Substituted bicyclic compounds as farnesoid x receptor modulators

Abstract

Disclosed is a compound of Formula (I), or a stereoisomer, tautomer, or salt or solvate thereof, wherein all variables are as defined herein. The compounds modulate the activity of farnesoid X receptor (FXR), e.g., as agonists. Also disclosed are pharmaceutical compositions comprising the compounds, and methods of treating diseases, disorders, or conditions associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 806,066, filed on February 15, 2019, the entire contents of which are incorporated herein by reference. [Technical Field]

[0003] This invention relates generally to compounds suitable for acting as farnesoid X receptor (FXR) modulators, pharmaceutical compositions comprising such compounds, and their use in therapy, particularly for the treatment or prevention of diseases, conditions, and symptoms to which FXR modulators are applicable. [Existing Technology]

[0004] 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, the entire gastrointestinal tract, colon, ovaries, adrenal glands, kidneys, and in the gallbladder and bile duct tree in humans. FXR forms a heterodimer with the retinoid X receptor (RXR) and binds to specific reactive components in the target gene to regulate gene transcription (BMForman 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 sequence (i.e., the IR-1 sequence) of a common hexanucleotide sequence (AGGTCA) separated by single nucleotides. The relevant physiological ligands of FXR are bile acids, including chenodeoxycholic acid and its taurine conjugate (DJParks et al., Science 1999; 284:1365; M. Makishima et al., Science 1999; 284:1362). FXR activation regulates the expression of multiple genes encoding enzymes and transport proteins involved in bile acid synthesis, influx, and efflux in the liver and intestine, thereby causing a net reduction in total endogenous bile acids in the negative feedback loop. FXR participates in paracrine and endocrine signaling by upregulating the expression of cytokinin fibroblast growth factor 15 (rodents) or 19 (primates), and it can also promote the regulation of bile acid concentration (Holt et al., Genes Dev. 2003; 17:1581; Inagaki et al., Cell Metab 2005; 2:217). Therefore, FXR is considered a major regulator of bile acid homeostasis.

[0005] One use of FXR agonists is in the treatment of bile acid dysbiosis, including cholestatic diseases (such as primary biliary cirrhosis and primary sclerosing cholangitis) that can lead to fibrosis, cirrhosis, cholangiocarcinoma, hepatocellular carcinoma, liver failure, and death. While elevated bile acid concentrations in the liver have adverse effects, bile acids also affect the small intestinal microbiota and integrity. Obstruction of bile flow in humans or rodents can lead to intestinal bacterial proliferation and mucosal damage, which can result in bacterial translocation across the mucosal barrier and systemic infection (Berg, Trends Microbiol. 1995; 3: 149-154). Mice lacking FXR exhibit increased ileal bacterial content and impaired epithelial barrier, while activation of intestinal FXR plays a crucial 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 knockout mice spontaneously developed hepatocellular carcinoma, a condition that could be eliminated by selectively reactivating FXR in the gut (Degirolamo et al., Hepatology 61:161-170). Pharmacological activation of FXR with small molecule agonists or transgenic expression of FXR in the gut normalized bile acid concentrations, reduced cell proliferation in the bile ducts, and decreased inflammatory cell infiltration, necrotic areas, and liver fibrosis in rodent cholestasis models (Liu et al., J. Clin. Invest. 2003; 112:1678-1687; Modica et al., Gastroenterology. 2012; 142:355-365). Some of the aforementioned beneficial effects observed in preclinical cholestasis models have transferred to human patients, and the FXR agonist obeticholic acid (OCA or OCALIVA) has been observed to contribute to this effect. TM It has been approved for the treatment of primary biliary cirrhosis (https: / / www.fda.gov / newsevents / newsroom / pressannouncements / ucm503964.htm).

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

[0007] FXR agonists are also being investigated in human clinical trials for the treatment of NAFLD (a more advanced form of fatty liver disease), non-alcoholic steatosis (NASH), and related complications. NAFLD is currently one of the most common causes of chronic liver disease worldwide (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, and dyslipidemia. In a 6-week clinical trial in T2DM patients with NAFLD, the FXR agonist OCA statistically significantly improved insulin sensitivity and reduced weight, demonstrating beneficial effects on some of the aforementioned risk factors (Mudaliar et al., Gastroenterology 2013; 145: 574-582). NASH is the most severe and progressive form of NAFLD, and includes histological outcomes of hepatic steatosis, inflammation and bloat, and varying degrees of pericellular fibrosis (Sanyal et al., Hepatology 2015; 61: 1392-1405). In a 72-week clinical trial in NASH patients, OCA statistically significantly improved hepatic steatosis, lobular inflammation, hepatocellular bloat, and fibrosis, as assessed by histological analysis of liver biopsies (Neuschwander-Tetri et al., Lancet 2015; 385: 956-965). Given that NASH is the second leading cause of hepatocellular carcinoma (HCC) and liver transplantation in the United States, the data also suggest the potential for FXR agonists to demonstrate clinical benefit (Wong et al., Hepatology 2014; 59: 2188-2195).

[0008] This invention provides novel compounds for treating diseases, conditions, or symptoms associated with farnesoid X receptor (FXR) activity in patients in need. [Summary of the Invention]

[0009] In one aspect, the present invention provides compounds of formula (I) suitable as FXR modifiers, as well as their subgenus and species, including their stereoisomers, tautomers, pharmaceutically acceptable salts and solvates.

[0010] In another aspect, the present invention also provides methods for preparing the compounds of the present invention and intermediates.

[0011] In 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 a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0012] In another aspect, the compounds of the present invention can be used alone or in combination with one or more other therapeutic agents for therapeutic purposes.

[0013] The compounds of the present invention can be used to treat diseases, conditions, or symptoms associated with farnesoid X receptor (FXR) activity in patients requiring such treatment by administering a therapeutically effective amount of the compound or its stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates to the patient. The disease, condition, or symptom may be related to pathological fibrosis. The compounds of the present invention can be used alone, in combination with one or more of the compounds of the present invention, or in combination with one or more (e.g., one or two) other therapeutic agents.

[0014] The compounds of the present invention can be used as a single agent or in combination with other agents to treat diseases, conditions, or symptoms selected from: non-alcoholic fatty liver disease (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC). The compounds of the present invention can also be used as a single agent or in combination with other agents to treat idiopathic pulmonary fibrosis (IPF).

[0015] The compounds of the present invention can be used to manufacture medicaments for treating diseases, conditions or symptoms in patients who require such treatment.

[0016] Other features and advantages of the present invention will become apparent from the following embodiments and claims.

[0017] [Simplified Explanation of the Diagram]

[0018] The invention will be described with reference to the accompanying drawings described below.

[0019] Figure 1 Display the general reaction flow 12.

[0020] Figure 2 Display the general reaction flow 13.

[0021] Figure 3 Display the general reaction process 15.

[0022]

Implementation Method

[0023] This application provides compounds according to formula (I), including all stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts and solvates thereof. This application also provides pharmaceutical compositions comprising at least one compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, and, if appropriate, at least one other therapeutic agent. Furthermore, this application provides a method for treating patients with FXR-regulated diseases or conditions such as 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, wherein the method involves administering a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, or, if appropriate, in combination with at least one other therapeutic agent, to a patient requiring such treatment.

[0024] The first aspect of the present invention provides a compound of formula (I):

[0025]

[0026] Or its stereoisomers, tautomers, salts, or solvates, wherein:

[0027] X 1 For CR 5a Or N;

[0028] X 2 For CR 5b Or N;

[0029] X 3 For CR 5c Or N;

[0030] X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 N can be 0, 1, or 2 of them;

[0031] Z 1 and Z 2 It can be CH2 or O independently; the limiting condition is Z.1 and Z 2 At least one of them is CH2;

[0032] a is 0 or 1;

[0033] b is 0, 1, or 2;

[0034] d is 0, 1, or 2; the constraint is that Z is zero when a, b, and d are all zero. 1 and Z 2 Each is CH2;

[0035] Q is a cyclic group selected from 3 to 8-membered carbocyclic groups, 6 to 10-membered aryl groups, 4 to 10-membered heterocyclic groups, and 5 to 10-membered heteroaryl groups, wherein the cyclic group is connected by 0 to 4 R groups. 1 replace;

[0036] Each R 1 Independently hydrogen, halogen, cyano, hydroxyl, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -NR x C(O)R y -C(O)OR x -C(O)NR w R w -S(O)2(C 1-6 Alkyl), -S(O)2(C 3-6 cycloalkyl), -NR x S(O)2(C 1-6 Alkyl), -NR x S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z -P(O)R y R y -(CH2) 0-3 (C 3-6 carbonyl group), -O(C 3-6 Cycloalkyl), -O (4 to 6-membered heterocyclic group), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (5 or 6 heteroaryl groups), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl groups is derived from 0 to 4 R groups. 1aThe cycloalkyl, heterocyclic and heteroaryl groups are substituted and each of them is subjected to 0 to 4 R... 1b replace;

[0037] Each R 1a Independently halogenated, hydroxylated, -NR w R w , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)OR x -C(O)NR w R w or -NR x C(O)R y ;

[0038] Each R 1b Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a replace;

[0039] R 2 for:

[0040] (i)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy or -NR v R v Each of the alkyl, alkenyl, alkynyl and alkoxy groups is derived from 0 to 6 R groups. 2a replace;

[0041] (ii)C 3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Replace; or

[0042] (iii)-CH2(C 3-6 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 5-8 (bicycloalkyl), -NR x(CH2) 0-2 (C 5-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (5 to 6 heteroaryl groups), -NR x (CH2) 0-2 (phenyl), -O(CH2) 0-2 (C 3-6 cycloalkyl), -O(CH2) 0-2 (C 5-8 Bicycloalkyl), -O(CH2) 0-2 (C 5-8 Spirobicyclic group), -O(CH2) 0-2 (4 to 6-membered heterocyclic group), -O(CH2) 0-2 (5 to 6 heteroaryl groups) or -O(CH2) 0-2 (phenyl), wherein each of the cycloalkyl, heterocyclic, bicycloalkyl, spirobicycloyl, aryl, and heteroaryl groups is determined by 0 to 3 R groups. 2b replace;

[0043] Each R 2a Independently, it can be a halogen group, cyano group, hydroxyl group, oxo group, or C group. 1-3 Halogenated, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR x R x -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -NR x C(O)R y -C(O)(C 1-6 Alkyl), -C(O)OR x -C(O)NR w R w -S(O)2R y -S(O)2(C 1-3 fluoroalkyl), -NR x S(O)2(C 1-3 Alkyl), -NR x S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z or -P(O)R y R y ;

[0044] Each R 2b Independently, it can be a halogen group, cyano group, hydroxyl group, oxo group, or C group.1-6 Alkyl, C 1-6 Alkoxy, -NR x R x -NR x C(O)O(C 1-4 Alkyl), -C(O)(C 1-3 alkyl) or -S(O)2(C 1-3 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 2a replace;

[0045] R 3a and R 3b Independently hydrogen, C 1-3 Alkyl, C 1-3 Halogenated or C 3-6 cycloalkyl, or R 3a and R 3b Together with the attached carbon atoms, they form C 3-6 cycloalkyl;

[0046] A is:

[0047] (i) Cyano group;

[0048] (ii) A phenyl group or a 5- or 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl group and the heteroaryl group is derived from 0 to 3 R atoms. 4a Replace; or

[0049]

[0050] Each R 4a Independently, it can be a halogen group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl group, -(CH2) 0-3 NH(C 1-6 Alkyl group), -(CH2) 0-2 N(C 1-6 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl groups is derived from 0 to 6 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e replace;

[0051] R 4b C 1-6 Alkyl group, -(CH2) 0-3 (C3-6 cycloalkyl), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (phenyl), wherein each of the alkyl groups is derived from 0 to 6 R... 4d The cycloalkyl, heterocyclic and phenyl groups are substituted and each of them is subjected to 0 to 3 R groups. 4e replace;

[0052] Each R 4c Independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl;

[0053] Each R 4d Independently halogenated, hydroxylated, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0054] Each R 4e Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R 4d replace;

[0055] R 5a R 5b R 5c and R 5d Each is independently hydrogen, halogen, hydroxyl, cyano, via 0 to 6 R groups. 5e Replacement C 1-6 Alkyl, via 0 to 6 R 5e Replacement C 1-6 Alkoxy, -C(O)OR x -C(O)NR w R w -S(O)2R y -S(O)2NR z R z Or via 0 to 3 R 5f Substituted phenyl;

[0056] Each R 5e Independently halogenated, hydroxylated, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0057] Each R 5f Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R 5e replace;

[0058] Each R v Independently hydrogen, C 1-6 Alkyl or alternatively, two R v Together with its attached nitrogen atom, it forms a 4- to 7-membered bicyclic or spirocyclic moiety containing 0 to 2 additional heteroatoms independently selected from N, O, and S, wherein each ring may be via 0 to 6 R... 2a replace;

[0059] Each R w Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or alternatively, two R w Together with the nitrogen atom to which it is attached, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

[0060] Each R x Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0061] Each R y Independently for C 1-6 Alkyl or C 3-6 cycloalkyl; and

[0062] Each R z Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or alternatively, two R z Together with the nitrogen atom attached thereto, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S.

[0063] The second aspect of the present invention provides a compound of formula (I):

[0064]

[0065] Or its stereoisomers, tautomers, salts, or solvates, wherein:

[0066] X 1 For CR 5a Or N;

[0067] X 2 For CR 5b Or N;

[0068] X 3 For CR 5c Or N;

[0069] X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 N can be 0, 1, or 2 of them;

[0070] Z 1 and Z 2 It can be CH2 or O independently; the limiting condition is Z. 1 and Z 2 At least one of them is CH2;

[0071] a is 0 or 1;

[0072] b is 0, 1, or 2;

[0073] d is 0, 1, or 2; the constraint is that Z is zero when a, b, and d are all zero. 1 and Z 2 Each is CH2;

[0074] Q is a cyclic group selected from 3 to 8-membered carbocyclic groups, 6 to 10-membered aryl groups, 4 to 10-membered heterocyclic groups, and 5 to 10-membered heteroaryl groups, wherein the cyclic group is connected by 0 to 4 R groups. 1 replace;

[0075] Each R 1 Independently hydrogen, halogen, cyano, hydroxyl, oxo group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2、-C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -NR x C(O)R y -C(O)OR x -C(O)NR w R w -S(O)2(C 1-6 Alkyl), -S(O)2(C 3-6 cycloalkyl), -NR x S(O)2(C 1-6 Alkyl), -NRx S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z -P(O)R y R y -(CH2) 0-3 (C 3-6 carbonyl group), -O(C 3-6 Cycloalkyl), -O (4 to 6-membered heterocyclic group), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (5 or 6 heteroaryl groups), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl groups is derived from 0 to 4 R groups. 1a The cycloalkyl, heterocyclic and heteroaryl groups are substituted and each of them is subjected to 0 to 4 R... 1b replace;

[0076] Each R 1a Independently halogenated, hydroxylated, -NR w R w , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -C(O)OR x -C(O)NR w R w or -NR x C(O)R y ;

[0077] Each R 1b Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a replace;

[0078] R 2 for:

[0079] (i)C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy or -NR v R v Each of the alkyl, alkenyl, alkynyl and alkoxy groups is derived from 0 to 6 R groups. 2a replace;

[0080] (ii)C3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Replace; or

[0081] (iii)-CH2(C 3-6 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 5-8 (bicycloalkyl), -NR x (CH2) 0-2 (C 5-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (5 to 6 heteroaryl groups), -NR x (CH2) 0-2 (phenyl), -O(CH2) 0-2 (C 3-6 cycloalkyl), -O(CH2) 0-2 (C 5-8 Bicycloalkyl), -O(CH2) 0-2 (C 5-8 Spirobicyclic group), -O(CH2) 0-2 (4 to 6-membered heterocyclic group), -O(CH2) 0-2 (5 to 6 heteroaryl groups) or -O(CH2) 0-2 (phenyl), wherein each of the cycloalkyl, heterocyclic, bicycloalkyl, spirobicycloyl, aryl, and heteroaryl groups is determined by 0 to 3 R groups. 2b replace;

[0082] Each R 2a Independently, it can be a halogen group, cyano group, hydroxyl group, oxo group, or C group. 1-3 Halogenated, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -NR x R x -C(O)(C 1-6 Alkyl), -C(O)(C 3-6 cycloalkyl), -NR x C(O)R y -C(O)(C 1-6 Alkyl), -C(O)OR x -C(O)NR w Rw -S(O)2R y -S(O)2(C 1-3 fluoroalkyl), -NR x S(O)2(C 1-3 Alkyl), -NR x S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z or -P(O)R y R y ;

[0083] Each R 2b Independently, it can be a halogen group, cyano group, hydroxyl group, oxo group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NR x R x -NR x C(O)O(C 1-3 Alkyl), -C(O)(C 1-3 alkyl) or -S(O)2(C 1-3 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 2a replace;

[0084] R 3a and R 3b Independently hydrogen, C 1-3 Alkyl, C 1-3 Halogenated or C 3-6 cycloalkyl, or R 3a and R 3b Together with the attached carbon atoms, they form C 3-6 cycloalkyl;

[0085] A is:

[0086] (i) Cyano group;

[0087] (ii) A phenyl group or a 5- or 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl group and the heteroaryl group is derived from 0 to 3 R atoms. 4a Replace; or

[0088]

[0089] Each R 4a Independently, it can be a halogen group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl group, -(CH2) 0-3 NH(C 1-6Alkyl group), -(CH2) 0-2 N(C 1-6 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl, alkoxy, alkenyl, and alkynyl groups is derived from 0 to 6 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e replace;

[0090] R 4b C 1-6 Alkyl group, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl groups is derived from 0 to 6 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e replace;

[0091] Each R 4c Independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocyclic, phenyl, or 5- to 6-membered heteroaryl;

[0092] Each R 4d Independently halogenated, hydroxylated, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0093] Each R 4e Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R 4d replace;

[0094] R 5a R 5b R 5c and R 5d Each is independently hydrogen, halogen, hydroxyl, cyano, via 0 to 6 R groups. 5e Replacement C 1-6 Alkyl, via 0 to 6 R 5e Replacement C 1-6 Alkoxy, -C(O)OR x -C(O)NRw R w -S(O)2R y -S(O)2NR z R z Or via 0 to 3 R 5f Substituted phenyl;

[0095] Each R 5e Independently halogenated, hydroxylated, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0096] Each R 5f Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R 5e replace;

[0097] Each R v Independently hydrogen, C 1-6 Alkyl or alternatively, two R v Together with its attached nitrogen atom, it forms a 4- to 7-membered bicyclic or spirocyclic moiety containing 0 to 2 additional heteroatoms independently selected from N, O, and S, wherein each ring may be via 0 to 6 R... 2a replace;

[0098] Each R w Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or alternatively, two R w Together with the nitrogen atom to which it is attached, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S;

[0099] Each R x Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0100] Each R y Independently for C 1-6 Alkyl or C 3-6 cycloalkyl; and

[0101] Each R z Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; or alternatively, two R zTogether with the nitrogen atom attached thereto, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S.

[0102] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, salt, or solvate thereof is provided, wherein X 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c ;X 4 For CR 5d The compound of this embodiment has the following structure:

[0103]

[0104] This embodiment includes the following compound, wherein R 5a R 5b R 5c and R 5d One of them is F, Cl, cyano, or -OCH3; and R 5a R 5b R 5c and R 5d The three components are hydrogen.

[0105] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For N; X 2 For CR 5b ;X 3 For CR 5c And X 4 For CR 5d The compound of this embodiment has the following structure:

[0106]

[0107] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For N; X 3 For CR 5c And X 4 For CR 5d The compound of this embodiment has the following structure:

[0108]

[0109] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For CR 5b ;X 3 Let N be the number of elements; and X be the number of elements. 4 For CR 5d The compound of this embodiment has the following structure:

[0110]

[0111] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c And X 4 The value is N. The compound of this embodiment has the following structure:

[0112]

[0113] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For N; X 3 For CR 5c And X 4 The value is N. The compound of this embodiment has the following structure:

[0114]

[0115] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For N; X 2 For CR 5b ;X 3 For CR 5c And X 4 The value is N. The compound of this embodiment has the following structure:

[0116]

[0117] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1For N; X 2 For N; X 3 For CR 5c And X 4 For CR 5d The compound of this embodiment has the following structure:

[0118]

[0119] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For N; X 3 Let N be the number of elements; and X be the number of elements. 4 For CR 5d The compound of this embodiment has the following structure:

[0120]

[0121] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For CR 5b ;X 3 Let N be the number of elements; and X be the number of elements. 4 The value is N. The compound of this embodiment has the following structure:

[0122]

[0123] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c ;X 4 For CR 5d And Z 1 and Z 2 Each is CH2. The compound of this embodiment has the following structure:

[0124]

[0125] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: X 1 For CR 5a ;X 2For CR 5b ;X 3 For CR 5c ;X 4 For CR 5d Z 1 and Z 2 Each is CH2; and a, b, and d are each 1. The compound of this embodiment has the following structure:

[0126]

[0127] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: a is 1; b is 1; and d is 1. The compound of this embodiment has the following structure:

[0128]

[0129] This embodiment includes the following compound, wherein X 1 For CR 5a Or N; X 2 For CR 5b Or N; X 3 For CR 5c Or N; and X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 The 0 or 1 in it is N.

[0130] This embodiment also includes the following compounds, wherein X 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c And X 4 For CR 5d Additionally, this embodiment includes the following compound, wherein R 5a R 5b R 5c and R 5d It is selected from hydrogen and F, with the restriction condition being R. 5a R 5b R 5c and R 5d The 0 or 1 in the value is F.

[0131] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: a is 1; b is 1; d is 1; Z is 1. 1It is CH2; and Z 2 It is CH2. The compound of this embodiment has the following structure:

[0132]

[0133] This embodiment includes the following compound, wherein X 1 For CR 5a Or N; X 2 For CR 5b Or N; X 3 For CR 5c Or N; and X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 The 0 or 1 in the form is N. This embodiment also includes compounds in which R is... 5a R 5b R 5c and R 5d It is selected from hydrogen and F, with the restriction condition being R. 5a R 5b R 5c and R 5d The 0 or 1 in the value is F.

[0134] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: a is 1; b is 1; d is 1; Z is 1. 1 It is CH2; and Z 2 The value is O. The compound of this embodiment has the following structure:

[0135]

[0136] This embodiment includes the following compound, wherein X 1 For CR 5a Or N; X 2 For CR 5b Or N; X 3 For CR 5c Or N; and X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 The 0 or 1 in X is N. This embodiment also includes compounds in which X 1 For CR 5a ;X 2 For CR 5b ;X3 For CR 5c And X 4 For CR 5d Additionally, this embodiment includes the following compound, wherein R 5a R 5b R 5c and R 5d It is selected from hydrogen and F, with the restriction condition being R. 5a R 5b R 5c and R 5d The 0 or 1 in the value is F.

[0137] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: a is 1; b is 1; d is 1; Z is 1. 1 It is O; and Z 2 It is CH2. The compound of this embodiment has the following structure:

[0138]

[0139] This embodiment includes the following compound, wherein X 1 For CR 5a Or N; X 2 For CR 5b Or N; X 3 For CR 5c Or N; and X 4 For CR 5d Or N; its constraint is X 1 X 2 X 3 and X 4 The 0 or 1 in X is N. This embodiment also includes compounds in which X 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c And X 4 For CR 5d Additionally, this embodiment includes the following compound, wherein R 5a R 5b R 5c and R 5d It is selected from hydrogen and F, with the restriction condition being R. 5a R 5b R 5c and R 5d The 0 or 1 in the value is F.

[0140] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein Q is a cyclic group selected from 3 to 8-membered carbocyclic groups, phenyl groups, 4 to 10-membered heterocyclic groups, and 5 to 10-membered heteroaryl groups, wherein the cyclic group is derived from 0 to 3 R... 1 replace;

[0141] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein Q is derived from 0 to 4 R... 1 3 to 8-membered carbon cyclic groups. This embodiment includes compounds in which Q is a C1 to C2 group. 3-6 Cycloalkyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[3.3]heptenyl, spiro[3.4]octyl or oxazhespiro[3.3]heptyl, each via 0 to 4 R 1 replace.

[0142] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein Q is derived from 0 to 4 R... 1 Substituted 6 to 10 aryl groups. This embodiment includes compounds in which Q is phenyl or naphthyl, each substituted with 0 to 4 R groups. 1 Substitution. This embodiment also includes compounds in which Q is derived from 0 to 3 R... 1 Substituted phenyl groups.

[0143] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein Q is derived from 0 to 4 R... 1 Substituted 4- to 10-membered heterocyclic groups. This embodiment includes compounds in which Q is a heterocyclic group consisting of 0 to 4 R groups. 1 Substituted 4- to 6-membered heterocyclic groups. This embodiment also includes compounds in which Q is an aza-butyl, pyrrolidyl, piperazine, piperidinyl, or morpholinyl group.

[0144] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein Q is derived from 0 to 4 R... 1 Substituted 5 to 10 heteroaryl groups. This embodiment includes compounds in which Q is derived from 0 to 4 R groups. 1Substituted 5 to 6 heteroaryl groups. This embodiment also includes compounds wherein Q is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, indazoleyl, indolyl, quinolinyl, isoquinolinyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, 1H-pyrazol[3,4-b]pyridyl, 2,3-dihydrobenzo[d] Oxazolyl, 7,8-dihydro-5H-piperano[4,3-b]pyridyl, benzo[d][1,3]m-dioxacyclopentenyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyridazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, thiazo[4,5-b]pyridyl, thiazo[5,4-b]pyridyl or thieno[3,2-b]pyridyl.

[0145] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein A is a phenyl group or a 5- or 10-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl and heteroaryl groups is derived from 0 to 3 R atoms. 4a replace.

[0146] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein A is a phenyl group or a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O, and S, wherein each of the phenyl and heteroaryl groups is derived from 0 to 3 R atoms. 4a Substitution. This embodiment includes compounds in which A is oxadiazolyl, oxazolyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, or thiazolyl, each substituted with 0 to 2 R groups. 4a Substitution. This embodiment also includes compounds in which A is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is substituted by 0 to 3 R... 4a Substitution. Additionally, this embodiment includes compounds wherein A is derived from 0 to 2 R groups. 4a Substituted phenyl groups.

[0147] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein A is:

[0148]

[0149] This embodiment includes the following compound, wherein A is:

[0150]

[0151] This embodiment also includes the following compounds, wherein A is -C(O)NH (cyclopropyl), -NHS(O)2CF3, -NHC(O)OCH(CH3)2, -NHC(O)NHCH(CH3)2 or -C(O)NHS(O)2 (cyclopropyl).

[0152] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein A is:

[0153]

[0154] This embodiment includes the following compound, wherein A is:

[0155]

[0156] This embodiment also includes the following compounds, wherein A is -C(O)NH (cyclopropyl), -NHS(O)2CF3, -NHC(O)OCH(CH3)2 or -NHC(O)NHCH(CH3)2.

[0157] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 alkoxy or -NR v R v Each of the alkyl, alkenyl, alkynyl and alkoxy groups is derived from 0 to 6 R groups. 2a Substitution. This embodiment includes the following compound, wherein R... 2 C 1-4 Alkyl, C 1-5 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Substitution. This embodiment also includes compounds wherein R... 2 It can be -CH(CH3)2, -NHCH2CH3 or -NHCH2C(CH3)3.

[0158] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 C 3-5 carbonyl group, C 6-8Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Substitution. This embodiment includes the following compound, wherein R... 2 C 3-5 carbonyl group, C 6-8 A spirobicyclic group or a 4- to 5-membered heterocyclic group, wherein each of the carbocyclic group, spirobicyclic group, and heterocyclic group is derived from 0 to 2 R groups. 2b Substitution. This embodiment also includes compounds wherein R... 2 C 3-5 Cycloalkyl, azirrobutyl, oxadiol, pyrrolidyl, and bicyclic [1.1.1]pentyl, each cyclic group being substituted by 0 to 2 independently selected substituents from the following: F, hydroxyl, -CH3, -CHF2, -CF3, -OCH3, -OCH2CH3, -NH2, -N(CH3)2, -NHC(O)OC(CH3)3 and -C(O)CF3.

[0159] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 for:

[0160]

[0161] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 -CH2(C 3-6 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 5-8 (bicycloalkyl), -NR x (CH2) 0-2 (C 5-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (5 to 6 heteroaryl groups), -NR x (CH2) 0-2 (phenyl), -O(CH2) 0-2 (C 3-6 cycloalkyl), -O(CH2) 0-2 (C 5-8 Bicycloalkyl), -O(CH2) 0-2(C 5-8 Spirobicyclic group), -O(CH2) 0-2 (4 to 6-membered heterocyclic group), -O(CH2) 0-2 (5 to 6 heteroaryl groups) or -O(CH2) 0-2 (phenyl), wherein each of the cycloalkyl, heterocyclic, bicycloalkyl, spirobicycloyl, aryl, and heteroaryl groups is determined by 0 to 3 R groups. 2b Substitution. This embodiment includes the following compound, wherein R... 2 -CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-5 cycloalkyl), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(phenyl) or -O(pyridyl), wherein each of the cycloalkyl, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Substitution. This embodiment also includes compounds wherein R... 2 It is -NH (methylcyclopropyl) or -NH (methoxyphenyl).

[0162] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 -CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 6-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O (4 to 6-membered heterocyclic), -O (phenyl) or -O (pyridyl), wherein each of the cycloalkyl, spirobicyclic, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Substitution. This embodiment includes the following compound, wherein R... 2 -CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NRx (CH2) 0-2 (C 6-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(tetrahydropiperanyl), -O(phenyl) or -O(pyridyl), wherein each of the cycloalkyl, spirobicyclo, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b replace.

[0163] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 3a and R 3b Independently hydrogen, C 1-3 Alkyl, C 1-3 fluoroalkyl or C 3-6 cycloalkyl, or R 3a and R 3b Together with the attached carbon atoms, they form C 3-6 Cycloalkyl. This embodiment includes compounds in which R... 3a and R 3b Independently hydrogen, C 1-2 Alkyl, C 1-2 fluoroalkyl or C 3-6 Cycloalkyl. This embodiment also includes compounds wherein R 3a and R 3b Independently, it is hydrogen, -CH3, or -CF3. Additionally, this embodiment includes compounds wherein R... 3a and R 3b One of them is hydrogen, and R 3a and R 3b The other one is hydrogen or -CH3.

[0164] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 1a Independently F, Cl, hydroxyl, -NR w R w , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy or -C(O)OH. This embodiment includes the following compounds, wherein each R... 1a Independently F, hydroxyl, -NR x R x , cyano, C 1-2 Alkoxy, C 1-2 Fluoroalkoxy or -C(O)OH.

[0165] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 1b Independently, it can be a halogen group, oxo group, cyano group, hydroxyl group, -NH2 group, or C group. 1-6 Alkyl, C 1-6 Alkoxy, -NH(C 1-6 alkyl), -N(C) 1-6 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a Substitution. This embodiment includes the following compounds, wherein each R... 1b Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a Substitution. This embodiment also includes the following compounds, wherein each R... 1a It can be F, cyano, hydroxyl, or -OCH3 independently.

[0166] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 1b Independently, it can be F, Cl, Br, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-6 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a Substitution. This embodiment includes the following compounds, wherein each R... 1b Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 alkyl)2 or -NR x C(O)(C 1-4 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1aSubstitution. This embodiment also includes the following compounds, wherein each R... 1b It can be F, Cl, cyano, hydroxyl, -CH3 or -OCH3 independently.

[0167] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R w Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; or alternatively, two R w Together with the nitrogen atom attached thereto, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S.

[0168] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R w Independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. This embodiment includes the following compounds, wherein each R... w Independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl. This embodiment also includes the following compounds, wherein each R... w Independently hydrogen or C 1-3 alkyl.

[0169] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R x Independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl. This embodiment includes the following compounds, wherein each R... x Independently hydrogen or C 1-4 alkyl.

[0170] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R y Independently for C 1-4 Alkyl or C 3-6 Cycloalkyl. This embodiment includes the following compounds, wherein each R... y Independently for C 1-4 alkyl.

[0171] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R z Independently hydrogen, C 1-4 Alkyl or C3-6 cycloalkyl; or alternatively, two R z Together with the nitrogen atom attached thereto, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S.

[0172] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R z Independently hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl. This embodiment includes the following compounds, wherein each R... w Independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl. This embodiment also includes the following compounds, wherein each R... z Independently hydrogen or C 1-3 alkyl.

[0173] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 2a Independently F, Cl, hydroxyl, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH. This embodiment includes the following compounds, wherein each R... 2a Independently F, Cl, hydroxyl, -NR x R x , cyano, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH.

[0174] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 2a Independently, it can be F, Cl, Br, cyano, hydroxyl, oxo group, or C. 1-3 Alkoxy, C 1-3 Fluoroalkoxy or -NR w R w This embodiment includes the following compounds, wherein each R 2a Independently, it is F, Cl, cyano, hydroxyl, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy or -NR x R x This embodiment also includes the following compounds, wherein each R 2a Independently, it is F, cyano, hydroxyl, C 1-2alkoxy or -NR x R x .

[0175] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 2b Independently, it is F, Cl, cyano, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, -NR x R x -NR x C(O)O(C 1-4 Alkyl), -C(O)(C 1-2 alkyl) or -S(O)2(C 1-2 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a replace.

[0176] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 2b Independently, it is F, Cl, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, -NR x R x -NR x C(O)O(C 1-3 Alkyl), -C(O)(C 1-2 alkyl) or -S(O)2(C 1-2 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Substitution. This embodiment includes the following compounds, wherein each R... 2b Independently, it is F, cyano, hydroxyl, C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-2 Alkoxy, -NR x R x -NR x C(O)O(C 1-3 Alkyl), -C(O)(C 1-2 Alkyl), -C(O)(C 1-2 fluoroalkyl) or -S(O)2(C 1-2 alkyl).

[0177] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 4a Independently, it can be F, Cl, Br, cyano, hydroxyl, -NH2, or C.1-6 Alkyl, C 1-4 Alkyl group, -(CH2) 0-3 NH(C 1-4 Alkyl group), -(CH2) 0-2 N(C 1-4 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e Substitution. This embodiment includes the following compounds, wherein each R... 4a Independently, it can be F, Cl, cyano, hydroxyl, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group, -(CH2) 0-3 NH(C 1-6 Alkyl group), -(CH2) 0-3 N(C 1-6 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 4d Substitution; and each of the cycloalkyl and heterocyclic groups is subjected to 0 to 3 R... 4e Substitution. This embodiment also includes the following compounds, wherein each R... 4a Independently, it is cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, -OCH3, -C(O)N(CH3)2, -CH2(cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetyl, tetrahydropiperanyl or fluorobicyclo[1.1.1]pentyl.

[0178] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 4b C 1-4 Alkyl group, -(CH2) 0-3 (C 3-6 cycloalkyl), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (phenyl), wherein each of the alkyl groups is derived from 0 to 6 R... 4dThe cycloalkyl, heterocyclic and phenyl groups are substituted and each of them is subjected to 0 to 3 R groups. 4e replace.

[0179] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 4b C 1-4 Alkyl group, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl groups is derived from 0 to 6 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e Substitution. This embodiment includes the following compound, wherein R... 4b C 1-4 Alkyl group, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl groups is derived from 0 to 4 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e replace.

[0180] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 4c Independently hydrogen, C 1-4 Alkyl or C 3-6 Cycloalkyl. This embodiment includes the following compounds, wherein each R... 4c Independently hydrogen, C 1-3 Alkyl or C 3-6 Cycloalkyl. This embodiment also includes the following compounds, wherein each R... 4c It can be hydrogen or -CH3 independently.

[0181] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 4d Independently F, Cl, hydroxyl, -NR x R x , cyano, C 1-3 Alkoxy or C 1-3 Haloalkoxy groups. This embodiment includes the following compounds, wherein each R... 4d Independently F, Cl, hydroxyl, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Fluoroalkoxy.

[0182] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein each R 4e Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl) or -N(C) 1-4 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R 4d Substitution. This embodiment includes the following compounds, wherein each R... 4e Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group or -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R 4d replace.

[0183] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 for:

[0184]

[0185] And A is through 0 to 2 R 4a Substituted oxadiazole group. This embodiment includes compounds in which Q is derived from 1 to 2 R groups. 1 Substituted phenyl groups. This embodiment also includes compounds wherein Q is a derivative of 0 to 2 R groups. 1 Substituted oxadiazole group.

[0186] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: Q is a cyclic group selected from 3 to 8-membered carbocyclic groups, phenyl groups, 4 to 10-membered heterocyclic groups, and 5 to 10-membered heteroaryl groups, wherein the cyclic group is derived from 0 to 3 R... 1 Replace; each R 1 Independently, it can be F, Cl, Br, cyano, hydroxyl, oxo, or -NR. x R x C 1-5 Alkyl, C 1-4 Alkoxy, -NR x (C 1-4 Alkyl), -NR x C(O)R y -C(O)(C1-4 Alkyl), -C(O)OR x -C(O)NR w R w -S(O)2(C 1-4 Alkyl), -S(O)2(C 3-6 cycloalkyl), -NR x S(O)2(C 1-4 Alkyl), -NR x S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z -P(O)R y R y -(CH2) 0-3 (C 3-6 carbonyl group), -O(C 3-6 Cycloalkyl), -O (4 to 6-membered heterocyclic groups), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (5 or 6 heteroaryl groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 1a The cycloalkyl, heterocyclic and heteroaryl groups are substituted and each of them is subjected to 0 to 3 R... 1b Replace; each R 1a Independently F, Cl, hydroxyl, -NR w R w , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH; each R 1b Independently, it can be F, Cl, cyano, hydroxyl, oxo group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a Replace; R 2 For: (i)C 1-4 Alkyl, C 1-5 alkoxy or -NR v R v Each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; (ii)C 3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2bSubstitution; or (iii)-CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 6-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O (4 to 6-membered heterocyclic), -O (phenyl) or -O (pyridyl), wherein each of the cycloalkyl, spirobicyclic, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Replace; each R 2a Independently F, Cl, hydroxyl, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH; each R 2b Independently, it is F, Cl, cyano, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, -NR x R x -NR x C(O)O(C 1-4 Alkyl), -C(O)(C 1-2 alkyl) or -S(O)2(C 1-2 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Substitution; A is: (i) cyano; (ii) phenyl or a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from N, O and S, wherein each of the phenyl and heteroaryl groups is subjected to 0 to 3 R atoms. 4a Replace; or

[0187]

[0188] Each R 4a Independently, it can be F, Cl, cyano, hydroxyl, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group, -(CH2) 0-3 NH(C 1-6 Alkyl group), -(CH2) 0-3 N(C 1-6 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3(4 to 6 heterocyclic groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 4d Substitution; and each of the cycloalkyl and heterocyclic groups is subjected to 0 to 3 R... 4e Replace; R 4b C 1-4 Alkyl group, -(CH2) 0-3 (C 3-6 cycloalkyl), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (phenyl), wherein each of the alkyl groups is derived from 0 to 6 R... 4d The cycloalkyl, heterocyclic and phenyl groups are substituted and each of them is subjected to 0 to 3 R groups. 4e Replace; each R 4c Independently hydrogen, C 1-3 Alkyl or C 3-6 cycloalkyl; each R 4d Independently F, Cl, hydroxyl, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Fluoroalkoxy; each R 4e Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group or -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R 4d Replace; R 5a R 5b R 5c and R 5d Each is independently hydrogen, F, Cl, hydroxyl, cyano, via 0 to 4 R groups. 5e Replacement C 1-3 Alkyl, via 0 to 4 R 5e Replacement C 1-3 Alkoxy, -C(O)OR x -C(O)NR w R w -S(O)2R y -S(O)2NR z R z Or via 0 to 3 R 5f Substituted phenyl groups; each R w Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; or alternatively, two R wTogether with its attached nitrogen atom, it forms a 4- to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O, and S; each R x Independently for H and C 1-4 Alkyl or C 3-6 cycloalkyl; R y C 1-4 Alkyl or C 3-6 cycloalkyl; and each R z Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; or alternatively, two R z Together with the nitrogen atom attached thereto, it forms a 4 to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O and S.

[0189] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein: each R 1 Independently hydrogen, F, Cl, Br, cyano, hydroxyl, oxo group, -NR x R x C 1-5 Alkyl, C 1-4 Alkoxy, -NR x (C 1-4 Alkyl), -NR x C(O)R y -C(O)(C 1-4 Alkyl), -C(O)OR x -C(O)NR w R w -S(O)2R y -S(O)2(C 1-2 fluoroalkyl), -NR x S(O)2(C 1-3 Alkyl), -NR x S(O)2(C 3-6 cycloalkyl), -S(O)2NR z R z -P(O)R y R y -(CH2) 0-3 (C 3-6 carbonyl group), -O(C 3-6 Cycloalkyl), -O (4 to 6-membered heterocyclic groups), -(CH2) 0-3 (4 to 6-membered heterocyclic group) or -(CH2) 0-3 (5 or 6 heteroaryl groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 1a The cycloalkyl, heterocyclic and heteroaryl groups are substituted and each of them is subjected to 0 to 3 R...1b Replace; each R 1a Independently F, Cl, hydroxyl, -NR x R x , oxo group, cyano group, C 1-3 Alkoxy, C 1-3 Haloalkoxy or -C(O)OH; each R 1b Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkoxy, -NH(C 1-4 alkyl), -N(C) 1-4 alkyl)2 or -NR x C(O)(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 6 R groups. 1a Replace; each R w Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; or alternatively, two R w Together with its attached nitrogen atom, it forms a 4- to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O, and S; each R x Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; each R y Independently for C 1-4 Alkyl or C 3-6 cycloalkyl; each R z Independently hydrogen, C 1-4 Alkyl or C 3-6 cycloalkyl; or alternatively, two R z Together with its attached nitrogen atom, it forms a 4- to 7-membered ring moiety containing 0 to 2 additional heteroatoms independently selected from N, O, and S; R 2 For: (i)C 1-4 Alkyl, C 1-4 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; (ii)C 3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Substitution; or (iii)-CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-5 cycloalkyl), -NR x (CH2)0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(phenyl) or -O(pyridyl), wherein each of the cycloalkyl, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Replace; each R 2a Independently, it is F, Cl, cyano, hydroxyl, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy or -NR x R x Each R 2b Independently, it is F, Cl, cyano, hydroxyl, C 1-4 Alkyl, C 1-3 Alkoxy, -NR x R x -NR x C(O)O(C 1-3 Alkyl), -C(O)(C 1-2 alkyl) or -S(O)2(C 1-2 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; each R 4a Independently, it can be F, Cl, cyano, hydroxyl, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group, -(CH2) 0-3 NH(C 1-6 Alkyl group), -(CH2) 0-3 N(C 1-6 Alkyl group 2, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 4d Substitution; and each of the cycloalkyl and heterocyclic groups is subjected to 0 to 3 R... 4e Replace; R 4b C 1-4 Alkyl group, -(CH2) 0-3 (C 3-6 (cycloalkyl) or -(CH2) 0-3 (4 to 6 heterocyclic groups), wherein each of the alkyl groups is derived from 0 to 4 R groups. 4d The cycloalkyl and heterocyclic groups are substituted and each of them is subjected to 0 to 3 R... 4e Replace; each R 4c Independently hydrogen, C 1-3 Alkyl or C 3-6 cycloalkyl; each R 4d Independently F, Cl, hydroxyl, -NR x Rx , oxo group, cyano group, C 1-3 Alkoxy or C 1-3 Fluoroalkoxy; each R 4e Independently, it can be F, Cl, oxo group, cyano group, hydroxyl group, -NH2, or C. 1-4 Alkyl, C 1-4 Alkyl group or -NH(C 1-6 alkyl) or -N(C) 1-6 Alkyl)2, wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R 4d Replace; and R 5a R 5b R 5c and R 5d Each is independently hydrogen, F, Cl, hydroxyl, cyano, via 0 to 4 R groups. 5e Replacement C 1-3 Alkyl, via 0 to 4 R 5e Replacement C 1-3 Alkoxy, -C(O)OR x -C(O)NR w R w -S(O)2R y -S(O)2NR z R z Or via 0 to 3 R 5f Substituted phenyl groups.

[0190] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein X 1 For CR 5a ;X 2 For CR 5b Or N; X 3 For CR 5c Or N; X 4 For CR 5d Or N; its constraint is X 2 X 3 and X 4 The 0 or 1 in Z represents N; 1 and Z 2 It can be CH2 or O independently; the limiting condition is Z. 1 and Z 2At least one of them is CH2; a is 1; b is 1; d is 1; Q is selected from cyclopropyl, spiro[3.3]heptenyl, phenyl, aziridine, morpholinyl, oxazaspiro[3.3]heptenyl, piperazine, piperidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 2,3-dihydrobenzo[d]oxazolyl, 7,8-dihydro-5H-piperano[4,3-b]pyridinyl, benzo[d][1,3]m-dioxane Cyclic groups of pentenyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazolyl, indazole, indololinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolo[2,1-f][1,2,4]triazinyl, quinolinyl, thiazo[4,5-b]pyridyl, thiazo[5,4-b]pyridyl, thiazolyl, thieno[3,2-b]pyridyl, and triazolyl, wherein the cyclic group is derived from 0 to 2 R... 1 Substitution; A is: (i) pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridinyl, or pyrimidinyl, each via 0 to 2 R groups. 4a Substitution; or (ii) -C(O)NH (cyclopropyl), -NHS(O)2CF3, -NHC(O)OCH(CH3)2 or -NHC(O)NHCH(CH3)2; each R 1 Independently, it can be hydrogen, F, Cl, Br, cyano, hydroxyl, oxo group, or C. 1-4 Alkyl, C 1-2 fluoroalkyl, -CH2Cl, C 1-4 Hydroxyalkyl, -CH2OCH3, C 1-3 Alkoxy, C 1-2 Fluoroalkoxy, -OC(CH3)2CN, -C(O)OCH2CH3, -O (cyclopropyl), -CH2 (cyclopropyl), -NHC(O)CH3, -NHS(O)2CH3, -NHS(O)2CH(CH3)2, -NHS(O)2CF3, -NHS(O)2 (cyclopropyl), -S(O)2CH3, -S(O)2 (cyclopropyl), -S(O)2NH2, acetamidocyclopropyl, cyanocyclopropyl, difluorocyclopropyl, hydroxycyclopropyl, methoxycyclopropyl, cyclohexenyl, dihydropiperanyl, oxetane, methyloxetane, tetrahydropiperanyl, pyridinyl or fluorobicyclo[1.1.1]pentyl; R 2 For: (i)C 1-4 Alkyl, C 1-4 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2aReplace; (ii)C 3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Substitution; or (iii)-CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-5 cycloalkyl), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(phenyl) or -O(pyridyl), wherein each of the cycloalkyl, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Replace; each R 2a Independently, it is F, cyano, hydroxyl, C 1-2 alkoxy or -NR x R x Each R 2b Independently, it is F, cyano, hydroxyl, C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, C 1-2 Alkoxy, -NR x R x -NR x C(O)O(C 1-3 Alkyl), -C(O)(C 1-2 Alkyl), -C(O)(C 1-2 fluoroalkyl) or -S(O)2(C 1-2 Alkyl); R 3a and R 3b One of them is hydrogen and R 3a and R 3b The other one is hydrogen or -CH3; each R 4a Independently, it is cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, -OCH3, -C(O)N(CH3)2, -CH2(cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetyl, tetrahydropiperanyl, or fluorobicyclo[1.1.1]pentyl; and R 5a R 5b R 5c and R 5d Each of them is hydrogen.

[0191] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein X 1 For CR 5a ;X 2 For CR 5b Or N; X 3 For CR 5c Or N; X 4 For CR 5d Or N; its constraint is X 2 X 3 and X 4 N can be 0, 1, or 2 of them;

[0192] Z 1 and Z 2 It can be CH2 or O independently; the limiting condition is Z. 1 and Z 2 At least one of them is CH2; a is 1; b is 1; d is 1; Q is selected from cyclopropyl, spiro[3.3]heptenyl, bicyclo[2.2.2]octyl, phenyl, aziridine, morpholinyl, oxazaspiro[3.3]heptenyl, piperazine, piperidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 2,3-dihydrobenzo[d]oxazolyl, 7,8-dihydro-5H-piperano[4,3-b]pyridinyl, benzo[d][1,3]m-di Cyclic groups of oxacyclopentenyl, benzo[d]oxazolyl, benzo[d]thiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazolyl, indazole, indololinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolo[2,1-f][1,2,4]triazinyl, quinolinyl, tetrahydropyridinyl, thiazo[4,5-b]pyridinyl, thiazo[5,4-b]pyridinyl, thiazolyl, thieno[3,2-b]pyridinyl and triazolyl, wherein the cyclic group is derived from 0 to 2 R... 1 Replace; each R 1 Independently, it can be hydrogen, F, Cl, Br, cyano, hydroxyl, oxo group, or C. 1-4 Alkyl, C 1-2 fluoroalkyl, -CH2Cl, C 1-4 Hydroxyalkyl, -C(CH3)2CN, -CH(OH)CHF2, -CH2OCH3, C 1-4 Alkoxy, C 1-2Fluoroalkoxy, -OCF2Cl, -OC(CH3)2CN, -C(CH3)2OCHF2, -OC(CH3)2C(O)NH2, -C(O)OH, -C(O)O(C 1-2 Alkyl), -C(O)NH2, -O(cyclopropyl), -CH2(cyclopropyl), -CH2(oxetyl), -NHC(O)CH3, -NHS(O)2CH3, -NHS(O)2CH(CH3)2, -NHS(O)2CF3, -NHS(O)2(cyclopropyl), -S(O)2CH3, -S(O)2(cyclopropyl), -S(O)2NH2, cyclopropyl, acetamidocyclopropyl, cyanocyclopropyl, difluorocyclobutyl, hydroxycyclopropyl, methoxycyclopropyl, cyclohexenyl, dihydropiperanyl, oxetyl, methyloxetyl, tetrahydropiperanyl, aminooxadiazolyl, pyridinyl or fluorobicyclo[1.1.1]pentyl; R 2 For: (i)C 1-4 Alkyl, C 1-5 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; (ii)C 3-5 carbonyl group, C 6-8 Spirobicyclic or 4- to 5-membered heterocyclic group, wherein each of the carbocyclic, spirobicyclic, and heterocyclic groups is derived from 0 to 3 R groups. 2b Substitution; or (iii)-CH2(C 3-5 cycloalkyl), -CH2 (4 to 6-membered heterocyclic), -NR x (CH2) 0-2 (C 3-6 cycloalkyl), -NR x (CH2) 0-2 (C 6-8 Spirobicyclic group), -NR x (CH2) 0-2 (4 to 6-membered heterocyclic group), -NR x (CH2) 0-2 (phenyl), -O(tetrahydropiperanyl), -O(phenyl) or -O(pyridyl), wherein each of the cycloalkyl, spirobicyclo, heterocyclic, phenyl and pyridyl groups is derived from 0 to 3 R groups. 2b Replace; each R 2a Independently, it is F, cyano, hydroxyl, C 1-2 alkoxy or -NR x R x Each R 2b Independently, it is F, cyano, hydroxyl, C 1-3 Alkyl, C 1-2 fluoroalkyl, C 1-3 Hydroxyalkyl, C1-2 Alkoxy, C 1-2 Fluoroalkoxy, -NR x R x -NR x C(O)O(C 1-4 Alkyl), -C(O)(C 1-2 Alkyl), -C(O)(C 1-2 fluoroalkyl) or -S(O)2(C 1-2 Alkyl); R 3a and R 3b One of them is hydrogen, and R 3a and R 3b The other one is hydrogen or -CH3; A is: (i) pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, phenyl, pyridinyl or pyrimidinyl, each with 0 to 2 R groups. 4a Substitution; or (ii) -C(O)NH (cyclopropyl), -NHS(O)2CF3, -NHC(O)OCH(CH3)2 or -NHC(O)NHCH(CH3)2 or -C(O)NHS(O)2 (cyclopropyl); each R 4a Independently, it is cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -CF2CH3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, -OCH3, -C(O)N(CH3)2, -CH2(cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetyl, tetrahydropiperanyl, or fluorobicyclo[1.1.1]pentyl; and R 5a R 5b R 5c and R 5d Each is hydrogen.

[0193] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein X 1 For CH; X 2 For CH or N; X 3 For CH or N; X 4 It is CH; its constraint is X. 2 and X 3 The 0 or 1 in Z represents N; 1 and Z 2 It can be CH2 or O independently; the limiting condition is Z. 1 and Z 2At least one of them is CH2; a is 1; b is 1; d is 1; Q is selected from cyclopropyl, aziridine, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazolyl, thiazolyl, triazolyl, morpholinyl, piperazine, phenyl, pyrazine, pyridinyl, pyridinyl, pyrimidinyl, indazole, indololinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 2,3-dihydro Cyclic groups of benzo[d]oxazolyl, 7,8-dihydro-5H-piperano[4,3-b]pyridyl, benzo[d]m-dioxacyclopentenyl, benzo[d]thiazolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyridazinyl, pyrrolo[2,1-f][1,2,4]triazinyl, thiazo[4,5-b]pyridyl, thiazo[5,4-b]pyridyl, thieno[3,2-b]pyridyl, and quinolinyl, wherein the cyclic group is derived from 0 to 2 R... 1 Substitution; A is -C(O)NH (cyclopropyl), phenyl, or a 5 to 6 heteroaryl group selected from oxadiazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, and thiazolyl, wherein each of the phenyl and heteroaryl groups is substituted by 0 to 2 independently selected substituents from: cyano, fluorobicyclo[1.1.1]pentyl, C 1-4 Alkyl, C 1-2 Fluoroalkyl, -C(CH3)2CN, -C(CH3)2OH, -OCH3, -C(O)N(CH3)2, -CH2 (cyclopropyl), cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, methylcyclopropyl, methyloxetyl, and tetrahydropiperanyl; R 2 -CH(CH3)2, -NHCH2CH3, -NHCH2C(CH3)3, -NH (methylcyclopropyl), -NH (methoxyphenyl) or selected from C 3-5 Cyclic groups of cycloalkyl, aziridine, oxadiazine, pyrrolidinyl, and bicyclic [1.1.1]pentyl, each cyclic group being substituted by 0 to 2 independently selected substituents from: F, hydroxyl, cyano, -CH3, -CHF2, -CF3, -C(CH3)2OH, -OCH3, -OCH2CH3, -NH2, -N(CH3)2, -NHC(O)OC(CH3)3, and -C(O)CF3; each R 1 Independently for C 1-4Alkyl, -CHF2, -CF3, -CH2CF3, -CF2CH3, -CH2CHF2, -CH2Cl, -C(CH3)2OH, -CH2OCH3, -C(CH3)2OCH3, -OCH3, -OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, -CH2(cyclopropyl), -S(O)2CH3, -S(O)2(cyclopropyl), oxo, difluorocyclobutyl, fluorobicyclo[1.1.1]pentyl, oxetane, methyloxetane, pyridinyl, tetrahydropiperanyl or cyclopropyl substituted with 0 to 1 substituent selected from hydroxyl, -CH3, -OCH3 and -NHC(O)CH3; R 3a It is hydrogen or -CH3; and R 3b It is hydrogen.

[0194] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein X 1 For CH; X 2 For CH; X 3 For CH; X 4 CH; Z 1 CH2; Z 2 CH2; a is 1; b is 1; d is 1; A is obtained through an R 4a Substituted oxadiazole group; R 2 For 0 to 2 R 2b Substituted cyclobutyl; and each R 2b Independently, it is F, hydroxyl, cyano, -CHF2, -CF3, -C(CH3)2OH, -OCH3, or -OCH2CH3. This embodiment includes compounds in which Q is benzo[d]thiazolyl, imidazolyl, isoxazolyl, oxazolyl, phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, each with 0 to 2 R... 1 Substitution. This embodiment also includes compounds in which Q is oxadiazolyl, oxazolyl, phenyl, or pyrimidinyl, each oxidized by 0 to 2 R... 1 replace.

[0195] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein R 2 For 0 to 6 R 2a Replacement C 1-6 Alkoxy. This embodiment includes compounds in which R... 2 For 0 to 3 R 2a Replacement C 2-4 Alkoxy. This embodiment also includes compounds in which R... 2The compounds are -OCH2CH3, -OCH(CH3)2, -OCH2CH(CH3)2, -OC(CH3)2CN, and -OC(CH3)2CF3. Additionally, this embodiment includes the following compounds, wherein R... 2 For -OC(CH3)2CN and -OC(CH3)2CF3; A is derived from 0 to 2 R 4a Substituted oxadiazole group; and Q is phenyl, oxazolyl, or derived from 0 to 2 R groups. 1b Substituted oxadiazole group.

[0196] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0197]

[0198] Where R 2 For 0 to 3 R 2a Replacement C 2-4 Alkoxy. This embodiment includes compounds in which R... 2 The compounds are -OC(CH3)2CN and -OC(CH3)2CF3. This embodiment also includes compounds in which A is an oxadiazolyl group with 0 to 2 R... 4a Substitution; and Q is phenyl, oxazolyl, or via 0 to 2 R groups. 1b Substituted oxadiazole group.

[0199] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0200]

[0201] This embodiment includes the following compound, wherein R 2b It is F, cyano, or -C(CH3)2OH. This embodiment also includes compounds in which X... 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c ;X 4 For CR 5d And R 5a R 5b R 5c and R 5d One of them is hydrogen, F, Cl, cyano, or -OCH3, and R 5a R 5b R 5c and R5d The other three components are each hydrogen. Additionally, this embodiment includes the following compound, wherein Z... 1 It is CH2 and Z 2 It is CH2.

[0202] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0203]

[0204] This embodiment includes the following compound, wherein R 2b It is F, cyano, or -C(CH3)2OH. This embodiment also includes compounds in which R... 5c and R 5d One of them is hydrogen, F, Cl, cyano, or -OCH3, and R 5c and R 5d The other component is hydrogen. Additionally, this embodiment includes the following compound, wherein R... 2b For F; R 5c It is hydrogen; and R 5d It is hydrogen.

[0205] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0206]

[0207] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0208]

[0209] This embodiment includes the following compound, wherein R 4a The compounds are -CH(CH3)2, -CH2F, -CF3, -CF2CH3, cyclopropyl, fluorocyclopropyl, or methylcyclopropyl. This embodiment also includes compounds in which Q is phenyl or derived from 1 to 2 R groups. 1 Substituted oxadiazolyl group. Additionally, this embodiment includes compounds wherein Q is a phenyl group substituted with -C(CH3)2OH, -C(CH3)2OCHF2, -OCH(CH3)2, or -OC(CH3)2CN or cyanocyclopropyl.

[0210] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0211]

[0212] Where R 5c and R 5d One of them is hydrogen and R 5c and R 5d The other one is hydrogen or F; one R 2b It is a hydroxyl group and another R 2b -CH3, -CH2CH3, or -CF3; R 1 It is -C(CH3)2OH, -C(CH3)2OCHF2, -OCH(CH3)2, -OC(CH3)2CN or cyanocyclopropyl; and R 4a The form is -CF2CH3, -CH(CH3)2, -C(CH3)2F, cyclopropyl, or fluorocyclopropyl. This embodiment includes compounds in which one R... 2b It is a hydroxyl group and another R 2b It is -CH3 or -CH2CH3. This embodiment also includes the following compounds, one of which R 2b It is a hydroxyl group and another R 2b It is -CF3.

[0213] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0214]

[0215] This embodiment includes the following compound, wherein Q is an R-transfer compound. 4a Substituted phenyl groups. Additionally, this embodiment includes compounds in which Q is a phenyl group and A is a phenyl group derived from R... 4a Substituted oxadiazole group; and R 2 For: (i)C 1-4 Alkyl, C 1-5 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; or (ii) via 0 to 3 R 2b Replacement C 3-6 Cycloalkyl.

[0216] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0217]

[0218] This embodiment includes the following compound, wherein R 2 For: (i)C 1-5 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; or (ii) via 1 to 3 R 2b Substituted cyclobutyl. This embodiment also includes compounds in which R... 4a For 1 to 6 R 4d Replacement C 2-3 Alkyl groups; each R 4d For F; R 1 For a R 1a Replacement C 2-3 Alkyl; and R 1a The hydroxyl group is present. Additionally, this embodiment includes the following compound, wherein R... 4a It is -CF3 or -C(CH3)2F. Furthermore, this embodiment includes the following compound, wherein R... 1 It is -C(CH3)2OH.

[0219] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0220]

[0221] This embodiment includes the following compound, wherein R 4a The compounds are cyano, -CH3, -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, -OCH3, -C(O)N(CH3)2, -CH2(cyclopropyl), cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, difluorocyclopropyl, methyloxetyl, tetrahydropiperanyl, or fluorobicyclo[1.1.1]pentyl. This embodiment also includes the following compounds, wherein each R... 1 Independently hydrogen, F, oxo group, C 1-3 Alkyl, -CHF2, -C(CH3)2OH, -CH2OCH3, C 1-3 Alkoxy, -OCHF2, -OC(CH3)2CN, -O (cyclopropyl), -CH2 (cyclopropyl), -NHS(O)2CH3, cyclopropyl, cyanocyclopropyl, dihydropiperanyl or tetrahydropiperanyl.

[0222] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0223]

[0224] Where R 4a For 0 to 6 R 4d Replacement C 1-3 Alkyl groups; each R 4d For F; R 1 For 0 to 2 R 1a Replacement C 1-3 Alkyl groups; and each R 1a The hydroxyl group is present. This embodiment includes the following compound, wherein R is a hydroxyl group. 4a For 1 to 6 R 4d Replacement C 2-3 Alkyl groups; each R 4d For F; R 1 For a R 1a Replacement C 2-3 Alkyl; and R 1a The hydroxyl group is present. Additionally, this embodiment includes the following compound, wherein R... 4a It is -CF3 or -C(CH3)2F. Furthermore, this embodiment includes the following compound, wherein R... 1 It is -C(CH3)2OH.

[0225] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0226]

[0227] Where R 2 -NH(C 1-6 Alkyl), wherein the alkyl group has 0 to 4 R 2a Substitution. This embodiment includes the following compound, wherein R... 2 -NH(C 2-4 Alkyl), wherein the alkyl group is derived from 0 to 2 R 2a Substitution. This embodiment also includes compounds wherein R... 2 The compounds are -NH(CH2CH3), -NH(CH(CH3)2), -NH(CH2CH(CH3)2), or -NH(C(CH3)3). Additionally, this embodiment includes the following compound, wherein R... 2 It is -NH(CH2CH3), -NH(CH(CH3)2), -NH(CH2CH(CH3)2) or -NH(C(CH3)3); and R1 It is C(CH3)2OH.

[0228] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0229]

[0230] This embodiment includes the following compound, wherein R 2b The radical is hydroxyl, -CH3, or -CF3. This embodiment also includes compounds in which X... 1 For CR 5a ;X 2 For CR 5b ;X 3 For CR 5c ;X 4 For CR 5d And R 5a R 5b R 5c and R 5d One of them is hydrogen, F, Cl, cyano, or -OCH3, and R 5a R 5b R 5c and R 5d The other three are each hydrogen; and Z 1 CH2 and Z 2 CH2. This embodiment includes compounds having the following structures:

[0231]

[0232] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt is provided, wherein the compound is:

[0233]

[0234]

[0235] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt is provided, wherein the compound is:

[0236]

[0237] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt is provided, wherein the compound is:

[0238]

[0239] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt is provided, wherein the compound is:

[0240]

[0241] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0242]

[0243] This embodiment includes the following compound, wherein Q is an R-transfer compound. 4a Substituted phenyl groups. This embodiment also includes compounds in which Q is a phenyl group and A is a substituted phenyl group. 4a Substituted oxadiazole or pyridinyl; and R 2 For: (i)C 1-4 Alkyl, C 1-5 Alkyl group or -NH(C 1-6 Alkyl), wherein each of the alkyl and alkoxy groups is derived from 0 to 4 R groups. 2a Replace; or (ii) via 0 to 3 R 2b Replacement C 3-5 Cycloalkyl. Additionally, this embodiment includes compounds in which A is an oxadiazolyl or pyridinyl group substituted with -CF2CH3.

[0244] In one embodiment, a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof is provided, wherein the compound has the structure:

[0245]

[0246] This embodiment includes the following compound, wherein R 2 C 1-5 Alkyl groups, wherein the alkoxy group is formed by 0 to 4 R groups. 2a Substitution. This embodiment also includes compounds wherein R... 1 The form is -C(CH3)2OH. Additionally, this embodiment includes the following compound, wherein A is an oxadiazolyl or pyridinyl group, each substituted with -CF2CH3; R... 1 It is -C(CH3)2OH; and R 2 It is -OC(CH3)2CF3.

[0247] In one embodiment, the present invention provides a compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

[0248] N-((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)isobutyramide (1);

[0249] N-((4-(4-cyclopropylphenyl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)cyclopropaneformamide (2);

[0250] N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (3);

[0251] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)cyclobutane-1-carboxamide (4);

[0252] (1s, 3s)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (5);

[0253] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (6);

[0254] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxyoxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (7);

[0255] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (8);

[0256] (1s, 3s)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (9);

[0257] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (10);

[0258] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (11);

[0259] 2-(3-(3-fluoro-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamido)phenyl)oxazol-4-carboxylic acid ethyl ester (12);

[0260] 2-(3-(N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carbamate)phenyl)oxazol-4-carboxylic acid ethyl ester (13);

[0261] N-(3-(4-(chloromethyl)oxazol-2-yl)phenyl)-N-((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 (14);

[0262] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-(2-hydroxypropane-2-yl)oxadiazol-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (15);

[0263] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(4-(2-hydroxypropane-2-yl)oxadiazol-2-yl)phenyl)cyclobutane-1-carboxamide (16);

[0264] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(4-(2-hydroxypropane-2-yl)oxadiazol-2-yl)phenyl)cyclobutane-1-carboxamide (17);

[0265] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(4-(2-hydroxypropane-2-yl)oxadiazol-2-yl)phenyl)cyclopentane-1-carboxamide (18);

[0266] (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(3-(3-(2-hydroxypropane-2-yl)-1,2,4-oxadiazol-5-yl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (19);

[0267] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)cyclobutaneformamide (20);

[0268] (1S,3S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (21);

[0269] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (22);

[0270] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (23);

[0271] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (24);

[0272] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxyisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (25);

[0273] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-propyloxazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (26);

[0274] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-propyloxazol-5-yl)phenyl)cyclobutane-1-carboxamide (27);

[0275] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(2-propyloxazol-5-yl)phenyl)cyclobutane-1-carboxamide (28);

[0276] 4-(3-(N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carbamate)phenyl)thiazole-2-carboxylic acid ethyl ester (29);

[0277] N-(3-(2-(chloromethyl)thiazolyl-4-yl)phenyl)-N-((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 (30);

[0278] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(2-hydroxypropane-2-yl)thiazolyl-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (31);

[0279] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (32);

[0280] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclopentane-1-carboxamide (33);

[0281] 3-Fluoro-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-(tetrahydro-2H-piperan-4-yl)oxazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (34);

[0282] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(tetrahydro-2H-piperan-4-yl)oxadiazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (35);

[0283] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-(tetrahydro-2H-piperan-4-yl)oxadiazol-5-yl)phenyl)cyclobutane-1-carboxamide (36);

[0284] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (37);

[0285] (1S,3S)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-hydroxy-N-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (38);

[0286] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclopentane-1-carboxamide (39);

[0287] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-(difluoromethyl)oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (40);

[0288] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-(difluoromethyl)oxadiazol-2-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (41);

[0289] (1s, 3s)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (42);

[0290] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(4-(difluoromethyl)oxadiazol-2-yl)phenyl)cyclobutane-1-carboxamide (43);

[0291] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-(difluoromethyl)oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (44);

[0292] N-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-fluoro-N-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (45);

[0293] (cis)-N-(3-(4-(difluoromethyl)oxazol-2-yl)phenyl)-3-hydroxy-N-((4-(5-methyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (46);

[0294] N-((1-(4-(2-cyanopropane-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (47);

[0295] N-((1-(4-(2-cyanopropane-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-ethyl-1,2,4-oxadiazol-5-yl)phenyl)cyclobutaneformamide (48);

[0296] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (49);

[0297] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (50);

[0298] N-((1-(4-(2-cyanopropane-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-ethoxyoxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (51);

[0299] 3-Fluoro-N-(3-(2-propyloxazol-5-yl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (52);

[0300] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxy-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (53);

[0301] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxy-1,3,4-oxadiazol-2-yl)phenyl)cyclobutaneformamide (54);

[0302] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxy-1,3,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (55);

[0303] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(5-ethoxy-1,3,4-oxadiazol-2-yl)phenyl)cyclobutane-1-carboxamide (56);

[0304] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (57);

[0305] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (58);

[0306] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (59);

[0307] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (60);

[0308] N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (61);

[0309] N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (62);

[0310] N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (63);

[0311] N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclobutaneformamide (64);

[0312] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (65);

[0313] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)cyclobutaneformamide (66);

[0314] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (67);

[0315] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (68);

[0316] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide (69);

[0317] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (70);

[0318] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-(cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutaneformamide (71);

[0319] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(methoxymethyl)thiazolyl-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (72);

[0320] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(2-(methoxymethyl)thiazolyl-4-yl)phenyl)cyclobutane-1-carboxamide (73);

[0321] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-(methoxymethyl)thiazolyl-4-yl)phenyl)cyclopentane-1-carboxamide (74);

[0322] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (75);

[0323] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (76);

[0324] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (77);

[0325] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (78);

[0326] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-(2-methoxypropane-2-yl)oxadiazol-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (79);

[0327] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-ethyl-2-oxo-2,3-dihydrooxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (80);

[0328] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-ethyl-2-oxo-2,3-dihydrooxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (81);

[0329] N-((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (82);

[0330] N-((4-(4-cyclopropyloxazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (83);

[0331] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(4-(methoxymethyl)oxazol-2-yl)phenyl)cyclobutane-1-carboxamide (84);

[0332] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-(methoxymethyl)oxazol-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (85);

[0333] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (86);

[0334] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (87);

[0335] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (88);

[0336] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (89);

[0337] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(3-(tetrahydro-2H-piperan-4-yl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (90);

[0338] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-1-carboxamide (91);

[0339] 1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-neopentylurea (92);

[0340] (S)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-(dimethylamino)pyrrolidone-1-carboxamide (93);

[0341] 1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-(1-methylcyclopropyl)urea(94);

[0342] 1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-ethylurea (95);

[0343] 1-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-(4-methoxyphenyl)urea(96);

[0344] N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (97);

[0345] N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (98);

[0346] N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclopentane-1-carboxamide (99);

[0347] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (100);

[0348] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(4-cyclopropylthiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (101);

[0349] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(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);

[0350] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-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);

[0351] N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-N-((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 (104);

[0352] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (105);

[0353] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (106);

[0354] N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((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 (107);

[0355] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (108);

[0356] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (109);

[0357] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-hydroxycyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (110);

[0358] 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]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (111);

[0359] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-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);

[0360] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(3-methyloxacyclobutane-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (113);

[0361] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentan-1-carboxamide (114);

[0362] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (115);

[0363] N-((4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (116);

[0364] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (117);

[0365] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (118);

[0366] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (119);

[0367] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (120);

[0368] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-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 (121);

[0369] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(5-(3-methyloxacyclobutane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (122);

[0370] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-(2,2-difluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (123);

[0371] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1-methyl-1H-pyrazole-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (124);

[0372] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1-methyl-1H-pyrazole-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (125);

[0373] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazole-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (126);

[0374] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazole-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (127);

[0375] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((1-(4-methoxyphenyl)-2-oxadiazol-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (128);

[0376] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluoro-N-((1-(4-methoxyphenyl)-2-oxadiazol-4-yl)methyl)cyclobutane-1-carboxamide (129);

[0377] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (130);

[0378] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (131);

[0379] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-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);

[0380] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (133);

[0381] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (134);

[0382] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (135);

[0383] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (136);

[0384] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (137);

[0385] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (138);

[0386] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (139);

[0387] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((1-(2-methoxypyrimidin-5-yl)-2-oxadiazol-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (140);

[0388] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (141);

[0389] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (142);

[0390] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (143);

[0391] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (144);

[0392] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (145);

[0393] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (146);

[0394] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methoxycyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (147);

[0395] N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluoro-N-((4-(2-methoxypyrimidin-4-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (148);

[0396] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(oxecyclobutane-3-yl)-1H-pyrazole-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (149);

[0397] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(oxacyclobutane-3-yl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (150);

[0398] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-methylthiazolyl-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (151);

[0399] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(pyridin-3-yl)-1H-pyrazol-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (152);

[0400] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (153);

[0401] N-(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]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (154);

[0402] N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluoro-N-((4-(5-(3-methyloxacyclobutane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (155);

[0403] N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (156);

[0404] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (157);

[0405] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(cyclopropylsulfonyl)-1H-pyrazole-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (158);

[0406] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(1-(methanesulfonyl)-1H-pyrazole-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (159);

[0407] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (160);

[0408] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (161);

[0409] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (162);

[0410] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (163);

[0411] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (164);

[0412] N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (165);

[0413] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (166);

[0414] N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (167);

[0415] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (168);

[0416] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (169);

[0417] N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (170);

[0418] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (171);

[0419] N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (172);

[0420] N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(3-methyloxetane-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (173);

[0421] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(3-methyloxetane-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (174);

[0422] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (175);

[0423] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (176);

[0424] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (177);

[0425] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (178);

[0426] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (179);

[0427] 3-Fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5-(3-methyloxacyclobutane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (180);

[0428] 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]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (181);

[0429] N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (182);

[0430] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (183);

[0431] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (184);

[0432] N-(3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (185);

[0433] 3-Fluoro-N-(3-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (186);

[0434] 3-Fluoro-N-(3-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenyl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (187);

[0435] N-(3-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (188);

[0436] N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (189);

[0437] N-(3-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (190);

[0438] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-methyloxetane-3-carboxamide (191);

[0439] (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-methoxycyclobutane-1-carboxamide (192);

[0440] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-1-(2,2,2-trifluoroacetyl)azacyclobutane-3-carboxamide (193);

[0441] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-(methylsulfonyl)-1H-pyrazole-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (194);

[0442] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(cyclopropylsulfonyl)-1H-pyrazole-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (195);

[0443] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (196);

[0444] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (197);

[0445] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (198);

[0446] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (199);

[0447] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3,3-difluorocyclobutane-1-carboxamide (200);

[0448] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3-(difluoromethyl)cyclobutane-1-carboxamide (201);

[0449] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3,3-difluorocyclopentane-1-carboxamide (202);

[0450] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-cyclopropylisoxazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (203);

[0451] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (204);

[0452] N-(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (205);

[0453] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (206);

[0454] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (207);

[0455] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(cyclopropylsulfonyl)-1H-pyrazole-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (208);

[0456] N-(3-(1H-pyrazol-4-yl)phenyl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (209);

[0457] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (210);

[0458] N-(4-(1H-pyrazol-4-yl)pyridin-2-yl)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (211);

[0459] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (212);

[0460] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (213);

[0461] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (214);

[0462] N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)ethyl)-N-(3-(2-cyclopropyloxazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (215-216);

[0463] N-(1-(4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)ethyl)-N-(3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (217-218);

[0464] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (219);

[0465] 3,3-Difluoro-N-(3′-methoxy-[1,1′-biphenyl]-3-yl)-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (220);

[0466] 3-Fluoro-N-(3′-methoxy-[1,1′-biphenyl]-3-yl)-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (221);

[0467] N-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (222);

[0468] N-((1-(4-(2-cyanopropane-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-methoxypyridin-4-yl)phenyl)cyclobutaneformamide (223);

[0469] N-((1-(4-(2-cyanopropan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-methoxypyridin-4-yl)phenyl)cyclopentaneformamide (224);

[0470] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(4-ethoxypyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (225);

[0471] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyridin-4-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (226);

[0472] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(3-(tetrahydro-2H-piperan-4-yl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (227);

[0473] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (228);

[0474] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (229);

[0475] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (230);

[0476] N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutaneformamide (231);

[0477] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (232);

[0478] N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclopentaneformamide (233);

[0479] 3,3-Difluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (234);

[0480] 3,3-Difluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclopentane-1-carboxamide (235);

[0481] (1S,3S)-3-hydroxy-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(5-methyl-1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (236);

[0482] 3,3-Difluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (237);

[0483] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(2-methylpyridin-4-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (238);

[0484] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (239);

[0485] N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutaneformamide (240);

[0486] 3-Fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (241);

[0487] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyrimidin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (242);

[0488] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-methoxypyrimidin-4-yl)phenyl)cyclobutane-1-carboxamide (243);

[0489] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-methoxypyrimidin-4-yl)phenyl)cyclobutaneformamide (244);

[0490] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-methoxypyrimidin-4-yl)phenyl)cyclopentane-1-carboxamide (245);

[0491] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (246);

[0492] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-fluoro-5-methylpyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (247);

[0493] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (248);

[0494] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-methoxypyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (249);

[0495] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3′,5′-dichloro-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (250);

[0496] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (251);

[0497] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (252);

[0498] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (253);

[0499] N-(3′-acetamido-[1,1′-biphenyl]-3-yl)-N-((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 (254);

[0500] N-(3-(benzo[d][1,3]m-dioxacyclopenten-5-yl)phenyl)-N-((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 (255);

[0501] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (256);

[0502] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3′-aminosulfonyl-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (257);

[0503] N-(3′-cyano-[1,1′-biphenyl]-3-yl)-N-((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 (258);

[0504] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (259);

[0505] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-fluoro-3′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (260);

[0506] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (261);

[0507] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (262);

[0508] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (263);

[0509] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (264);

[0510] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (265);

[0511] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (266);

[0512] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-((trifluoromethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (267);

[0513] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-((1-methylethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (268);

[0514] N-(4′-(cyclopropanesulfonamide)-[1,1′-biphenyl]-3-yl)-N-((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 (269);

[0515] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-(methylsulfonamido)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (270);

[0516] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (271);

[0517] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(methylsulfonamido)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (272);

[0518] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methoxymethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (273);

[0519] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-(methoxymethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (274);

[0520] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (275);

[0521] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (276);

[0522] N-(3-(benzo[d]thiazolyl-6-yl)phenyl)-N-((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);

[0523] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylthiazo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (278);

[0524] N-(4′-(1-cyanocyclopropyl)-[1,1′-biphenyl]-3-yl)-N-((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 (279);

[0525] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (280);

[0526] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (281);

[0527] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (282);

[0528] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-ethoxypyridazin-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (283);

[0529] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,2-difluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (284);

[0530] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethyl-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (285);

[0531] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3′,4′-dichloro-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (286);

[0532] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-fluoropyridin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (287);

[0533] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(imidazo[1,2-a]pyridin-7-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (288);

[0534] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (289);

[0535] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (290);

[0536] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-(trifluoromethyl)pyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (291);

[0537] N-(3-(6-cyanopyridin-2-yl)phenyl)-N-((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 (292);

[0538] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (293);

[0539] N-(3′-cyano-4′-fluoro-[1,1′-biphenyl]-3-yl)-N-((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 (294);

[0540] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-methylpyridazin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (295);

[0541] N-(3′-cyano-4′-methoxy-[1,1′-biphenyl]-3-yl)-N-((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 (296);

[0542] N-(3-(5-cyanopyridin-2-yl)phenyl)-N-((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 (297);

[0543] N-(3-([1,2,4]triazolo[1,5-a]pyridin-7-yl)phenyl)-N-((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 (298);

[0544] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3′-(1,1,2,2-tetrafluoroethoxy)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (299);

[0545] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (300);

[0546] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3′,4′-dimethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (301);

[0547] N-(4′-cyano-[1,1′-biphenyl]-3-yl)-N-((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 (302);

[0548] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (303);

[0549] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(1-methyl-1H-indazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (304);

[0550] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]oxadiazol-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (305);

[0551] 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]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (306);

[0552] N-(3-([1,2,4]triazolo[4,3-a]pyridin-7-yl)phenyl)-N-((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 (307);

[0553] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (308);

[0554] N-(3-([1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl)-N-((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 (309);

[0555] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methylpyrazin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (310);

[0556] N-(3-(8-cyanoquinoline-5-yl)phenyl)-N-((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 (311);

[0557] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (312);

[0558] N-(3-(5-cyano-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl)-N-((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 (313);

[0559] 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]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (314);

[0560] N-(3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)-N-((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 (315);

[0561] N-(3-(6-cyanothiophene[3,2-b]pyridin-5-yl)phenyl)-N-((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 (316);

[0562] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(8-fluoroimidazo[1,2-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (317);

[0563] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(imidazo[1,2-b]pyridazin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (318);

[0564] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(7-methylimidazo[1,2-b]pyridazin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (319);

[0565] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (320);

[0566] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methyl-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (321);

[0567] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (322);

[0568] N-(3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)-N-((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 (323);

[0569] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (324);

[0570] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methylpyridin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (325);

[0571] N-(3-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl)-N-((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 (326);

[0572] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(7-methylthiazo[5,4-b]pyridin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (327);

[0573] N-(3-(3-cyano-7,8-dihydro-5H-piperano[4,3-b]pyridin-2-yl)phenyl)-N-((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 (328);

[0574] N-(3-(7-chloroimidazolo[1,2-b]pyridazin-3-yl)phenyl)-N-((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 (329);

[0575] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(imidazo[1,2-a]pyridin-8-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (330);

[0576] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-hydroxyquinoline-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (331);

[0577] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-oxoindoline-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (332);

[0578] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (333);

[0579] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methoxypyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (334);

[0580] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (335);

[0581] N-(3-(2-acetamidoimidazo[1,2-b]pyridazin-6-yl)phenyl)-N-((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 (336);

[0582] N-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-N-((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 (337);

[0583] N-(3-(2-cyclopropoxypyrimidin-4-yl)phenyl)-N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluorocyclobutane-1-carboxamide (338);

[0584] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (339);

[0585] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(2′-methoxy-[4,4′-bipyridine]-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (340);

[0586] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (341);

[0587] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (342);

[0588] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-methoxypyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (343);

[0589] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (344);

[0590] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (345);

[0591] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (346);

[0592] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (347);

[0593] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (348);

[0594] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (349);

[0595] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(6-methoxypyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (350);

[0596] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (351);

[0597] N-((1-(4-(1-cyanocyclopropyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (352);

[0598] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (353);

[0599] N-(4′-(cyclopropanesulfonamide)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (354);

[0600] 3-Fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (355);

[0601] 3-Fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)-N-((4-(4-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (356);

[0602] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (357);

[0603] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (358);

[0604] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (359);

[0605] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (360);

[0606] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (361);

[0607] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (362);

[0608] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (363);

[0609] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(6-(methylsulfonamido)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (364);

[0610] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylthiazo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (365);

[0611] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (366);

[0612] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(methylsulfonamido)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (367);

[0613] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (368);

[0614] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methoxypyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (369);

[0615] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (370);

[0616] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (371);

[0617] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-((trifluoromethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (372);

[0618] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (373);

[0619] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (374);

[0620] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (375);

[0621] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (376);

[0622] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (377);

[0623] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (378);

[0624] N-(4′-(cyclopropanesulfonamide)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (379);

[0625] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (380);

[0626] N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (381);

[0627] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-methoxypyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (382);

[0628] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-methoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (383);

[0629] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (384);

[0630] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (385);

[0631] N-(3-(2,2-difluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (386);

[0632] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (387);

[0633] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-(trifluoromethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (388);

[0634] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-methylthiazo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (389);

[0635] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-((trifluoromethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (390);

[0636] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-(methoxymethyl)pyridin-3-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (391);

[0637] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(methoxymethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (392);

[0638] 3-Fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (393);

[0639] N-(3-(5-ethylpyrimidin-2-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (394);

[0640] N-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluoro-N-((4-(3-isopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (395);

[0641] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (396);

[0642] N-(4′-(cyclopropanesulfonamide)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (397);

[0643] 3-Fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (398);

[0644] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (399);

[0645] 3-Fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (400);

[0646] N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (401);

[0647] 3-Fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (402);

[0648] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (403);

[0649] 3-Fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (404);

[0650] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1-methylcyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (405);

[0651] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methanesulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (406);

[0652] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (407);

[0653] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (408);

[0654] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (409);

[0655] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (410);

[0656] N-((4-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (411);

[0657] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (412);

[0658] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (413);

[0659] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (414);

[0660] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (415);

[0661] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-methylpiperazin-1-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (416);

[0662] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-N-morpholinylphenyl)bicyclo[1.1.1]pentane-1-carboxamide (417);

[0663] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (418);

[0664] 3-Fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (419);

[0665] 3-Fluoro-N-(4′-methoxy-[1,1′-biphenyl]-3-yl)-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (420);

[0666] 3-Fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (421);

[0667] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((1-(2-(trifluoromethyl)pyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (422);

[0668] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(2-ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (423);

[0669] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(4-ethoxyphenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (424);

[0670] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-methylbenzo[d]thiazolyl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (425);

[0671] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(6′-ethoxy-[3,3′-bipyridine]-5-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (426);

[0672] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (427);

[0673] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (428);

[0674] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (429);

[0675] 3-Fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (430);

[0676] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (431);

[0677] N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (432);

[0678] 3-Fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (433);

[0679] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (434);

[0680] 3-Fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (435);

[0681] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (436);

[0682] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (437);

[0683] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (438);

[0684] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (439);

[0685] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (440);

[0686] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (441);

[0687] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (442);

[0688] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (443);

[0689] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (444);

[0690] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (445);

[0691] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-((trifluoromethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (446);

[0692] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (447);

[0693] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-((1-methylethyl)sulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (448);

[0694] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylthiazo[4,5-b]pyridin-6-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (449);

[0695] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methoxypyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (450);

[0696] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (451);

[0697] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (452);

[0698] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-ethylpyrimidin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (453);

[0699] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-methylpyrimidin-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (454);

[0700] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (455);

[0701] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethyl-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (456);

[0702] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,2-difluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (457);

[0703] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethyl-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (458);

[0704] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2,2-difluorobenzo[d][1,3]m-dioxacyclopenten-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (457);

[0705] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (458);

[0706] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (459);

[0707] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (460);

[0708] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (460);

[0709] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (462);

[0710] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (463);

[0711] N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (464);

[0712] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(difluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (465);

[0713] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (466);

[0714] N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (467);

[0715] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (468);

[0716] N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (469);

[0717] N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (470);

[0718] N-((4-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (471);

[0719] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(2-ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (472);

[0720] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(2-cyclopropylpyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (473);

[0721] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-methylbenzo[d]thiazolyl-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (474);

[0722] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(4-(methylsulfonamido)phenyl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (475);

[0723] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(4-ethoxyphenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (476);

[0724] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(6′-ethoxy-[3,3′-bipyridine]-5-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (477);

[0725] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(2-ethoxypyrimidin-5-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (478);

[0726] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (479);

[0727] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (480);

[0728] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(4-(methylsulfonamido)phenyl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (481);

[0729] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(4-ethoxyphenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (482);

[0730] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(4-(difluoromethoxy)phenyl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (483);

[0731] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(5-(2-methylbenzo[d]thiazolyl)pyridin-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (484);

[0732] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(5-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (485);

[0733] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(difluoromethoxy)-[2,3′-bipyridine]-5′-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (486);

[0734] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (487);

[0735] 3-Fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (488);

[0736] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (489);

[0737] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (490);

[0738] 3-Fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-(trifluoromethyl)pyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (491);

[0739] N-(3-(6-ethoxypyridin-3-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (492);

[0740] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (493);

[0741] 3-Fluoro-N-(3-(2-methoxypyrimidin-5-yl)phenyl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (494);

[0742] N-(3-(5-(difluoromethoxy)pyridin-2-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (495);

[0743] N-(3-(5-ethylpyrimidin-2-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (496);

[0744] N-(4′-ethyl-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (497);

[0745] N-(3-(5-ethoxypyrimidin-2-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (498);

[0746] N-(3-(5-(difluoromethoxy)pyrimidin-2-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (499);

[0747] 3-Fluoro-N-(3-(5-methoxypyrimidin-2-yl)phenyl)-N-((4-(5-(trifluoromethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (500);

[0748] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxycyclobutane-1-carboxamide (501);

[0749] (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxycyclobutane-1-carboxamide (502);

[0750] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methyloxetane-3-carboxamide (503);

[0751] (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide (504);

[0752] (3-(((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(3-(2-ethoxypyrimidin-5-yl)phenyl)carbamoyl)bicyclo[1.1.1]pentane-1-yl)carbamate tert-butyl (505);

[0753] 3-Amino-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (506);

[0754] (1S,3S)-N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (507);

[0755] (cis)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methylcyclobutane-1-carboxamide (508);

[0756] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (509);

[0757] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methyloxetane-3-carboxamide (510);

[0758] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxycyclobutane-1-carboxamide (511);

[0759] (cis)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-methyl-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)cyclobutane-1-carboxamide (512);

[0760] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (513);

[0761] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-methoxy-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)cyclobutane-1-carboxamide (514);

[0762] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-methyloxetane-3-carboxamide (515);

[0763] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (516);

[0764] (1S,3S)-N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-hydroxy-3-methylcyclobutane-1-carboxamide (517);

[0765] (cis)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-methoxy-N-((4-(5-(3-methyloxetane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (518);

[0766] (1S,3S)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-3-methyl-N-((4-(5-(3-methyloxetane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (519);

[0767] (1S,3S)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-hydroxy-N-((4-(5-(3-methyloxetane-3-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (520);

[0768] N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (521);

[0769] N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (522);

[0770] 3-Fluoro-N-(4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (523);

[0771] 3-Fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (524);

[0772] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (525);

[0773] N-(3-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)phenyl)-3-fluoro-N-((4-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (526);

[0774] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-ethoxy-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (527);

[0775] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (528);

[0776] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (529);

[0777] N-(3-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)phenyl)-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 (530);

[0778] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(2-ethoxypyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (531);

[0779] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(4-ethoxyphenyl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (532);

[0780] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(4-(4-(difluoromethoxy)phenyl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (533);

[0781] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(4-(4-(methylsulfonamido)phenyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (534);

[0782] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(2-cyclopropylthiazo[4,5-b]pyridin-6-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (535);

[0783] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(6-ethoxy-[3,4′-bipyridine]-2′-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (536);

[0784] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methylbenzo[d]thiazolyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (537);

[0785] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methoxypyrimidin-5-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (538);

[0786] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(2-cyclopropylpyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (539);

[0787] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (540);

[0788] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(5-(difluoromethoxy)pyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (541);

[0789] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(5-ethoxypyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (542);

[0790] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(5-ethylpyrimidin-2-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (543);

[0791] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(5-(difluoromethoxy)-[2,4′-bipyridine]-2′-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (544);

[0792] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(4-(4-(difluoromethoxy)phenyl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (545);

[0793] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methylbenzo[d]thiazolyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (546);

[0794] N-((4-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(4-(4-(methylsulfonamido)phenyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (547);

[0795] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(2-ethoxypyrimidin-5-yl)pyridin-2-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (548);

[0796] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methylbenzo[d]thiazolyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (549);

[0797] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methylbenzo[d]oxazol-6-yl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (550);

[0798] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(4-(2-methylbenzo[d]thiazolyl)pyridin-2-yl)bicyclo[1.1.1]pentane-1-carboxamide (551);

[0799] N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-methoxypyrimidin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (552);

[0800] N-((4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(2-ethoxypyrimidin-5-yl)phenyl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (553);

[0801] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclobutane-1-carboxamide (554);

[0802] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (555);

[0803] 3-Fluoro-N-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (556);

[0804] 3,3-Difluoro-N-((1-(4-methoxyphenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclobutane-1-carboxamide (557);

[0805] 3-Fluoro-N-((1-(2-methoxypyrimidin-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (558);

[0806] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(5-fluorobenzo[d]oxazol-2-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (559);

[0807] N-((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(5-fluorobenzo[d]oxazol-2-yl)phenyl)cyclobutane-1-carboxamide (560);

[0808] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (561);

[0809] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclobutane-1-carboxamide (562);

[0810] N-((4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3,3-difluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclopentane-1-carboxamide (563);

[0811] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (564);

[0812] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3,3-difluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclobutane-1-carboxamide (565);

[0813] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-(difluoromethyl)-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclobutane-1-carboxamide (566);

[0814] N-((1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3,3-difluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)cyclopentane-1-carboxamide (567);

[0815] N-((1-(4-cyanophenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (376);

[0816] N-((1-(4-(dimethylaminoformyl)phenyl)-2-oxabicyclo[2.2.2]octane-4-yl)methyl)-3-fluoro-N-(3-(2-methylbenzo[d]thiazolyl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (377);

[0817] N-cyclopropyl-4-((3-fluoro-N-(3-(2-methoxypyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carbamate)methyl)bicyclo[2.2.2]octane-1-carbamate (570);

[0818] N-(3-Cyclopropylphenyl)-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 (571);

[0819] N-(3-Cyclopropylphenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (572);

[0820] N-(3-cyclopropylphenyl)-3-fluoro-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (573);

[0821] 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);

[0822] N-(3-(azacyclobutan-1-yl)-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 (575);

[0823] (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-3-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (576);

[0824] (cis)-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-methylcyclobutane-1-carboxamide (577);

[0825] (cis)-N-(4′-(1-cyanocyclopropyl)-3′-fluoro-[1,1′-biphenyl]-3-yl)-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (578);

[0826] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (579);

[0827] N-(3-(2-cyclopropylpyrimidin-5-yl)phenyl)-3-fluoro-N-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamide (580);

[0828] (cis)-N-(6-fluoro-4′-isopropoxy-[1,1′-biphenyl]-3-yl)-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (581);

[0829] (cis)-N-(4′-((2-cyanopropan-2-yl)oxy)-6-fluoro-[1,1′-biphenyl]-3-yl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (582);

[0830] (cis)-N-(4′-((2-cyanopropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (583);

[0831] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-isopropoxy-[1,1′-biphenyl]-3-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (584);

[0832] 3-Cyano-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)bicyclo[1.1.1]pentane-1-carboxamide (585);

[0833] 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]octane-1-yl)methyl)urea (586);

[0834] (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-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 (587);

[0835] (cis)-N-(3-(3,6-dihydro-2H-piperan-4-yl)phenyl)-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (588);

[0836] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-fluoro-N-(3-(4-hydroxypiperidin-1-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (589);

[0837] (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(3-(6-(2-hydroxypropan-2-yl)spiro[3.3]hept-1-en-2-yl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (590);

[0838] (4′-(1-cyanocyclopropyl)-3′-fluoro-[1,1′-biphenyl]-3-yl)((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (591);

[0839] (cis)-N-(3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)phenyl)-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (592);

[0840] (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(3-(6-(2-hydroxypropan-2-yl)pyridazin-3-yl)phenyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (593);

[0841] 3-Fluoro-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(6-oxo-1,6-dihydropyridazin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (594);

[0842] (cis)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(6-(4-(2-hydroxypropan-2-yl)phenyl)pyridin-2-yl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (595);

[0843] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(2-(2-ethoxypyrimidin-5-yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (596);

[0844] N-((4-(5-(tert-butyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(2-(2-cyclopropylpyrimidin-5-yl)pyridin-4-yl)-3-fluorobicyclo[1.1.1]pentane-1-carboxamide (597);

[0845] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)carbamate 2-cyanopropane-2-yl ester (598);

[0846] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-((trans)-4-hydroxy-4-methylcyclohexyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(599);

[0847] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(4-hydroxy-4-(trifluoromethyl)cyclohexyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea (600-601);

[0848] (4-(((cis)-3-hydroxy-N-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-(trifluoromethyl)cyclobutane-1-carbamate)methyl)bicyclo[2.2.2]octane-1-yl)carbamate (602);

[0849] (cis)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)-N-((4-((trifluoromethyl)sulfonamido)bicyclo[2.2.2]octane-1-yl)methyl)cyclobutane-1-carboxamide (603);

[0850] (cis)-3-hydroxy-N-(4′-isopropoxy-[1,1′-biphenyl]-3-yl)-N-((4-(3-isopropylureo)bicyclo[2.2.2]octane-1-yl)methyl)-3-(trifluoromethyl)cyclobutane-1-carboxamide (604);

[0851] ((4-(5-(1,1-difluoroethyl)pyridine-2-1)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-(2-hydroxypropane-2-yl)phenyl)pyridine-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (605);

[0852] (4-(4-((2-cyanopropane-2-yl)oxy)phenyl)pyridin-2-yl)((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (606);

[0853] ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)(5-(2-hydroxypropane-2-yl)-[2,4′-bipyridin]-2′-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (607);

[0854] ((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(5-(2-hydroxypropane-2-yl)pyrimidin-2-yl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (608);

[0855] ((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (609);

[0856] ((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 1,1,1-trifluoro-2-methylpropane-2-yl ester (610);

[0857] 3-(tert-butyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea(611);

[0858] 3-(tert-butyl)-1-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea (612);

[0859] 3-(tert-butyl)-1-(4′-(2-(difluoromethoxy)propane-2-yl)-[1,1′-biphenyl]-3-yl)-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea (613);

[0860] 1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-(spiro[2.3]hexane-5-ylmethyl)-1-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea(614);

[0861] (4-(4-(chlorodifluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (615);

[0862] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(5-fluoro-4-(4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (616);

[0863] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(5-fluoro-4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (617);

[0864] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(5-fluoro-4-(3-fluoro-4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (618);

[0865] ((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(5-fluoro-4-(4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)carbamate neopentyl ester (619);

[0866] (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]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropan-2-yl ester (620);

[0867] (5-Fluoro-4-(1-(oxacyclobutan-3-ylmethyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (621);

[0868] (4-(4-((2-cyanopropane-2-yl)oxy)phenyl)pyridin-2-yl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (622);

[0869] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (623);

[0870] (4-(4-(difluoromethoxy)phenyl)pyridin-2-yl)((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (624);

[0871] (4-(4-((2-cyanopropane-2-yl)oxy)phenyl)pyridin-2-yl)((4-(5-(1-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (625);

[0872] N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4-(4-(4-isopropoxyphenyl)pyridin-2-yl)morpholine-4-carboxamide (626);

[0873] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate tetrahydro-2H-piperan-4-yl ester (627);

[0874] (cis)-N-(4′-(2,2-difluoro-1-hydroxyethyl)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (628);

[0875] (cis)-(4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 3-hydroxy-3-(trifluoromethyl)cyclobutyl ester (629);

[0876] (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 3,3-difluorocyclobutyl ester (630);

[0877] (4-(4-(difluoromethoxy)phenyl)-5-fluoropyridin-2-yl)((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 4,4-difluorocyclohexyl ester (631);

[0878] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-isopropoxy-[1,1′-biphenyl]-3-yl)carbamate 3-(trifluoromethyl)oxetane-3-yl ester (632);

[0879] 3-(bicyclo[1.1.1]pentan-1-yl)-1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4-fluoro-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)phenyl)urea (633);

[0880] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (634);

[0881] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(2-(4-(2-hydroxypropane-2-yl)phenyl)pyrimidin-4-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (635);

[0882] ((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-isopropoxyphenyl)pyrimidin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (636);

[0883] N-(4-(((cis)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamido)methyl)bicyclo[2.2.2]octane-1-yl)-4-fluorobenzamide (637);

[0884] 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 (638);

[0885] (cis)-N-(4′-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (639);

[0886] (cis)-N-((4-(5-(1,1-difluoroethyl)pyridin-2-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(difluoromethoxy)-N-(4-(4-isopropoxyphenyl)pyridin-2-yl)-3-methylcyclobutane-1-carboxamide (640);

[0887] N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-2-thia-6-azaspiro[3.3]heptane-6-carboxamide 2,2-dioxide (641);

[0888] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-((1-methylsulfonyl)cyclopropyl)methyl)urea(642);

[0889] N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-N-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-(trifluoromethyl)azacyclobutane-1-carboxamide (643);

[0890] 3-(1,1-dioxo-tetrahydro-2H-thiopiperan-4-yl)-1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(644);

[0891] 3-(2,2-difluoro-3-hydroxypropyl)-1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(646);

[0892] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-((4-(hydroxymethyl)tetrahydro-2H-piperan-4-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(647);

[0893] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-((1-hydroxycyclopropyl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(648);

[0894] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-(2-N-morpholinylethyl)urea (649);

[0895] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-(2-(1-hydroxycyclopentyl)ethyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)urea(650);

[0896] N-(4′-((2-cyanopropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-4-(2-hydroxypropan-2-yl)piperidine-1-carboxamide (651);

[0897] 1-((4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-isopropoxy-[1,1′-biphenyl]-3-yl)-3-(tetrahydro-2H-piperan-4-yl)urea (652);

[0898] 3-((trans)-4-(difluoromethoxy)-4-methylcyclohexyl)-1-(6-fluoro-4′-isopropoxy-[1,1′-biphenyl]-3-yl)-1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea(653);

[0899] (cis)-N-(4′-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (654);

[0900] (cis)-N-(4′-((2-cyanopropan-2-yl)oxy)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (654A);

[0901] ((4-(3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-isopropoxy-[1,1′-biphenyl]-3-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (655);

[0902] ((4-(5-(1,1-difluoroethyl)isoxazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4′-isopropoxy-[1,1′-biphenyl]-3-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (656);

[0903] ((4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-isopropoxyphenyl)pyridin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (657);

[0904] ((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 1,1,1-trifluoro-2-methylpropane-2-yl ester (658);

[0905] 3-(tert-butyl)-1-((4-(3-(1,1-difluoroethyl)-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-isopropoxy-[1,1′-biphenyl]-3-yl)urea(659);

[0906] 3-(tert-butyl)-1-(5-(4-(difluoromethoxy)phenyl)pyridazin-3-yl)-1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)urea (660);

[0907] (4-(4-(2-hydroxypropane-2-yl)phenyl)pyridin-2-yl)((4-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (661);

[0908] (cis)-N-(4′-(4-amino-1,2,5-oxadiazol-3-yl)-[1,1′-biphenyl]-3-yl)-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carboxamide (662);

[0909] 3-Fluoro-N-((4-(5-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1-(2-hydroxy-2-methylpropyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (663);

[0910] 4-(3-(3-fluoro-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)bicyclo[1.1.1]pentane-1-carboxamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (663C);

[0911] 3-Fluoro-N-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)bicyclo[1.1.1]pentane-1-carboxamide (663D);

[0912] 1-((4-(5-(2-fluoropropane-2-yl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octane-1-yl)methyl)-1-(4′-(2-hydroxypropane-2-yl)-[1,1′-biphenyl]-3-yl)-3-((2S,4S,6S)-6-hydroxyspiro[3.3]heptane-2-yl)urea(664);

[0913] (4-(4-cyanobicyclo[2.2.2]octane-1-yl)pyrimidin-2-yl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (665);

[0914] 4-(2-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)carbonyl)amino)pyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (665E);

[0915] 4-(2-(((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(((1,1,1-trifluoro-2-methylpropane-2-yl)oxy)carbonyl)amino)pyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylic acid (665F);

[0916] (4-(4-carbamoylbicyclo[2.2.2]octane-1-yl)pyrimidin-2-yl)((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (665G); or

[0917] ((4-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)bicyclo[2.2.2]octane-1-yl)methyl)(4-(4-(2-hydroxypropane-2-yl)bicyclo[2.2.2]octane-1-yl)pyrimidin-2-yl)carbamate 1,1,1-trifluoro-2-methylpropane-2-yl ester (666).

[0918] II. Pharmaceutical Compositions, Therapeutic Uses, and Combinations

[0919] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0920] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0921] In 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, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0922] In another embodiment, the present invention provides a method for preparing the compounds of the present invention.

[0923] In another embodiment, the present invention provides an intermediate for preparing the compounds of the present invention.

[0924] In another embodiment, the present invention provides a pharmaceutical composition as defined above, which further comprises one or more other therapeutic agents.

[0925] In another embodiment, the present invention provides a method for treating a patient in need of such treatment for a disease, condition, or symptom related to bile acid dysregulation, the method comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0926] In another embodiment, the present invention provides a method for treating a disease, condition, or symptom associated with farnesoid X receptor (FXR) activity in a patient requiring such treatment, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0927] In another embodiment, the present invention provides a method for treating a disease, condition, or symptom, comprising administering, alone or as appropriate, in combination with another compound of the present invention and / or at least one other type of therapeutic agent, a therapeutically effective amount of at least one compound of the present invention to a patient in need of such treatment.

[0928] In another embodiment, the present invention provides a method for inducing farnesoid X receptor (FXR) agonist action in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[0929] In some implementations, diseases, conditions, or symptoms are associated with FXR dysfunction, including pathological fibrosis, cancer, inflammatory conditions, metabolic conditions, or cholestatic conditions.

[0930] In some implementations, diseases, conditions, or symptoms are associated with fibrosis, including liver fibrosis, gallbladder fibrosis, kidney fibrosis, heart fibrosis, skin fibrosis, eye fibrosis, and pancreatic fibrosis.

[0931] In other embodiments, the disease, condition, or symptom is associated with a proliferative cellular condition such as cancer. In some embodiments, cancer includes the growth of a solid tumor or the formation of a neoplasm. In other embodiments, cancer includes tumor metastasis. In some embodiments, cancer is cancer of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, reproductive organs, genitourinary tract, head, larynx, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testis, or thyroid. In other embodiments, cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[0932] Diseases, conditions, or symptoms related to FXR activity that can be prevented, modulated, or treated according to the present invention include (but are not limited to) transplantation injections, fibrotic conditions (e.g., liver fibrosis, kidney fibrosis), inflammatory conditions (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatosis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and proliferative conditions (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaposi's sarcoma, solid tumors).

[0933] The fibrotic, inflammatory, and proliferative diseases suitable for prevention or treatment by the compounds of this invention include (but are not limited to) non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatosis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, cholecystitis, portal hypertension, aplastic disorders, hepatic insufficiency, hepatic blood flow disorders, kidney disease, and irritable bowel syndrome (IBS). Inflammatory bowel disease (IBD), pancreatic secretion disorders, benign prostatic hyperplasia, neuropathic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, kidney fibrosis, chronic kidney disease (CKD), diabetic nephropathy (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, idiopathic pulmonary fibrosis (IPF), and interstitial lung disease. Interstitial lung disease, nonspecific interstitial pneumonia (NSIP), common interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, respiratory tract fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumors, 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, Kaburg sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuralgia, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid glaucoma filtration surgery scars, Crohn's disease or systemic lupus erythematosus; keloid formation due to abnormal wound healing; fibrosis, myelofibrosis, and fibrosis occurring after organ transplantation. In one embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering, alone or as appropriate, in combination with another compound of the present invention and / or at least one other type of therapeutic agent, a therapeutically effective amount of at least one compound of the present invention to a patient in need of such treatment.

[0934] In another embodiment, the present invention provides a compound of the present invention for use in a therapy.

[0935] In another embodiment, the present invention provides a compound for use in a therapy for treating fibrotic, inflammatory, or proliferative conditions.

[0936] In another embodiment, the present invention also provides the use of the compounds of the present invention for manufacturing agents for treating fibrotic, inflammatory, or proliferative conditions.

[0937] In another embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering therapeutically effective amounts of first and second therapeutic agents to a patient in need, wherein the first therapeutic agent is a compound of the present invention.

[0938] In another embodiment, the present invention provides a combination formulation of the compound of the present invention used simultaneously, separately, or sequentially in a therapy with other therapeutic agents.

[0939] In another embodiment, the present invention provides a combination formulation of the compounds of the present invention with other therapeutic agents for the simultaneous, separate, or sequential treatment of fibrotic conditions, inflammatory conditions, or proliferative conditions.

[0940] The compounds of the present invention can be used in combination with other therapeutic agents, such as one or more antifibrotic and / or anti-inflammatory therapeutic agents.

[0941] In one embodiment, the other therapeutic agent used in the combination pharmaceutical composition or method of combination or use in combination is selected from one or more, preferably one to three, of the following: TGFβ receptor inhibitors (e.g., galunisertib), TGFβ synthesis inhibitors (e.g., pirfenidone), inhibitors of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptor kinases (e.g., nintedanib), humanized anti-α Vβ6 integrin monoclonal antibodies (e.g., 3G9), recombinant human pentameric protein-2, recombinant human serum amyloid protein P, recombinant human antibodies against TGFβ-1, TGFβ-2, and TGFβ-3, endothelin receptor antagonists (e.g., macitentan), interferon-γ, c-Jun N-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purine-2-yl]amino] [3-trans-cyclohexanol, 3-pentylphenylacetic acid (PBI-4050), tetra-substituted porphyrin derivatives containing manganese(III), monoclonal antibodies targeting eotaxin-2, interleukin-13 (IL-13) antibodies (e.g., lebrikizumab, tralokinumab), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar 9 Met(O2) 11-P substance), Cintredekin Besudotox, human recombinant DNA-derived IgG1κ monoclonal antibodies against connective tissue growth factor and fully human IgG1κ antibodies selective for CC-chemokine ligand 2 (e.g., carlumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), and agents for treating obstructive tracheal diseases (e.g., muscarinic antagonists such as tiotropium, ipatropium bromide). bromide), adrenaline β2 agonists (e.g., methylphenidate, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and agents indicated for the treatment of fibrotic conditions (such as liver, gallbladder, and kidney fibrosis), non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Suitable treatments for this type of fibrotic condition include (but are not limited to) FXR agonists (e.g., OCA, GS-9674, and LJN452); LOXL2 inhibitors (e.g., simtuzumab); LPA1 antagonists (e.g., BMS-986020 and SAR 100842); PPAR modulators (e.g., elafibrinor, pioglitazone, saroglitazar, and IVA337); SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302); ASK-1 inhibitors (e.g., GS-4997 or selonsertib); ACC inhibitors (e.g., CP-640186 and NDI- 010976 or GS-0976); FGF21 mimics (e.g. LY2405319 and BMS-986036); apoptosis protease inhibitors (e.g. emricasan); NOX4 inhibitors (e.g. GKT137831); MGAT2 inhibitors (e.g. BMS-963272); αV integrin inhibitors (e.g. abituzumab); and bile acid / fatty acid conjugates (e.g., aramchol).The FXR agonists of various embodiments of the present invention can also be used in combination with one or more therapeutic agents, such as CCR2 / 5 inhibitors (e.g., cenicriviroc); galactoglobin-3 inhibitors (e.g., TD-139, GR-MD-02); leukotriene receptor antagonists (e.g., tipelukast, montelukast); SGLT2 inhibitors (e.g., dapagliflozin, remogliflozin); GLP-1 receptor agonists. Autocrine agonists (e.g., liraglutide and semaglutide); FAK inhibitors (e.g., GSK-2256098); CB1 inverse agonists (e.g., JD-5037); CB2 agonists (e.g., APD-371 and JBT-101); autocrine motor factor inhibitors (e.g., GLPG1690); prolyl t-RNA synthetase inhibitors (e.g., halofugenone); FPR2 agonists (e.g., ZK-994); and THR agonists (e.g., MGL:3196). In another embodiment, the other therapeutic agent used in the combination of the pharmaceutical composition or combination method or combination use is selected from one or more, preferably one to three, immuno-oncology agents such as alemtuzumab, atezolizumab, ipilimumab, nivolumab, offatumumab, pembrolizumab, and rituximab.

[0942] The compounds of the present invention can be administered by any suitable means for any of the uses described herein, such as: oral administration, such as tablets, capsules (each comprising sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions; sublingual administration; buccal administration; non-enteral administration, such as subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasal administration, including administration to the nasal mucosa, such as by inhalation spray; topical administration, such as in the form of creams or ointments; or rectal administration, such as in the form of suppositories. They can be administered alone, but are generally administered co-administered with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0943] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering bioactive agents to animals (particularly mammals), including (i.e.) adjuvants, excipients, or mediators, such as diluents, preservatives, fillers, flow modifiers, disintegrants, humectants, emulsifiers, suspending agents, sweeteners, flavorings, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the nature of the administration method and dosage form. Pharmaceutically acceptable carriers are formulated based on several factors within the scope of those skilled in the art. These factors include (but are not limited to): the type and nature of the active agent being formulated; the individual to whom the composition containing the pharmaceutical agent will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. In addition to active agents, such carriers may include a variety of different components and additives, which are included in formulations for various reasons well known to those skilled in the art, such as stabilizing active agents and binders. Descriptions of pharmaceutically acceptable suitable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 18th edition (1990).

[0944] As used herein, the term "treatment" refers to a method of obtaining a beneficial or desired outcome (including clinical outcomes) by using the compounds or compositions of the present invention. For the purposes of this invention, beneficial or desired clinical outcomes include (but are not limited to) one or more of the following: reducing the severity and / or frequency of one or more symptoms caused by a disease, condition, or symptom; reducing the degree of a disease, condition, or symptom or causing its resolution; stabilizing a disease, condition, or symptom (e.g., preventing or delaying nausea of ​​a disease, condition, or symptom); delaying or slowing the progression of a disease, condition, or symptom; improving the state of a disease, condition, or symptom; reducing the dosage of one or more other agents required to treat a disease, condition, or symptom; and / or improving quality of life.

[0945] The dosing regimen of the compounds of this invention will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode of administration and route of administration; the species, age, sex, health status, medical condition and weight of the recipient; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect.

[0946] According to general guidelines, the daily oral dose of each active ingredient for the specified action will be between about 0.01 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.01 to about 250 mg per day. When administered intravenously, the optimal dose during a constant-rate infusion will be in the range of about 0.01 to about 10 mg / kg per minute. The compounds of the present invention can be administered as a single daily dose, or the total daily dose can be divided into two, three, or four divided doses per day.

[0947] Compounds are typically administered in a mixture with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier) that is appropriately selected for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and is consistent with known pharmaceutical practices.

[0948] Suitable dosage forms (pharmaceutical compositions) may contain an active ingredient in amounts of about 0.1 mg to about 2000 mg per dose unit. In said 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.

[0949] Typical capsules for oral administration contain at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0950] A typical injectable formulation is prepared by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing it. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0951] This invention includes pharmaceutical compositions comprising, alone or in combination with a drug carrier, a therapeutically effective amount of at least one compound of the invention as an active ingredient. Where appropriate, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more (preferably one to three) other therapeutic agents, such as ASK-1 inhibitors, CCR2 / 5 antagonists, autocrine motor factor inhibitors, LPA1 receptor antagonists, or other pharmaceutically active substances.

[0952] When the other therapeutic agents described above are used in combination with the compounds of the present invention, they may be used in amounts indicated, for example, in Physicians' Desk Reference (as stated in the patents mentioned above) or in amounts otherwise determined by those skilled in the art.

[0953] Especially when provided in single-dose units, chemical interactions may exist between the combined active ingredients. Therefore, when the compounds and second therapeutic agents of the present invention are combined in single-dose units, they are formulated such that, although the active ingredients are combined in single-dose units, physical contact between the active ingredients is minimized (i.e., reduced). For example, an active ingredient may be coated with an enteric coating. By coating one of the active ingredients with an enteric coating, not only is contact between the combined active ingredients minimized, but the release of one of the components in the gastrointestinal tract can also be controlled, such that one of the components is released in the intestine rather than in the stomach. One of the active ingredients may also be coated with a substance that influences sustained release throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. Furthermore, a sustained-release component may be additionally coated with an enteric coating so that this component is released only in the intestine. Another approach involves the formulation of a combination product in which one component is coated with a sustained-release and / or enteric polymer, and another component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or other suitable substances known in the art, to further separate the active component. The polymer coating serves to form an additional barrier to interaction with the other component.

[0954] Once the present invention is mastered, those skilled in the art will readily appreciate the methods described above and others used to minimize contact between the components of the combined product of the present invention, whether administered in a single dosage form or simultaneously in separate forms but in the same manner.

[0955] The compounds of the present invention can be administered alone or in combination with one or more (preferably one to three) other therapeutic agents. "Combination administration" or "combination therapy" means administering the compounds of the present invention and one or more (preferably one to three) other therapeutic agents simultaneously to the mammal being treated. When administered in combination, the components can be administered simultaneously or sequentially at different time points in any order. Therefore, the components can be administered individually but at sufficiently close temporal proximity to provide the desired therapeutic effect.

[0956] The compounds of this invention are also suitable as standard or reference compounds in tests or analyses involving FXR agonists, for example, as quality standards or controls. Such compounds are available, for example, in commercially available kits for drug studies involving FXR agonist activity. For instance, the compounds of this invention can be used in analyses to compare their known activities with those of compounds with unknown activities. This ensures that researchers perform analyses correctly and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new analytical methods or protocols, the compounds according to this invention can be used to test their effectiveness.

[0957] This invention also covers articles. As used herein, articles include (but are not limited to) kits and packages. Articles of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert stating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert states that the pharmaceutical composition can be combined with a second therapeutic agent (as defined above) for the treatment of fibrosis and its sequelae. Articles 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. Located within the first and second containers means that each container holds the entry within its boundaries.

[0958] The first container is a vessel for containing a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually or in whole. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream formulations), or any other container used for manufacturing, containing, storing, or dispensing pharmaceutical products.

[0959] The second container is used to contain the first container and, where appropriate, the instruction leaflet. Embodiments of the second container include (but are not limited to) boxes (e.g., cardboard or plastic), cartons, cardboard boxes, bags (e.g., paper or plastic bags), pouches, and large bags. The instruction leaflet may be physically attached to the exterior of the first container by tape, glue, nails, or another attachment method, or it may remain inside the second container without being physically attached to the first container. Alternatively, the instruction leaflet may be located on the exterior of the second container. When located on the exterior of the second container, the instruction leaflet is preferably physically attached by tape, glue, nails, or another attachment method. Alternatively, it may be adjacent to or in contact with the exterior of the second container but not physically attached.

[0960] A drug package insert is a label, tag, marker, or other label that describes information related to the drug composition located within a first container. This information is typically determined by the regulatory agency in the region where the product is sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically describes the approved indications for which the drug composition may be used. The package insert can be made of any material, and the information contained therein or on it can be read by an individual. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the required information has already been formed (e.g., printed or coated).

[0961] III. Definition

[0962] Those skilled in the art will more readily understand the features and advantages of the present invention after reading the following embodiments. It should be understood that, for clarity, certain features of the invention described above and below in individual embodiments may also be combined to form a single embodiment. Conversely, for brevity, various features of the invention described in single embodiments may also be combined to form sub-combinations thereof. Embodiments identified herein as illustrative or preferred are intended to be explanatory and not restrictive.

[0963] Unless otherwise specified in this document, singular references may also include plural references. For example, "a / an" may refer to one, or one or more.

[0964] As used herein, the phrase "compound and / or its salt" means at least one compound, at least one salt of said compound, or a combination thereof. For example, a compound of formula (I) and / or its salt includes one compound of formula (I); two compounds of formula (I); a salt of compound (I); a compound of formula (I) and one or more salts of compound (I); and two or more salts of compound (I).

[0965] Unless otherwise specified, it is assumed that any atom with an unsaturated valence has enough hydrogen atoms to saturate the valence.

[0966] The definitions set forth herein take precedence over those set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0967] The following lists definitions of various terms used to describe the invention. The definitions apply to the terms used individually or as part of a larger group throughout this specification (unless otherwise limited in specific circumstances).

[0968] Throughout the specification, those skilled in the art may select groups and their substituents to provide stable moieties and compounds.

[0969] According to the conventions used in this field,

[0970]

[0971] In the structural formulas described herein, bonds are used to describe the attachment points between parts or substituents and the core or main chain structure.

[0972] As used in this article, the terms "halogen" and "halogen" refer to F, Cl, Br, and I.

[0973] The term "cyano" refers to the -CN group.

[0974] The term "hydroxyl group" refers to the -OH group.

[0975] The term "amino" refers to the group -NH2.

[0976] The term "oxo" refers to the =O group.

[0977] As used herein, the term "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group 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 (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, dibutyl, and tributyl), and pentyl (e.g., n-pentyl, isopentyl, and neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript form after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular group may contain. For example, "C 1-4 Alkyl groups refer to straight-chain and branched alkyl groups having one to four carbon atoms.

[0978] As used herein, the term "haloalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more halogen atoms. For example, "C 1-4 "Halogenated" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more halogen atoms. Representative examples of halogenated alkyl groups include (but are not limited to) -CF3, -CCl3, -CHF2, and -CF2CCl3.

[0979] As used herein, the term "fluoroalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, "C 1-4 "Fluoroalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include (but are not limited to) -CF3 and -CH2CF3.

[0980] As used herein, the term "hydroxyalkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more hydroxyl groups. For example, "C 1-4 "Hydroxyalkyl" is intended to include C1, C2, C3, and C4 alkyl groups substituted with one or more hydroxyl groups. Representative examples of fluoroalkyl groups include (but are not limited to) -CH2OH, -CH2CH2OH, and -C(CH3)2OH.

[0981] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Illustrative examples of such groups include vinyl or allyl groups. For instance, "C 2-6 "Alkenyl" refers to straight-chain and branched alkenyl groups having two to six carbon atoms.

[0982] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing 2 to 12 carbon atoms and at least one carbon-carbon linkage. Illustrative examples of such groups include the ethynyl group. For instance, "C 2-6 "Alkyne" refers to straight-chain and branched alkynyl groups having two to six carbon atoms.

[0983] As used herein, the term "alkoxy" refers to an alkyl group, such as a methoxy group (-OCH3), which is attached to the parent molecule via an oxygen atom. For example, "C 1-3 "Alkoxy" refers to an alkoxy group having one to three carbon atoms.

[0984] The terms "haloalkoxy" and "-O (haloalkyl)" refer to alkyl halides as defined above, attached via an oxygen bond (-O-). For example, "C 1-4 "Haloalkoxy" is intended to include C1, C2, C3 and C4 haloalkoxy groups.

[0985] The terms "fluoroalkoxy" and "-O (fluoroalkyl)" refer to fluoroalkyl groups as defined above, attached via an oxygen bond (-O-). For example, "C 1-4 "Fluoroalkoxy" is intended to include C1, C2, C3, and C4 fluoroalkoxy groups.

[0986] As used herein, the term "cycloalkyl" refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing a hydrogen atom from a self-saturated ring carbon atom. Representative examples of cycloalkyl groups include (but are not limited to) cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears in subscript form after the symbol "C", the subscript more specifically defines the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C..." 3-6 "Cycloalkyl" refers to a cycloalkyl group having three to six carbon atoms.

[0987] The terms "carbocyclo", "carbocyclic", or "carbocyclic group" are used interchangeably and refer to a cyclic group having at least one saturated or partially saturated non-aromatic ring, wherein all atoms of all rings are carbon, and include groups having one or more bridging rings, wherein bridging rings occur when one or more carbon atoms are connected to two non-adjacent carbon atoms. The term includes non-aromatic rings such as cycloalkyl and cycloalkenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, adamantyl, and tetrahydronaphthyl.

[0988] As used herein, the term "bicycloalkyl" refers to a carbocyclic group having at least one bridge. Representative examples of bicycloalkyl groups include (but are not limited to) bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, and adamantyl.

[0989] As used herein, the term "aryl" refers to an atomic group derived from a molecule containing an aromatic ring by removing a hydrogen atom bonded to the aromatic ring. Representative examples of aryl groups include (but are not limited to) phenyl and naphthyl groups. The aromatic ring may be unsubstituted or may contain one or more substituents, depending on the valence state.

[0990] The term "heteroatoms" refers to oxygen (O), sulfur (S), and nitrogen (N).

[0991] The terms "heterocyclo," "heterocyclic," or "heterocyclic group" are used interchangeably and refer to a cyclic group having at least a saturated or partially saturated non-aromatic ring, wherein one or more rings have at least one heteroatom (O, S, or N), preferably having one to three heteroatoms independently selected from O, S, and / or N. Such heteroatom-containing groups may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, limited by the total number of heteroatoms in each ring being four or less, and further limited by the ring containing at least one carbon atom. The nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may be quadrature ammoniumized, depending on the situation. The heterocyclic group may be attached at any available nitrogen or carbon atom. The heterocycle may be unsubstituted or, where the valence state allows, may contain one or more substituents.

[0992] Exemplary monocyclic heterocyclic groups include pyrrolidinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazoponyl, 4-piperidinoneyl, tetrahydropiperanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxacyclopentane, tetrahydro-1,1-dioxothiopheneyl, dihydroisoindolyl, and tetrahydroquinolinyl.

[0993] The terms "spirobicycloyl" and "spirobicyclo" are used interchangeably and refer to a bicyclic group in which two rings are attached to a single carbon atom that is a member of each of the two rings. The term includes spirobicycloalkyl, wherein the two rings are cycloalkyl rings attached to a single carbon atom that is a member of each of the two rings; and spirobicycloheteralkyl, wherein one ring is a heterocycle and the other ring is a cycloalkyl ring attached to a single carbon atom that is a member of each of the two rings, or wherein the two rings are heterocycles attached to a single carbon atom that is a member of each of the two rings. Examples of spirobicycloyl groups include spiro[3.3]heptenyl, spiro[3.4]octyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, and azaspiro[3.4]octyl.

[0994] The term "heteroaryl" refers to a substituted or unsubstituted aromatic 5- or 6-membered monocyclic group and a 9- or 10-membered bicyclic group having at least one heteroatom (O, S, or N) in at least one ring, wherein the heteroatom-containing ring preferably has one, two, or three heteroatoms independently selected from O, S, and / or N. Each ring of the heteroatom-containing heteroaryl group may contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, limited by the total number of heteroatoms in each ring being four or less and each ring having at least one carbon atom. The fused ring constituting the bicyclic group is aromatic and may contain only carbon atoms. The nitrogen and sulfur atoms may be oxidized as appropriate, and the nitrogen atom may be quadrature ammonized as appropriate. The bicyclic heteroaryl group must consist only of aromatic rings. The heteroaryl group may be linked at any available nitrogen or carbon atom in any ring. The heteroaryl ring may be unsubstituted or may contain one or more substituents.

[0995] Exemplary monocyclic heteroaryl groups include pyrrole, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.

[0996] Examples of bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzo-m-dioxacyclopentenyl, benzoxazolyl, benzothiophene, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopiperanyl, indoleazinyl, benzofuranyl, chromonel, coumarinyl, and benzopiperanyl. Linoyl, quinolinyl, indazole, and pyrrolopyridyl.

[0997] The term "glycosyl" refers to a monovalent radical or substituent moiety obtained by removing a hemiacetal hydroxyl group from a low-carbon oligosaccharide in a self-cyclic form. In one embodiment, the glycosyl has the following structure:

[0998]

[0999] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable due to the migration of atoms or groups within the molecule. For example, those skilled in the art will readily understand that 1,2,3-triazole exists in two tautomeric forms as defined above:

[1000]

[1001] Therefore, this invention is intended to cover all possible tautomers, even when the structure only describes one of them. For example, when R 5c It is a hydroxyl group and R 5a R 5b and R 5d Compounds of formula (Ia) with hydrogen atoms can exist in tautomeric form:

[1002]

[1003] The phrase "pharmaceutically acceptable" in this document refers to compounds, substances, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[1004] Compounds of formula (I) can form salts that are also within the scope of this invention. Unless otherwise indicated, reference to compounds of this invention should be understood to include reference to one or more of their salts. The term "salt" means an acidic salt and / or a basic salt formed with inorganic acids and bases and / or organic acids and bases. Additionally, the term "salt" can include zwitterions (internal salts), for example when a compound of formula (I) contains a basic moiety (such as an amine or pyridine or imidazole ring) and an acidic moiety (such as a carboxylic acid). Pharmaceutically acceptable (i.e., physiologically acceptable and non-toxic) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not significantly promote the toxicity or biological activity of the salt. However, other salts may be applicable, for example, in separation or purification steps employed during preparation, and are therefore covered within the scope of this invention. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with a certain amount (such as an equal amount) of an acid or base in a medium (such as a medium for precipitating salts) or in an aqueous medium, followed by lyophilization. A list 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.

[1005] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrogen sulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglucuronate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), and hydrobromide (formed with hydrogen bromide). Hydroiodates, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pentanoates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates (such as toluenesulfonates), undecanoates and similar salts.

[1006] Exemplary basic salts include ammonium salts; alkali metal salts, such as sodium, lithium, and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts formed with organic bases (e.g., organic amines), such as trialkylamines (e.g., triethylamine), procaine, diphenylmethylamine, N-phenylmethyl-β-phenylethylamine, 1-diphenylhydroxymethylamine, N,N′-diphenylmethylethyldiamine, dehydrorosinamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or pharmaceutically acceptable analogues; and salts formed with amino acids (e.g., arginine, lysine, and similar compounds). Basic nitrogen-containing groups can be quaternarily ammonized with reagents such as low-carbon alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, methyl, ethyl, propyl, and butyl bromides, and methyl, ethyl, propyl, and butyl iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, decyl, lauryl, myristyl, and stearyl bromides, and decyl, lauryl, myristyl, and stearyl iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and other substances. Preferred salts include monohydrochlorides, hydrogen sulfates, methanesulfonates, phosphates, or nitrates.

[1007] Compounds of formula (I) may be provided in amorphous or crystalline solid form. Lyophilization may be used to obtain compounds of formula (I) in solid form.

[1008] It should be further understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of this 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 includes hydrogen bonding. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include hydrates, ethanolides, methanolides, isopropanolides, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[1009] Various forms of prodrugs are well known in the art and are described below:

[1010] a) The Practice of Medicinal Chemistry, Camille G.Wermuth et al., Chapter 31, (Academic Press, 1996);

[1011] b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);

[1012] c) A Textbook of Drug Design and Development, edited by P. Krogsgaard-Larson and H. Bundgaard, Chapter 5, pp. 113-191 (Harwood Academic Publishers, 1991); and

[1013] d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003).

[1014] e) Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587, (2018).

[1015] Additionally, compounds of formula (I) can be isolated and purified after their preparation to obtain compositions containing 99% or more by weight of compound ("substantially pure"), which are subsequently used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also covered herein as part of the present invention.

[1016] "Stable compound" and "stable structure" mean a compound that is sufficiently robust to withstand separation from the reaction mixture to a suitable purity and formulation into an effective therapeutic agent. This invention is intended to include stable compounds.

[1017] "Therapeutic effective amount" is intended to include the amount of a single compound of the invention, or a combination of the claimed compounds, or a combination of the compounds of the invention with other active ingredients, that effectively act as an FXR agonist or effectively treat or prevent conditions associated with bile acid dysregulation, such as pathological fibrosis, cancer, inflammatory conditions, metabolic conditions, or cholestatic conditions.

[1018] The compounds of this invention are intended to include all isotopes of the atoms appearing in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example and without limitation, hydrogen isotopes include deuterium (D) and tritium (T). Carbon isotopes include... 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using appropriately isotopically labeled reagents instead of the originally used unlabeled reagents. Such compounds have a variety of potential uses, such as as standards and reagents for determining the ability of potential drug compounds to bind to target proteins or receptors, or for imaging of the compounds of the present invention binding to biological receptors in vivo or in vitro.

[1019] In another embodiment, the present invention provides a composition comprising at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1020] In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1021] In 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, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1022] In another embodiment, the present invention provides a method for preparing the compounds of the present invention.

[1023] In another embodiment, the present invention provides an intermediate for preparing the compounds of the present invention.

[1024] In another embodiment, the present invention provides a pharmaceutical composition as defined above, which further comprises one or more other therapeutic agents.

[1025] practicality

[1026] In one embodiment, the present invention provides a method for treating a patient in need of such treatment for a disease, condition, or symptom related to bile acid dysregulation, and the method comprises administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1027] In another embodiment, the present invention provides a method for treating a disease, condition, or symptom associated with farnesoid X receptor (FXR) activity in a patient requiring such treatment, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1028] In another embodiment, the present invention provides a method for treating a disease, condition, or symptom, comprising administering, alone or as appropriate, in combination with another compound of the present invention and / or at least one other type of therapeutic agent, a therapeutically effective amount of at least one compound of the present invention to a patient in need of such treatment.

[1029] In another embodiment, the present invention provides a method for inducing farnesoid X receptor (FXR) agonist action in a patient, comprising administering to the patient a therapeutically effective amount of the compound of the present invention or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof.

[1030] In some implementations, diseases, conditions, or symptoms are associated with FXR dysfunction, including pathological fibrosis, cancer, inflammatory conditions, metabolic conditions, or cholestatic conditions.

[1031] In some implementations, diseases, conditions, or symptoms are associated with fibrosis, including liver fibrosis, gallbladder fibrosis, kidney fibrosis, heart fibrosis, skin fibrosis, eye fibrosis, and pancreatic fibrosis.

[1032] In other embodiments, the disease, condition, or symptom is associated with a proliferative cellular condition such as cancer. In some embodiments, cancer includes the growth of a solid tumor or the formation of a neoplasm. In other embodiments, cancer includes tumor metastasis. In some embodiments, cancer is cancer of the liver, gallbladder, small intestine, large intestine, kidney, prostate, bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, reproductive organs, genitourinary tract, head, larynx, lungs, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, skin, spleen, stomach, testis, or thyroid. In other embodiments, cancer is carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma.

[1033] Examples of diseases, conditions, or symptoms related to FXR activity that can be prevented, modulated, or treated according to the present invention include (but are not limited to) transplantation injections, fibrotic conditions (e.g., liver fibrosis, kidney fibrosis), inflammatory conditions (e.g., acute hepatitis, chronic hepatitis, non-alcoholic steatosis (NASH), irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), and proliferative conditions (e.g., cancer, myeloma, fibroma, hepatocellular carcinoma, colorectal cancer, prostate cancer, leukemia, Kaburg sarcoma, solid tumors).

[1034] Fibrotic conditions, inflammatory conditions, and proliferative conditions suitable for prevention or treatment by the compounds of the present invention include (but are not limited to) non-alcoholic fatty liver disease (NAFLD), alcoholic or non-alcoholic steatosis (NASH), acute hepatitis, chronic hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced hepatitis, cholangitis, portal hypertension, aplastic disorders, hepatic insufficiency, hepatic blood flow disorders, nephropathy, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), pancreatic secretory disorders, benign prostatic hyperplasia, neuropathic bladder disease, diabetic nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, drug- or transplant-induced nephropathy, autoimmune nephropathy, lupus nephritis, liver fibrosis, kidney fibrosis, chronic kidney disease (CKD), diabetic nephropathy (DKD), skin fibrosis, keloids, systemic sclerosis, scleroderma, virus-induced fibrosis, and idiopathic pulmonary fibrosis. Interstitial lung disease (IPF), nonspecific interstitial pneumonia (NSIP), common interstitial pneumonia (UIP), radiation-induced fibrosis, familial pulmonary fibrosis, respiratory tract fibrosis, chronic obstructive pulmonary disease (COPD), spinal cord tumors, 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, Kaburg sarcoma, solid tumors, cerebral infarction, cerebral hemorrhage, neuralgia, peripheral neuropathy, age-related macular degeneration (AMD), glaucoma, ocular fibrosis, corneal scarring, diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid glaucoma filtration surgery scars, Crohn's disease or systemic lupus erythematosus; keloid formation due to abnormal wound healing; fibrosis, myelofibrosis, and fibrosis occurring after organ transplantation. In one embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering, alone or as appropriate, in combination with another compound of the present invention and / or at least one other type of therapeutic agent, a therapeutically effective amount of at least one compound of the present invention to a patient in need of such treatment.

[1035] In another embodiment, the present invention provides a compound of the present invention for use in a therapy.

[1036] In another embodiment, the present invention provides a compound for use in a therapy for treating fibrotic, inflammatory, or proliferative conditions.

[1037] In another embodiment, the present invention also provides the use of the compounds of the present invention for manufacturing agents for treating fibrotic, inflammatory, or proliferative conditions.

[1038] In another embodiment, the present invention provides a method for treating fibrotic conditions, inflammatory conditions, or proliferative conditions, comprising administering therapeutically effective amounts of first and second therapeutic agents to a patient in need, wherein the first therapeutic agent is a compound of the present invention.

[1039] In another embodiment, the present invention provides a combination formulation of the compound of the present invention used simultaneously, separately, or sequentially in a therapy with other therapeutic agents.

[1040] In another embodiment, the present invention provides a combination formulation of the compounds of the present invention with other therapeutic agents for the simultaneous, separate, or sequential treatment of fibrotic conditions, inflammatory conditions, or proliferative conditions.

[1041] The compounds of the present invention can be used in combination with other therapeutic agents, such as one or more antifibrotic and / or anti-inflammatory therapeutic agents.

[1042] In one embodiment, the other therapeutic agent used in the combination pharmaceutical composition or method of combination or use in combination is selected from one or more, preferably one to three, of the following therapeutic agents: TGFβ receptor inhibitors (e.g., golentibub), TGFβ synthesis inhibitors (e.g., pirfenidone), inhibitors of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) receptor kinases (e.g., nintedanib), humanized anti-α Vβ6 integrin monoclonal antibodies (e.g., 3G9), recombinant human pentameric protein-2, recombinant human serum amyloid protein P, recombinant human antibodies against TGFβ-1, TGFβ-2 and TGFβ-3, endothelin receptor antagonists (e.g., macitentan), interferon-γ, c-Jun N-terminal kinase (JNK) inhibitors (e.g., 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino] [9H-purin-2-yl]amino]-trans-cyclohexanol, 3-pentylphenylacetic acid (PBI-4050), tetra-substituted porphyrin derivatives containing manganese(III), monoclonal antibodies targeting eosinophil-2, interleukin-13 (IL-13) antibodies (e.g., raprecizumab, tarozymeb), bispecific antibodies targeting interleukin-4 (IL-4) and interleukin-13 (IL-13), NK1 tachykinin receptor agonists (e.g., Sar... 9 Met(O2) 11-P substance), sinecurde ketosuto, human recombinant DNA-derived IgG1 κ monoclonal antibody against connective tissue growth factor, and fully human IgG1 selective for CC-chemokine ligand 2. κ antibodies (e.g., kalurumab, CCX140), antioxidants (e.g., N-acetylcysteine), phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil), agents for treating obstructive tracheal diseases (e.g., muscarinic antagonists (e.g., tiotropium bromide, pratropium bromide), adrenaline β2 agonists (e.g., methylphenidate, salmeterol), corticosteroids (e.g., triamcinolone, dexamethasone, fluticasone), immunosuppressants (e.g., tacrolimus, rapamycin, pimecrolimus), and agents indicated for treating fibrotic conditions (e.g., liver, gallbladder, and kidney fibrosis), non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatitis (NASH), cardiac fibrosis, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis. Suitable treatments for this type of fibrosis include (but are not limited to) FXR agonists (e.g., OCA, GS-9674, and LJN452); LOXL2 inhibitors (e.g., cintuzumab); and LPA1 antagonists (e.g., BMS-986020 and SAR). 100842); PPAR modulators (e.g., efenporno, pioglitazone, sarografezil, IVA337); SSAO / VAP-1 inhibitors (e.g., PXS-4728A and SZE5302); ASK-1 inhibitors (e.g., GS-4997 or seloselte); ACC inhibitors (e.g., CP-640186 and NDI-010976 or GS-0976); FGF21 mimics (e.g., LY2405319 and BMS-986036); apoptosis protease inhibitors (e.g., entrilesen); NOX4 inhibitors (e.g., GKT137831); MGAT2 inhibitors (e.g., BMS-963272); αV integrin inhibitors (e.g., atezolizumab); and bile acid / fatty acid conjugates (e.g., areramerol).The FXR agonists of various embodiments of the present invention may also be used in combination with one or more therapeutic agents, such as CCR2 / 5 inhibitors (e.g., senevirox); galactoglobulin-3 inhibitors (e.g., TD-139, GR-MD-02); leukotriene receptor antagonists (e.g., tylucalkast, montelukast); SGLT2 inhibitors (e.g., dapagliflozin, repaggliflozin); GLP-1 receptor agonists (e.g., liraglutide and smeglutide); FAK inhibitors (e.g., GSK-2256098); CB1 inverse agonists (e.g., JD-5037); CB2 agonists (e.g., APD-371 and JBT-101); autocrine motor factor inhibitors (e.g., GLPG1690); prolyl t-RNA synthetase inhibitors (e.g., halofurone); FPR2 agonists (e.g., ZK-994); and THR agonists (e.g., MGL:3196). In another embodiment, the other therapeutic agents used in the combination of the pharmaceutical composition or combination method or combination use are selected from one or more immuno-oncology agents, preferably one to three, such as alemtuzumab, atezolizumab, ipalizumab, nivolumab, ovalimumab, pelizumab, and rituximab.

[1043] The compounds of the present invention can be administered by any suitable means for any of the uses described herein, such as: oral administration, such as tablets, capsules (each comprising sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions; sublingual administration; buccal administration; non-enteral administration, such as subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasal administration, including administration to the nasal mucosa, such as by inhalation spray; topical administration, such as in the form of creams or ointments; or rectal administration, such as in the form of suppositories. They can be administered alone, but are generally administered co-administered with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[1044] The term "pharmaceutical composition" means a composition comprising the compounds of the present invention and at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for delivering bioactive agents to animals (particularly mammals), including (i.e.) adjuvants, excipients, or mediators, such as diluents, preservatives, fillers, flow modifiers, disintegrants, humectants, emulsifiers, suspending agents, sweeteners, flavorings, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the nature of the administration method and dosage form. Pharmaceutically acceptable carriers are formulated based on several factors within the scope of those skilled in the art. These factors include (but are not limited to): the type and nature of the active agent being formulated; the individual to whom the composition containing the pharmaceutical agent will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers may include a variety of different components and additives, which are included in the formulation for a variety of reasons well known to those skilled in the art, such as binders for stabilizing the active agent. Descriptions of pharmaceutically acceptable suitable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Remington's Pharmaceutical Sciences, 18th edition (1990).

[1045] As used herein, the term "treatment" refers to a method of obtaining a beneficial or desired outcome (including clinical outcomes) by using the compounds or compositions of the present invention. For the purposes of this invention, beneficial or desired clinical outcomes include (but are not limited to) one or more of the following: reducing the severity and / or frequency of one or more symptoms caused by a disease, condition, or symptom; reducing the degree of a disease, condition, or symptom or causing its resolution; stabilizing a disease, condition, or symptom (e.g., preventing or delaying nausea of ​​a disease, condition, or symptom); delaying or slowing the progression of a disease, condition, or symptom; improving the state of a disease, condition, or symptom; reducing the dosage of one or more other agents required to treat a disease, condition, or symptom; and / or improving quality of life.

[1046] Pharmaceutically acceptable carriers are formulated based on several factors within the scope of the art. These factors include (but are not limited to): the type and nature of the active agent being formulated; the individual to whom the composition containing the pharmaceutical agent will be administered; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers may include a variety of different components and additives, which are included in the formulation for a variety of reasons well known to the art, such as binders to stabilize the active agent. Descriptions of pharmaceutically acceptable suitable carriers and the factors involved in their selection can be found in a variety of readily available sources, such as Allen, LV Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd ed. (2012), Pharmaceutical Press.

[1047] The dosing regimen of the compounds of this invention will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode of administration and route of administration; the species, age, sex, health status, medical condition and weight of the recipient; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; the patient's renal and hepatic function; and the desired effect.

[1048] According to general guidelines, the daily oral dose of each active ingredient for the specified action will be between about 0.01 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.01 to about 250 mg per day. When administered intravenously, the optimal dose during a constant-rate infusion will be in the range of about 0.01 to about 10 mg / kg per minute. The compounds of the present invention can be administered as a single daily dose, or the total daily dose can be divided into two, three, or four divided doses per day.

[1049] Compounds are typically administered in a mixture with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier) that is appropriately selected for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and is consistent with known pharmaceutical practices.

[1050] Suitable dosage forms (pharmaceutical compositions) may contain about 1 mg to about 2000 mg of active ingredient per dose unit. In said 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.

[1051] Typical capsules for oral administration contain at least one compound of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[1052] A typical injectable formulation is prepared by aseptically placing at least one compound of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing it. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

[1053] This invention includes pharmaceutical compositions comprising, alone or in combination with a drug carrier, a therapeutically effective amount of at least one compound of the invention as an active ingredient. Where appropriate, the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more (preferably one to three) other therapeutic agents, such as ASK-1 inhibitors, CCR2 / 5 antagonists, autocrine motor factor inhibitors, LPA1 receptor antagonists, or other pharmaceutically active substances.

[1054] When the other therapeutic agents described above are used in combination with the compounds of the present invention, they may be used in amounts indicated, for example, in Physicians' Desk Reference (as stated in the patents mentioned above) or in amounts otherwise determined by those skilled in the art.

[1055] Especially when provided in single-dose units, chemical interactions may exist between the combined active ingredients. Therefore, when the compounds and second therapeutic agents of the present invention are combined in single-dose units, they are formulated such that, although the active ingredients are combined in single-dose units, physical contact between the active ingredients is minimized (i.e., reduced). For example, an active ingredient may be coated with an enteric coating. By coating one of the active ingredients with an enteric coating, not only is contact between the combined active ingredients minimized, but the release of one of the components in the gastrointestinal tract can also be controlled, such that one of the components is released in the intestine rather than in the stomach. One of the active ingredients may also be coated with a substance that influences sustained release throughout the gastrointestinal tract and also minimizes physical contact between the combined active ingredients. Furthermore, a sustained-release component may be additionally coated with an enteric coating so that this component is released only in the intestine. Another approach involves the formulation of a combination product in which one component is coated with a sustained-release and / or enteric polymer, and another component is also coated with a polymer such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) or other suitable substances known in the art, to further separate the active component. The polymer coating serves to form an additional barrier to interaction with the other component.

[1056] Once the present invention is mastered, those skilled in the art will readily appreciate the methods described above and others used to minimize contact between the components of the combined product of the present invention, whether administered in a single dosage form or simultaneously in separate forms but in the same manner.

[1057] The compounds of the present invention can be administered alone or in combination with one or more (preferably one to three) other therapeutic agents. "Combination administration" or "combination therapy" means administering the compounds of the present invention and one or more (preferably one to three) other therapeutic agents simultaneously to the mammal being treated. When administered in combination, the components can be administered simultaneously or sequentially at different time points in any order. Therefore, the components can be administered individually but at sufficiently close temporal proximity to provide the desired therapeutic effect.

[1058] Combination therapy is intended to include the sequential administration of the therapeutic agents, i.e., the individual therapeutic agents are administered at different times, and the therapeutic agents or at least two therapeutic agents are administered substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering to an individual a single dosage form of each therapeutic agent in a fixed ratio or multiple single dosage forms of each therapeutic agent. Sequential or substantially simultaneous administration of the therapeutic agents can be achieved via any suitable route, including (but not limited to) oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents can be administered via the same route or via different routes. For example, the first therapeutic agent in a selected combination may be administered intravenously, while the other therapeutic agents in the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered intravenously. Combination therapy may also include further administration of the therapeutic agents as described above in combination with other bioactive ingredients and non-pharmacological therapies (e.g., surgery or radiation therapy). Where the combination therapy further includes non-pharmacological therapies, the non-pharmacological therapies may be administered at any suitable time, provided that the synergistic effect of the combination of the therapeutic agents and the non-pharmacological therapies achieves a beneficial effect. For example, in appropriate circumstances, when non-pharmacological treatments are temporarily removed from the administration of therapeutic agents, beneficial effects may still be achieved even after several days or even weeks.

[1059] The compounds of this invention are also suitable as standard or reference compounds in tests or analyses involving FXR agonists, for example, as quality standards or controls. Such compounds are available, for example, in commercially available kits for drug studies involving FXR agonist activity. For instance, the compounds of this invention can be used in analyses to compare their known activities with those of compounds with unknown activities. This ensures that researchers perform analyses correctly and provides a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new analytical methods or protocols, the compounds according to this invention can be used to test their effectiveness.

[1060] This invention also covers articles. As used herein, articles are intended to include (but are not limited to) sets and packages. Articles of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises: a first therapeutic agent comprising the compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert stating that the pharmaceutical composition can be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert states that the pharmaceutical composition can be combined with a second therapeutic agent (as defined above) for the treatment of fibrosis and its sequelae. Articles 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. Located within the first and second containers means that each container holds the entry within its boundaries.

[1061] The first container is a vessel for containing a pharmaceutical composition. This container may be used for manufacturing, storing, transporting, and / or selling individually or in whole. The first container is intended to encompass bottles, jars, vials, flasks, syringes, tubes (e.g. for cream formulations), or any other container used for manufacturing, containing, storing, or dispensing pharmaceutical products.

[1062] The second container is used to contain the first container and, where appropriate, the instruction leaflet. Embodiments of the second container include (but are not limited to) boxes (e.g., cardboard or plastic), cartons, cardboard boxes, bags (e.g., paper or plastic bags), pouches, and large bags. The instruction leaflet may be physically attached to the exterior of the first container by tape, glue, nails, or another attachment method, or it may remain inside the second container without being physically attached to the first container. Alternatively, the instruction leaflet may be located on the exterior of the second container. When located on the exterior of the second container, the instruction leaflet is preferably physically attached by tape, glue, nails, or another attachment method. Alternatively, it may be adjacent to or in contact with the exterior of the second container but not physically attached.

[1063] A drug package insert is a label, tag, or marker that describes information relating to a pharmaceutical composition located within a first container. This information is typically determined by the regulatory agency in the region where the product is sold (e.g., the U.S. Food and Drug Administration). Preferably, the package insert specifically describes the approved indications for which the pharmaceutical composition may be used. The package insert can be made of any material from which an individual can read the information contained therein. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper, or plastic, etc.) on which the desired information has already been formed (e.g., printed or coated).

[1064] Preparation method

[1065] The compounds of this invention can be synthesized by a variety of methods well known in the field of organic chemistry. A general synthetic procedure for preparing the compounds of this invention is described below. This procedure is illustrative and is not intended to limit the possible techniques that those skilled in the art can use to prepare the compounds disclosed herein. Different methods for preparing the compounds of this invention will be apparent to those skilled in the art. Examples of compounds of this invention prepared by the methods described in the general procedure are provided in the Examples section below. The preparation of single-chiral examples can be carried out by techniques known to those skilled in the art. For example, single-chiral compounds can be prepared by separating racemic products or diastereomers by chiral phase-preparative HPLC. Alternatively, the example compounds can be prepared by methods known to yield enantiomerically or diastereomeric enriched products.

[1066] The reactions and techniques described in this section are carried out in solvents suitable for the reagents and materials used and for the transformations achieved. Furthermore, in the description of the synthetic methods given below, it should be understood that all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental duration, and processing procedures) are chosen as standard conditions for the reaction that should be readily identifiable to those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on various parts of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with reaction conditions are apparent to those skilled in the art, where alternatives are required when incompatible substituents are present. Sometimes judgments must be made to change the order of synthetic steps or to choose a particular process flow over another to obtain the compounds of the present invention. It is also recognized that another major consideration in the planning of any synthetic route in the art is the careful selection of protecting groups for protecting the reactive functional groups present in the compounds described herein. An authoritative description of many alternatives to trained practitioners is provided in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley and Sons (2007). Example

[1067] The following examples illustrate specific and preferred embodiments of the invention and do not limit the scope of the invention. Unless otherwise specified, chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their common and conventional meanings. Examples and other abbreviations used elsewhere in this application are defined below. Common intermediates are generally used to prepare more than one example and are sequentially identified (e.g., intermediate 1, intermediate 2) and abbreviated as Int.1 or I1, Int.2 or I2. Compounds of examples are identified by the examples and steps in which they are prepared (e.g., "1-A" indicates step A of Example 1), or simply by the example identifier that the compound is the title compound of the example (e.g., "1" indicates the title compound of Example 1). In some cases, alternative preparations of intermediates or examples are described. Chemists in the art of synthesis can often design potentially suitable alternative preparations based on one or more considerations such as: shorter reaction time, cheaper starting materials, ease of operation or separation, improved yield, catalytic capability, avoidance of toxic reagents, availability of specialized instruments, and reduction of the number of linear steps. The intention of describing alternative preparations is to further enable the preparation of examples of the invention. In some cases, some functional groups in the outlined embodiments and claims can be replaced by well-known bioelectron isosteric substitutes known in the art, such as partially replacing carboxylic acid groups with tetrazolium or phosphate esters. The deuterated dimethyl sulfoxide collected... 1 The H NMR data were processed with water suppression. The reported spectrum is uncorrected for the water suppression effect. Protons near the water suppression frequency of 3.35 ppm exhibited reduced signal strength.

[1068] abbreviation

[1069] The abbreviations used in this article are defined as follows: "1×" for once, "2×" for twice, "3×" for three times, "℃" for degrees Celsius, "eq" for equivalent, "g" for gram, "mg" for milligram, "L" for liter, "mL" for milliliter, "μL" for microliter, "N" for equivalent, "M" for mole, "mmol" for millimole, "min" for minute, "h" for hour, "rt" for room temperature, "RBF" for round-bottom flask, "atm" for atmosphere, "psi" for pounds per square hour, "conc." for concentration, "RCM" for dead-cycle metathesis, "sat" or "sat'd" for saturation, "SFC" for supercritical fluid chromatography, "MW" for molecular weight, "mp" for melting point, "ee" for enantiomer excess, "MS" or "Mass" for mass fraction. "Spec" indicates mass spectrometry; "ESI" indicates electrospray ionization mass spectrometry; "HR" indicates high resolution; "HRMS" indicates high resolution mass spectrometry; "LCMS" indicates liquid chromatography-mass spectrometry; "HPLC" indicates high performance liquid chromatography; "RPHPLC" indicates reversed-phase HPLC; "TLC" or "tlc" indicates thin-layer chromatography; "NMR" indicates nuclear magnetic resonance spectroscopy; "nOe" indicates nuclear overhauser effect spectroscopy. 1 "H" represents a proton, "δ" represents δ (delta), "s" represents a singlet, "d" represents a doublet, "t" represents a triplet, "q" represents a quartet, "m" represents a multiplet, "br" represents a broad peak, "Hz" represents Hertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical symbols familiar to those skilled in the art.

[1070] The following abbreviations are used in processes, examples, and elsewhere in this document:

[1071] EtOAc = Ethyl acetate

[1072] PE = Petroleum Ether

[1073] DMF = dimethylformamide

[1074] THF = Tetrahydrofuran

[1075] K₂CO₃ = Potassium carbonate

[1076] Na₂CO₃ = Sodium carbonate

[1077] MgSO4 = Magnesium sulfate

[1078] DCM = CH₂Cl₂ = dichloromethane

[1079] DCE = 1,2-dichloroethane

[1080] MeOH = methanol

[1081] HCl = hydrochloric acid

[1082] AcOH = Acetic acid

[1083] Cs₂CO₃ = Cesium carbonate

[1084] DMSO = dimethyl sulfoxide

[1085] TEA = Triethylamine

[1086] BOP = hexafluorophosphate (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium

[1087] DMAc = dimethylacetamide

[1088] DMAP = 4-Dimethylaminopyridine

[1089] 2-DMAP = 2-Dimethylaminopyridine

[1090] PCC = Pyridium Chlorochromate

[1091] PDC = Pyridium dichromate

[1092] DIBAL-H = Diisobutylaluminum hydride

[1093] Rotovap = Rotary evaporation

[1094] min = minutes

[1095] h or hr = hours

[1096] d = day

[1097] rt = room temperature

[1098] mL = milliliters

[1099] g = gram

[1100] mg = milligram

[1101] mmol = millimole

[1102] LRMS = Low Resolution Mass Spectrometry

[1103] NMR = Nuclear Magnetic Resonance

[1104] HPLC = High Performance Liquid Chromatography

[1105] synthesis

[1106] The compounds of the present invention can be prepared in a variety of ways well known to those skilled in organic synthesis. The compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in organic chemistry or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated herein by reference in their entirety.

[1107] Compounds of Formula I can be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents suitable for the reagents and substances used and conducive to achieving the transformation. Furthermore, in the description of the synthetic methods below, it should be understood that all proposed reaction conditions (including solvents, reaction atmospheres, reaction temperatures, experimental durations, and procedures) are selected as standard conditions readily identifiable to those skilled in the art for the reaction. Those skilled in organic synthesis will understand that the functional groups present on each part of the disclosed molecule must be compatible with the proposed reagents and reactants. Not all compounds of Formula (I) within the established category are compatible with some of the reaction conditions required in the described methods. Those skilled in the art will readily recognize the limitations on substituents compatible with the reaction conditions and the necessity of using alternative methods.

[1108] Process 1

[1109]

[1110] Procedure 1 describes the synthesis of compounds of Formula I. Intermediate 3 can be synthesized by treating intermediates 1 and 2 under reductive amination conditions known to those skilled in the art. Imine synthesis can be carried out 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 reflux temperature, followed by reduction of the imine with a reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxyborohydride) to give intermediate 3. Intermediate 3 can be subjected to various transformations to obtain variations of Formula I using a variety of known methods recognized by those skilled in the art, including (but not limited to) the following:

[1111] Amide: Intermediate 4 is available from commercial sources or can be synthesized by known methods readily identifiable to those skilled in the art. Intermediate 4 can be activated to acylate in a polar aprotic solvent (e.g., DCM, THF) using a variety of reagents identifiable to those skilled in the art (e.g., phosphorus oxychloride, thionyl chloride, oxaloyl chloride, and methyl or ethyl chloroformate) at a temperature between 130°C and 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 produce a compound of formula I.

[1112] Urea: Intermediate 3 can be treated with isocyanate in a polar aprotic solvent (e.g., DCM or DCE) in the presence of a base (e.g., Et3N, DIPEA, or pyridine) at room temperature to obtain urea represented by Formula I. Alternatively, intermediate 3 can be treated with triphosgene in a solvent (e.g., DCM or DCE) in the presence of a base (e.g., Et3N or DIPEA) at 0°C to room temperature, followed by treatment with an amine in a solvent (e.g., DCM or DCE) in the presence of a base (e.g., Et3N or DIPEA) at room temperature to obtain urea represented by Formula I.

[1113] Carbamate: Intermediate 3 can be treated with chloroformate (or alcohol, activated to carbonate) in a polar aprotic solvent (e.g., DCM, DCE or THF) in the presence of a base (e.g., Et3N, DIPEA or pyridine) at 0°C to room temperature to obtain carbamate represented by formula I.

[1114] Intermediate 1 (an) (process 1) can be obtained using a variety of known methods recognized by those skilled in the art, including (but not limited to) the following methods, in various ways as described in processes 2-10.

[1115] Process 2

[1116]

[1117] Procedure 2 describes the synthesis of intermediate 1a. Intermediates 5 and 6 are available from commercial sources or can be synthesized by known methods readily identifiable to those skilled in the art. Intermediates 5 or 6 can be coupled with various substituted amamidoximes (derived from their corresponding nitriles via reaction with hydroxylamine; see Hirawat, S. et al., WO 2006 / 110483) at room temperature in a polar aprotic solvent (e.g., THF, 1,4-dioxane, or DMF). The acyclic intermediate can then be cyclized at high temperatures (60°C to 100°C) to give intermediate 1a or intermediate 7. Alternatively, in-situ cyclization can be achieved by coupling compounds 5 or 6 with an amamidoxime at high temperatures (60°C to 100°C). The resulting nitro intermediate 7 can be reduced using conditions recognized by those skilled in the art, including (but not limited to) reduction at ambient pressure and temperature in the presence of a catalyst such as Pd and hydrogen, to give intermediate 1a.

[1118] Process 3

[1119]

[1120] Procedure 3 describes the synthesis of intermediate 1b. Intermediate 8 can be prepared from intermediate 6 using a variety of reagents recognizable to those skilled in the art, (but not limited to) those described herein (e.g., phosphorus oxychloride, thionyl chloride, oxaloyl chloride, methyl chloroformate, or ethyl chloroformate) in a polar aprotic solvent (e.g., DCM or THF) at a temperature between -30°C and reflux. Intermediate 8 can be treated with methyl acetate pretreated with a base (e.g., n-BuLi) in a solvent (such as, but not limited to, THF or diethyl ether)...

Claims

1. A compound of formula (I): ， Or its pharmaceutically acceptable salt, wherein: X 1 For CR 5a ; X 2 For CR 5b ; X 3 For CR 5c ; X 4 For CR 5d ; Z 1 and Z 2 It is CH2; a = 1; b is 1; d is 1; Q is the distance from 0 to 2 R. 1 Substituted phenyl; Each R 1 Independently hydrogen, F, Cl, Br, C 1-4 Hydroxyalkyl, -CH(OH)CHF2, C 1-4 Alkoxy, C 1-2 Fluoroalkoxy, -OC(CH3)2CN, -OC(CH3)2C(O)NH2 or cyanocyclopropyl; R 2 For 0 to 3 R 2b Replacement C 3-5 carbon cyclo group; Each R 2b Independently hydroxyl, C 1-3 Alkyl or C 1-2 fluoroalkyl; R 3a and R 3b It is hydrogen; A represents 0 to 2 R's. 4a Substituted oxadiazole group; Each R 4a Independently, it is -CH(CH3)2, -C(CH3)3, -CHF2, -CF3, -CF2CH3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, cyclopropyl, fluorocyclopropyl, methylcyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, or difluorocyclopropyl; R 5a R 5b and R 5c Each of them is hydrogen; and R 5d It is hydrogen or halogen.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following structure: 。 3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein: Q is the result of R 1 Substituted phenyl; A is via R 4a Substituted oxadiazole group; R 2 For 0 to 3 R 2b Replacement C 3-5 cycloalkyl; Each R 2b Independently hydroxyl, C 1-3 Alkyl or C 1-2 fluoroalkyl; and Each R 4a It can be independently -C(CH3)3, -CF2CH3, -C(CH3)2F, -C(CH3)2OH, -C(CH3)2CN, fluorocyclopropyl or cyanocyclopropyl.

4. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: 、 、 、 、 、 、 、 、 、 、 or 。 5. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: 。 6. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: 。 7. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: 。 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. Use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating pathological fibrosis, inflammatory conditions, metabolic disorders or cholestatic conditions associated with farnesoid X receptor (FXR) activity.

10. The use according to claim 9, wherein the pathological fibrosis associated with farnesoid X receptor (FXR) activity is liver fibrosis, kidney fibrosis, biliary fibrosis, or pancreatic fibrosis.

11. Use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, in the preparation of a medicament for treating nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic nephropathy, primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC) associated with farnesoid X receptor (FXR) activity.

12. Use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating nonalcoholic steatosis (NASH) associated with farnesoid X receptor (FXR) activity.

13. Use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 8 in the preparation of a medicament for treating idiopathic pulmonary fibrosis (IPF) associated with farnesoid X receptor (FXR) activity.

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