8 Hz, 2H), 3.77 (s, 4H), 0.96 (s, 6H ).

Step B. Example 615. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-(4(chlorodifluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1,1- difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 609B and intermediate 615A where necessary: (15.2 mg, 0.021 mmol, 50% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J=5.1 Hz, 1H), 8.03-7.92 (m, 2H), 7.85 (s, 1H), 7.61 (dd, J=1.6, 5.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 3.87 (s, 2H), 2.12 (t, J=19.7 Hz, 3H), 1.83-1.72 (m, 6H), 1.70 (m, 6H ), 1.481.32 (m, 6H). FXR EC ₅₀ (nM) = 473. MS (ESI) 679 (M+H).

Example 616.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)(5 -fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl)-pyridin-2-yl)carbamate

Step A: Intermediate 616A. Preparation of U((4-(3-cyclopropyl-'1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-fluoro-4-iodopyridin-2-amine

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 4C and 5-fluoro-4-iodopyridin-2amine where necessary: (light yellow solid, 300 mg, 0.641 mmol, yield 20%). MS (ESI) 469 (M+H).

Stage B. Intermediate 616B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(3cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 5-fluoro-4-iodopyridin-2yl)carbamate

- 427 047337

The indicated compound was synthesized in accordance with the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl-(1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 616A where necessary: (off-white semi-solid, 95 mg, 0.153 mmol, 72% yield). MS (ESI) 623 (M+H).

Step C Example 616 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)(5-fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin2-yl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149 by replacing intermediate 616B and the corresponding boronic acid where necessary: (22.9 mg, 0.036 mmol, 74% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ = 8.48 (d, J=2.0 Hz, 1H), 7.71 (d, J=5.9 Hz, 1H), 7.67-7.54 (m, 4H), 5.16 (s, 1H), 3.79 (s, 2H), 2.08-1.98 (m, 1H), 1.81-1.72 (m, 6H), 1.68 (s, 6H), 1.47 (s, 6H), 1.42-1.33 (m, 6H) , 1.050.94 (m, 2H), 0.86-0.72 (m, 2H). FXR EC ₅₀ (nM) = 21. MS (ESI) 631 (M+H).

Example 617.

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)(5 -fluoro-4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 616B and the corresponding boronic acid where necessary: (7.3 mg, 10.70 μmol, 22% yield).

¹ H NMR (400 MHz, DMSO-d ₀ ) δ 8.44 (d, J=2.2 Hz, 1H), 7.71-7.66 (m, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.09 (d, J=8.8 Hz, 2H), 4.72 (td, J=6.2, 12.1 Hz, 1H), 3.78 (s, 2H), 2.08-1.98 (m, 1H), 1.81-1.70 (m, 6H), 1.67 (s , 6H), 1.42-1.33 (m, 6H), 1.30 (d, J=5.9 Hz, 6H), 1.04-0.96 (m, 2H), 0.84-0.78 (m, 2H). FXR EC ₅₀ (nM) = 81. MS (ESI) 631 (M+N).

Example 618.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)( 5-fluoro-4-(3-fluoro-4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate

Step A: Intermediate 618A. Preparation of 2-(4-bromo-2-fluorophenyl)propan-2-ol

The title compound was prepared according to the general method described for the synthesis of intermediate 607A, replacing methyl 4-bromo-2-fluorobenzoate where necessary: (yellow liquid, 2.5 g, 11.62 mmol, 83% yield) .

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.60 (dd, J=7.5, 8.5 Hz, 1H), 7.41 (dd, J=2.0, 11.0 Hz, 1H), 7.25 (dd, J=2.0, 8.5 Hz , 1H), 5.24 (s, 1H), 1.41 (s, 6H).

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Stage B. Intermediate 618B. Preparation of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)propan-2-ol

The title compound was prepared according to the general method described for the synthesis of intermediate 607B, replacing intermediate 618A where necessary: (2.1 g, 6.37 mmol, 59% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.61 (m, 1H), 7.48-7.42 (m, 1H), 7.25 (dd, J=1.0, 12.5 Hz, 1H), 5.29 (s, 1H ), 1.47 (d, J=1.0 Hz, 6H), 1.29 (s, 12H).

Step C Example 618 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)(5-fluoro-4-(3-fluoro-4-(2-hydroxypropan-2yl)phenyl)pyridin-2-yl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149 by replacing intermediate 616B and intermediate 618B where necessary: (5.2 mg, 7.87 µmol, 17% yield).

¹ H NMR (400 MHz, DMSO-de) δ 8.50 (d, J=2.2 Hz, 1H), 7.87-7.69 (m, 2H), 7.51 (td, J=1.5, 8.2 Hz, 1H), 7.45 (d , J=13.2 Hz, 1H), 5.46-5.39 (m, 1H), 3.79 (s, 2H), 2.03 (tt, J=4.9, 8.3 Hz, 1H), 1.81-1.72 (m, 6H), 1.68 ( s, 6H), 1.52 (s, 6H), 1.44-1.29 (m, 6H), 1.05-0.96 (m, 2H), 0.85-0.77 (m, 2H). FXR EC ₅₀ (nM) = 49. MS (ESI) 649 (M+N).

Example 619.

Neopentyl ((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)(5-fluoro4-(4- (2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate

Step A: Intermediate 619A. Preparation of D-((4-(5-(1,'1-difluoroethyl)-'1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-5-fluoro-4 -iodopyridin-2-amine

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 574C and 5-fluoro-4-iodopyridin-2amine where necessary: (brown solid, 850 mg, 1.727 mmol, 62% yield .2%). MS (ESI) 493 (M+H).

Stage B. Intermediate 619B. Preparation of neopentyl((4-(5-(1,1-difluoroethyl)-1,2,4 oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)(5-fluoro-4-iodopyridine -2-yl)carbamate

Pyridine (0.074 mL, 0.914 mmol) was added to a stirred solution of intermediate 619A (150 mg, 0.305 mmol) in DCM (1 mL). The reaction mixture was cooled to 0°C and neopentyl carbonochloridate (92 mg, 0.609 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (25 ml) and the organic solution was washed

10% aqueous sodium bicarbonate solution (2x15 ml) followed by brine (15 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure with

- 429 047337 to receive the balance. The crude product was purified by flash silica gel column chromatography (silica gel column, 4 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (brown solid, 130 mg, 0.214 mmol, 70% yield). MS (ESI) 607 (M+H).

Step C. Example 619. Preparation of neopentyl((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)(5- fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 619B and the corresponding boronic acid where necessary: (10 mg, 0.016 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J=2.2 Hz, 1H), 7.72 (d, J=5.9 Hz, 1H), 7.68-7.54 (m, 4H), 5.13 (s, 1H ), 3.84 (s, 2H), 3.77 (s, 2H), 2.12 (t, J=19.6 Hz, 3H), 1.89-1.69 (m, 6H), 1.46 (s, 6H), 1.44-1.36 (m, 6H), 0.83 (s, 9H). FXR EC ₅₀ (nM) = 28. MS (ESI) 615 (M+N).

Example 620.

1,1,1-trifluoro-2-methylpropan-2-yl(5-fluoro-4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)((4-(5(2 -fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Stage A. Intermediate 620A. Preparation of 5-fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4 -iodopyridin-2-amine

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 576E and 5-fluoro-4-iodopyridin-2amine where necessary: (light yellow solid, 200 mg, 0.418 mmol, yield 56%). MS (ESI) 489 (M+H).

Stage B. Intermediate connection 620V. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(5-fluoro4-iodopyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4- Oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

The indicated compound was synthesized in accordance with the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl(1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 620A where necessary: ( off-white semi-solid, 140 mg, 0.218 mmol, 79% yield). MS (ESI) 643 (M+H).

Step C. Example 620. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(5-fluoro-4-(4-(2hydroxypropan-2-yl)phenyl)pyridin-2-yl)((4 -(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 620B and the corresponding boronic acid where necessary: (12.2 mg, 0.019 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J=2.2 Hz, 1H), 7.72 (d, J=6.1 Hz, 1H), 7.68-7.54 (m, 4H), 5.16 (s, 1H ), 3.80 (s, 2H), 1.82-1.70 (m, 12H), 1.68 (s, 6H), 1.46 (s, 6H), 1.43-1.28 (m, 6H). FXR EC ₅₀ (nM) = 29. MS (ESI) 651 (M+H).

Example 621.

1,1,1-trifluoro-2-methylpropan-2-yl(5-fluoro-4-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-pyridin-2yl)((4- (5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

- 430 047337

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 620B and the corresponding boronic acid where necessary: (4.4 mg, 0.006 mmol, 17% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=2.2 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.09 (s, 1H), 7.81 (d, J= 5.4 Hz, 1H), 4.65 (dd, J=6.2, 7.7 Hz, 2H), 4.51 (d, J=7.1 Hz, 2H), 4.44 (t, J=6.1 Hz, 2H), 3.76 (s, 2H) , 3.44 (br d, J=7.6 Hz, 1H), 1.81-1.70 (m, 12H), 1.68 (s, 6H), 1.43-1.29 (m, 6H). FXR EC50 (nM) = 84. MS (ESI) 653 (M+H).

Example 622.

1,1,1-trifluoro-2-methylpropan-2-yl(4-(4-((2-cyanopropan-2-yl)oxy)phenyl)pyridin-2-yl)((4-(3 cyclopropyl-1 ,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Step A: Intermediate 622A. Preparation of 4-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 4C and 4-bromopyridin-2-amine where necessary: (white solid, 1.0 g, 2.479 mmol, yield 67 %).

¹ H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=5.0 Hz, 1H), 6.75 (d, 7=1.5 Hz, 1H), 6.71-6.67 (m, 1H), 6.60 (dd, J =2.0, 5.5 Hz, 1H), 3.12 (d, J=6.0 Hz, 2H), 2.06 (tt, J=4.8, 8.3 Hz, 1H), 1.87-1.79 (m, 6H), 1.53-1.45 (m, 6H), 1.06-0.98 (m, 2H), 0.88-0.81 (m, 2H). MS (ESI) 403 (M+H).

Stage B. Intermediate 622B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4bromopyridin-2-yl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2] octan-1-yl)methyl)carbamate

The indicated compound was synthesized in accordance with the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 622A where necessary: ( resin, 0.65 mg, 1.166 mmol, yield 78%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31-8.27 (m, 1H), 7.81-7.79 (m, 1H), 7.52-7.48 (m, 1H), 3.85-3.81 (m, 2H), 2.06 -2.01 (m, 1H), 1.79-1.73 (m, 6H), 1.71-1.66 (m, 6H), 1.38-1.30 (m, 6H), 1.03-0.98 (m, 2H), 0.85-0.80 (m, 2H). MS (ESI) 557 (M+H).

Step C. Example 622. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-((2-cyanopropan-2yl)oxy)phenyl)pyridin-2-yl)((4- (3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149, replacing intermediate 622B and the corresponding boronate ester where necessary: (12.1 mg, 0.019 mmol, 42% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=5.20 Hz, 1H), 7.88 (d, J=11.60 Hz, 2H), 7.79 (s, 1H), 7.58 (dd,

- 431 047337

J=6.80 Hz, 1H), 7.34 (d, J=12.00 Hz, 2H), 3.85 (s, 2H), 2.05-2.01 (m, 1H), 1.77-1.74 (m, 12H), 1.70 (s, 6H ), 1.39-1.37 (m, 6H), 1.03-1.01 (m, 2H), 0.82-0.80 (m, 2H). FXR EC ₅₀ (nM) = 34. MS (ESl) 638 (M+H).

Example 623.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)(4 '-(2-hydroxypropan-2-yl)-[1,1 '-biphenyl]-3-yl)carbamate

Step A: Intermediate 623A. Preparation of 3-bromo-N-((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, replacing intermediate 4C and 3-bromoaniline where necessary: (brown solid, 0.78 g, 1.745 mmol, 57% yield). MS (ESI) 403 (M+H).

Stage B. Intermediate 623B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(3bromophenyl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1- yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 623A where necessary: ( resin, 300 mg, 0.539 mmol, yield 72%). MS (ESI) 556 (M+H).

Step C. Example 623. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 623B and the corresponding boronic acid where necessary: (11 mg, 0.018 mmol, 39.9% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (d, J=8.40 Hz, 3H), 7.53 (q, J=23.20 Hz, 3H), 7.42 (t, J=15.60 Hz, 1H), 7.36- 7.27 (m, 1H), 5.06 (s, 1H), 3.63 (s, 2H), 2.08-2.01 (m, 1H), 1.78-1.74 (m, 6H), 1.65 (s, 6H), 1.45 (s, 6H), 1.41-1.37 (m, 6H), 1.01-0.99 (m, 2H), 0.82-0.80 (m, 2H). FXR EC50 (nM) = 50. MS (ESI) 612 (M+H).

Example 624.

1,1,1-trifluoro-2-methylpropan-2-yl(4-(4-(difluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1fluorocyclopropyl)-1,2,4-oxadiazole -3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Step A: Intermediate 624A. Preparation of 4-bromo-N-((4-(5-(1-fluorocyclopropyl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The specified compound was prepared in accordance with the general method described for the synthesis of prome

- 432 047337 compound 1I, by replacing intermediate 586D and 4-bromopyridin-2-amine where needed: (off-white solid, 100 mg, 0.237 mmol, 63% yield). MS (ESI) 421 (M+H).

Stage B. 624V intermediate connection. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4bromopyridin-2-yl)((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[ 2.2.2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 624A where necessary: ( pale yellow liquid, 0.39 g, 0.142 mmol, yield 12%). MS (ESI) 575 (M+H).

Step C. Example 624. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4-(4(difluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1-fluorocyclopropyl) -1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate compound 624B and the corresponding boronic acid where necessary: (24.6 mg, 0.039 mmol, 55% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J=5.4 Hz, 1H), 7.96-7.86 (m, 2H), 7.80 (s, 1H), 7.58 (dd, J=1.6, 5.3 Hz , 1H), 7.55-7.11 (m, 3H), 3.86 (s, 2H), 1.81-1.61 (m, 14H), 1.48-1.29 (m, 8H). FXR EC ₅₀ (nM) = 50. MS (ESI) 639 (M+H).

Example 625.

1,1,1-trifluoro-2-methylpropan-2-yl(4-(4-((2-cyanopropan-2-yl)oxy)phenyl)pyridin-2-yl) ((4-(5-(1fluorocyclopropyl )-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

CH ₃ O

AC ³ χ

H ₃ C O N

A -A n ₃ s sn ₃ G| pp ^and _(I5)

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 624B and the corresponding boronate ester where necessary: (22.9 mg, 0.035 mmol, 50% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=5.4 Hz, 1H), 7.93-7.82 (m, 2H), 7.80 (s, 1H), 7.58 (dd, J=1.6, 5.3 Hz , 1H), 7.38-7.28 (m, 2H), 3.86 (s, 2H), 1.80-1.63 (m, 20H), 1.48-1.32 (m, 8H). FXR EC ₅₀ (nM) = 18. MS (ESI) 656 (M+N).

Example 626.

N((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(4-(4isopropoxyphenyl )pyridin-2-yl)morpholine-4-carboxamide

Step A. Intermediate A. Preparation of N(4-bromopyridin-2-yl)-N-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)morpholine-4-carboxamide

The title compound was prepared according to the general method described for the synthesis of Example 586, by replacing intermediate 609A and the corresponding amine where necessary: (gum solid, 100 mg, 0.185 mmol, 99% yield) . MS (ESI) 540 (M+H).

Step B. Example 626. Preparation of N((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-N- (4-(4-isopropoxyphenyl)pyridin-2-yl)morpholine-4-carboxamide

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 626A and the corresponding boronic acid where necessary: (6.5 mg, 10.91 μmol, 24% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (d, J=5.1 Hz, 1H), 7.75-7.64 (m, 2H), 7.23 (dd, J=1.5, 5.4 Hz, 1H), 7.09-6.97 (m, 3H), 4.69 (td, J=6.1, 12.0 Hz, 1H), 3.68 (s, 2H), 3.51 (t, J=4.8 Hz, 4H), 3.32-3.26 (m, 4H), 2.15 ( t, J=19.7 Hz, 3H), 1.93-1.81 (m, 6H), 1.66-1.52 (m, 6H), 1.29 (d, J=6.1 Hz, 6H). FXR EC ₅₀ (nM) = 72. MS (ESI) 596 (M+N).

Example 627.

tetrahydro-2H-pyran-4-yl((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)(4-(4- isopropoxyphenyl)pyridin-2-yl)carbamate

Step A: Intermediate 627A. Preparation of 4-nitrophenyl (tetrahydro-2H-pyran-4yl) carbonate

To a stirred solution of tetrahydro-2H-pyran-4-ol (500 mg, 4.90 mmol) in DCM (10 ml) was added TEA (2.047 ml, 14.69 mmol), and then 4-nitrophenylcarbonochloridate (1085 mg, 5.39 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (25 ml), washed with water (2x15 ml). The organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 30% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (800 mg, 2.99 mmol, 61% yield) as a white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 8.29-8.35 (m, 2H) 7.55-7.61 (m, 2H), 4.91 (dt, J=8.78, 4.49 Hz, 1H), 3.82 (dt, J=11.90 , 4.63 Hz, 2H), 3.49 (ddd, J=11.80, 8.97, 3.02 Hz, 2H), 2.00 (dq, J=13.13, 3.68 Hz, 2H), 1.68 (dtd, J=13.08, 8.95, 8.95, 4.15 Hz, 2H).

Stage B. Intermediate 627B. Preparation of tetrahydro-2H-pyran-4-yl-(4bromopyridin-2-yl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl )methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing intermediate 627A and intermediate 622A where necessary: (yellow resin, 100 mg, 0.188 mmol, 76% yield). MS (ESI) 531 (M+H).

Step C. Example 627. Preparation of tetrahydro-2H-pyran-4-yl((4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octan-1-yl)methyl)( 4-(4-isopropoxyphenyl)-pyridin-2-yl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149, by replacing intermediate 627B and the corresponding boronic acid where necessary: (12.5 mg, 0.021 mmol, 44% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J=5.4 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.76-7.66 (m, 2H), 7.49 (dd, J =1.7, 5.4 Hz, 1H), 7.14-6.97 (m, 2H), 4.92-4.81 (m, 1H), 4.71 (m, 1H), 3.90 (s, 2H), 3.74-3.62 (m, 2H), 3.45 (m, 2H), 2.02 (m, 1H), 1.95 -1.84 (m, 2H), 1.82-1.68 (m, 6H), 1.54 (m, 2H), 1.44-1.34 (m, 6H), 1.29 ( d,

- 434 047337

J=6.1 Hz, 6H), 1.05-0.93 (m, 2H), 0.85-0.76 (m, 2H). FXR EC ₅₀ (nM) = 63. MS (ESI) 587 (M+H).

Example 628.

(cis)4U-(4'-(2,2-difluoro-1-hydroxyethyl)-[1,1'-biphenyl]-3-yl)-U-((4-(5-(1,1-difluoroethyl )-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1carboxamide

Step A: Intermediate 628A. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 574C and 3-bromoaniline where necessary: (white solid, 9.0 g, 21.06 mmol, 63% yield) .

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.98-6.92 (m, 1H), 6.76 (t, J=2.0 Hz, 1H), 6.62-6.55 (m, 2H), 5.79-5.71 (m, 1H) , 2.80 (d, J=6.0 Hz, 2H), 2.20-2.08 (m, 3H), 1.90-1.81 (m, 6H), 1.60-1.50 (m, 6H). MS (ESI) 427 (M+H).

Stage B. Intermediate connection 628V. Preparation of (cis)-U-(3-bromophenyl)-N-((4-(5-(1,1difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1- yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamide

The title compound was prepared according to the general method described for the synthesis of intermediate 576G, replacing intermediate 628A where necessary: (brown solid, 140 mg, 0.236 mmol, 67% yield). MS (ESI) 592 (M+H).

Step C. Intermediate 628C. Preparation of 1-(4-bromophenyl)-2,2-difluoroethan-1-ol (racemate)

To a stirred solution of 4-bromobenzaldehyde (500 mg, 2.70 mmol) and (difluoromethyl)trimethylsilane (671 mg, 5.40 mmol) in DMF (13 ml) was added cesium fluoride (82 mg, 0.540 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. To this reaction mixture was added TBAF in H2O (2.97 mL, 8.11 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2x20 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (colorless gum, 300 mg, 1.266 mmol, 47% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.61-7.56 (m, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.29 (d, J=5.0 Hz, 1H), 6.175.86 (m , 1H), 4.84-4.72 (m, 1H).

Stage D. Intermediate 628D. Preparation of 2,2-difluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)ethan-1-ol (racemate)

- 435 047337

The title compound was prepared according to the general method described for the synthesis of intermediate 607B, replacing intermediate 628C where necessary: (grey-white solid, 0.26 g, 0.915 mmol, 72% yield).

1H NMR (400 MHz, DMSO-d ₀ ) δ 7.67 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 6.23 (d, J=5.0 Hz, 1H), 6.15- 5.78 (m, 1H), 4.83-4.72 (m, 1H), 1.37-1.25 (m, 6H), 1.20-1.11 (m, 6H).

Step E. Example 628. Preparation of (cis)-No-(4'-(2,2-difluoro-1-hydroxyethyl)-[1,G-biphenyl]-3-yl)-No((4-(5- (1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1-carboxamide

The specified compound (racemate) was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 628B and intermediate 628D where necessary. Isomers were separated by the SFC method.

Preparative SFC conditions: column/dimensions: Whelk (R,R) (250x21) mm, 5 µm % CO2: 85% % co-solvent: 15% 0.2% ammonia solution in MeOH. Total flow rate: 80.0 g/min, return flow pressure: 100 bar; temperature: 30°C. UV detection: 240 nM.

First isomer eluted (3.2 mg, 4.78 µmol, 6% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.69 (m, 1H), 7.61-7.59 (m, 3H), 7.57-7.45 (m, 3H), 7.42-7.24 (m, 1H), 6.53 ( s, 1H), 6.26 (d, J=5.1 Hz, 1H), 6.23-5.84 (m, 1H), 4.89-4.74 (m, 1H), 3.79-3.59 (m, 2H), 2.85 (br t, J =8.9 Hz, 1H), 2.40-2.27 (m, 2H), 2.19-1.95 (m, 5H), 1.82-1.65 (m, 6H), 1.55-1.35 (m, 6H). FXR EC ₅₀ (nM) = 92. MS (ESI) 670 (M+H). (RT = 8.2 min or peak-1).

Second eluting isomer (2.2 mg, 3.29 µmol, 3.89% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81-7.70 (m, 3H), 7.66 (d, J=7.8 Hz, 1H), 7.59-7.47 (m, 3H), 7.38 (dd, J=1.0 , 7.8 Hz, 1H), 6.53 (s, 1H), 6.26 (br d, J=4.9 Hz, 1H), 6.21-5.88 (m, 1H), 4.89-4.74 (m, 1H), 3.69 (br dd, J=1.0, 3.2 Hz, 2H), 2.85 (br t, J=9.0 Hz, 1H), 2.39-2.26 (m, 2H), 2.21-1.93 (m, 5H), 1.85-1.72 (m, 6H), 1.57-1.36 (m, 6H). FXR EC ₅₀ (nM) = 128. MS (ESI) 670 (M+H). (RT=10.3 min or peak-2).

Example 629.

(cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2yl)((4-(5-(2-fluoropropan-2-yl)-1 ,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Step A: Intermediate 629A. Preparation of (cis)-3-(benzyloxy)-1(trifluoromethyl)cyclobutan-1-ol

To a stirred solution of 3-(benzyloxy)cyclobutan-1-one (0.50 g, 2.84 mmol) in THF (10 ml), cooled to 0°C, was added (trifluoromethyl)trimethylsilane (2.128 ml, 4.26 mmol ), followed by TBAF in THF (0.851 mL, 0.851 mmol). The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 2 hours. The reaction mixture was quenched with aq. 1.5N HCl solution (15 ml), stirred for 2 hours and extracted with ethyl acetate (2x25 ml). The combined organic layers were washed with brine (2x20 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (15% ethyl acetate:hexane, silica gel column, 12 g) to give the title compound (490 mg, 1.990 mmol, 70% yield) as a brown liquid.

1H NMR (400 MHz, CDCl ₃ ) δ 7.36 (d, J=2.5 Hz, 5H), 4.47 (s, 2H), 3.94-3.86 (m, 1H), 2.90-2.81 (m, 2H), 2.38-2.34 (m, 1H), 2.32-2.24 (m, 2H).

Stage B. Intermediate connection 629V. Preparation of (cis)-1-(trifluoromethyl)cyclobutane-1,3diol

BUT,,, F ₃ cY

HE

Pd-C (150 mg, 1.828 mmol) was added to a stirred solution of intermediate 629A (450 mg, 1.828 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature under 15 Psi hydrogen pressure for 4 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound (270 mg, 1.730 mmol, 95% yield) as a brown solid .

- 436 047337

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.49 (s, 1H), 5.35 (d, J=6.0 Hz, 1H), 3.83 (m, 1H), 2.71-2.63 (m, 2H), 2.11-2.01 (m, 2H).

Step C. Intermediate 629C. Preparation of (cis)-3-hydroxy-3(trifluoromethyl)cyclobutyl(5-fluoro-4-iodopyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4- Oxadiazol-3 yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

To a stirred solution of intermediate 620A (450 mg, 0.922 mmol) in DCM (10 mL) phosgene (0.585 mL, 1.106 mmol) and TEA (0.642 mL, 4.61 mmol) were added dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. To this reaction mixture was added DCM (5 ml), intermediate 629B (56.7 mg, 0.363 mmol) and potassium tert-butoxide (102 mg, 0.908 mmol) at 0°C . The reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was diluted with DCM (15 ml), washed with water (2x10 ml), then brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (90 mg, 0.063 mmol, 17% yield). MS (ESI) 671 (M+H).

Step D. Example 629. Preparation of (cis)-3-hydroxy-3-(trifluoromethyl)cyclobutyl-(4-(4(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4-(5-(2 -fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate 629C and the corresponding boronic acid where necessary: (6.4 mg, 9.32 μmol, 25% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=2.0 Hz, 1H), 7.81 (d, J=5.9 Hz, 1H), 7.79-7.70 (m, 2H), 7.577.10 (m, 3H), 6.81 (s, 1H), 4.70 (t, J=7.1 Hz, 1H), 3.87 (s, 2H), 2.91-2.79 (m, 2H), 2.34-2.19 (m, 2H), 1.82-1.68 (m, 12H), 1.49-1.30 (m, 6H). FXR EC ₅₀ (nM) = 99. MS (ESI) 687 (M+H).

Example 630.

3,3-difluorocyclobutyl(4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Stage A. Intermediate 630A. Preparation of 3,3-difluorocyclobutyl(5-fluoro-4iodopyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2 .2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 629C, by replacing intermediate 620A and the corresponding alcohol where necessary: (white solid, 110 mg, 0.113 mmol, 31% yield). MS (ESI) 623 (M+H).

Step B. Example 630. Preparation of 3,3-difluorocyclobutyl (4-(4-(difluoromethoxy)phenyl)-5fluoropyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1, 2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 630A and the corresponding boron

- 437 047337 new acid where needed: (12.1 mg, 0.019 mmol, 47% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J=2.0 Hz, 1H), 7.83 (d, J=6.1 Hz, 1H), 7.79-7.71 (m, 2H), 7.587.15 (m, 3H), 4.91 (br dd, J=4.9, 7.8 Hz, 1H), 3.87 (s, 2H), 3.13-2.99 (m, 2H), 2.81-2.63 (m, 2H), 1.81-1.68 (m, 12H ), 1.48-1.31 (m, 6H). FXR EC ₅₀ (nM) = 160. MS (ESI) 639 (M+H).

Example 631.

4,4-difluorocyclohexyl (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl) ((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Step A: Intermediate 631A. Preparation of 4,4-difluorocyclohexyl(5-fluoro-4iodopyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo-[2.2 .2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 629C, by replacing intermediate 620A and the corresponding alcohol where necessary: (white solid, 110 mg, 0.12 mmol, 33% yield). MS (ESI) 651 (M+H).

Step B. Example 631. Preparation of 4,4-difluorocyclohexyl (4-(4-(difluoromethoxy)phenyl)-5fluoropyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1, 2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 631A and the corresponding boronic acid where necessary: (8.5 mg, 0.012 mmol, 33% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J=2.0 Hz, 1H), 7.80 (d, J=5.9 Hz, 1H), 7.78-7.72 (m, 2H), 7.577.11 (m , 3H), 4.86 (br dd, J=1.1, 2.1 Hz, 1H), 3.85 (s, 2H), 1.99-1.65 (m, 20H), 1.47-1.33 (m, 6H). FXR EC ₅₀ (nM) = 117. MS (ESI) 667 (M+H).

Example 632 3-(trifluoromethyl)oxetan-3-yl ((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl )methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

Step A: Intermediate 632A. Preparation of 3-bromo-X-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, replacing intermediate 576E and 3-bromoaniline where necessary: (light yellow solid, 200 mg, 0.418 mmol, 56% yield). MS (ESI) 422 (M+H).

Stage B. Intermediate 632B. Preparation of 3-(trifluoromethyl)oxetan-3-ol

- 438 047337 | ^but >By

To a stirred solution of oxetan-3-one (2 g, 27.8 mmol) in tetrahydrofuran (80 ml) was added trimethyl(trifluoromethyl)silane (13.88 ml, 13.88 mmol) at 0°C. TBAF in THF (13.88 mL, 27.8 mmol) was added slowly over 10 minutes under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. To this reaction mixture was added aqueous 1.5N HCl solution (60 ml) at room temperature and the reaction mixture was stirred for another 1 hour. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (2x 30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (silica gel column, 24 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (3 g, 20.06 mmol, 72% yield) as a white solid .

1H NMR (400 MHz, DMSO-de) δ 7.55-6.97 (m, 1H), 4.72-4.63 (m, 2H), 4.56 (qd, J=1.7, 8.6 Hz, 2H).

Step C. Intermediate 632C. Preparation of pyridin-2-yl (3-(trifluoromethyl)oxetan-3yl) carbonate

Sodium hydride in mineral oil (60%) (141 mg, 3.52 mmol) was added to a solution of intermediate 632B (500 mg, 3.52 mmol) in tetrahydrofuran (20 ml) at 0°C. The reaction mixture was stirred at the same temperature for 30 minutes. To the above reaction mixture was added a solution of di(pyridin-2-yl)carbonate (761 mg, 3.52 mmol) in tetrahydrofuran (20 ml) over 5 minutes at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice, diluted with water (30 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (450 mg, 1.710 mmol, 49% yield) as a colorless liquid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.45-8.39 (m, 1H), 8.08-8.00 (m, 1H), 7.51-7.35 (m, 2H), 4.86-4.77 (m, 2H), 4.70- 4.64 (m, 2H).

Stage D. Intermediate 632D. Preparation of 3-(trifluoromethyl)oxetan-3-yl(3bromophenyl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]- octan-1-yl)methyl) carbamate

This compound was synthesized according to the general method described for the synthesis of intermediate 584A by replacing intermediate 632A and intermediate 632C where necessary: (off-white solid, 120 mg, 0.193 mmol, 82% yield). MS (ESI) 590 (M+H).

Step E. Example 632. Preparation of 3-(trifluoromethyl)oxetan-3-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2] octan-1-yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 632D and the corresponding boronic acid where necessary: (14 mg, 0.022 mmol, 43% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.48-7.55 (m, 1H), 7.43 (t, J=7.8 Hz, 1H ), 7.26-7.37 (m, 1H), 7.01 (d, J=8.8 Hz, 2H), 4.84-5.08 (m, 2H), 4.61-4.82 (m, 3H), 3.58-3.76 (m, 2H), 1.631.82 (m, 12H), 1.35-1.51 (m, 6H), 1.29 (d, J=6.1 Hz, 6H). FXR EC50 (nM) = 222. MS (ESI) 646 (M+H).

Example 633.

3-(bicyclo[1.1.1]pentan-1-yl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2 ]octan1 -yl)methyl)-1 -(4-fluoro-3 -(1 -(2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)phenyl)urea

- 439 047337

Step A: Intermediate 633A. Preparation of 3-bromo-U-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-fluoroaniline

The title compound was prepared according to the method described for the synthesis of intermediate 1I by replacing intermediate 574C and 3-bromo-4-fluoroaniline where necessary: (white solid, 9.0 g, 21.06 mmol, yield 63%). MS (ESI) 444 (M+H).

Stage B. Intermediate 633B. Preparation of 3-(bicyclo[1.1.1]pentan-1-yl)-1-(3-bromo-4fluorophenyl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4- Oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

The title compound was prepared according to the general method described for the synthesis of Example 586, replacing intermediate 633A and the corresponding amine where necessary: (100 mg, 0.181 mmol, 80% yield) as an off-white solid. MS (ESI) 553 (M+H).

Step C Example 633 Preparation of 3-(bicyclo[1.1.1]pentan-1-yl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)-1-(4-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-Spirazol-4-yl)phenyl)urea

This compound was synthesized according to the general method described for the synthesis of Example 149, by replacing intermediate 633B and the corresponding boronic acid where necessary: (8.3 mg, 0.013 mmol, 23% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J=2.2 Hz, 1H), 7.98 (s, 1H), 7.67 (dd, J=2.6, 7.0 Hz, 1H), 7.24 (dd, J=8.8, 10.8 Hz, 1H), 7.15-7.06 (m, 1H), 6.22 (s, 1H), 4.74 (s, 1H), 4.07 (s, 2H), 3.52 (s, 2H), 2.30 (s , 1H), 2.13 (t, J=19.7 Hz, 3H), 1.89 (s, 6H), 1.81-1.69 (m, 6H), 1.48-1.34 (m, 6H), 1.09 (s, 6H). FXR EC50 (nM) = 32. MS (ESI) 613 (M+H).

Example 634.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane -1-yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-carbamate

Step A: Intermediate 634A. Preparation of 4-bromo-U-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin- 2-amine

The indicated compound was prepared in accordance with the general method described for the synthesis of intermediate 1I, by replacing intermediate 576E and 4-bromopyridin-2-amine

- 440 047337 where required: (light yellow solid, 200 mg, 0.418 mmol, 56% yield). MS (ESI) 423 (M+H).

Stage B. Intermediate 634B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4bromopyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 634A where necessary: ( off-white semi-solid, 140 mg, 0.218 mmol, 79% yield). MS (ESI) 577 (M+H).

Step C Example 634 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 634B and the corresponding boronic acid where necessary: (13.4 mg, 0.021 mmol, 61% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, J=5.4 Hz, 1H), 7.76 (d, J=8.3 Hz, 3H), 7.62 (d, J=8.3 Hz, 2H), 7.57 (dd, J=1.3, 5.3 Hz, 1H), 5.12 (s, 1H), 3.89-3.79 (m, 2H), 1.89-1.62 (m, 18H), 1.47 (s, 6H), 1.39 (br dd, J=7.3, 8.1 Hz, 6H). FXR EC50 (nM) = 31. MS (ESI) 633 (M+H).

Example 635.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane -1-yl)methyl)(2-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)carbamate

Step A: Intermediate 635A. Preparation of 2-chloro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidin- 4-amine

Titanium(IV) isopropoxide (0.660 mL, 2.253 mmol) was added to a stirred solution of 2-chloropyrimidine-4-amine (146 mg, 1.126 mmol) and intermediate 576E (300 mg, 1.126 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with DCM (2x25 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (15% EA:hexane, silica gel column, 12 g) to give the title compound (30 mg, 0.079 mmol, 7% yield) as a white solid. MS (ESI) 380 (M+H).

Stage B. Intermediate 635V. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl-(2chloropyrimidin-4-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

This compound was synthesized according to the general method described for the synthesis of intermediate 584A by substituting pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2

- 441 047337 yl)carbonate and intermediate 635A where needed: (brown liquid, 20 mg, 0.037 mmol, 71% yield). MS (ESI) 534 (M+H).

Step C Example 635 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)(2-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin4-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 635B and the corresponding boronic acid where necessary: (12.5 mg, 0.020 mmol, 42% yield).

¹ H NMR (400 MHz, DMSO-de) δ 8.80 (d, J=5.9 Hz, 1H), 8.32 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.60 ( d, J=5.6 Hz, 1H), 5.12 (s, 1H), 4.13 (s, 2H), 1.84-1.70 (m, 18H), 1.54-1.37 (m, 12H). FXR EC ₅₀ (nM) = 1278. MS (ESI) 634 (M+H).

Example 636.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane -1-yl)methyl)(4-(4-isopropoxyphenyl)pyrimidin-2-yl)carbamate

Step A: Intermediate 636A. Preparation of 4-chloro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyrimidin- 2-amine ^ΗΝ ^ΥΥ?1

Λ A/ r ⁿ z

Ν^Ν — _(-F _ri AM No^ CH ₃

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 635A, by replacing intermediate 576E and the corresponding aniline where necessary: (40 mg, 0.095 mmol, 8% yield) as a white solid. MS (ESI) 380 (M+H).

Stage B. Intermediate 636B. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4chloropyrimidin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3- yl)bicyclo[2.2.2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 636A where necessary: ( resinous solid, 40 mg, 0.075 mmol, 57% yield). MS (ESI) 534 (M+H).

Step C Example 636 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl) bicyclo[2.2.2]octan-1-yl)methyl)(4-(4-isopropoxyphenyl)pyrimidin-2yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound in example 149, by replacing intermediate compound 636B and the corresponding boronic acid where necessary: (6.2 mg, 9.78 μmol, 21% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J=5.1 Hz, 1H), 8.17 (d, J=9.0 Hz, 2H), 7.83 (d, J=5.4 Hz, 1H), 7.09 (d, J=9.0 Hz, 2H), 4.80-4.72 (m, 1H), 3.84 (s, 2H), 1.84-1.65 (m, 18H), 1.46-1.35 (m, 6H), 1.31 (d, J =6.1 Hz, 6H). FXR EC ₅₀ (nM) = 68. MS (ESI) 634 (M+H).

Example 637.

No.(4-(((cis)-No-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)-cyclobutane1-carboxamido)methyl) bicyclo[2.2.2]octan-1-yl)-4-fluorobenzamide

- 442 047337

Step A: Intermediate 637A. Preparation of c-(4-(((cis)-A(3-bromophenyl)-3-hydroxy3-(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)-4-fluorobenzamide

The title compound was prepared according to the general method described for the synthesis of Example 114A using intermediate 604A and 4-fluorobenzoic acid where needed: (0.08 g, 0.082 mmol, 19% yield) as pale brown liquids. MS (ESI) 597 (M+H).

Step B. Example 637. Preparation of A(4-(((cis)-N-(4'-(difluoromethoxy)-[1,G-biphenyl]-3-yl)-3hydroxy-3-(trifluoromethyl)cyclobutane-1 -carboxamido)methyl)bicyclo[2.2.2]octan-1-yl)-4fluorobenzamide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, using intermediate compound 637A and the corresponding boronic acid where necessary: (9.5 mg, 0.014 mmol, 34% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.86-7.74 (m, 4H), 7.71 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.55-7.10 (m, 7H), 6.52 (s, 1H), 3.63 (m, 2H), 2.84 (m, 1H), 2.39-2.27 (m, 2H), 2.13-1.96 (m, 2H), 1.91-1.75 (m , 6H), 1.52-1.31 (m, 6H). FXR EC ₅₀ (nM) = 384; MS (ESI) 661 (M+H).

Example 638.

A(cyclopropylsulfonyl)-4-(((cis)-N-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamido )methyl)bicyclo[2.2.2]octane-1-carboxamide

Step A: Amino)methyl)bicyclo[2.2.2]octane-1-carboxylate intermediate

638A. Preparation of methyl 4-(((3-bromophenyl)-

The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 88B and 3-bromoaniline where necessary: (900 mg, 2.044 mmol, 33% yield) as an off-white solid.

1H NMR (300 MHz, DMSO-d ₆ ) δ 6.99-6.91 (m, 1H), 6.76 (s, 1H), 6.58 (br d, J=7.9 Hz, 2H), 5.77-5.65 (m, 1H), 3.56 (s, 3H), 2.78-2.70 (m, 2H), 1.74-1.63 (m, 6H), 1.51-1.38 (m, 6H). MS (ESI) 352 (M+H).

Stage B. Intermediate 638B. Preparation of methyl 4-(((cis)-N-(3-bromophenyl)-3hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo-[2.2.2]octane-1-carboxylate

The indicated compound was synthesized in accordance with the general method described for the synthesis of the compound of example 3, by replacing intermediate 638A and (cis)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxylic acid where necessary: (480 mg , 0.694 mmol, yield

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61%) as an off-white solid. MS (ESI) 518 (M+H).

Step C. Intermediate 638C. Preparation of 4-(((cis)-N-(3-bromophenyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

To a stirred solution of intermediate 638B (400 mg, 0.772 mmol) in MeOH (3 mL) and tetrahydrofuran (3 mL) was added a solution of LiOH (92 mg, 3.86 mmol) in H ₂ O (1.5 mL). The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (10 ml). The aqueous solution was acidified with aqueous 1.5N HCl and extracted with ethyl acetate (2x20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (350 mg, 0.541 mmol, 70% yield) as a pale yellow liquid. MS (ESI) 504 (M+H).

Stage D. Intermediate 638D. Preparation of 4-(((cis)-N-(3-bromophenyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamido)methyl)-N-cyclopropylsulfonyl)bicyclo[2.2.2]octane-1carboxamide

DIPEA (0.069 mL, 0.397 mmol) was added to a stirred solution of intermediate 638C (0.2 g, 0.397 mmol) and cyclopropanesulfonamide (48.0 mg, 0.397 mmol) in DCM (5 mL) at room temperature. The reaction mixture was cooled to 0°C and BOP (175 mg, 0.397 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (20 ml) and the organic solution was washed with water (10 ml) and then brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (silica gel cartridge, 4 g; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 35% B) to give the title compound (0.180 g, 0.142 mmol, 36% yield) as a white solid. MS (ESI) 607 (M+H).

Step E. Example 638. Preparation of N(cyclopropylsulfonyl)-4-(((cis)-N-(4'-(difluoromethoxy)[1,1'-biphenyl]-3-yl)-3-hydroxy-3-( trifluoromethyl)cyclobutane-1 carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, using intermediate compound 638D and the corresponding boronic acid where necessary: (22.8 mg, 0.034 mmol, 52% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.71-7.60 (m, 2H), 7.56-7.06 (m, 5H), 6.58 -6.43 (m, 1H), 3.64 (br s, 2H), 2.94-2.82 (m, 2H), 2.37-2.23 (m, 2H), 2.09-1.93 (m, 2H), 1.70-1.51 (m, 6H ), 1.40-1.24 (m, 6H), 1.06-0.96 (m, 4H). FXR EC ₅₀ (nM) = 2000; MS (ESI) 671 (M+H).

Example 639.

(cis)<No-(4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)-No-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazole -3yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1-carboxamide

Step A: Intermediate 639A. Preparation of 3-bromo-N-((4-(5-(4-fluorophenyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

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The title compound was synthesized according to the general method described for the synthesis of intermediate 3A by replacing intermediate 194E and 4-fluorobenzoic acid where needed: (0.27 g, 0.592 mmol, 83% yield) as a brown solid . MS (ESI) 456 (M+H).

Stage B. Intermediate 639B. Preparation of (cis)-N-(3-bromophenyl)-N-((4-(5-(4 fluorophenyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl )methyl)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxamide

This compound was synthesized in accordance with the general method described for the synthesis of the compound of Example 3, by replacing intermediate 639A and (cis)-3-hydroxy-3(trifluoromethyl)cyclobutane-1-carboxylic acid where necessary: (120 mg , 0.193 mmol, 80% yield) as a brown solid. MS (ESI) 622 (M+H).

Step C. Example 639. Preparation of u(cyclopropylsulfonyl)-4-(((cis)-N-(4'-(difluoromethoxy)[1,1'-biphenyl]-3 -yl)-3-hydroxy-3-( trifluoromethyl)cyclobutane-1 carboxamido)methyl)bicyclo[2.2.2]octane-1-carboxamide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, using intermediate compound 639B and the corresponding boronic acid where necessary: (22.8 mg, 0.034 mmol, 52% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.17-8.05 (m, 2H), 7.85-7.77 (m, 2H), 7.73 (d, J=1.7 Hz, 1H), 7.65 (d, J=8.3 Hz , 1H), 7.56-7.09 (m, 7H), 6.53 (s, 1H), 3.77-3.63 (m, 2H), 2.85 (br t, J=9.2 Hz, 1H), 2.38-2.34 (m, 2H) , 2.11-1.98 (m, 2H), 1.90-1.67 (m, 6H), 1.57-1.34 (m, 6H). FXR EC ₅₀ (nM) = 221; MS (ESI) 686 (M+H).

Example 640.

(cis)<Ni-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(difluoromethoxy)Ni(4- (4-isopropoxyphenyl)pyridin-2-yl)-3-methylcyclobutan-1-carboxamide |n y °A ^/ A DDxM.

H ₃ C^O^^ ₍₆₄₀₎

Stage A. Intermediate 640A. Preparation of benzyl (cis)-3-(difluoromethoxy)-3methylcyclobutane-1-carboxylate

Potassium hydrofluoride (5.67 g, 72 .6 mmol) followed by (bromodifluoromethyl)trimethylsilane (3.55 mL, 22.70 mmol) under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (30 ml), washed with water (2x20 ml), then brine (20 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (silica gel column, 24 g, conditions: 5-15% ethyl acetate in petroleum ether) to give the title compound (colorless liquid, 1.1 g, 4.07 mmol, yield 45 %).1H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.30 (m, 5H), 6.89-6.49 (m, 1H), 5.12 (s, 2H), 3.05-2.95 (m, 1H), 2.46 -2.37 (m, 2H), 2.34-2.26 (m, 2H), 1.47 (s, 3H).

Stage B. 640V intermediate connection. Preparation of (cis)-3-(difluoromethoxy)-3methylcyclobutane-1-carboxylic acid

The title compound was prepared according to the general method described for the synthesis of intermediate 629B, using intermediate 640A where required: (0.55 g, 3.05 mmol, 75% yield) as a colorless liquid .

Ή NMR (400 MHz, DMSO-d ₆ ) δ 12.41-12.27 (m, 1H), 6.90-6.46 (m, 1H), 2.81 (quin, J=8.8 Hz, 1H), 2.36 (br dd, J=9.5 , 12.0 Hz, 2H), 2.30-2.16 (m, 2H), 1.49-1.43 (m, 3H).

Step C. Intermediate 640C. Preparation of (cis)-A-(4-bromopyridin-2-yl)-A-((4-(5(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl) methyl)-3-(difluoromethoxy)-3-methylcyclobutane1-carboxamide

To a stirred solution of intermediate 605E (100 mg, 0.229 mmol) and intermediate 640B (49.5 mg, 0.275 mmol) in DCM (3 mL) was added DIPEA (0.200 mL, 1.146 mmol) followed by a solution of propylphosphonic anhydride (50% in EtOAc) (438 mg, 0.688 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (10 ml) and washed with brine (10 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (10% EA: hexane, 24 g, silica gel column) to give the title compound (85 mg, 0.142 mmol, 62% yield). as a brown solid. MS (ESI) 598 (M+H).

Step D. Example 640. Preparation of (cis)-No-((4-(5-(1,1-difluoroethyl)pyridin-2yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-(difluoromethoxy )F-(4-(4-isopropoxyphenyl)-pyridin-2-yl)-3methyl cyclobutane-1-carboxamide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, using intermediate compound 640C and the corresponding boronic acid where necessary: (120 mg, 0.184 mmol, 73% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.49 (d, J=5.20 Hz, 1H), 7.85 (d, J=8.80 Hz, 3H), 7.77 (s, 1H), 7.64 (d, J=6.40 Hz, 1H), 7.38 (d, J=8.40 Hz, 1H), 7.07 (d, J=9.20 Hz, 2H), 6.61 (t, J=152.00 Hz, 1H), 4.73 ( m, 1H), 3.81 (s, 2H), 3.05-2.98 (m, 1H), 2.39-2.33 (m, 2H), 2.00 (t, J=19.20 Hz, 3H), 1.88-1.81 (m, 2H) , 1.761.73 (m, 6H), 1.42-1.38 (m, 6H), 1.31-1.28 (m, 9H). FXR EC50 (nM) = 27. MS (ESI) 654 (M+H).

Example 641.

F((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(4' -(2hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-2-thia-6-azaspiro[3.3]heptane-6-carboxamide 2,2-dioxide

Step A: Intermediate 641A. Preparation of 2-(3'-(((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino )-[1,1'-biphenyl]-4-yl)propan-2-ol

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 632A and the corresponding boronic acid where necessary: (400 mg, 0.837 mmol, 74% yield). MS (ESI) 478 (M+H).

Step B. Example 641. Preparation of F((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)- N-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-2-thia-6azaspiro[3.3]heptan-6-carboxamide 2,2-dioxide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 586, by replacing intermediate 641A and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide where necessary: (2 mg, 3 .07 µmol, yield 7%).

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1H NMR (400 MHz, DMSO-d ₆ ) δ 7.53-7.67 (m, 6H) 7.44-7.51 (m, 1H) 7.27-7.34 (m, 1H) 5.07 (s, 1H) 4.24 (s, 4H) 3.58 -3.69 (m, 6H) 1.79 (s, 3H) 1.68-1.77 (m, 9H) 1.36-1.50 (m, 12H). FXR EC50 (nM) = 1302. MS (ESI) 651 (M+H).

The following compounds were synthesized according to the general method described for the synthesis of Example 586, replacing intermediate 641A and the corresponding amines where necessary.

Etc. No. Structure MS (ESI) (M+H) FXR ec ₅₀ (hM) 642 °sV A /x^ 1-1 s X ^NN rAl H ₃ C n 1 \ _gn Lx *x Dx ,3 f ] Ύ yA ^F DdAA No ^Z CH ₃ n ₃ s. JL J-V 653 294 643 C~N nVa ^but “V /LL Αχ/Ν r ⁿ z F ₃ C ί| η |f Ν—£-F DdAA ^Ν 'Ο CH ₃ H ₃ c^JLV ^but 1n ₃ 645 235

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644 0 °Cl a YAN'AN ^H A. ΙΛ.Ν СИз f I Ύ yV ^жА-А ^N 'O CH ₃ H ₃ C. JL J 653 743 645 0 Ρ ₃ Ο^νΆ As, AA ⁿ / ^СНз II A yv ^F zYA Nq ^Z ch ₃ H ₃ C. JL J -ΪΑ 672 229 646 0 HO NN F ^FH A kA.N рНз Ii η Ύ yA ^F хчАА ^ν ό ch ₃ h ₃ c^X^J ^but 1н ₃ 615 270 647 BUT. 0 \ / ^Н А=х kXk/N СНз ⁰ ί Ί A Yv ^F ЖуАка ^N 'O СН ₃ HO^Jl^iJ ^НзС СН ₃ 649 581 648 ^but huLuu, Η Αϊ>. \Α\^Ν рНз [II Ύ у-А ^уА<А ^Ν 'Ο CH ₃ n ₃ s. AJ ⁿ °k/ 591 509

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649 ι ί Γ°\ Ο ο \ / Μ < \=/ τζ \ ₄ )=ο Ο ^-2 ? O L Ζ ^Ζ -Π'Ί^ ⁰ Ο τ co 634 600 650 ο Μγγο OH Η ϊ Cui Ν ₄ \ |Ι V /0 Ν=/ ΜΙ A~ ^sn z H ₃ Cyx4Y H ₃ c F ^HO CH3 633 472 642 Ή NMR (400 MHz, DMS0-d ₆ ) δ 7.62-7.66 (m, 2H) 7.54-7.61 (m, 4H) 7.50 (t, J= 7.70 Hz, 1H) 7.31 (d, J= 8.07 Hz, 1H) 5.86 (t, J= 6.11 Hz, 1H) 5.06 (s, 1H) 3.55-3.65 (m, 4H) 2.98 (s, 3H) 1.79 (s, 3H) 1.70-1.78 (m, 9H) 1.36-1.50 (m , 12H) 1.13-1.19 (m, 2H) 1.01-1.06 (m, 2H) 643 Ή NMR (400 MHz, DMS0-d ₆ ) δ 7.63 (d, J= 8.56 Hz, 3H) 7.58 (s, 1H) 7.537.57 (m, 2H) 7.46-7.52 (m, 1H) 7.34 (d, J = 7.83 Hz, 1H) 7.06 (s, 1H) 5.07 (s, 1H) 3.61 (s, 2H) 3.51 (s, 4H) 1.79 (s, 3H) 1.68-1.77 (m, 9H) 1.39-1.50 (m, 12H) 644 Ή NMR (400 MHz, DMS0-d ₆ ) δ 7.65-7.59 (m, 2H), 7.56 (d, J= 7.8 Hz, 3H), 7.53-7.49 (m, 1H), 7.48-7.41 (m, 1H) , 7.28 (d, 7=8.1 Hz, 1H), 5.86 (d, 7=7.8 Hz, 1H), 5.05 (s, 1H), 3.93-3.81 (m, 1H), 3.61 (s, 2H), 3.29- 3.16 (m, 2H), 2.97 (br d, J= 11.5 Hz, 2H), 2.04-1.90 (m, 4H), 1.79 (s, 3H), 1.77-1.64 (m, 9H), 1.46 (s, 6H ), 1.45-1.33 (m, 6H) 645 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.57 (s, 4H), 7.45-7.37 (m, 1H), 7.37-7.29 (m, 1H), 7.20 (s, 1H), 7.04-6.91 (m, 1H), 5.06 (s, 1H), 3.50 (s, 2H), 3.23 (br d, J= 4.6 Hz, 4H), 3.13 (q, J= 10.3 Hz, 2H), 2.48-2.43 (m, 4H) , 1.90-1.79 (m, 9H), 1.76 (s, 3H), 1.63-1.52 (m, 6H), 1.46 (s, 6H) 646 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.61 (m, 2H), 7.61-7.54 (m, 4H), 7.547.46 (m, 1H), 7.32 (br d, J= 7.8 Hz, 1H ), 5.95 (t, J= 6.0 Hz, 1H), 5.39 (t, J = 6.6 Hz, 1H), 5.07 (s, 1H), 3.69-3.60 (m, 2H), 3.60-3.44 (m, 4H) , 1.79 (s, 3H), 1.73 (s, 9H), 1.52-1.36 (m, 12H)

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647 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.60 (m, 2H), 7.60-7.53 (m, 4H), 7.537.43 (m, 1H), 7.31 (br d, J= 7.8 Hz, 1H ), 5.75 (t, J= 5.9 Hz, 1H), 5.07 (s, 1H), 4.65 (t, J= 5.7 Hz, 1H), 3.61 (s, 2H), 3.57-3.45 (m, 4H), 3.18 (dd, J= 1.7, 5.6 Hz, 2H), 3.11 (br d, J= 5.6 Hz, 2H), 1.79 (s, 3H), 1.77-1.61 (m, 9H), 1.51-1.34 (m, 12H) , 1.31-1.19 (m, 4H) 648 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.59 (m, 3H), 7.55 (d, J= 8.6 Hz, 3H), 7.52-7.45 (m, 1H), 7.33 (d, J= 7.8 Hz , 1H), 5.51 (t, J= 5.6 Hz, 1H), 5.29 (s, 1H), 5.06 (s, 1H), 3.62 (s, 2H), 3.17 (d, J= 5.6 Hz, 2H), 1.78 (s, 3H), 1.76-1.68 (m, 9H), 1.45 (s, 6H), 1.44-1.36 (m, 6H), 0.55-0.28 (m, 4H) 649 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.47 (m, 7H), 7.35-7.30 (m, 1H), 5.545.47 (m, 1H), 5.04 (s, 1H), 3.63-3.58 ( m, 2H), 3.35 (br s, 4H), 3.14-3.03 (m, 2H), 2.32-2.20 (m, 6H), 1.80-1.66 (m, 12H), 1.48-1.36 (m, 12H) 650 Ή NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.60 (m, 2H), 7.56-7.42 (m, 5H), 7.307.24 (m, 1H), 5.67-5.60 (m, 1H), 5.05 ( s, 1H), 4.06 (s, 1H), 3.59 (s, 2H), 3.14 (q, J= 6.3 Hz, 2H), 1.80-1.67 (m, 12H), 1.65-1.51 (m, 4H), 1.50 -1.34 (m, 18H)

Example 651.

\-(4'-((2-cyanopro11an-2-yl)o1<ci)-[1,1 '-biphenyl]-3 -yl)-U-((4-(5-(2-fluoropropan-2 -yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4-(2-hydroxypropan-2-yl)piperidin-1-carboxamide

Step A: Intermediate 651A. Preparation of ethyl 1-((3-bromophenyl)((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )-carbamoyl) piperidine-4carboxylate

The title compound was prepared according to the general method described for the synthesis of Example 586 by replacing intermediate 632A and ethyl piperidine-4carboxylate where needed: (160 mg, 0.264 mmol, 80% yield) as a brown solid. MS (ESI) 605 (M+H).

Stage B. Intermediate 651B. Preparation of Ch-(3-bromophenyl)-Ch-((4-(5-(2-fluoropropan2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)-4-(2-hydroxypropan-2-yl)piperidin-1carboxamide

To a stirred solution of intermediate 651A (160 mg, 0.264 mmol) in THF (2 mL) was added methyl magnesium bromide in diethyl ether (3M) (0.264 mL, 0.793 mmol) dropwise at 20°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture

- 450 047337 was quenched with saturated aqueous ammonium chloride, diluted with water (30 ml) and extracted with ethyl acetate (2x15 ml). The combined organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column, 4 g, conditions: 30% ethyl acetate in petroleum ether) to give the title compound (white solid, 120 mg, 0.203 mmol, 77% yield). MS (ESI) 591 (M+H).

Step C. Example 651. Preparation of D-(4'-((2-cyanopropan-2-yl)oxy)-[1,G-biphenyl]-3-yl)-D-((4-(5(2- fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]-octan-1-yl)methyl)-4-(2-hydroxypropan-2yl)piperidin-1-carboxamide

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 651B and the corresponding boronate ester where necessary: (3.4 mg, 4.91 μmol, 12% yield).

1H NMR (DMSO-d ₆ ) δ 7.73-7.59 (m, 2H), 7.45-7.37 (m, 1H), 7.36-7.31 (m, 1H), 7.30-7.22 (m, 2H), 7.18 (s, 1H ), 7.04-6.94 (m, 1H), 4.07 (s, 1H), 4.00-3.91 (m, 2H), 3.53-3.42 (m, 2H), 2.53 (br s, 1H), 1.91-1.79 (m, 9H), 1.78-1.65 (m, 9H), 1.63-1.46 (m, 8H), 1.33-1.18 (m, 2H), 1.00-0.78 (m, 8H). FXR EC ₅₀ (nM) = 273. MS (ESI) 672 (M+H).

Example 652.

1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1-(4'isopropoxy - [1,1'-biphenyl]-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea

Step A: Intermediate 652A. Preparation of D-((4-(5-(1,1-difluoroethyl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-4'-isopropoxy-[1 ,1'-biphenyl]-3-amine

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 628A and the corresponding boronic acid where necessary: (210 mg, 0.386 mmol, 93% yield). MS (ESI) 481 (M+H).

Step B. Example 652. Preparation of 1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)-1 -(4'-isopropoxy-[1,1'-biphenyl]-3-yl)-3-(tetrahydro-2H-pyran-4 yl)urea

The title compound was prepared according to the general method described for the synthesis of Example 586, by replacing intermediate 652A and tetrahydro-2H-pyran-4-amine where necessary: (3.4 mg, 4.91 µmol, yield 12%).

1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=8.56 Hz, 2H) 7.54 (s, 1H) 7.42-7.51 (m, 2H) 7.25 (d, J=7.58 Hz, 1H) 7.01 ( d, J=8.80 Hz, 2H) 5.38 (d, J=7.83 Hz, 1H) 4.67 (quin, J=5.99 Hz, 1H) 3.76 (br d, J=10.52 Hz, 2H) 3.59-3.70 (m, 3H ) 3.29 (d, J=1.71 Hz, 1H) 3.27 (s, 1H) 2.18 (s, 1H) 2.13 (s, 1H) 2.08 (s, 1H) 1.71-1.80 (m, 6H) 1.60-1.69 (m, 2H) 1.31-1.46 (m, 8H) 1.29 (d, J=6.11 Hz, 6H). FXR EC ₅₀ (nM) = 379. MS (ESI) 609 (M+H).

Example 653.

-((trans)-4-(difluoromethoxy)-4-methylcyclohexyl)-1 -(6-fluoro-4'-isopropoxy-[1,1'-biphenyl]-3 -yl)1-((4-(5 -(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea -F

CH ₃

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Step A: Intermediate 653A. Preparation of 1-(3-bromo-4-fluorophenyl)-1-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane- 1-yl)methyl)-3-((trans)-4-hydroxy-4methylcyclohexyl)urea

The title compound was prepared according to the general method described for the synthesis of Example 586, by replacing intermediate 582A and (trans)-4-amino-1methylcyclohexan-1-ol where necessary: (400 mg, 0.672 mmol, yield 75%) as an off-white solid. MS (ESI) 595(M+H).

Stage B. Intermediate 653B. Preparation of 1-(3-bromo-4-fluorophenyl)-3-((trans)-4(difluoromethoxy)-4-methylcyclohexyl)-1-((4-(5-(2-fluoropropan-2-yl)-1 ,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

Copper iodide (£ (9.59 mg, 0.050 mmol) was added to a stirred solution of intermediate 653A (150 mg, 0.252 mmol) in MeCN (15 ml). The reaction mixture was heated at 50°C. The solution was added dropwise over 5 minutes 2,2-difluoro-2-(fluorosulfonyl)acetic acid (67.3 mg, 0.378 mmol) in 2 ml acetonitrile. The reaction mixture was heated at 50°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate. (20 ml) and the insoluble solid was filtered off. The resulting EtOAc solution was concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography (silica gel column, 12 g, conditions: 30% ethyl acetate in petroleum ether) to obtain the title. compound (off-white semi-solid, 80 mg, 0.124 mmol, 49% yield MS (ESI) 645 (M+H).

Step C. Example 654. Preparation of 3-((trans)-4-(difluoromethoxy)-4-methylcyclohexyl)-1-(6-fluoro-4'isopropoxy-[1,1'-biphenyl]-3-yl)- 1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 653B and the corresponding boronic acid where necessary: (5.8 mg, 8.28 μmol, 18% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.62-7.44 (m, 2H), 7.40 (q, J=6.7 Hz, 1H), 7.35-7.20 (m, 2H), 7.17-6.98 (m, 2H) , 6.98-6.47 (m, 1H), 5.46-5.19 (m, 1H), 4.74-4.53 (m, 1H), 3.61-3.46 (m, 3H), 1.88-1.68 (m, 12H), 1.681.47 ( m, 6H), 1.47-1.33 (m, 8H), 1.33-1.13 (m, 9H). FXR EC ₅₀ (nM) = 145. MS (ESI) 701 (M+H).

Example 654.

(cis)<Ni-(4'-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)-[1,G-biphenyl]-3-yl)4N-((4- (5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3(trifluoromethyl)cyclobutan-1- carboxamide

Step A: Intermediate 654A. Preparation of (cis)-No-(4'-((2-cyanopropan-2-yl)oxy)[1,1'-biphenyl]-3 -yl)-No-((4-(5-(2-fluoropropane) -2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo[2.2.2]octan-1 yl)methyl)-3-hydroxy-3-(trifluoromethyl)-cyclobutane-1-carboxamide

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The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 576G and the corresponding boronate ester where necessary: (35 mg, 0.052 mmol, 77% yield). MS (ESI) 669 (M+H).

Step B. Example 654. Preparation of (cis)<No-(4'-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)-[1,Hbiphenyl]-3-yl)-No -((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3hydroxy-3 -( trifluoromethyl)cyclobutane-1-carboxamide

To a stirred solution of intermediate 654A (30 mg, 0.045 mmol) in DMSO (1 ml) was added K ₂ CO ₃ (18.60 mg, 0.135 mmol) followed by H ₂ O ₂ (0.023 ml, 0.224 mmol) at 10° WITH. The reaction mixture was stirred at 10°C for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative LC/MS using the following conditions: column: Waters XBridge C18, 19x150 mm, 5 µm; mobile phase A: 10 mM ammonium acetate; mobile phase B: acetonitrile; gradient: 20-75% B for 25 minutes, then hold at 100% B for 5 minutes; flow rate: 15 ml/min. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (15.3 mg, 0.124 mmol, 50% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.70-7.62 (m, 3H), 7.60 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.48 (t, J=7.8 Hz, 1H ), 7.36-7.23 (m, 2H), 7.03-6.91 (m, 2H), 6.51 (s, 1H), 3.76-3.57 (m, 2H), 2.84 (quin, J=8.9 Hz, 1H), 2.38- 2.27 (m, 2H), 2.13-1.96 (m, 2H), 1.82-1.67 (m, 12H), 1.53-1.36 (m, 12H). FXR EC ₅₀ (nM) = 169. MS (ESI) 687 (M+H).

Example 655.

1,1,1 -trifluoro-2-methylpropan-2-yl((4-(3-( 1 -fluorocyclopropyl)-1 -methyl-1 H-pyrazol-5yl)bicyclo[2.2.2]octan-1-yl )methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

Step A: Intermediate 655A. Preparation of methyl 4-(1hydroxyethyl)bicyclo[2.2.2]octane-1-carboxylate

H ₃ C /—< O but ⁷ '—' O-CH3

To a stirred solution of intermediate 88B (500 mg, 2.55 mmol) in THF (5 mL) was added methyl magnesium bromide (3.4 M in diethyl ether) (0.899 mL, 3.06 mmol) dropwise at 0° C. The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column, 12 g, conditions: 40% ethyl acetate in petroleum ether) to give the title compound (brown solid, 350 mg, 1.649 mmol, 64.7% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 4.23 (d, J=5.10 Hz, 1H), 3.57 (s, 3H), 3.19 (m, 1H), 1.63-2.00 (m, 6H), 1.30-1.44 (m, 6H), 0.92 (d, J=6.30 Hz, 3H).

Stage B. 655V Intermediate. Preparation of methyl 4-acetylbicyclo[2.2.2]octane-1carboxylate |H ₃ C /—\O

O ⁷ '—' O-CHz

The title compound was synthesized according to the general method described for the synthesis of intermediate 3C, replacing intermediate 655A where necessary: (250 mg, 1.189 mmol, 70% yield) as an off-white solid.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 3.61-3.54 (s, 3H), 2.06-2.01 (s, 3H), 1.75-1.58 (m, 12H).

Step C. Intermediate 655C. Preparation of methyl 4-(3-(1-fluorocyclopropyl)-3oxopropanoyl)bicyclo[2.2.2]octane-1-carboxylate

ABOUT

To a stirred solution of 1-fluorocyclopropane-1-carboxylic acid (0.916 g, 8.80 mmol) in THF (18.5 mL) was added 1-chloro-HH2-trimethyl-1-propenylamine (3.03 mL, 22.88 mmol ) at room temperature. The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was co-distilled with DCM twice to give 1-fluorocyclopropane-1-carbonyl chloride (1.5 g, 6.63 mmol) as an off-white solid.

Intermediate 655B (1.85 g, 8.80 mmol) was added to a stirred solution of LiHMDS (26.4 mL, 26.4 mmol) in THF at -78°C and the reaction mixture was stirred at -78°C for 1 hour A solution of 1-fluorocyclopropane-1-carbonyl chloride (1.5 g, 6.63 mmol) in tetrahydrofuran (18.5 ml) was added to the reaction mixture and stirred for an additional 1 hour at -78°C. The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride (20 ml). The reaction mixture was extracted with EtOAc (2x50 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (12 g silica gel cartridge; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 12 ml/min) to give the title compound (1.9 g, 6.41 mmol, 73% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.59 (s, 3H), 3.58 (s, 2H), 1.76-1.70 (m, 12H), 1.54-1.45 (m, 2H), 1.381.31 (m, 2H).

Stage D. Intermediate connection of 655D1 and 655D2. Preparation of methyl 4-(5-(1fluorocyclopropyl)-1-methyl-III-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate (655D1) and methyl 4-(3(1-fluorocyclopropyl)-1 -methyl-1 H-pyrazol-5-yl)bicyclo[2.2.2]-octane-1-carboxylate (655D2)

To a solution of intermediate 655C (1.0 g, 3.37 mmol) in IPA (10 ml) was added dropwise at 0°C methylhydrazine sulfate (0.584, 4.05 mmol) followed by TEA (1.411 ml, 10.12 mmol). The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was poured into water (15 ml) and extracted with EtOAc (25 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 12 ml/min). The purified fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compounds. The first isomer eluted was methyl 4-(5-(1-fluorocyclopropyl)-1methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate (655D1) (100 mg, 0.326 mmol, yield 10 %). MS (ESI) 307 (M + H) (RT = 0.78 min or peak-1).

The second isomer eluted was methyl 4-(3-(1-fluorocyclopropyl)-1-methyl-Spirazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate (655D2) (900 mg, 2.94 mmol, yield 87%). MS (ESI) 307 (M + N). (RT = 0.82 min or peak-2).

Step E. Intermediate 655E. Preparation of (4-(3-(1-fluorocyclopropyl)-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanol

The title compound was synthesized according to the general method described for the synthesis of intermediate 1G, replacing intermediate 655D2 where necessary: (720 mg, 2.59 mmol, 79% yield) as an off-white solid.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 6.19-6.15 (m, 1H), 4.33-4.29 (m, 1H), 3.85-3.80 (m, 3H), 3.09-3.02 (m, 2H), 1.73- 1.65 (m, 6H), 1.45-1.32 (m, 8H), 1.10-0.99 (m, 2H). MS (ESI) 279 (M+H).

Stage F. Intermediate 655F. Preparation of 4-(3-(1-fluorocyclopropyl)-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

H ₃ C

The title compound was synthesized according to the general method described for the synthesis of intermediate 3C, replacing intermediate 655E where necessary: (470 mg, 1.701 mmol, 68% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ 9.45-9.42 (m, 1H), 6.20 (d, J=2.5 Hz, 1H), 3.84 (d, J=1.0 Hz, 3H), 1.801.71 (m, 6H), 1.67-1.59 (m, 6H), 1.45-1.35 (m, 2H), 1.11-1.04 (m, 2H).

Stage G. Intermediate 655G. Preparation of 3-bromo-N-((4-(3-(1-fluorocyclopropyl)-1methyl-III-pyrazol^-yl^icyclo^^^octane-PilDethyl^niline

The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 655F and 3-bromoaniline where needed: (150 mg, 0.347 mmol, 33% yield) as an off-white solid. MS (ESI) 432 (M+H).

Stage H. Intermediate 655H. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (3bromophenyl)((4-(3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2] octan-1yl)methyl)carbamate

The indicated compound was synthesized in accordance with the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 655G where necessary: ( brown solid, 60 mg, 0.102 mmol, 74% yield). MS (ESI) 586 (M+H).

Step I. Example 655. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-(1-fluorocyclopropyl)-1methyl-III-pyrazol-5-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)(4'-isopropoxy-[1,G-biphenyl]-3-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 655H and the corresponding boronic acid where necessary: (10 mg, 0.016 mmol, 31% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.51 (m, 3H), 7.48-7.43 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.29-7.19 (m, 1H) , 7.00 (d, J=8.8 Hz, 2H), 6.12 (d, J=2.2 Hz, 1H), 4.70-4.61 (m, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 1.69- 1.56 (m, 12H), 1.46-1.16 (m, 14H), 1.08-0.98 (m, 2H). FXR EC ₅₀ (nM) 819; MS (ESI) 642 (M+H).

Example 656.

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)isoxazol-3-yl)bicyclo[2.2.2]octan-1yl)methyl)(4 '-isopropoxy-[1,1 '-biphenyl]-3-yl)carbamate

Step A: Intermediate 656A. Preparation of methyl 4-(4,4-difluoro-3oxopentanoyl)bicyclo[2.2.2]octane-1-carboxylate

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The compound was synthesized according to the general method described for the synthesis of intermediate 655C by replacing intermediate 655B and 2,2difluoropropanoyl chloride where needed: (500 mg, 1.654 mmol, 87% yield) as a gummy liquid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.59 (s, 3H), 1.85-1.58 (m, 15H), 2H hidden under the moisture peak. MS (ESI) 303 (M+H).

Stage B. Intermediate connection 656B1 & 656B2. Preparation of methyl 4-(5-(1,1-difluoroethyl)-5hydroxy-4,5-dihydroisoxazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate 656B1 and methyl 4-(3-(1,1difluoroethyl) )-5-hydroxy-4,5-dihydroisoxazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate (656B2)

To a solution of intermediate 656A (1.0 g, 3.31 mmol) in IPA (10 mL) was added hydroxylamine hydrochloride (0.276 g, 3.97 mmol) followed by TEA (1.383 mL, 9.92 mmol) dropwise at 0°C. The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (20 ml) and extracted

EtOAc (2 x 30 ml). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica gel cartridge; A = hexanes, B = EtOAc; 30 min gradient; 0% B to 40% B; flow rate = 12 mL/min).

The first isomer was methyl 4-(5-(1,1-difluoroethyl)-5-hydroxy-4,5-dihydroisoxazol-3yl)bicyclo[2.2.2]octane-1-carboxylate (656B1) (main peak) (830 mg , 2.62 mmol, yield 79%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J=1.00 Hz, 1 H) 3.58 (s, 3H) 3.20 (d, J=18.57 Hz, 1H) 2.82 (dd, J=18.32, 2.26 Hz, 1H) 1.56-1.81 (m, 15H). MS (ESI) 318 (M+H).

The second isomer was 4-(3-(1,1-difluoroethyl)-5-hydroxy-4,5-dihydroisoxazol-5yl)bicyclo[2.2.2]octane-1-carboxylate (656B2) (minor peak) (100 mg, 0.315 mmol, yield 10%).

1H NMR (400 MHz, DMSO-d ₆ ) 6.87 (s, 1H) 3.52-3.64 (s, 3H) 3.27 (s, 1H) 2.69 (d, J=19.07 Hz, 1H) 1.88 (t, J=19.07 Hz , 3H) 1.65-1.73 (m, 6H) 1.48-1.56 (m, 6H). MS (ESI) 318 (M+H).

Step C. Intermediate 656C. Preparation of methyl 4-(5-(1,1-difluoroethyl)isoxazol-3yl)bicyclo[2.2.2]octane-1-carboxylate

To a solution of intermediate 656B1 (750 mg, 2.363 mmol) in ACN (20 mL) was added triphenylphosphine (1302 mg, 4.96 mmol) followed by CCl ₄ (0.684 mL, 7.09 mmol) at room temperature. The reaction mixture was stirred for 1 hour at 90°C. The reaction mixture was poured into saturated aqueous ammonium chloride, diluted with water (15 ml) and extracted with EtOAc (2x25 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound: (425 mg, 1.420 mmol, 60% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.00-6.98 (m, 1H), 3.59 (s, 3H), 2.09-1.97 (m, 3H), 1.86-1.76 (m, 12H). MS (ESI) 300 (M+H).

Stage D. Intermediate 656D. Preparation of (4-(5-(1,1-difluoroethyl)isoxazol-3yl)bicyclo[2.2.2]octan-1-yl)methanol

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The title compound was synthesized according to the general method described for the synthesis of intermediate 1G, replacing intermediate 656C where necessary: (140 mg, 0.516 mmol, 52% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-de) δ 7.02-6.97 (m, 1H), 4.40 (t, J=5.5 Hz, 1H), 3.08 (d, J=5.5 Hz, 2H), 2.111.97 (m, 3H), 1.83-1.72 (m, 6H), 1.49-1.38 (m, 6H). MS (ESI) 272(M+H).

Step E. Intermediate 656E. Preparation of 4-(5-(1,1-difluoroethyl)isoxazol-3yl)bicyclo[2.2.2]octane-1-carbaldehyde

ХХДу] urn ₃ YH ^F No F

The title compound was synthesized according to the general method described for the synthesis of intermediate 3C, replacing intermediate 656D where necessary: (130 mg, 0.483 mmol, 44% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48-9.44 (m, 1H), 7.06-7.02 (m, 1H), 2.11-2.00 (m, 3H), 1.90-1.81 (m, 6H), 1.72- 1.63 (m, 6H).

Step F: Intermediate 656F. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)isoxazol3 -yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 656E and 3-bromoaniline where necessary: (60 mg, 0.141 mmol, 58% yield) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.02-6.94 (m, 2H), 6.80-6.75 (m, 1H), 6.63-6.53 (m, 2H), 5.80-5.74 (m, 1H), 2.80 ( d, J=5.9 Hz, 2H), 2.11-1.98 (m, 3H), 1.86-1.76 (m, 6H), 1.60-1.50 (m, 6H). MS (ESI) 427 (M+H).

Stage G. Intermediate 656G. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(3bromophenyl)((4-(5-(1,1-difluoroethyl)isoxazol-3-yl)bicyclo-[2.2.2]octane-1- yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 656F where necessary: ( solid, 100 mg, 0.173 mmol, yield 73%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.58 (m, 1H), 7.45-7.29 (m, 3H), 6.97-6.91 (m, 1H), 3.61-3.54 (m, 2H), 2.09- 1.95 (m, 3H), 1.79-1.68 (m, 6H), 1.65-1.59 (m, 6H), 1.42-1.31 (m, 6H). MS (ESI) 579 (M+H).

Step H. Example 656. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-(1,1difluoroethyl)isoxazol-3-yl)bicyclo[2.2.2]octane-1- yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3yl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149, replacing intermediate 656G and the corresponding boronic acid where necessary: (17.7 mg, 0.028 mmol, 54% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.66-7.50 (m, 3H), 7.50-7.44 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.27 (br d, J=2.2 Hz, 1H), 7.06-6.97 (m, 2H), 6.95-6.88 (m, 1H), 4.67 (td, J=6.1, 12.0 Hz, 1H), 3.63 (s, 2H), 2.02 (t, J= 19.2 Hz, 3H), 1.79-1.54 (m, 12H), 1.51-1.35 (m, 6H), 1.29 (d, J=6.1 Hz, 6H). FXR EC50 (nM) 1063; MS (ESI) 635 (M+H).

Example 657.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octane-1 - yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate

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Stage A. Intermediate 657A1 and 657A2. Preparation of methyl 4-(5-(1,1-difluoroethyl)-1methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate and methyl 4-(3-(1,1-difluoroethyl) -1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octane-1-carboxylate

To a solution of intermediate 656A (2.0 g, 6.62 mmol) in IPA (15 mL) was added methylhydrazine sulfate (1.144 g, 7.94 mmol) followed by TEA (2.77 mL, 19.85 mmol) at drops at 0°C. The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (30 ml) and extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (silica gel cartridge, 40 g; A = hexanes, B = EtOAc; gradient 30 minutes; 0% B to 10% B; flow rate = 40 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compounds.

The first isomer eluted was methyl 4-(5-(1,1-difluoroethyl)-1-methyl-III-pyrazol-3yl)bicyclo[2.2.2]octane-1-carboxylate (657A1) (550 mg, 1.761 mmol, yield 27%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.46-6.37 (m, 1H), 3.83 (s, 3H), 3.64-3.54 (m, 3H), 2.09-1.95 (m, 3H), 1.77 (s, 12H). MS (ESI) 313 (M+H) (RT = 1.72 min or peak-1).

The second eluted isomer was methyl 4-(3-(1,1-difluoroethyl)-1-methyl-III-pyrazol-5yl)bicyclo[2.2.2]octane-1-carboxylate (657A2) (950 mg, 3.04 mmol , yield 46%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 6.21 (s, 1H), 3.91 (s, 3H), 3.60 (s, 3H), 1.91 (s, 3H), 1.88-1.75 (m, 12H). MS (ESI) 313 (M+H) (RT = 1.65 min or peak-2).

Stage B. Intermediate 657B. Preparation of (4-(3-(1,1-difluoroethyl)-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanol

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 1G, by replacing intermediate 657A2 where necessary: (0.42 g, 1.477 mmol, 49% yield) as a colorless liquid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.20-6.16 (m, 1H), 4.43-4.38 (m, 1H), 3.91 (s, 3H), 3.08 (d, J=5.6 Hz, 2H), 1.98-1.86 (m, 3H), 1.86-1.78 (m, 6H), 1.49-1.40 (m, 6H).

Step C. Intermediate 657C. Preparation of 4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol5-yl)bicyclo[2.2.2]octane-1-carbaldehyde

The title compound was synthesized according to the general method described for the synthesis of intermediate 3C, replacing intermediate 657B where necessary: (0.4 g, 1.417 mmol, 50% yield) as a white resinous solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48-9.44 (m, 1H), 6.22 (s, 1H), 3.92 (s, 3H), 1.99-1.91 (m, 3H), 1.901.81 (m, 6H), 1.72-1.65 (m, 6H).

Stage D. Intermediate 657D. Preparation of 4-bromo-K-((4-(3-(1,1-difluoroethyl)-1-methyl1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2- amine

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The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 657C and 4-bromopyridin-2amine where needed: (290 mg, 0.660 mmol, 93% yield) as an off-white solid substances

Ή NMR (400 MHz, chloroform-d) δ 7.94-7.87 (m, 1H), 6.84-6.78 (m, 1H), 6.74-6.70 (m, 1H), 6.59 (d, J=1.5 Hz, 1H), 6.20-6.15 (m, 1H), 4.00-3.96 (m, 3H), 3.10 (d, J=6.0 Hz, 2H), 2.11-1.99 (m, 3H), 1.98-1.88 (m, 6H), 1.67- 1.53 (m, 6H).

Step E. Intermediate 657E. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4bromopyridin-2-yl)((4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl) bicyclo[2.2.2]octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 657D where necessary: ( solid, 0.1 g, 0.169 mmol, yield 74%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.32-8.28 (m, 1H), 7.79 (s, 1H), 7.52-7.48 (m, 1H), 6.13 (s, 1H), 3.873.82 (m, 5H), 1.89-1.84 (m, 3H), 1.79-1.72 (m, 6H), 1.69 (s, 6H), 1.38-1.31 (m, 6H). MS (ESI) 593 (M+H).

Step F Example 657 Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-(1,1-difluoroethyl)-1methyl-1H-pyrazol-5-yl)bicyclo[2.2 .2]octan-1-yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2yl)carbamate

This compound was synthesized according to the general method described for the synthesis of Example 149, by replacing intermediate 657E and the corresponding boronic acid where necessary: (15.9 mg, 0.025 mmol, 49% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.40 (d, J=5.4 Hz, 1H), 7.81-7.63 (m, 3H), 7.52 (dd, J=1.5, 5.4 Hz, 1H), 7.07 (d , J=8.8 Hz, 2H), 6.11 (s, 1H), 4.72 (td, J=6.0, 12.0 Hz, 1H), 3.89-3.73 (m, 5H), 1.88 (t, J=18.7 Hz, 3H) , 1.79-1.62 (m, 12H), 1.44-1.33 (m, 6H), 1.30 (d, J=5.9 Hz, 6H). FXR EC50 (nM) 67; MS (ESI) 649 (M+H).

Example 658.

1,1,1-trifluoro-2-methylpropan-2-yl((4-(5-( 1,1-difluoroethyl)-1 -methyl-1H-pyrazol-3 yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

Step A: Intermediate 658A. Preparation of (4-(5-(1,1-difluoroethyl)-1-methyl-1Hpyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol

NO'DuD < A /k R ⁿ z pu-A Nn F

CH ₃

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 1G, by replacing intermediate 657A1 where necessary: (0.41 g, 1.442 mmol, 85% yield) as a colorless liquid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 6.43-6.37 (m, 1H), 4.37-4.30 (m, 1H), 3.83 (s, 3H), 3.06 (d, J=5.5 Hz, 2H), 2.04 (t, J=19.1 Hz, 3H), 1.77-1.66 (m, 6H), 1.45-1.36 (m, 6H).

Stage B. Intermediate 658B. Preparation of 4-(5-(1,1-difluoroethyl)-1-methyl-1H-pyrazol3 -yl)bicyclo[2.2.2]octane-1-carbaldehyde

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The title compound was synthesized according to the general method described for the synthesis of intermediate 3C, replacing intermediate 658A where necessary: (0.22 g, 0.779 mmol, 55% yield) as a gummy white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.47-9.44 (m, 1H), 6.46-6.43 (m, 1H), 3.85 (s, 3H), 2.10-1.98 (m, 3H), 1.81-1.74 (m, 6H), 1.69-1.60 (m, 6H).

Step C. Intermediate 658C. Preparation of 3-bromo-N-((4-(5-(1,1-difluoroethyl)-1-methylN-pyrazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 658B and 3-bromoaniline where needed: (162 mg, 0.370 mmol, 87% yield) as an off-white solid. MS (ESI) 438 (M+H).

^1H NMR (400 MHz, chloroform-d) δ 7.04-6.98 (m, 1H), 6.90-6.83 (m, 1H), 6.81-6.75 (m, 2H), 6.55-6.48 (m, 1H), 6.17 ( t, J=1.5 Hz, 1H), 3.98 (s, 3H), 2.88 (s, 2H), 2.09-1.96 (m, 3H), 1.91-1.84 (m, 6H), 1.63-1.55 (m, 6H) .

Stage D. Intermediate 658D. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (3bromophenyl)((4-(5-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2. 2]octan-1-yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 658C where necessary: ( solid, 100 mg, 0.169 mmol, yield 74%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.60 (br s, 1H), 7.47-7.35 (m, 2H), 7.35-7.22 (m, 1H), 6.37 (s, 1H), 3.81 (s, 3H), 3.62-3.51 (m, 2H), 2.02 (t, J=19.0 Hz, 3H), 1.74-1.55 (m, 12H), 1.41-1.25 (m, 6H). MS (ESI) 592 (M+H).

Step E. Example 658. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(5-(1,1-difluoroethyl)-1methyl-1H-pyrazol-3-yl)bicyclo[2.2 .2]octan-1-yl)methyl)(4'-isopropoxy-[1,1'-biphenyl]-3-yl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 658D and the corresponding boronic acid where necessary: (13 mg, 0.020 mmol, 40% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67-7.50 (m, 3H), 7.49-7.43 (m, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.32-7.20 (m, 1H ), 7.07-6.88 (m, 2H), 6.36 (s, 1H),4.67 (m, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 2.01 (t, J=19.0 Hz, 3H) , 1.761.52 (m, 12H), 1.44-1.32 (m, 6H), 1.29 (d, J=5.9 Hz, 6H). FXR EC50 (nM) 917; MS (ESI) 648 (M+H).

Example 659.

3-(tert-butyl)-1-((4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1yl)methyl)- 1-(4'-isopropoxy-[1,1'-biphenyl]-3-yl)urea

Step A: Intermediate 659A. Preparation of 3-bromo-N-((4-(3-(1,1-difluoroethyl)-1-methyl1H-pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

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The title compound was synthesized according to the general method described for the synthesis of intermediate 1I by replacing intermediate 657C and 3-bromoaniline where needed: (290 mg, 0.660 mmol, 93% yield) as an off-white solid. MS (ESI) 438 (M+H).

Stage B. Intermediate 659B. Preparation of 1-(3-bromophenyl)-3-(tert-butyl)-1-((4-(3(1,1-difluoroethyl)-1 -methyl-1 H-pyrazol-5-yl)bicyclo [2.2. 2]octan-1-yl)methyl)urea

The title compound was prepared according to the general method described for the synthesis of Example 586, by replacing intermediate 659A and 2-methylpropan-2-amine where necessary: (90 mg, 0.167 mmol, 92% yield) as crude -white solid. MS (ESI) 537 (M+H).

Step C. Example 659. Preparation of 3-(tert-butyl)-1-((4-(3-(1,1-difluoroethyl)-1-methyl-III-pyrazol-5yl)bicyclo[2.2.2]octane- 1-yl)methyl)-1-(4'-isopropoxy-[1,1'-biphenyl]-3-yl)urea

This compound was synthesized according to the general method described for the synthesis of Example 149, replacing intermediate 659B and the corresponding boronic acid where necessary: (14.4 mg, 0.024 mmol, 44% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.65-7.58 (m, 2H), 7.56-7.52 (m, 1H), 7.51-7.41 (m, 2H), 7.26 (d, J=8.1 Hz, 1H) , 7.01 (d, J=8.8 Hz, 2H), 6.13 (s, 1H), 4.76-4.63 (m, 2H), 3.86 (s, 3H), 3.58 (s, 2H), 1.96-1.82 (m, 3H ), 1.79-1.70 (m, 6H), 1.47-1.36 (m, 6H), 1.29 (d, J=6.1 Hz, 6H), 1.20 (s, 9H). FXR EC50 (nM) 53; MS (ESI) 593 (M+H).

Example 660.

3-(tert-butyl)-1-(5-(4-(difluoromethoxy)phenyl)pyridazin-3-yl)-1-((4-(5-(2-fluoropropan-2-yl)-1,2 ,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)urea

Stage A. Intermediate 660A. Preparation of 2-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)isoindolin-1,3- Diona

To a stirred solution of intermediate 576D (500 mg, 1.863 mmol) in THF (10 mL) was added isoindoline-1,3-dione (0.302 g, 2.050 mmol), triphenylphosphine (0.977 g, 3.73 mmol), followed by DIAD ( 1.087 ml, 5.59 mmol) at 0°C. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM (30 ml) and washed with saturated sodium bicarbonate solution (2x15 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (40 g silica gel cartridge; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 30% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound: (0.5 g, 1.258 mmol, 68% yield). MS (ESI) 398 (M+H).

Stage B. Intermediate connection 660V. Preparation of (4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanamine

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To a stirred solution of intermediate 660A (500 mg, 1.258 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.611 mL, 12.58 mmol) at room temperature. The reaction mixture was refluxed for 12 hours. The reaction mixture was filtered and washed with ethanol. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (335 mg, 1.25 mmol, 67% yield) as a semi-solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 2.28-2.22 (m, 2H), 1.85-1.74 (m, 6H), 1.47-1.35 (m, 6H), 1.22-1.05 (m, 6H).

Step C. Intermediate 660C. Preparation of 3-chloro-5-(4(difluoromethoxy)phenyl)pyridazine

FCI

DdudCh \=/ \= _N

To a stirred solution of 3,5-dichloropyridazine (100 mg, 0.671 mmol) in toluene (2 ml) was added (4-(difluoromethoxy)phenyl)boronic acid (107 mg, 0.571 mmol) and potassium phosphate (285 mg, 1.343 mmol). The resulting reaction mixture was degassed and refilled with argon and bis(tri-tert-butylphosphine)-palladium(0) (34.3 mg, 0.067 mmol) was added. The reaction mixture was heated at 75°C for 12 hours. The reaction mixture was concentrated under reduced pressure; the residue was diluted with water (10 ml) and extracted with EtOAc (2x15 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound: (25 mg, 0.097 mmol, 15% yield). MS (ESI) 257 (M+H).

Stage D. Intermediate 660D. Preparation of 5-(4-(difluoromethoxy)-phenyl)-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane- 1-yl)methyl)pyridazin-3-amine

To a stirred solution of intermediate 660C (100 mg, 0.390 mmol) in toluene (2 ml) was added intermediate 660B (104 mg, 0.390 mmol) and sodium t-butoxide (112 mg, 1.169 mmol). The resulting reaction mixture was degassed and refilled with argon and Pd ₂ (dba) ₃ (35.7 mg, 0.039 mmol) and t-Bu Xphos (33.1 mg, 0.078 mmol) were added. The reaction mixture was heated at 110°C for 12 hours. The reaction mixture was concentrated under reduced pressure; the residue was diluted with water (10 ml) and extracted with EtOAc (2x15 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound: (80 mg, 0.164 mmol, 42% yield). MS (ESI) 488 (M+H).

Step E. Example 660. Preparation of X((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl)- N-(4'-(2-hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-2-thia-6azaspiro[3.3]heptan-6-carboxamide 2,2-dioxide

The title compound was prepared according to the general method described for the synthesis of Example 586, replacing intermediate 660D and 2-methylpropan-2-amine where necessary: (2.8 mg, 4.58 µmol, 7% yield ).

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (d, J=1.7 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.83-7.76 (m, 1H ), 7.61-7.13 (m, 2H), 7.07 (d, J=2.0 Hz, 1H), 6.80-6.69 (m, 1H), 4.00 (s, 2H), 1.91-1.69 (m, 8H), 1.611. 54 (m, 4H), 1.51-1.43 (m, 6H), 1.32 (s, 9H). FXR EC50 (nM) = 2188. MS (ESI) 587 (M+H).

Example 661.

1,1,1-trifluoro-2-methylpropan-2-yl(4-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)((4-(3isopropyl-1-methyl-1H -pyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

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Step A: Intermediate 661A. Preparation of methyl ochopentanoyl)bicyclo[2.2.2]octane-1-carboxylate

4-(4-methyl-3-

The compound was synthesized according to the general method described for the synthesis of intermediate 655C by replacing intermediate 655B and isobutyryl chloride where necessary: (650 mg, 2.318 mmol, 49% yield) as a resin.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.58-3.55 (m, 3H), 2.56-2.51 (m, 1H), 1.77-1.64 (m, 12H), 1.06 (d, J=7.0 Hz, 6H) , 2H are hidden under the humidity peak.

Stage B. Intermediates 661B1 and 661B2. Preparation of methyl 4-(5-isopropyl-1-methyl1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-carboxylate and methyl 4-(3-isopropyl-1-methyl-1H-pyrazol-5yl) bicyclo[2.2.2]octane-1-carboxylate

The specified compound was synthesized in accordance with the general method described for the synthesis of intermediate 124C, replacing intermediate 661A where necessary. Fractions containing the compound were concentrated to obtain a mixture of compounds. The mixture was purified using SFC to obtain individual regioisomers. Column: Lux Cellulose C4 (250x4.6) mm, 5 µm, flow rate: 3 ml/min, co-solvent: 15% Vial No: LA5, co-solvent: 0.2% ammonia in methanol; injection volume: 10 µl, outlet pressure: 100 bar, temperature: 40°C.

The first isomer eluted was methyl 4-(5-isopropyl-1-methyl-1H-pyrazol-3yl)bicyclo[2.2.2]octane-1-carboxylate (661B1) (120 mg, 0.413 mmol, 24% yield).

1H NMR (400 MHz, DMSO-de) δ 5.82-5.79 (m, 1H), 3.64 (s, 3H), 3.58 (s, 3H), 2.91 (td, J=6.8, 13.6 Hz, 1H), 1.79- 1.68 (m, 12H), 1.15 (d, J=6.5 Hz, 6H). MS (ESI) 291 (M+H) (RT = 1.68 min or peak-1).

The second isomer eluted was methyl 4-(3-isopropyl-1-methyl-III-pyrazol-5yl)bicyclo[2.2.2]octane-1-carboxylate (661B2) (190 mg, 0.654 mmol, 37% yield). MS (ESI) 291 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.79 (s, 1H), 3.79 (s, 3H), 3.59 (s, 3H), 2.74 (td, J=6.8, 13.9 Hz, 1H), 1.87- 1.76 (m, 12H), 1.13 (d, J=7.0 Hz, 6H). MS (ESI) 291 (M+H). (RT=1.71 min or peak-2).

Step C. Intermediate 661C. Preparation of (4-(3-isopropyl-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octan-1-yl)methanol

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 1G, replacing intermediate 661B2 where necessary: (0.1 g, 0.381 mmol, 58% yield) as a colorless liquid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 5.79-5.75 (m, 1H), 4.38-4.33 (m, 1H), 3.82-3.76 (m, 3H), 3.09-3.04 (m, 2H), 2.78- 2.69 (m, 1H), 1.83-1.74 (m, 6H), 1.48-1.39 (m, 6H), 1.17-1.08 (m, 6H).

Stage D. Intermediate 661D. Preparation of 4-(3-isopropyl-1-methyl-1H-pyrazol-5yl)bicyclo[2.2.2]octane-1-carbaldehyde

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The indicated compound was synthesized according to the general method described for the synthesis of intermediate 3C, by replacing intermediate 661C where necessary: (50 mg, 0.192 mmol, 50% yield) as a white solid.

1H NMR (400 MHz, chloroform-d) δ 9.52-9.49 (m, 1H), 5.81 (s, 1H), 3.91 (s, 3H), 2.94-2.85 (m, 1H), 2.00-1.93 (m, 6H ), 1.81-1.74 (m, 6H), 1.23 (d, J=7.0 Hz, 6H).

Step E. Intermediate 661E. Preparation of 4-bromo-N-((4-(3-isopropyl-1-methyl-1Hpyrazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine

The title compound was synthesized according to the general method described for the synthesis of intermediate 1I, by replacing intermediate 661D and 4-bromopyridin-2amine where needed: (15 mg, 0.036 mmol, 37% yield) as an off-white solid substances. MS (ESI) 417 (M+H).

Step F: Intermediate 661F. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4bromopyridin-2-yl)((4-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2] octan-1yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 661E where necessary: ( solid, 22 mg, 0.038 mmol, yield 56%). MS (ESI) 571 (M+H).

Step G. Example 661. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-(2-hydroxypropan-2yl)phenyl)pyridin-2-yl)((4-(3- isopropyl-1-methyl-1 H-pyrazol-5-yl)bicyclo[2.2.2]octan-1 yl)methyl)carbamate

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 661F and the corresponding boronic acid where necessary: (5.4 mg, 0.008 mmol, 24% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J=5.1 Hz, 1H), 7.79-7.68 (m, 3H), 7.66-7.58 (m, 2H), 7.56 (dd, J=1.6, 5.3 Hz, 1H), 5.70 (s, 1H), 5.13 (s, 1H), 3.84 (s, 2H), 3.56 (s, 3H), 2.75-2.65 (m, 1H), 1.77-1.61 (m, 12H ), 1.46 (s, 6H), 1.40-1.29 (m, 6H), 1.09 (d, J=6.8 Hz, 6H). FXR EU ₅₀ (nM) 53; MS (ESI) 627 (M+H).

Example 662.

(cis)F-(4'-(4-amino-1,2,5-oxadiazol-3-yl)-[1,G-biphenyl]-3-yl)-N-((4-(5-( 2-fluoropropan-2-yl)1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutan-1carboxamide

Step A: Intermediate 662A. Preparation of (7)-4-bromo-N-hydroxybenzimidoyl cyanide

To a stirred solution of 2-(4-bromophenyl)acetonitrile (3 g, 15.30 mmol) in DMF (75 ml) to

- 464 047337 potassium tert-butoxide (18.36 ml, 18.36 mmol) was added at 0°C. The reaction mixture was stirred for 5 minutes. tert-Butyl nitrite (3.16 g, 30.6 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with 1.5 N HCl (5 ml). The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with brine (5 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The crude product was purified by silica gel flash column chromatography (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 30% B; flow rate = 80 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound (colorless liquid, 3.1 g, 13.78 mmol, 90% yield).

¹ H NMR (400 MHz, DMSO-d6) δ 13.93 (d, J=1.7 Hz, 1H), 7.77-7.70 (m, 2H), 7.69-7.64 (m, 2H).

Stage B. Intermediate 662B. Preparation of 4-(4-bromophenyl)-1,2,5-oxadiazol-3-amine

Hydroxylamine (0.954 g, 28.9 mmol) was added to a stirred solution of intermediate 662A (3.25 g, 14.44 mmol) in MeOH (50 mL). The reaction mixture was heated at 40°C for 12 hours. The reaction mixture was concentrated under reduced pressure and distilled with dichloromethane (3 ml). The resulting solid was dissolved in tetrahydrofuran (50 ml) and CDI (3.51 g, 21.66 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 30% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound: (2.0 g, 8.33 mmol, 58% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 7.79-7.69 (m, 4H), 6.27 (s, 2H).

Step C. Example 662. Preparation of (cis)F-(4'-(4-amino-1,2,5-oxadiazol-3-yl)-[1,G-biphenyl]-3-yl)H-(( 4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3 -yl)bicyclo-[2.2.2]octan-1 -yl)methyl)-3-hydroxy-3(trifluoromethyl )cyclobutane-1-carboxamide

The specified compound was synthesized in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 662B and intermediate 593 A where necessary: (7.2 mg, 0.0107 mmol, 26% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.03-7.91 (m, 2H), 7.91-7.84 (m, 2H), 7.81 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.50-7.41 (m, 1H), 6.54 (s, 1h), 6.27 (s, 2H), 3.80-3.54 (m, 2H), 3.01-2.77 (m, 1H ), 2.40-2.24 (m, 2H), 2.13-1.91 (m, 2H), 1.85-1.65 (m, 12H), 1.56-1.37 (m, 6H). FXR EC ₅₀ (nM) 574; MS (ESI) 669 (M+H).

Example 663.

3-fluoro-U-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)- Y-(3(1-(2-hydroxy-2-methylpropyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1 carboxamide

Step A: Intermediate 663A. Preparation of dihydropyridine-1(2H)-carboxylate tert-butyl 4-(3-aminophenyl)-3,6-

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, by replacing 3-bromoaniline and 5-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl )-3,6-dihydropyridine-1(2H)-carboxylate where needed: (pale yellow liquid, 1.1 g, 4.01 mmol, 69% yield).

1H NMR (300 MHz, DMSO-d ₆ ) δ 6.97 (t, J=7.8 Hz, 1H), 6.64-6.52 (m, 2H), 6.50-6.41 (m, 1H), 5.99 (br s, 1H), 5.08-4.96 (m, 2H), 3.95 (s, 2H), 3.50 (br t, J=5.6 Hz, 2H), 2.37 (br s, 2H), 1.46-1.35 (m, 9H). MS (ESI) 275 (M+H).

- 465 047337

Stage B. Intermediate 663B. Preparation of tert-butyl 4-(3-(((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl )amino)-phenyl)-3,6-dihydropyridine-1(2H)carboxylate

The title compound was prepared according to the general method described for the synthesis of intermediate 1I, replacing intermediates 576E and 663A where necessary: (pale brown liquid, 620 mg, 1.087 mmol, 58% yield).

Ή NMR (300 MHz, chloroform-d) δ 7.26 (s, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.72-6.67 (m, 1H), 6.60 (s, 1H), 6.55-6.49 ( m, 1H), 4.05 (br s, 3H), 3.65-3.57 (m, 4H), 2.92 (s, 2H), 2.01-1.92 (m, 6H), 1.86 (s, 3H), 1.79 (s, 3H ), 1.66-1.56 (m, 6H), 1.49 (s, 9H). MS (ESI) 525 (M+H).

Step C. Intermediate 663C. Preparation of tert-butyl 4-(3-(3-fluoro-N-((4-(5-(2fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane -1-yl)methyl)bicyclo[1.1.1]pentane-1carboxamido)phenyl)-3,6-dihydropyridine-1 (2H)-carboxylate

The specified compound was prepared in accordance with the general method described for the synthesis of intermediate 576G, replacing intermediate 663B where necessary. (tarry liquid, 0.18 g, 0.260 mmol, yield 68%). MS (ESI) 637(M+H).

Stage D. Intermediate 663D. Preparation of 3-fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-N -(3-(1,2,3,6-tetrahydropyridin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

To a stirred solution of intermediate 663C (100 mg, 0.157 mmol) in DCM (5 ml) was added TFA (0.06 ml, 0.785 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (70 mg, 0.130 mmol, 70% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.50-7.36 (m, 3H), 7.27 (br d, J=7.6 Hz, 1H), 6.34 (br s, 1H), 3.56 (br s, 2H), 3.46 (br d, J=1.2 Hz, 3H), 3.00 (br t, J=5.7 Hz, 2H), 2.46-2.31 (m, 2H), 1.96-1.68 (m, 18H), 1.53-1.38 (m, 6H). MS (ESI) 537 (M+H).

Step E. Example 663. Preparation of 3-fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octane-1- yl)methyl)-N-(3-(1-(2-hydroxy-2-methylpropyl)-1,2,3,6-tetrahydropyridin-4yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide

To a stirred solution of intermediate 663D (20 mg, 0.037 mmol) in isobutylene oxide (2 mL) was added cesium carbonate (1.214 mg, 3.73 μmol) at room temperature. The reaction mixture was stirred at 110°C in a microwave oven at 70 W for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative LC/MS under the following conditions: column: Waters XBridge C18, 19x150 mm, 5 µm particles; mobile phase A: 10 mM ammonium acetate; mobile phase B: acetonitrile; gradient: 28-85% B for 20 minutes, then hold for 5 minutes at 100% B; flow rate: 15 ml/min. Fractions containing product were combined and dried by centrifugal evaporation to give the title compound (9.1 mg, 0.015 mmol, 40% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.50-7.32 (m, 3H), 7.24 (br d, J=7.6 Hz, 1H), 6.27 (br s, 1H), 4.23-4.09 (m, 1H) , 3.65-3.56 (m, 1H), 3.54-3.46 (m, 1H), 3.26 (br s, 2H), 2.87-2.72 (m, 2H), 2.47-2.40 (m, 2H), 2.37-2.24

- 466 047337 (m, 2H), 1.93-1.65 (m, 18H), 1.54-1.34 (m, 6H), 1.12 (s, 6H). FXR EC50 (nM) = 159. MS (ESI) 609 (M+H).

Example 664.

1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-1-(4 '-(2hydroxypropan-2-yl)-[1,G-biphenyl]-3-yl)-3-(^^^)-6-hydroxyspiro[3.3]heptan-2-yl)urea

Step A: Intermediate 664A. Preparation of 1-(3-bromophenyl)-1-((4-(5-(2-fluoropropan-2yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)-3-(^^^)-6-hydroxyspiro[3.3]heptan-2yl)urea

The indicated compound was prepared in accordance with the general method described for the synthesis of the compound of example 586, by replacing intermediate 632A and (2S,4S,6S)-6aminospiro[3.3]heptan-2-ol hydrochloride where necessary: (50 mg , 0.087 mmol, yield 61.2%) as a brown wax. MS (ESI) 575 (M+H).

Step B. Example 664. Preparation of 1-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3yl)bicyclo[2.2.2]octan-1-yl)methyl) -1-(4'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-3-yl)-3-((2S,4S,6S)-6hydroxyspiro[3.3] heptane-2- silt)urea

The specified compound was prepared in accordance with the general method described for the synthesis of the compound of example 149, by replacing intermediate 664A and the corresponding boronic acid where necessary: (13.2 mg, 0.021 mmol, 30% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64-7.60 (m, 2H), 7.58-7.51 (m, 4H), 7.49-7.44 (m, 1H), 7.28-7.19 (m, 1H), 5.71 (d, J=7.8 Hz, 1H), 5.06 (s, 1H), 4.84 (d, J=6.4 Hz, 1H), 4.06-3.99 (m, 1H), 3.94-3.86 (m, 1H), 3.58 ( s, 2H), 2.31-2.25 (m, 1H), 2.18-2.09 (m, 1H), 2.08-1.98 (m, 2H), 1.91-1.81 (m, 2H), 1.79 (s, 4H), 1.76- 1.70 (m, 10H), 1.46 (s, 6H), 1.43-1.36 (m, 6H). FXR EC50 (nM) = 47. MS (ESI) 631 (M+H).

Example 665.

1,1,1-trifluoro-2-methylpropan-2-yl (4-(4-cyanobicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)((4-(3cyclopropyl-1,2, 4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

Step A: Intermediate 665A. Preparation of methyl 4-(2-chloropyrimidin-4yl)bicyclo[2.2.2]octane-1-carboxylate

To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1 g, 4.71 mmol) and 2-chloropyrimidine (0.594 g, 5.18 mmol) in DCM (183 ml) and water (183 ml) ammonium persulfate (1.075 g, 4.71 mmol) was added, followed by silver nitrate (0.480 g, 2.83 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with DCM (100 ml) and filtered through celite. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (silica gel cartridge, 24 g; A = hexanes, B = EtOAc; gra

- 467 047337 dient 30 min; from 0% B to 30% B; flow rate = 24 ml/min). The pure fractions were combined, concentrated and dried in vacuo to give the title compound: (800 mg, 2.85 mmol, 61% yield) as a white solid. MS (ESI) 281 (M+H).

Stage B. Intermediate 665V. Preparation of 2-((4-(3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)isoindolin-1,3-dione

To a stirred solution of intermediate 4B (1.1 g, 4.43 mmol) in THF (22 mL) was added phthalimide (0.782 g, 5.32 mmol) followed by triphenylphosphine (1.394 g, 5.32 mmol). The reaction mixture was cooled to 0°C and DEAD (0.842 mL, 5.32 mmol) was added dropwise over 2 minutes. The reaction mixture was gradually warmed to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml) and then brine (20 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (25% EA:hexane, 24 g, silica gel column) to give the title compound (1.2 g, 3.18 mmol, yield 72%) as a white solid. MS (ESI) 378 (M+H).

Step C. Intermediate 665C. Preparation of (4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methanamine

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 660B, by replacing intermediate 665B where necessary: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.31 (s, 2H), 2.06 (tt , J=8.3, 4.8 Hz, 1H), 1.88-1.76 (m, 6H), 1.48-1.36 (m, 6H), 1.06-0.97 (m, 2H), 0.89-0.80 (m, 2H).

Stage D. Intermediate 665D. Preparation of methyl 4-(2-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)-pyrimidin-4-yl) bicyclo[2.2.2]octane-1carboxylate

To a stirred solution of intermediate 665A (600 mg, 2.137 mmol) in 2propanol (12 mL) was added intermediate 665C (529 mg, 2.137 mmol) followed by DIPEA (1.120 mL, 6.41 mmol). The reaction mixture was heated to 110°C overnight. The reaction mixture was concentrated under reduced pressure. The crude product was diluted with water (20 ml) and extracted with EtOAc (2x30 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column (silica gel cartridge, 12 g; A = hexanes, B = EtOAc; gradient 30 min; 0% B to 40% B; flow rate = 12 ml/min). The pure fractions were combined, concentrated under reduced pressure and dried in vacuo to give the title compound (250 mg, 0.509 mmol, 24% yield) as a brown solid. MS (ESI) 492 (M+H).

Step E. Intermediate 665E. Preparation of methyl 4-(2-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)(((1,1,1- trifluoro-2-methylpropan-2yl)oxy)carbonyl)amino)pyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate

The indicated compound was synthesized in accordance with the general method described for the synthesis

- 468 047337 intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 665D where necessary: (white solid, 150 mg, 0.232 mmol , yield 76%). MS (ESI) 646 (M+H).

Stage F. Intermediate 665F. Preparation of 4-(2-(((4-(3-cyclopropyl-1,2,4-oxadiazol5-yl)bicyclo[2.2.2]octan-1-yl)methyl)(((1,1,1-trifluoro -2-methylpropan-2yl)oxy)carbonyl)amino)pyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylic acid

The compound was synthesized according to the general method described for the synthesis of intermediate 88E, replacing intermediate 665E where necessary (colorless liquid, 5.4 mg, 8.55 µmol, 37% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (d, J=5.4 Hz, 1H), 7.28 (d, J=5.4 Hz, 1H), 3.72 (s, 2H), 2.08-1.98 (m, 1H ), 1.90-1.77 (m, 12H), 1.77-1.69 (m, 12H), 1.64 (s, 6H), 1.05-0.94 (m, 2H), 0.86-0.76 (m, 2H). MS (ESI) 632(M+H).

Stage G. Intermediate 665G. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-(4carbamoylbicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)((4-(3-cyclopropyl-1,2 ,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The compound was synthesized according to the general method described for the synthesis of intermediate 114A, replacing intermediate 665F where necessary: (white solid, 7 mg, 10.8 µmol, 46% yield).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J=5.1 Hz, 1H), 7.28 (d, J=5.4 Hz, 1H), 6.98 (s, 1H), 6.75 (s, 1H), 3.72 (s, 2H), 2.09-1.97 (m, 1H), 1.87-1.68 (m, 18H), 1.65 (s, 6H), 1.37-1.22 (m, 6H), 1.04-0.96 (m, 2H), 0.860.77 (m, 2H). MS (ESI) 631 (M+H).

Step H: Intermediate 665. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl (4-(4cyanobicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)((4-( 3-cyclopropyl-1,2,4-oxadiazol-5yl)bicyclo[2.2.2]octan-1-yl)methyl)carbamate

The indicated compound was synthesized according to the general method described for the synthesis of intermediate 114B, replacing intermediate 665G where necessary: (8 mg, 0.013 mmol, 28% yield).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (d, J=5.1 Hz, 1H), 7.28 (d, J=5.1 Hz, 1H), 3.72 (s, 2H), 2.10-1.95 (m, 7H), 1.92-1.80 (m, 6H), 1.79-1.68 (m,6H), 1.64 (s, 6H), 1.32-1.28 (m, 6H), 1.06-0.93 (m, 2h), 0.86-0.70 ( m, 2H)). FXR EC ₅₀ (nM) = 2000. MS (ESI) 613 (M+H).

Example 666.

1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octan1-yl)methyl)(4 -(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1-yl)pyrimidin-2-yl)carbamate

Step A: Intermediate 666A. Preparation of 2-(4-(2-(((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)pyrimidin-4-yl )bicyclo[2.2.2]octan-1- 469 047337 yl)propan-2-ol

This compound was synthesized according to the general method described for the synthesis of intermediate 607A, replacing intermediate 665D where necessary: (white solid, 35 mg, 0.071 mmol, 50% yield). MS (ESI) 492 (M+H).

Step B. Example 666. Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((4-(3-cyclopropyl-1,2,4oxadiazol-5-yl)bicyclo[2.2.2]octane-1 -yl)methyl)(4-(4-(2-hydroxypropan-2-yl)bicyclo[2.2.2]octan-1yl)pyrimidin-2-yl)carbamate

This compound was synthesized according to the general method described for the synthesis of intermediate 584A, by replacing pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2yl)carbonate and intermediate 666A where necessary: ( white solid, 13 mg, 0.020 mmol, yield 33%).

¹ HNMR (400 MHz, DMSO-d ₆ ) δ 8.63 (d, J=5.4 Hz, 1H), 7.26 (d, J=5.4 Hz, 1H), 3.89 (s, 1H), 3.72 (s, 2H), 2.07-1.96 (m, 1H), 1.82-1.68 (m, 12H), 1.64 (s, 6H), 1.59-1.49 (m, 6H), 1.38-1.21 (m, 6H), 1.07-0.93 (m, 8H ), 0.86-0.72 (m, 2H). FXR EC ₅₀ (nM) = 496. MS (ESI) 646 (M+H).

Biological honey agaric

The exemplary compounds of the present invention were tested in a luciferase reporter gene assay using a transient human FXR/Gal4 construct, and the assay results are presented in Table. 1. The Gal4-hFXR fusion reporter system was used as the primary assay to characterize the activity of the compound. A construct including 5 copies of the GaU-responsive element promoter upstream of the firefly luciferase reporter cDNA was stably expressed in HEK293 cells. This reporter cell line was maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco) supplemented with 1% penicillin-streptomycin (P/S), 500 μg/ml zeocin, and 10% charcoal/dextran-treated fetal bovine serum. (cs-FBS) at 37°C in a humidified atmosphere containing 5% CO2. Another plasmid was constructed in which the human cytomegalovirus promoter in the pcDNA3.1 vector drives expression of a cDNA encoding a fusion protein consisting of the DNA binding domain from the transcription factor Gal4 fused to the ligand binding domain from human FXR.

The day before transfection, reporter cells in culture were removed from the plate using trypsin and placed in a T75 flask at a density sufficient to achieve approximately 90% confluence the next morning. Transfection reagents were prepared by separately diluting 25 μg of pcDNA3.1-Gal4-FXR plasmid in 1.87 ml Opti-MEM (Thermo-Fisher) and 40 μl Lipofectamine 2000 (Thermo-Fisher) in 1.87 ml Opti-MEM, and then adding the diluted DNA solution to the diluted Lipofectamine 2000 solution and incubating at room temperature for 15-20 minutes. The mixture was then diluted with 10 ml of a solution containing DMEM, 10% cs-FBS and 1% P/S immediately before transfer to cells. Maintenance culture medium was aspirated from the cells and the final transfection mixture was added before incubating the cells overnight at 37°C in a humidified atmosphere containing 5% CO2. This protocol can be scaled up and transiently transfected cells can be cryopreserved in an assay-ready format.

For compound testing, 100 nL of compounds (serial dilutions in DMSO) were dispensed using an Echo acoustic dispenser (Labcyte) into the wells of a 384-well white Corning/Costar clear-bottom plate. Transfected cells were collected, counted, and diluted to provide 10–25,000 cells per 25 μl per well of a 384-well compound assay plate. Cells treated with the compound were incubated overnight at 37°C in a humidified atmosphere containing 5% CO2. The next morning, 25 μl of Steady-Glo (Promega) was added to each well of the plate, the mixture was incubated for 15 min with shaking, and luminescence was measured on an Envision plate reader (Perkin Elmer). Background counts of cells treated with DMSO alone were subtracted from all crude counts, and adjusted values were converted to the percentage of control response achieved with 8 μM GW-4064. These data fit a 4-parameter log agonist-response equation to calculate the EC ₅₀ value.

In vivo analysis of acute disease in mice:

Male C57BL6/NTac mice weighing 25–28 g were purchased from Taconic Labs (Hudson, NY) and maintained on a Teklad Global 18% protein rodent diet (Harlan Laboratories). After 1 week of acclimatization, mice were divided into groups depending on body weight. Mice are given a single dose of oral

- 470 047337 dose of vehicle or experimental compound. Systemic exposure of the compound was assessed in plasma obtained from blood collected through the submandibular vein, 1 hour after dosing and at the end of the study (6 hours). At the end of the study, the animals were sacrificed and quickly dissected. The medial lobe of the liver was divided: one half was homogenized and analyzed for compound effects, and the other half was stored in RNAlater (Thermo-Fisher Scientific). The ileum was also dissected and preserved in RNAlater. Tissue samples in RNAlater were homogenized using MP Biomedicals beads. RNA was extracted using the MagMax-96 Total RNA Isolation kit (Thermo-Fisher Scientific) according to the manufacturer's protocol. RNA concentration was determined using a Nano-Drop 8000 spectrophotometer (Thermo Fisher). Reverse transcription was performed using the Superscript® VILO cDNA Synthesis Kit from Invitrogen according to the manufacturer's protocol. Real-time PCR was performed with Taqman PCR master mix from Applied Biosystems according to the manufacturer's protocol. All primers were purchased from Thermo-Fisher Scientific. Mouse genes analyzed include Nr0b2 (which encodes the small heterodimeric partner, SHP), Abcb11 (which encodes the bile salt export pump, BSEP), Cyp7a1 and Cyp8Y in the liver, and Fgf15, Fabp6 (which encodes the ileal bile acid binding protein, IBABP ), Slc51a (which encodes the organic solute transporter alpha subunit, OSTA) and Slc51b (which encodes the organic solute transporter beta subunit, OSTB) in the ileum. Statistically significant changes in FGF15 gene expression are expressed as a fold increase, and CYP _7A1 expression as a percentage decrease relative to the vehicle control.

Other features of the invention will become apparent from the above description of illustrative embodiments, which are presented to illustrate the invention and are not intended to be limiting thereof. The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. This invention covers all combinations of the preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It will also be understood that each individual element of the embodiments represents its own independent embodiment. In addition, any element of an embodiment is intended to be combined with any or all other elements from any embodiment to describe a further embodiment.

Biological assessment

The exemplary compounds of the present invention were tested in a luciferase reporter gene assay using a transient human FXR/Gal4 construct, and the results of the assay are described herein above in the Examples section.

The Gal4-hFXR fusion reporter system was used as the primary assay to characterize the activity of the compound. A construct including 5 copies of the Gal4 promoter response element upstream of the firefly luciferase reporter cDNA was stably expressed in HEK293 cells. This reporter cell line was maintained in Dulbecco's modified Eagle's medium (DMEM; Gibco) supplemented with 1% penicillin-streptomycin (P/S), 500 μg/ml zeocin, and 10% charcoal/dextran-treated fetal bovine serum. (cs-FBS) at 37°C in a humidified atmosphere containing 5% CO ₂ . Another plasmid was constructed in which the human cytomegalovirus promoter in the pcDNA3.1 vector drives expression of a cDNA encoding a fusion protein consisting of the DNA binding domain from the transcription factor Gal4 fused to the ligand binding domain from human FXR.

The day before transfection, reporter cells in culture were removed from the plate using trypsin and placed in a T75 flask at a density sufficient to achieve approximately 90% confluence the next morning. Transfection reagents were prepared by separately diluting 25 μg of pcDNA3.1-Gal4-FXR plasmid in 1.87 ml Opti-MEM (Thermo-Fisher) and 40 μl Lipofectamine 2000 (Thermo-Fisher) in 1.87 ml Opti-MEM, and then adding the diluted DNA solution to the diluted Lipofectamine 2000 solution and incubating at room temperature for 15-20 minutes. The mixture was then diluted with 10 ml of a solution containing DMEM, 10% cs-FBS and 1% P/S immediately before transfer to cells. Maintenance culture medium was aspirated from the cells and the final transfection mixture was added before incubating the cells overnight at 37°C in a humidified atmosphere containing 5% CO2. This protocol can be scaled up and transiently transfected cells can be cryopreserved in an assay-ready format.

For compound testing, 100 nL of compounds (serial dilutions in DMSO) were dispensed using an Echo acoustic dispenser (Labcyte) into the wells of a 384-well white Corning/Costar clear-bottom plate. Transfected cells were collected, counted, and diluted to provide 10–25,000 cells per 25 μl per well of a 384-well compound assay plate. Cells treated with the compound were incubated overnight at 37°C in a humidified atmosphere

- 471 047337 sphere containing 5% CO2. The next morning, 25 μl of Steady-Glo (Promega) was added to each well of the plate, the mixture was incubated for 15 min with shaking, and luminescence was measured on an Envision plate reader (Perkin Elmer). Background counts of cells treated with DMSO alone were subtracted from all crude counts, and adjusted values were converted to the percentage of control response achieved with 8 μM GW-4064. These data fit a 4-parameter log agonist-response equation to calculate the EC ₅₀ value.

Example of in vivo testing: PK/PD in mice with acute disease Male C57BL6/NTac mice weighing 25-28 g were purchased from Taconic Labs (Hudson, NY) and maintained on a Teklad Global 18% protein rodent diet (Harlan Laboratories). After 1 week of acclimatization, mice were divided into groups depending on body weight. Mice are administered a single oral dose of vehicle or experimental compound. Systemic exposure of the compound was assessed in plasma obtained from blood collected through the submandibular vein, 1 hour after dosing and at the end of the study (6 hours). At the end of the study, the animals were sacrificed and quickly dissected. The medial lobe of the liver was divided: one half was homogenized and analyzed for compound effects, and the other half was stored in RNAlater (Thermo-Fisher Scientific). The ileum was also dissected and preserved in RNAlater. Tissue samples in RNAlater were homogenized using MP Biomedicals beads. RNA was extracted using the MagMax-96 Total RNA Isolation kit (Thermo-Fisher Scientific) according to the manufacturer's protocol. RNA concentration was determined using a Nano-Drop 8000 spectrophotometer (Thermo Fisher). Reverse transcription was performed using the Superscript® VILO cDNA Synthesis Kit from Invitrogen according to the manufacturer's protocol. Real-time PCR was performed with Taqman PCR master mix from Applied Biosystems according to the manufacturer's protocol. All primers were purchased from Thermo-Fisher Scientific. Mouse genes analyzed include Nr0b2 (which encodes the small heterodimeric partner, SHP), Abcb11 (which encodes the bile salt export pump, BSEP), Cyp7a1 and Cyp8Y in the liver, and Fgf15, Fabp6 (which encodes the bile salt binding protein in the ileum, I -BABP), Slc51a (which encodes the organic solute transporter alpha subunit, OSTA) and Slc51b (which encodes the organic solute transporter beta subunit, OSTB) in the ileum. Statistically significant changes in FGF15 gene expression are expressed as a fold increase, and CYP _7A1 expression as a percentage decrease relative to the vehicle control.

Other features of the invention will become apparent from the above description of illustrative embodiments, which are presented to illustrate the invention and are not intended to be limiting thereof. The present invention may be embodied in other specific forms without departing from its spirit or essential attributes. This invention covers all combinations of the preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It will also be understood that each individual element of the embodiments represents its own independent embodiment. In addition, any element of an embodiment is intended to be combined with any or all other elements from any embodiment to describe a further embodiment.

Claims (13)

1. A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Q is phenyl substituted with 0-1 R ¹ ; X ¹ represents CH; X ² represents CH or N; X ³ represents CH or N; X ⁴ represents CH; with the proviso that 0 or 1 of X ² and X ³ represent N; Z ¹ and Z ² are independently CH2 or O; with the proviso that at least one of Z ¹ and Z ² is CH2; A is oxadiazolyl or pyridinyl substituted with R ^4a ; - 472 047337 a is equal to 1; b is equal to 1; d is 1; each R ¹ independently represents C1. ₄ -alkyl, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CH2CHF2, -C(CH3)2OH, -CH2OCH3, -C(CH3)2OCH3, -OCH3, -OCH2CH3, -OCCH^CN, -CCCHbOCH^, -C(O)OCH3, _-C (O)OCH _{2 CH3} , _-CH2 (cyclopropyl), -S(O) _2CH3 , ^(O) ₂ (cyclopropyl) , =O, difluorocyclobutyl, fluorobicyclo[1.1.1]pentyl, oxetanyl, methyloxetanyl, pyridinyltetrahydropyranyl or cyclopropyl substituted with 0-1 substituent selected from hydroxyl, -CH ₃ , -OCH ₃ and -NHC(O)CH ₃ ; R ² represents: (i) C _1-4 alkyl, C _1-5 alkoxy or -NH(C _1-6 alkyl), wherein each of said alkyl and alkoxy is substituted with 0-4 R ^2a ; or (ii) C ₃ . ₅ cycloalkyl substituted with 0-3 R ^2b ; R ^2a is independently halogen, cyano or hydroxyl; R ^2b independently represents halogen, cyano, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy, where alkyl is substituted with 0-6 R ^2a ; R ^3a represents hydrogen or -CH3; And R ^3b represents hydrogen; And R ^4a represents cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -CF2CH3, -C(CH3ZH -C( _CH3 ) ₂ OH, -C( _CH3 ) ₂ CN, -OCH ₃ , -C(O)N(CH ₃ ) ₂ , -CH ₂ (cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetanyl, tetrahydropyranyl or fluorobicyclo[1.1.1]pentyl . 2. Connection structure according claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt having 3. Connection structure according clause 1 or 4. Connection structure according clause 1 or 5. Connection structure according clause 1 a stereoisomer thereof or a pharmaceutically acceptable salt having pharmaceutically its stereoisomer or pharmaceutically or a stereoisomer thereof or a suitable acceptable salt, a salt having - 473 047337 6. A compound according to claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, wherein A is pyridinyl substituted with R ^4a . 7. A compound according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt having the structure 8. A compound according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt having the structure 9. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 8 or a stereoisomer or pharmaceutically acceptable salt thereof. 10. Use of a compound according to any one of claims 1 to 8 or a stereoisomer or pharmaceutically acceptable salt thereof for the treatment of pathological fibrosis, cancer, inflammatory disorders, metabolic or cholestatic disorders. 11. Use according to claim 10, wherein the pathological fibrosis is liver fibrosis, renal fibrosis, biliary fibrosis or pancreatic fibrosis. 12. Use of a compound according to any one of claims 1 to 8 or a stereoisomer or pharmaceutically acceptable salt thereof for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). 13. Use of a compound according to any one of claims 1 to 8 or a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of idiopathic pulmonary fibrosis (IPF).