EA040704B1 - FARNESOID X-RECEPTOR AGONISTS AND THEIR USE - Google Patents

Description

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The present application claims priority under US Provisional Application No. 62/471,511, filed March 15, 2017; U.S. Provisional Application No. 62/471,517, filed March 15, 2017; U.S. Provisional Application No. 62/471,525, filed March 15, 2017; U.S. Provisional Application No. 62/563488, filed September 26, 2017, and U.S. Provisional Application No. 62/535,502, filed September 26, 2017; each of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

This document describes compounds that are farnesoid X receptor agonists, methods for preparing such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods for using such compounds to treat conditions, diseases, or disorders associated with farnesoid X receptor activity.

Background of the Invention

The farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver, intestine, kidney, adrenal gland, and adipose tissue. FXR regulates a wide range of target genes involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis. FXR agonism is a method of treating many metabolic disorders, liver diseases or conditions, inflammatory conditions, gastrointestinal diseases or cell proliferation related diseases.

Brief summary of the present invention

In one aspect, farnesoid X receptor agonists and their uses are described herein. In one aspect, this document describes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

Formula (I) wherein ring A is a 5-membered heteroaryl which is oxazolyl, thiazolyl, pyrazolyl or isothiazolyl;

or ring A is a 6-membered heteroaryl which is pyridinyl or pyrimidinyl;

X ¹ represents CH or N;

R ¹ is H, D, halogen, -CN, -OH, -N(R ¹⁵ ) ₂ , C1-C ₄ alkyl, C1-C ₄ alkoxy, C1-C ₄ deuteroalkyl, C1-C ₄ deuteroalkoxy, C1- C ₄ fluoroalkyl or C 1 -C ₄ fluoroalkoxy;

X ² is CR ² or N;

R ² is H, D, halogen, -CN, -OH, -N(R ¹⁵ ) ₂ , C1-C ₄ alkyl, C1-C ₄ alkoxy, C1-C ₄ deuteroalkyl, C1-C ₄ deuteroalkoxy, C1- C ₄ fluoroalkyl or C 1 -C ₄ fluoroalkoxy;

or R ¹ and R ² are taken together with intermediate atoms to form a fused 5-membered ring with 2 N atoms, where said ring is optionally substituted with 2 substituents selected from fluorine and methyl;

X ³ is CR ³ or N;

R ³ is H, D, halogen, -CN, -OH, -N(R ¹⁵ ) ₂ , C ₁ -C ₄ alkyl, C1 -C ₄ alkoxy, C1 -C ₄ deuteroalkyl, C1 -C ₄ deuteroalkoxy, C1 -C ₄ fluoroalkyl or C 1 -C ₄ fluoroalkoxy;

each X ⁴ is independently CH or N;

R ⁴ is H;

R ⁵ is H;

or R ⁴ and R ⁵ are taken together to form a bridge which is -CH ₂ CH ₂ -;

each R ⁶ is independently H, D, F, -OH or -CH ₃ ;

m is 0;

R ⁷ is H;

L is absent or is -Y2-L ¹ -;

Y ² represents -C=C-;

L ¹ is missing;

R ⁸ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ fluoroalkyl or unsubstituted C ₃ -C ₆ cycloalkyl;

R ⁹ is H;

R ¹⁰ is -CO2H, -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ¹⁵ S(=O)2R ¹⁴ ,

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-NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2 or -NR ¹⁵ C(=O)N(R ¹² ) ₂ ;

or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is an unsubstituted C ₁ -C ₆ alkylene;

L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O) ₂ ., -NR ¹⁵ -, -C(=O)-, -C(=O) NR ^15- ,

-NR ¹⁵ C(=O)-, -C(=O)O-, -OC(=O)- or -OC(=O)NR ¹⁵ -;

L ⁴ is unsubstituted Ci-Sbalkylene;

R ¹³ is H, -CN, -OH, -N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -SR ¹² , -S(=O)R ¹⁴ , -S(=O) 2R ¹⁴ , -OC(=O)R ¹⁴ , -CO2H, -CO ₂ R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, unsubstituted C ₁ -C ₆ αkyl, unsubstituted C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl , which is optionally substituted with methoxy or dimethylamino; phenyl which is optionally substituted with methoxy; tetrazolyl or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl;

R ¹¹ is H or -CH ₃ ; or

R ⁹ and R ¹¹ are taken together to form a bridge which is -CH2CH2-; each R ¹² is independently H, C1-C4 alkyl, hydroxycarbonylmethyl, methoxycarbonyl, methoxycarbonylmethyl, 2-hydroxyethyl, 2-aminoethyl, 2-methoxyethyl, 2-(dimethylamino)ethyl, 3-hydroxypropyl, 2hydroxypropyl, 1-hydroxypropan-2-yl , 1,3-dihydroxypropan-2-yl, 2,3-dihydroxypropyl, 2hydroxy-2-methylpropyl, 3-(dimethylamino)propyl, 4-(dimethylamino)butyl, 2-hydroxy-2-methylbutyl, 2-hydroxy-3 -methylbutyl, 3-hydroxybutan-2-yl, 2-hydroxy-2,3-dimethylbutyl, 5-(dimethylamino)pentyl, methylsulfonyl, methylcarbonyl, cyclopropyl, oxetanyl, azetidinyl, which is optionally substituted with methyl or t-butoxycarbonyl; piperidinyl which is optionally substituted with methyl; 1H-imidazol-2-ylmethyl, 1H-pyrazol-4-ylmethyl or 2-((N-methyl-N-tert-butoxycarbonyl)amino)ethyl;

R ¹⁴ is C ₁ -C ₄ alkyl; cyclohexyl which is optionally substituted with hydroxy, 2(methylamino)ethyl or hydroxycarbonylmethoxy; cyclobutyl which is optionally substituted with methoxy or dimethylamino; azetinidyl which is optionally substituted with -CN, methyl, ethyl, isopropyl, t-butyl, ethynyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, methylthio, methylthiomethyl, methylsulfonyl, hydroxycarbonyl, methoxycarbonyl, hydroxymethyl, methoxymethyl, hydroxycarbonylmethyl, methoxycarbonylmethyl, 2- hydroxyethoxy, 2-methoxyethoxy, 2hydroxypropan-2-yl, amino, methylamino, dimethylamino, dimethylamino-methyl, methylsulfinyl, methylsulfinylmethyl, methylsulfonylmethyl, t-butoxycarbonylamino, t-butoxycarbonyl-(N-methyl)amino, oxetanyl, 4-hydroxyazetidin-1-yl; oxetanil; morpholinyl which is optionally substituted with 1-2 methyls; thiomorpholinyl; thiomorpholinyl-1-oxide; thiomorpholinyl-1,1-dioxide; or piperazinyl which is optionally substituted with methyl, ethyl or isopropyl;

R ¹⁵ represents H or unsubstituted C ₁ -C ₆ αkil;

R ¹⁶ is -N(R ¹⁵ ) ₂ or C1-C ₄ alkoxy; and n is 0, 1 or 2.

In one embodiment, Ring A is a 5-membered heteroaryl which is thiazolyl, oxazolyl, or pyrazolyl. In one embodiment

(1 is X rv nA/ R ¹⁶ X _x . v- ^r8 , X Υ ^ν _R 16^N ^Κ , , R16 In one embodiment, ( is l A D-R ⁸ RY e16 j R ⁸ A ¹⁶ ^aY ¹⁶ _o16 YYr ¹⁶ YJY ¹⁶ ' 16 , R ¹⁶ N , R ¹⁶ 0 , R ¹⁶ , XR ¹⁶ Υ Y , R ¹⁶ or R ¹⁶ N A Yr ⁸ rY

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In one embodiment, is

In one embodiment, L is absent. In one embodiment, L is -C=C-. In one embodiment, R ¹¹ is H, or R ⁹ and R ¹¹ are taken together to form a bridge that is -CH2CH2-.

In one embodiment, the compound is characterized by the structure of formula (II)

In one embodiment, the compound is characterized by the structure of formula (III)

In one embodiment, the compound is characterized by the structure of formula (IV)

Formula (IV).

In one embodiment, the compound is characterized by the structure of formula (V)

-NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ or -OC(=O)N(R ¹² )2; or R ¹⁰ is -L2-L ³ L ⁴ -R ¹³ ;

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L ² is absent or is -CH2-;

L ³ is absent or represents -O-, -NH-, -C(=O)NH-, -NHC(=O)- or -NHC(=O)O-;

L ⁴ is -CH2-, -CH2CH2- or -CH2CH2CH2-.

In one embodiment, R ¹³ is H, -CN, -OH, -CH ₃ , -CH ₂ CH ₃ , -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3 )3, -CO2H, -C(=O)NHCH3, -OC(=O)NHCH ₃ , cyclobutyl which is optionally substituted with methoxy or dimethylamino, phenyl which is optionally substituted with methoxy or tetrazolyl.

In one embodiment, X ² is CR ² ;

X ³ is CR ³ or N;

each X ⁴ is CH or each X ⁴ is N; or one X ⁴ is N and the other X ⁴ is CH.

In one embodiment, R ¹ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH ₃ ), -N(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3 , -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; R ² is H, D, F, Cl, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3 ; R ³ is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2 or -OCF3.

In one embodiment, R ¹ is -OH, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3 , -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

R ² is H, D, F, Cl, -CH3, -CD3, -CH2F, -CHF2 or -CF3;

R ³ is H.

In one embodiment, is is is

In one embodiment

In one embodiment, R8 is H, -CH ₃ , -CH2CH ₃ , -CH2CH2CH ₃ , -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -C^CHCHS^b, -C(CH3) h, -CD3, -CH2F, -CHF2, -CF3, -CH2CF ₃ , -CHFCH ₃ , -CH2CH2F, unsubstituted cyclopropyl or unsubstituted cyclobutyl.

In one embodiment, each R ¹⁶ is independently -NH2, -NH(CH3), -N(CH3)2, -OCH3, -OCH2CH3, or -OCH(CH3)2.

In one embodiment, n is 0.

This document considers any combination of the groups described above for various variables. Throughout the description, the groups and their substituents are chosen by those skilled in the art to provide stable moieties and compounds.

In one aspect, provided herein are the individual compounds of the present invention.

In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. According to another aspect, provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount for the treatment of a liver disease or condition or a gastrointestinal disease or condition in a mammal.

In one embodiment, the disease or condition of the liver or gastrointestinal disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), fatty liver disease (steatosis), cirrhosis, alcoholic hepatitis, intrahepatic

- 4 040704 cholestasis, extrahepatic cholestasis, hepatitis C virus (HCV), Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and liver cirrhosis, chronic viral hepatitis, alcoholic steatohepatitis (ASH), biliary cirrhosis, inflammatory bowel disease , necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease disease, postoperative inflammation, gastric carcinogenesis, graft versus host disease, or any combination thereof.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, as various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

Detailed description of the present invention

The farnesoid X nuclear hormone receptor (also known as FXR or nuclear receptor subfamily 1, group H, member 4 (NR1H4)) (OMIM: 603826) functions as a regulator of bile acid metabolism. FXR is a ligand-activated transcriptional receptor expressed in various tissues, including the adrenal gland, kidney, stomach, duodenum, jejunum, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissue. FXRs are highly expressed in tissues involved in bile acid metabolism such as the liver, intestines and kidneys. Bile acids function as endogenous ligands for FXR, so that the release of bile acids in the gut and in the body induces FXR-targeted changes in gene expression networks. Bile acids are the main product of cholesterol oxidation, and in some cases, when secreted into the intestine, they are regulators of cholesterol absorption. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by the cytochrome p450 enzyme cholesterol 7-a-hydroxylase (CYP7A1) and occurs in the liver. The cytochrome p450 enzyme 12-a-hydroxylase (CYP8B1) mediates bile acid production and determines the relative amounts of the two primary bile acids, bile acid and chenodeoxycholic acid. Activation of FXR can suppress transcription of CYP7A1 and CYP8B1 by upregulating expression of the hepatic small heterodimer partner (SHP) (also known as nuclear receptor subfamily 0, group B, member 2, or NR0B2) and intestinal expression of fibroblast growth factor 15 (FGF15) in mice and factor fibroblast growth 19 (FGF19) in humans. SFLP represses the liver receptor homologue (LRH-1) and hepatocyte nuclear factor 4alpha (HNFa4), transcription factors that regulate the expression of the CYP7A1 and CYP8B1 genes. Repression of CYP8B1 by FXR may be species-specific, and FXR activation may in some cases increase CYP8B1 expression in humans (Sanyal et al PNAS, 2007, 104, 15665). In some cases, gut-released FGF15/19 then activates hepatic fibroblast growth factor receptor 4, leading to activation of the mitogen-activated protein kinase (MAPK) signaling pathway that downregulates CYP7A1 and CYP8B1.

In some embodiments, elevated bile acids have been associated with insulin resistance. For example, insulin resistance sometimes results in decreased uptake of glucose from the blood and increased de novo production of glucose in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by stimulating the secretion of glucagon-like peptide-1 (GLP1) from intestinal L cells. GLP-1 is an incretin derived from a transcription product of the proglucagon gene. It is released in response to food intake and controls appetite and gastrointestinal function and promotes insulin secretion from the pancreas. Biologically active forms of GLP-1 include GLP-1(7-37) and GLP-1-(7-36)NH2, which result from selective cleavage of the proglucagon molecule. In such cases, FXR activation leading to a decrease in bile acid production correlates with a decrease in insulin resistance.

In some embodiments, FXR activation also correlates with secretion of a folded pancreatic polypeptide, such as a YY peptide (PYY or PYY3-36). In some cases, the YY peptide is a gut hormone peptide that modulates neuronal activity in the hypothalamus and brainstem, regions of the brain involved in reward processing. In some cases, a decrease in the content of PYY correlates with an increase in appetite and weight gain.

In some cases, FXR activation indirectly leads to a decrease in plasma triglycerides. The removal of triglycerides from the bloodstream is due to lipoprotein lipase (LPL). LPL activity is enhanced by the induction of its activator apolipoprotein CII, and repression of its inhibitor apolipoprotein CIII in the liver occurs after FXR activation.

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In some cases, FXR activation further modulates energy expenditure such as adipocyte differentiation and function. Adipose tissue contains adipocytes or fat cells. In some cases, adipocytes further differentiate into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to produce body heat, while WAT functions as fat-storing tissues.

In some cases, FXR is widely expressed in the gut. In some cases, FXR activation has been shown to induce expression and secretion of FGF19 (or FGF15 in mice) in the gut. FGF19 is a hormone that regulates bile acid synthesis as well as influences glucose metabolism, lipid metabolism and energy expenditure. In some cases, FGF19 has also been observed to modulate adipocyte function and differentiation. Indeed, a study showed that administration of FGF19 to mice fed a high-fat diet increased energy expenditure, modulated adipocyte differentiation and function, reversed weight gain, and improved insulin resistance (see Fu et al., Fibroblast growth factor 19 increases metabolic rate). and reverses dietary and leptin-deficient diabetes Endocrinology 145: 2594-2603 (2004)).

In some cases, intestinal FXR activity has also been shown to be involved in reducing microbiome overgrowth, such as during feeding (Li et al., Nat Commun 4:2384, 2013). For example, a study has shown that FXR activation correlates with increased expression of several genes in the ileum, such as Ang2, iNos, and Il18, which have antimicrobial effects (Inagaki et al., Proc Natl Acad Sci USA 103: 3920-3925,2006).

In some cases, FXR is involved in barrier function and immune modulation in the gut. FXR modulates the transcription of genes involved in the synthesis, transport, and metabolism of bile salts in the liver and intestines and has been shown in some cases to improve gut inflammation and prevent bacterial translocation into the intestinal tract (Gadaleta et al., Gut. 2011 Apr. ; 60(4): 463-72).

In some cases, excessive production of bile acids or improper transport and recycling of bile acids can lead to diarrhea. FXR modulates the transcription of genes involved in the synthesis, transport and metabolism of bile salts in the liver and intestines, and in some cases can lead to improvement in diarrhea (Camilleri, Gut Liver. 2015 May; 9(3): 332-339).

G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, membrane-type bile acid receptor, or M-BAR, or TGR5) is a cell surface receptor for bile acids. After activation by bile acid, TGR5 induces the production of intracellular cAMP, which then causes an increase in triiodothyronine levels due to the activation of deiodinase (DIO2) in BAT, which leads to an increase in energy expenditure.

Therefore, in some embodiments, regulation of metabolic processes such as bile acid synthesis, bile acid circulation, glucose metabolism, lipid metabolism, or insulin sensitivity is modulated by FXR activation. In addition, in some embodiments, dysregulation of metabolic processes such as bile acid synthesis, bile acid circulation, glucose metabolism, lipid metabolism, or insulin sensitivity results in metabolic diseases such as diabetes mellitus or diabetes-related conditions or disorders, alcoholic or non-alcoholic liver disease or condition, intestinal inflammation, or cell proliferative disorders.

In certain embodiments, disclosed herein are compounds that have activity as FXR agonists. In some embodiments, the FXR agonists described herein are structurally different from bile acids, other synthetic FXR ligands, and other natural FXR ligands.

In some embodiments, the present document also discloses methods for treating or preventing metabolic disorders such as diabetes mellitus, obesity, glucose intolerance, dyslipidemia, or insulin resistance by administering a therapeutically effective amount of an FXR agonist. In some instances, the compounds are administered to the subject's gastrointestinal tract.

In additional embodiments, disclosed herein are methods for treating or preventing alcoholic or non-alcoholic liver disease or conditions (e.g., cholestasis, primary biliary cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC) or elevated liver enzymes) by administering a therapeutically effective amount of an FXR agonist to a subject in need (eg, via the gastrointestinal tract). In additional embodiments, methods disclosed herein for treating or preventing cholestasis, cirrhosis, primary biliary cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis (PSC) by administering a therapeutically effective amount of an FXR agonist to a person in need thereof. subject. In some embodiments, provided herein are methods of treating or preventing cholestasis by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, provided herein are methods of treating or preventing primary biliary cirrhosis by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, provided herein are methods of treating or preventing NASH by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, provided herein are methods of treating or preventing NAFLD by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof.

In additional embodiments, provided herein are methods of treating or preventing intestinal inflammation and/or cell proliferation disorders, such as cancer, by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof (eg, via the gastrointestinal tract).

In still other embodiments, provided herein are FXR agonists that modulate one or more proteins or genes associated with a metabolic process, such as bile acid synthesis, glucose metabolism, lipid metabolism, or insulin sensitivity, such as, for example, increased FGF19 activity. (FGF15 in mouse), increased secretion of GLP-1, or increased secretion of PYY.

Metabolic disorders

In some embodiments, disclosed herein are methods for treating a metabolic disorder in a subject in need thereof. Also described herein are methods for preventing a metabolic disorder in a subject in need thereof. In some instances, these methods involve administering to a subject in need a therapeutically effective amount of one or more of the compounds disclosed herein. In some instances, one or more of the compounds disclosed herein are absorbed from the gastrointestinal (GI) tract. In additional instances, one or more of the disclosed compounds, when absorbed in the gastrointestinal tract, activates FXR receptors, thereby treating or preventing a metabolic disorder in the subject.

In some embodiments, the disclosed compounds exhibit systemic effects. In some cases, the disclosed compounds are characterized by local action in the intestine, but limited action in the liver or systemically. In some embodiments, the local effect of the disclosed compounds in the gut can be demonstrated by regulating target FXR genes in the gut. In some embodiments, targeted genes may include: SHP, FGF19 (FGF15), IBABP, C3, OST α/β. In some embodiments, exposure of the disclosed compounds is about 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, or more in the gut. In some cases, the exposure of the disclosed compounds is approximately 0.5, 1, 5, 10, 15, 20, 25, 30, 40, 50% or less in the systemic circulation. In some embodiments, exposure to FXR agonists in the intestinal lumen reduces the likelihood of side effects resulting from systemic action, thereby improving the safety profile of therapy. In additional embodiments, the disclosed compounds enhance expression of the target FXR gene in the gut. In additional embodiments, the disclosed compounds further modulate gene expression in an FXR-mediated pathway, such as, for example, FGF19 (FGF15), which inhibits the expression of CYP7A1 and CYP8B1 genes in the liver. In some instances, the disclosed compounds enhance gene expression in an FXR-mediated pathway. In other instances, the disclosed compounds reduce or inhibit gene expression in an FXR-mediated pathway. In some cases, the improvement is approximately 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 500, 1000, 5000, 10000%, 50000, 100000 , 500,000% or higher in gene expression in the intestine, liver, kidney, or other tissues relative to gene expression in the absence of the disclosed compound. In some cases, the reduction is approximately 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1% or less in gene expression in the intestine, liver, kidney or other tissues compared to with gene expression in the absence of the disclosed compound.

In some embodiments, the method substantially enhances gut expression of the target FXR gene while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances gut and liver expression of the target FXR gene while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method significantly enhances intestinal expression of the target FXR gene while not significantly increasing liver or kidney expression of the target FXR gene, and also minimizes systemic plasma levels. In some embodiments, the method substantially enhances gut and liver expression of the target FXR gene and provides a stable systemic plasma level of the delivered compound.

In some embodiments, a metabolic disorder refers to any

- 7 040704 disruption, which involves a change in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. In some cases, the metabolic disorder is associated with either a deficiency or an excess of the metabolic pathway, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids and/or carbohydrates. Factors affecting metabolism include, without limitation, the endocrine (hormonal) control system (e.g., the insulin pathway, enteroendocrine hormones including GLP-1, oxyntomodulin, PYY, or the like) or the neural control system (e.g., , GLP-1 in the brain). Illustrative metabolic disorders include, without limitation, diabetes mellitus, insulin resistance, dyslipidemia, liver disease, inflammation-related intestinal conditions, cell proliferative disorders, or the like.

Diabetes mellitus and diabetes-related conditions or disorders

In some embodiments, disclosed herein are methods of treating a subject suffering from diabetes mellitus or a diabetes-related condition or disorder by administering an FXR agonist as described herein. In some instances, the diabetes mellitus is type II diabetes mellitus or non-insulin dependent diabetes mellitus (NIDDM). In some instances, diabetes-related conditions or disorders include obesity, impaired glucose tolerance, dyslipidemia, and insulin resistance. In some cases, diabetes-related conditions or disorders further include secondary complications such as atherosclerosis, stroke, fatty liver, blindness, gallbladder disease, or polycystic ovaries. In some cases, an FXR agonist is administered to treat type II diabetes mellitus, obesity, impaired glucose tolerance, dyslipidemia, insulin resistance, or secondary complications such as atherosclerosis, stroke, fatty liver, blindness, gallbladder disease, or polycystic ovaries.

In some embodiments, the diabetic subject (e.g., type II diabetic subject) is further characterized by a body mass index (BMI) of 25 or more, 30 or more, 35 or more, 40 or more, such as a BMI of 25 to 29, of 30 up to 34 or from 35 to 40.

In some examples, the FXR agonist described herein reduces or prevents weight gain in a subject. In some cases, weight gain is diet-induced weight gain. In other cases, weight gain is not related to diet, such as familial/genetic obesity or drug-induced obesity. In some examples, such methods reduce or prevent weight gain in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least by 50% or more. In some cases, weight gain is reduced or prevented by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the reduction or prevention of weight gain is presented in relation to the reduction or prevention of weight gain observed in a subject who has not been treated with an FXR agonist.

Similarly, in some cases, the FXR agonist reduces the subject's BMI. In some examples, such methods reduce the subject's BMI by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more relative to a subject who has not been treated with an FXR agonist. In some cases, the subject is overweight but not obese. In other cases, the subject is neither overweight nor obese.

In some cases, administration of an FXR agonist results in a decrease in serum lipids. In some examples, the reduction in serum lipids is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75% or more. In some instances, the reduction in serum lipids is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, from about 10% to about 70%, or from about 10% to about 30%. In some instances, the decrease in serum lipids is presented in relation to the amount of serum lipids observed in a subject who has not been treated with an FXR agonist.

In some examples, administration of an FXR agonist results in a decrease in triglycerides (eg, liver triglycerides). In some cases, the reduction in triglycerides (for example, liver triglycerides) is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, according to at least 60%, at least 70%, at least 75% or more. In some instances, the reduction in triglycerides (eg, liver triglycerides) is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, from about 10% to about 70%, or from about 10% to about thirty%. In some instances, the reduction in triglycerides (eg, liver triglycerides) is presented in relation to the triglycerides (eg, liver triglycerides) observed in a subject who has not been treated with an FXR agonist.

In some examples, administration of an FXR agonist results in increased insulin sensitivity in the liver. In some cases, the increase in insulin sensitivity is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, the increase in insulin sensitivity is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the increase in insulin sensitivity is presented in relation to the sensitivity observed in a subject who has not been treated with an FXR agonist.

In some embodiments, administration of an FXR agonist results in a decrease in the amount of serum insulin in the subject. In some examples, the reduction in serum insulin is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75% or more. In some cases, serum insulin is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, the decrease in serum insulin levels is presented in relation to the level observed in a subject who has not been treated with an FXR agonist.

In some embodiments, administration of an FXR agonist results in a decrease in the amount of glucose in the subject's serum. In some examples, the reduction in serum glucose is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60% , at least 70%, at least 75% or more. In some cases, serum glucose is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, the reduction in serum glucose is presented relative to that observed in a subject who has not been treated with an FXR agonist.

In some examples, the FXR agonist described herein enhances white adipose tissue darkening in a subject. In some examples, the rate of increase in white to brown adipose tissue conversion in a subject is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more relative to a subject not treated with an FXR agonist.

In some embodiments, administration of an FXR agonist does not result in a significant change in food intake and/or fat intake in the subject. In some cases food intake and/or fat intake is reduced, for example less than 15%, less than 10% or less than 5%. In some embodiments, there is no significant change in the subject's appetite. In other embodiments, the decrease in appetite is minimal, as reported by the subject.

In some embodiments, administration of an FXR agonist results in an increase in the subject's metabolic rate. In some instances, an FXR agonist increases the metabolic rate of a subject. In some cases, the subject's metabolic rate is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75% or more. In some cases, the metabolic rate is increased by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, from about 10 to about 70%, or from about 10 to about 30% . In some cases, the increase in metabolic rate is presented in relation to the rate observed in a subject who has not been treated with an FXR agonist.

In some embodiments, the increase in metabolism is the result of increased oxidative phosphorylation in the subject, which in turn leads to increased energy expenditure in tissues (such as BAT). In such cases, the FXR agonist helps increase BAT activity. In some examples, BAT activity is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least at least 60%, at least 70%, at least 75% or more. In some instances, BAT activity is increased by an amount that is about 5 to about 50%, about 5 to about 25%, about 10 to about 20%, about 10 to about 70%, or about 10 to about 30%. . In some instances, the increase in BAT activity is presented in relation to the BAT activity observed in a subject who has not been treated with an FXR agonist.

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Alcoholic and non-alcoholic liver disease or condition

Disclosed herein are methods for the prevention and/or treatment of alcoholic or non-alcoholic diseases or conditions of the liver. Typical alcoholic or non-alcoholic liver diseases or conditions include, without limitation, cholestasis, cirrhosis, steatosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), elevated liver enzymes, and elevated triglycerides. In some embodiments, an FXR agonist is used to prevent or treat alcoholic or non-alcoholic liver disease. In some embodiments, an FXR agonist is used to prevent or treat cholestasis, cirrhosis, steatosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis (PSC).

cholestasis

In some embodiments, an FXR agonist disclosed herein is used to treat cholestasis in a subject. Cholestasis, the disruption or cessation of bile flow, which in some cases causes hepatotoxicity due to the accumulation of bile acids and other toxins in the liver. In some cases, cholestasis is a component of many liver diseases, including gallstone disease, cholestasis of pregnancy, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). In some cases, the obstruction is caused by gallstones, trauma, drugs, one or more additional liver diseases, or cancer. In some cases, enterohepatic circulation of bile acids allows the absorption of fats and fat-soluble vitamins from the intestines and allows the removal of cholesterol, toxins, and metabolic by-products such as bilirubin from the liver. In some cases, FXR activation induces the expression of bile tubular transporters BSEP (ABCB11) and multidrug resistance-associated protein 2 (MRP2; ABCC2, cMOAT) and represses genes involved in bile acid biosynthesis, such as, for example, sterol 12a-hydroxylase. (CYP8B1) and CYP7A1.

In some examples, an FXR agonist reduces cholestasis in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 40%, at least 50% or more. In some cases, cholestasis is reduced by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, or from about 10 to about 30%. In some cases, the level of cholestasis is presented in relation to the level of cholestasis in a subject who has not been treated with an FXR agonist.

Primary biliary cirrhosis and liver cirrhosis

In some embodiments, an FXR agonist disclosed herein is used in the treatment of primary biliary cirrhosis (PBC) in a subject. PBC is a liver disease that is primarily the result of autoimmune destruction of the bile ducts that transport bile acids (BA) from the liver, leading to cholestasis. As PBC progresses, persistent toxic accumulation of VA causes progressive liver damage. Chronic inflammation and fibrosis can progress to cirrhosis of the liver. In some examples, an FXR agonist reduces RBC in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40% , at least 50% or more. In some cases, the PBC is reduced by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, or from about 10 to about 30%. In some cases, the level of PBC is presented in relation to the level of PBC in a subject who has not been treated with an FXR agonist.

In some embodiments, an FXR agonist disclosed herein reduces cirrhosis in a subject. In some examples, an FXR agonist reduces cirrhosis in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40% , at least 50% or more. In some cases, cirrhosis of the liver is reduced by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, or from about 10 to about 30%. In some cases, the level of cirrhosis is presented in relation to the level of cirrhosis in a subject who is not being treated with an FXR agonist.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (steatosis) and in some cases progresses to NASH, as defined by histological signs of inflammation, cell death, and fibrosis. In some cases, primary NASH is associated with insulin resistance, while secondary NASH is caused by medical or surgical conditions or drugs such as, but not limited to, tamoxifen. In some cases, NASH progresses to progressive fibrosis, hepatocellular carcinoma, or terminal

- 10 040704 stages of liver disease requiring liver transplantation.

In some cases, NASH develops as a result of triglyceride (TG) imbalance. For example, dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines, resulting in insulin resistance and an inability to suppress lipolysis in adipocytes. In some cases, this failure to suppress lipolysis results in the release of free fatty acids (FFA) into the circulation and uptake in the liver. In some cases, excessive accumulation of FFA in the form of triglycerides (TG) in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and increased activity of pro-inflammatory molecules.

In some cases, FXR activation inhibits triglyceride (TC)/fatty acid (FA) synthesis, facilitating suppression of sterol regulatory element-binding protein 1c (SREBP1c) via SHP activation. In some cases, FXR further increases TG clearance by stimulating lipoprotein lipase (LPL) activity as well as hepatic uptake of residues and low-density lipoproteins by induction of syndecan 1 (SDC1) and the VLDL receptor (VLDLR).

In some embodiments, an FXR agonist disclosed herein is used to treat non-alcoholic steatohepatitis (NASH). In some examples, an FXR agonist reduces the subject's NASH by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some cases, NASH is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the level of NASH is presented in relation to the level of NASH in a subject who has not been treated with an FXR agonist.

In some embodiments, an FXR agonist disclosed herein is used in the treatment of NAFLD. In some examples, an FXR agonist reduces NAFLD in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40% , at least 50% or more. In some instances, NAFLD is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the level of NAFLD is presented in relation to the level of NAFLD in a subject who has not been treated with an FXR agonist.

Steatosis

In some embodiments, an FXR agonist disclosed herein reduces fatty liver (steatosis) in a subject. In some examples, an FXR agonist reduces steatosis in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40% , at least 50% or more. In some cases, steatosis is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the level of steatosis is presented in relation to the level of steatosis in a subject who has not been treated with an FXR agonist.

Ballooning

Ballooning of hepatocytes, a sign denoting cellular damage, is a sign of NASH. Ballooning is a feature that denotes progressive NAFL (types 3 and 4). The term is applied to enlarged, swollen hepatocytes; the affected cells are often mixed in areas of steatosis and, in classical steatohepatitis, in perivenular areas. Hepatocellular ballooning is most commonly seen in areas of H- and E-detectable perisinusoidal fibrosis. Swollen hepatocytes are most easily seen when they contain MNs (typical or poorly formed). Ballooning of hepatocytes is a structural manifestation of microtubule destruction and severe cell damage.

In some embodiments, an FXR agonist disclosed herein reduces hepatic ballooning in a subject. In some examples, an FXR agonist reduces liver ballooning in a subject by at least 5%, at least 10%, at least 15%, at least 30%, at least 40%, at least 50 % or more. In some cases, liver ballooning is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, liver ballooning is presented in relation to the level of liver ballooning in a subject who has not been treated with an FXR agonist.

Alcoholic hepatitis

In some embodiments, an FXR agonist disclosed herein reduces alcoholic hepatitis in a subject. In some examples, an FXR agonist reduces alcoholic hepatitis in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40% %, at least 50% or

- 11 040704 more. In some cases, the level of alcoholic hepatitis is reduced by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, or from about 10 to about 30%. In some cases, the level of alcoholic hepatitis is presented in relation to the level of alcoholic hepatitis in a subject who has not been treated with an FXR agonist.

Primary sclerosing cholangitis

In some embodiments, an FXR agonist disclosed herein is used to treat primary sclerosing cholangitis (PSC). PSC is a chronic and progressive cholestatic liver disease.

PSC is characterized by progressive inflammation, fibrosis, and stenosis in the liver ducts. Common symptoms include itching and jaundice. The disease is closely associated with inflammatory bowel disease (IBD) - approximately 5% of patients with ulcerative colitis will present with PSC. Up to 70% of patients with PSC also have IBD, most commonly ulcerative colitis.

Additional alcoholic and non-alcoholic liver diseases or conditions

In some embodiments, an FXR agonist disclosed herein reduces liver enzymes in a subject. In some examples, an FXR agonist reduces liver enzymes (e.g., serum ALT and/or AST) in a subject by at least 5%, at least 10%, at least 15%, at least 20% , at least 30%, at least 40%, at least 50% or more. In some cases, liver enzymes are reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, the liver enzyme content is presented in relation to the liver enzyme content of a subject who has not been treated with an FXR agonist.

In some embodiments, an FXR agonist disclosed herein reduces hepatic triglycerides in a subject. In some examples, an FXR agonist reduces hepatic triglycerides in a subject by at least 5%, at least 10%, at least 15%, at least 30%, at least 40%, at least by 50% or more. In some instances, liver triglycerides are reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, hepatic triglycerides are presented relative to hepatic triglycerides in a subject who has not been treated with an FXR agonist.

inflammatory bowel disease

Disclosed herein are methods for treating or preventing an inflammatory bowel condition. Exemplary inflammatory conditions include necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, pseudomembranous colitis, gastroenteritis, radiation-induced enteritis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease, gastrointestinal complications after bariatric surgery, gastric carcinogenesis or gastric carcinogenesis after gastric or intestinal resection. In some embodiments, the inflammatory condition is NEC and the subject is a neonate or premature infant. In some embodiments, the subject is an enterally fed or formula fed infant.

In some embodiments, an FXR agonist disclosed herein is administered to a subject suffering from inflammatory bowel disease. In some embodiments, an FXR agonist disclosed herein is administered to a subject having necrotizing enterocolitis (NEC), gastritis, ulcerative colitis, inflammatory bowel disease, irritable bowel syndrome, pseudomembranous colitis, gastroenteritis, radiation-induced enteritis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, gastrointestinal complications after bariatric surgery, gastric carcinogenesis or gastric carcinogenesis after gastric or intestinal resection.

In some embodiments, an FXR agonist disclosed herein reduces intestinal inflammation in a subject (such as a human). In some examples, an FXR agonist reduces intestinal inflammation in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40 %, at least 50% or more. In some cases, intestinal inflammation is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the level of intestinal inflammation is presented in relation to the level of intestinal inflammation in a subject who has not been treated with an FXR agonist.

Gastrointestinal diseases

In some embodiments, disclosed herein are methods for treating or preventing gastrointestinal disease in a subject in need thereof, comprising administering to the subject a farnesoid X receptor (FXR) agonist described herein. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), undivided subtypes of IBS (IBS-U) or choline diarrhea (BAD).

irritable bowel syndrome

Irritable bowel syndrome (IBS) is a combination of symptoms including abdominal pain and changes in intestinal motility patterns that persist for an extended period of time, often years. The causes of IBS remain unclear; however, problems with intestinal motility, food sensitivities, genetic factors, overdevelopment of microflora in the small intestine, and problems with the gut-brain connection are thought to play a potential role. In some cases, IBS is accompanied by diarrhea and is classified as IBS with diarrhea (IBS-D). In some cases, IBS is accompanied by constipation and is categorized as IBS with constipation (IBS-C). In some cases, IBS is accompanied by alternating diarrhea and constipation and is classified as mixed IBS (IBS-M). In some cases, IBS is not accompanied by either diarrhea or constipation and is classified as non-subtyped IBS (IBS-U). In some cases, IBS has four different variants: IBS-D, IBS-C, IBS-M, and IBS-U.

In some embodiments, the symptoms of IBS are mimicked by another condition. In some embodiments, sugar indigestion, celiac disease, non-celiac gluten intolerance, exocrine pancreatic insufficiency, small intestinal microflora overgrowth, microscopic colitis, or bile acid malabsorption (BAM) mimic IBS-D. In some embodiments, the anismus, pelvic floor dyssynergy or puborectal spasm or descending perineum syndrome mimics IBS-C.

In some embodiments, an FXR agonist disclosed herein is used in the treatment of IBS or any of its variations in a mammal. In some examples, an FXR agonist therapeutic agent reduces symptoms of IBS in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 40%, at least by 50% or more.

Bile acid malabsorption

Bile acid malabsorption (BAD), also known as chologenoic diarrhea (BAD), bile acid-induced diarrhea associated with cholera or choleretic enteropathy or malabsorption of bile salts, is a condition in which the presence of bile acids in the colon causes diarrhea. VAM is caused by a number of conditions such as Crohn's disease, cholecystectomy, celiac disease, radiation therapy, and pancreatic disease. In some cases, VAM is caused by drugs such as metformin. In some embodiments, BAM is caused by an overproduction of bile acids. Bile acid synthesis is negatively regulated by iliac hormone fibroblast growth factor 19 (FGF-19); low levels of FGF-19 lead to an increase in bile acids. Activation of FXR promotes the synthesis of FGF19, which leads to a decrease in the content of bile acids.

In some embodiments, an FXR agonist disclosed herein is used in the treatment of VAM in a mammal. In some embodiments, an FXR agonist disclosed herein reduces bile acid synthesis. In some embodiments, an FXR agonist disclosed herein reduces bile acids. In some embodiments, an FXR agonist and an additional therapeutic agent disclosed herein prevent BAD. In some examples, an FXR agonist reduces symptoms of VAM in a mammal by at least 5%, at least 10%, at least 15%, at least 30%, at least 40%, at least 50% % or more.

Graft-versus-host disease (GvHD)

Graft-versus-host disease (GvHD) is a medical complication that occurs after transplantation of tissue or cells from a histocompatible donor (ie, a genetically or immunologically different donor). Immune cells in the donor tissue or cells (graft) recognize the recipient (host) as foreign and initiate and attack. Non-limiting examples of transplanted tissue or cells that cause GvHD are blood products, stem cells such as bone marrow cells, and organs. There are different types of GvHD depending on where the symptoms appear or develop: skin GvHD, liver GvHD, ocular GvHD, neuromuscular GvHD, genitourinary GvHD, and gastrointestinal (GI) GvHD.

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GvHD symptoms of the gastrointestinal tract include difficulty swallowing, pain when swallowing, weight loss, nausea, vomiting, diarrhea, and/or abdominal cramps. GvHD of the gastrointestinal tract leads to mucosal detachment and severe intestinal inflammation. Inflammation of the bile epithelium can be controlled by nuclear receptors such as the glucocorticoid receptor (GR),

FXR or peroxisome proliferator-activated receptors (PPAR).

In some embodiments, an FXR agonist disclosed herein is used to treat GvHD or a complication of GvHD in a mammal. In some embodiments, an FXR agonist disclosed herein is used to treat GvHD of the gastrointestinal tract or a complication of GvHD of the gastrointestinal tract in a mammal. In some examples, an FXR agonist reduces GvHD of the gastrointestinal tract or complication of GvHD of the gastrointestinal tract in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least at least 30%, at least 40%, at least 50% or more. In some cases, GvHD of the gastrointestinal tract or a complication of GvHD of the gastrointestinal tract is reduced by an amount that is from about 5 to about 50%, from about 5 to about 25%, from about 10 to about 20%, or from about 10 to about thirty%. In some embodiments, an FXR agonist disclosed herein reduces gut inflammation caused by GvHD of the gastrointestinal tract. In some embodiments, an FXR agonist disclosed herein reduces gut inflammation caused by GvHD of the gastrointestinal tract by about 5 to about 50%, about 5 to about 25%, about 10 to about 20%, or about 10 to about 30%.

kidney disease

In some embodiments, disclosed herein are methods of treating or preventing kidney disease in a subject in need thereof, comprising administering to the subject a farnesoid X receptor (FXR) agonist described herein. In some embodiments, the kidney disease is associated with liver disease. In some embodiments, the kidney disease is associated with fibrotic liver disease. In some embodiments, the kidney disease is associated with metabolic liver disease. In some embodiments, the kidney disease is associated with a metabolic condition such as, but not limited to, diabetes mellitus, metabolic syndrome, NAFLD, insulin resistance, impaired fatty acid metabolism, and cholestasis. In some embodiments, the kidney disease is diabetic nephropathy, fibrosis-related kidney disease, non-fibrosis-related kidney disease, kidney fibrosis, or any combination thereof.

diabetic nephropathy

Diabetic nephropathy is a kidney disease characterized by damage to the glomeruli of the kidneys. Diabetes mellitus contributes to the excessive production of reactive oxygen species, which leads to nephrotic syndrome and glomerular scarring. As diabetic nephropathy progresses, the glomerular filtering barrier (GFB) is increasingly destroyed and, consequently, proteins in the blood leak through the barrier and accumulate in Bowman's space.

In some embodiments, an FXR agonist disclosed herein is used in the treatment of diabetic nephropathy in a mammal.

Renal fibrosis

Renal fibrosis is characterized by fibroblast activation and excessive deposition of extracellular matrix or connective tissue in the kidney, which is a hallmark of chronic kidney disease. FXR plays an important role in protection against renal fibrosis. Activation of FXR suppresses renal fibrosis and reduces the accumulation of extracellular matrix proteins in the kidney.

In some embodiments, an FXR agonist disclosed herein is used to treat renal fibrosis in a mammal.

In one aspect, provided herein is a method for treating or preventing a kidney disease or condition in a mammal, comprising administering to the mammal an FXR agonist disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the kidney disease or condition is diabetic nephropathy, fibrosis-related kidney disease, non-fibrosis-related kidney disease, renal fibrosis, metabolic disease-related kidney disease, chronic kidney disease, polycystic kidney disease, acute kidney disease, or any combination thereof. .

cell proliferation related disease

Also disclosed herein are methods for preventing or treating diseases associated with cell proliferation, such as certain types of cancer. In some embodiments, the FXR agonists disclosed herein are used to prevent or treat adenocarcinoma or carcinoma derived from glandular tissue or in which tumor cells form recognizable glandular structures. In some embodiments, adenocarcinomas are classified according to their predominant cell type, as papillary, alveolar, or according to a specific cell product, as mucinous adenocarcinoma. In some cases, adenocarcinomas are observed, for example, in the colon, kidney, breast, cervix, esophagus, stomach, pancreas, prostate, or lung.

In some embodiments, the compounds disclosed herein are used to prevent or treat bowel cancer, such as colon cancer, for example, cancer that forms in the tissues of the colon (the longest part of the colon), or cancer of another part of the intestine, such as the jejunum. intestine and/or ileum. In some cases, colon cancer is also called colorectal cancer. In some cases, the most common type of colon cancer is colon adenocarcinoma.

In some cases, cancer progression is characterized by the stages or extent of cancer in the body. Staging is generally based on the size of the tumor, the presence of cancer in the lymph nodes, and the presence of cancer in a site other than the primary site of the cancer. The stages of colon cancer include stage I, stage II, stage III and stage IV. In some embodiments, colon adenocarcinoma occurs at any stage. In other embodiments, the colon adenocarcinoma is stage I cancer, stage II cancer, or stage III cancer.

In some embodiments, an FXR agonist described herein is administered to a subject suffering from stage I, stage II, stage III, or stage IV cancer. In some cases, the FXR agonist described herein is administered to a subject suffering from stage I, stage II, or stage III colon adenocarcinoma.

In some embodiments, an FXR agonist disclosed herein further reduces tumor burden in a subject. In some examples, an FXR agonist reduces tumor burden (such as colon tumor burden) in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 40%, at least 50% or more. In some cases, the tumor burden is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the level of tumor burden is presented in relation to the level of tumor burden in a subject who has not been treated with an FXR agonist.

In some cases, the FXR agonist disclosed herein further reduces the size and/or volume of a tumor in a subject. In some instances, an FXR agonist reduces the size and/or volume of a tumor (e.g., colon tumor) in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some cases, the size of the tumor is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some instances, tumor size is presented in relation to tumor size in a subject who has not been treated with an FXR agonist.

In additional embodiments, an FXR agonist disclosed herein reduces the effects of tumor-induced cachexia in a subject. In some examples, an FXR agonist reduces the effect of cachexia (e.g., due to a colon tumor) in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some cases, the effect of cachexia is reduced by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the effect of cachexia is presented in relation to the effect of cachexia in a subject who has not been treated with an FXR agonist.

In other embodiments, an FXR agonist disclosed herein increases the survival of a subject with a tumor. In some cases, an FXR agonist increases the survival of a subject with a tumor (such as colon cancer) in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least by 30%, at least 40%, at least 50% or more. In some cases, the survival rate is increased by an amount that is from about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the survival rate is presented in relation to the survival rate in a subject who has not been treated with an FXR agonist.

Connections

The compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are farnesoid X receptor agonists.

In one aspect, this document describes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

Formula (I) wherein ring A is a 5-membered heteroaryl which is thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl;

or ring A is a 6-membered heteroaryl which is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl;

or ring A is phenyl;

X ¹ represents CH or N;

R ¹ is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C1-C4 alkyl), -S(=O)2N(R ¹⁵ ) 2, -OC (= O) (C ₁ -C ₄ alkyl), -CO 2 H, -CO ₂ (C ₁ -C ₄ alkyl), -C (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C ( \u003d O) (C1-C ₄ alkyl),

-NR ¹⁵ C(=O)O(C1-C4alkyl), -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -SH, ^(C^ alkyl), ^ (= O) (C _g C4 alkyl), -S (= O) ₂ (C ₁ -C ₄ alkyl), C 1 -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C1- _C4 alkoxy, CrC4 deuteroalkyl, C1- _C4 deuteroalkoxy, C1-C4fluoroalkyl, C1-C4fluoroalkoxy, C1-C4 heteroalkyl or substituted or unsubstituted monocyclic _C2 - _C5 heterocycloalkyl;

X ² is CR ² or N;

R ² is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C1-C4 alkyl), -S(=O)2N(R ¹⁵ ) 2, -OC(=O)(C1-C4alkyl), -CO2H, -^(CLalkyl), -C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)(C1-C4alkyl),

-NR ¹⁵ C(=O)O(C1-C4alkyl), -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, -SH, -S(C1 -C4alkyl), -8(=O)(C _g C4alkyl), -S(=O) ₂ (C ₁ -C ₄ alkyl), C1-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C 1 -C ₄ alkoxy, C 1 -C ₄ deuteroalkyl, C _g C ₄ deuteroalkoxy, C _g C ₄ fluoroalkyl, C _g C ₄ fluoroalkoxy, C 1 -C ₄ heteroalkyl or substituted or unsubstituted monocyclic C ₂ -C ₅ heterocycloalkyl;

or R ¹ and R ² are taken together with intermediate atoms to form a substituted or unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring;

X ³ is CR ³ or N;

R ³ is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ -C ₄ alkyl), -OC(=O)(C ₁ C ₄ alkyl), -CO2H, -CO ₂ (C ₁ -C ₄ alkyl), -C (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C (= O) (C 1 -C ₄ alkyl), C1- _C4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, C1- _C4 alkoxy, C1- _C4 deuteroalkyl, _C1 - _C4 deuteroalkoxy, C1- _C4 fluoroalkyl, C1- _C4 fluoroalkoxy or C1- _C4 heteroalkyl;

each X ⁴ is independently CH or N;

R ⁴ is H, D, F or —CH ₃ ;

R ⁵ is H, D, F or -CH ₃ ;

or R ⁴ and R ⁵ are taken together to form a bridge which is -CH ₂ -or -CH2CH2-;

each R ⁶ is independently H, D, F, -OH or -CH ₃ ;

m is 0, 1 or 2;

R ⁷ is H, D, halogen, -CN, -OH, C1-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C 1 -C ₄ alkoxy, C 1 -C ₄ deuteroalkyl, C _g C ₄ deuteroalkoxy, C 1 -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C 1 -C ₄ heteroalkyl;

L is absent or represents -Y2-L ¹ -, -L ¹ -Y ² -, cyclopropylene, cyclobutylene or bicyclo[1.1.1 ]pentylene;

Y ² is absent or is -O-, -S-, -S(=O)-, -S(=O) ₂ -, -S(=O)2NR ¹⁵ -, -CH2-, -CH=CH- , -C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR ¹⁵ - , -NR ¹⁵ C(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O-, -NR ¹⁵ C(=O)NR ¹⁵ -, -NR ¹⁵ S(= O)2- or -NR ¹⁵ -;

L ¹ is absent or represents a substituted or unsubstituted C ₁ -C ₄ alkylene;

R ⁸ is H, D, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, -C(=O)(C1-C4 alkyl), -^(C^alkyl), -C(=O) N(R ¹⁵ )2, ^(^(C^alkyl), -S(=OhN(R ¹⁵ )2, substituted or unsubstituted C3-C ₆ cycloalkyl or substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl;

R ⁹ is H, D, F or -CH ₃ ;

- 16 040704

R ¹⁰ is -CH2OH, -CH2CH2OH, Ci—C6heteroalkyl, -CO2H, -C(=O)R ¹⁴ , -C(=O)OR ¹⁴ ,

-OC(=O)R ¹⁴ , -OC(=O)OR ¹⁴ , tetrazolyl, imidazol, 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl,

-S(=O)2N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , S(=O)2NR ¹⁵ C(= O)R ¹⁴ , -CH2N(R ¹² )2, -NR ¹⁵ C(=O)R ¹⁴ ,

-C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, -NR ¹⁵ C(=O)N(R ¹² ) ₂ , -C(=NH)NH2, -NHC(=NH)NH2,

-c(=o)nHC(=NH)NH ₂ , -S(=O) ₂ OH or -Op(=O)(OR ¹⁵ ) ₂ ;

or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or represents a substituted or unsubstituted C ₁ -C ₆ alkylene or a substituted or unsubstituted C ₁ -C6 heteroalkylene;

L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -NR ¹⁵ -, -C(=O)-, -C(=O) NR ¹⁵ -, -NR ¹⁵ C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O-, -OP(=O)(OR ¹⁵ )O- or -(OCH2CH ₂ ) _r -, r is 1 or 2;

L ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene;

R ¹³ is H, -CN, -OH, -N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2N(R ¹² )2, -SR ¹² , -S (=O)R ¹⁴ , -S(=O)2R ¹⁴ , -SO3H, -OP(=O)(OR ¹⁵ )2, -C(=O)R ¹⁴ , -OC(=O)R ¹⁴ , - CO2H, -CO2R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;

R ¹¹ is H, D, F or —CH ₃ ;

or R ⁹ and R ¹¹ are taken together to form a bridge which is -CH2- or -CH2CH2-; each R ¹² is independently H, C1-C ₄ alkyl, C1-C ₄ deuteroalkyl, C ₁ -C ₄ Fluoroalkyl, C ₁ -C ₄ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ - C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl;

R ¹⁴ is C 1 -C ₄ alkyl, C 1 -C ₄ deuteroalkyl, C 1 -C ₄ fluoroalkyl, C ₁ -C ₄ heteroαalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl;

R ¹⁵ is H or substituted or unsubstituted C ₁ -C 6 alkyl;

each R ¹⁶ is independently H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ C ₄ alkyl), -S(C ₁ -C ₄ alkyl), -S (=O) (C ₁ -C ₄ alkyl), -S (=O) ₂ (C ₁ -C ₄ alkyl), -S (=O) ₂ N (R ¹⁵ ) 2, - C(=O)(C1-C4alkyl), OS(=O)(C1-C4alkyl), -CO2H, -CO2(C1-C4alkyl), -NR ¹⁵ C(=O)(C1- _C4 alkyl), - C (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C (= O) O (C1 C ₄ alkyl), -OC (= O) N (R ¹⁵ ) ₂ , C ₁ -C ₄ alkyl, C ₂ - C ₄ alkenyl, C ₂ -C ₄ alkynyl, C1-C ₄ alkoxy, C1-C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C1-C ₄ fluoroalkyl, CrC ₄ fluoroalkoxy, C1-C ₄ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; n is 0, 1 or 2.

In another aspect, this document describes a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

Formula (I) wherein Ring A is a 5-membered heteroaryl which is furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl;

or ring A is a 6-membered heteroaryl which is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl;

or ring A is phenyl;

X ¹ represents CH or N;

R ¹ is H, D, halo, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ -C ₄ alkyl), -OC(=O)(C1C4 alkyl ), -CO2H, -CO2(C1-C4alkyl), -C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)(C1-C4alkyl), -NR ¹⁵ C(=O)O( C1-C4 alkyl), -OC(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)N(R ¹⁵ )2, C1-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C1-C ₄ alkoxy, C1-C ₄ deu- 17 040704 teroalkyl, C1-C4 deuteroalkoxy, C1-C ₄ fluoroalkyl, C1-C ₄ fluoroalkoxy, C1-C ₄ heteroalkyl or substituted or unsubstituted monocyclic C ₂ -C ₅ heterocycloalkyl;

X2 is CR2 or N;

R2 is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ -C ₄ alkyl), -OC(=O)(C ₁ C4alkyl), -CO2H, -CO2(C1-C4alkyl), -C(=O)N(R ¹⁵ )2, -NR ¹⁵ C(=O)(C1-C4αkyl), -NR ¹⁵ C(=O)O (C1-C4 alkyl), -OC (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C (= O) N (R ¹⁵ ) 2, C 1-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ - C ₄ alkynyl, C 1 -C ₄ alkoxy, C 1 -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy or C ₁ -C ₄ heteroalkyl;

or R ¹ and R ² are taken together with intermediate atoms to form a substituted or unsubstituted fused 5-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring;

X ³ is CR ³ or N;

R ³ is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ -C ₄ alkyl), -OC(=O)(C1C ₄ alkyl), -CO ₂ H, -CO ₂ (C1-C ₄ alkyl), -C (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C (= O) (C 1-C ₄ alkyl), C 1 -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C 1 -C ₄ alkoxy, C 1 -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C 1 -C ₄ fluoroalkyl, C 1 -C ₄ fluoroalkoxy or C1-C4 heteroalkyl;

each X ⁴ is independently CH or N;

R ⁴ is H, D, F or —CH ₃ ;

R ⁵ is H, D, F or -CH ₃ ;

or R ⁴ and R ⁵ are taken together to form a bridge which is -CH ₂ -or -CH2CH2-;

each R ⁶ is independently H, D, F, -OH or -CH ₃ ;

m is 0, 1 or 2;

R ⁷ is H, D, halogen, -CN, -OH, C1-C ₄ alkyl, C1-C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C1C ₄ deuteroalkoxy, C1-C ₄ fluoroalkyl, C1-C ₄ fluoroalkoxy or C ₁ -C ₄ heteroalkyl;

L is absent or represents -Y2-L ¹ -, -L1-Y ² -, cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene;

Y ² is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁵ -, -CH2-, -CH=CH- , -C^C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR ¹⁵ - , -NR ¹⁵ C(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O, -NR ¹⁵ C(=O)NR ¹⁵ -, -NR ¹⁵ S(=O )2- or -NR ¹⁵ -;

L ¹ is absent or represents a substituted or unsubstituted C ₁ -C ₄ alkylene;

R ⁸ is H, D, C1-C6αalkyl, C1-C6deuteroalkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, -C(=O)(C1-C4alkyl), -CO2(C1-C4alkyl), -C(=O) N(R ¹⁵ )2, -S(=O) ₂ (C ₁ -C ₄ alkyl), -S(=O) ₂ N(R ¹⁵ ) ₂ , substituted or unsubstituted C ₃ -C ₆ cycloalkyl or substituted or unsubstituted monocyclic C ₂ C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;

R ⁹ is H, D, F or -CH ₃ ;

Y is -CR ¹⁰ R ¹¹ -;

R ¹⁰ is -CH2OH, -CH2CH2OH, C ₁ -C ₆ heteroalkyl, -CO ₂ H, -C(=O)R ¹⁴ , -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , - OC(=O)OR ¹⁴ , tetrazolyl, imidazole, -S(=O)2N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -C(=O)NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2NR ¹⁵ C(=O)R ¹⁴ , -CH2N(R ¹² )2, -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, -NR ¹⁵ C(=O)N(R ¹² )2, -C(=NH)NH2, -NHC( =NH)NH2, -C(=O)NHC(=NH)NH2, -S(=O)2OH or

-OP(=O)(OR ¹⁵ ) ₂ ; or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is a substituted or unsubstituted C ₁ -C ₆ alkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene;

L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -NR ¹⁵ -, -C(=O)-, -C(=O) NR ¹⁵ -, -NR ¹⁵ C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O-, -OP(=O)(OR ¹⁵ )O- or -(OCH2CH ₂ ) _r -, r is 1 or 2;

L ⁴ is a substituted or unsubstituted C ₁ -C ₆ alkylene or a substituted or unsubstituted C ₁ -C ₆ heteroalkylene;

R ¹³ is H, -CN, -OH, -N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -S(=O)2N(R ¹² )2, -SR ¹² , -S (=O)R ¹⁴ , -S(=O)2R ¹⁴ , -SO3H, -OP(=O)(OR ¹⁵ )2, -C(=O)R ¹⁴ , -OC(=O)R ¹⁴ , - CO2H, -CO2R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl;

R ¹¹ is H, D or -CH3; or R ⁹ and R ¹¹ are taken together to form a bridge which is -CH2- or -CH2CH2-; each R ¹² is independently H, C1- _C4 alkyl, C1- _C4 deuteroalkyl, _C1 - _C4 fluoroalkyl, C1- _C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl;

R ¹⁴ is C 1 -C ₄ alkyl, C 1 -C ₄ deuteroalkyl, C 1 -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl,

- 18 040704 substituted or unsubstituted phenyl, substituted or unsubstituted benzyl or substituted or unsubstituted monocyclic heteroaryl;

R ¹⁵ is H or substituted or unsubstituted Cl-C6 alkyl; each R ¹⁶ is independently H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, -NR ¹⁵ S(=O)2(C ₁ -C ₄ alkyl), -8(C ₁ - C4alkyl), S (=O) ₂ (C ₁ -C ₄ alkyl), -C (=O) (C1-C ₄ alkyl), -OC (= O) (C1-C ₄ alkyl), -CO ₂ H , -CO ₂ (C ₁ -C ₄ alkyl), -NR ¹⁵ C (= O) (C ₁ C ₄ alkyl), -C (= O) N (R ¹⁵ ) 2, -NR ¹⁵ C (= O) O (C1-C ₄ alkyl), -OC (= O) N (R ¹⁵ ) ₂ , C1-C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C1-C ₄ deuteroalkoxy, C1-C ₄ fluoroalkyl, C1-C ₄ fluoroalkoxy, C ₁ C ₄ heteroalkyl, substituted or unsubstituted C3-C ₆ cycloalkyl, substituted or unsubstituted monocyclic C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl; n is 0, 1 or 2.

For any and all embodiments, substituents are selected from a subset of the listed alternatives. For example, in some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0.

In some embodiments, Ring A is a 5-membered heteroaryl that is thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl. In some embodiments, ring A is thiazolyl. In some embodiments, Ring A is an oxazolyl. In some embodiments, Ring A is a 5-membered heteroaryl that is pyrazolyl, pyrrolyl, or oxadiazolyl. In some embodiments, ring A is pyrazolyl. In some embodiments, Ring A is a 5-membered heteroaryl that is imidazolyl, triazolyl, tetrazolyl, or thiadiazolyl.

According to some embodiments

represents

According to some embodiments

- 19 040704 is is is is is

In some embodiments, is

According to some embodiments

According to some embodiments

- 20 040704

In some embodiments, or is

In some embodiments, is

According to some embodiments

represents

According to some embodiments

represents

According to some embodiments

represents

According to some embodiments

represents

According to some embodiments

- 21 040704

In some embodiments, is

represents

According to some embodiments

represents

In some embodiments, is

represents

According to some embodiments

In some embodiments, is

- 22 040704

In some embodiments, is

According to some embodiments

represents

In some embodiments, Y is -CR ¹⁰ R ⁿ -.

In some embodiments, L is absent or is -O-, -S-, -CH2-, -CH2CH2-, -CH2O-, -OCH2-, -CH2NR ¹⁵ -, -nr ¹⁵ ch2-, -ch=ch-, -c=c-, -c(=o)-, -c(=o)o-, -oc(=o)-, -OC(=O)O-, -C(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O-, -NR ¹⁵ C(=O)NR ¹⁵ -, -NR ¹⁵ S(=O )2-, -NR ¹⁵ -, cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene.

In some embodiments, L is absent or is -O-, -S-, -CH2-, -CH2CH2-, -CH2O-, -OCH2-, -CH2NR ¹⁵ -, -NR ¹⁵ CH2-, -CH=CH-, -C C-, -C(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)-, -OC(=O)NR ¹⁵ -, -NR ¹⁵ C(=O)O-, -NR ¹⁵ C (=O)NR ¹⁵ -, -NR ¹⁵ S(=O) ₂ -, -NR ¹⁵ -, cyclopropylene, cyclobutylene or bicyclo[1.1.1]pentylene. In some embodiments, L is absent or is -C=C-. In some embodiments, L is absent. In some embodiments, L is -C=C-.

In some embodiments, R ⁹ is H; R ¹¹ is H or R ⁹ and R ¹¹ are taken together to form a bridge which is -CH ₂ CH ₂ -.

In some embodiments, a compound of formula (I) is characterized by the structure of formula (II) or a pharmaceutically acceptable salt or solvate thereof <r% g JL 4 jC *x ⁴

R ¹ X ^{3 L-} r ^A R-R ⁸

R V / J (r4

Formula (II).

In some embodiments, R ⁴ is H; R ⁵ is H, or R ⁴ and R ⁵ are taken together to form a bridge which is -CH2CH2-.

In some embodiments, L is absent.

In some embodiments, a compound of formula (I) is characterized by the structure of formula (III) or a pharmaceutically acceptable salt or solvate thereof

Formula (III)

In some embodiments, a compound of formula (I) is characterized by the structure of formula (IV) or a pharmaceutically acceptable salt or solvate thereof

- 23 040704

In some embodiments, a compound of formula (I) is characterized by the structure of formula (V) or a pharmaceutically acceptable salt or solvate thereof

In some embodiments, a compound of formula (I) is characterized by the structure of formula (VII) or a pharmaceutically acceptable salt or solvate thereof

In some embodiments, a compound of formula (I) is characterized by the structure of formula (VIII), or a pharmaceutically acceptable salt or solvate thereof:

Formula (VIII).

In some embodiments, R ¹⁰ is -CH2OH, -CH2CH2OH, exC6heteroalkyl, -CO2H, -C(=O)R ¹⁴ , -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -OC(= O)OR ¹⁴ , -NR ¹⁵ S(=O)2R ¹⁴ , -CH2N(R ¹² )2, -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, -NR ¹⁵ C(=O)N(R ¹² )2, -S(=O)2OH or -OP(=O )(OR ¹⁵ ) ₂ or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is -CH2-, -CH2CH2-, -CH2OCH2-, -CH2SCH2- or -CH2NHCH2-;

L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O) ₂ -, -NH-, -C(=O)-, -C(=O)NH -, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -OC(=O)NH-, -NHC(=O) )NH-, -NHC(=O)O-,

-OP(=O)(OR ¹⁵ )O- or -(OCH2CH2V, r is 1 or 2;

L ⁴ is -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH(OH)-, -CH(CH2OH)-, -CH(CH2OH)CH2-, -CH2CH2CH2-, -CH2CH(OH) CH2-, -CH2CH(CH3)-, -CH2OCH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2CH2OCH2CH2-, -CH2SCH2-, -CH2SCH2CH2-, -CH2NHCH2- or -CH2NHCH2CH2-.

In some embodiments, R ¹⁰ is -CH2OH, C1-C6 heteroalkyl, -CO2H, -C(=O)R ¹⁴ , -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -OC(=O )OR ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2,

-NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2 or -NR ¹⁵ C(=O)N(R ¹² )2 or

R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is -CH ₂ -;

L ³ is absent or is -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)NH- or -NHC(=O)O-;

L ⁴ is -CH2-, -CH2CH2-, -CH(CH2OH)CH2-, -CH2CH2CH2- or -CH2CH(OH)CH2-.

In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl, C ₁ -C ₄ heteroalkyl, monosubstituted or unsubstituted C ₃ -C ₆ cycloalkyl, monosubstituted or unsubstituted C2-C6 heterocycloalkyl, monosubstituted or unsubstituted phenyl, monosubstituted or unsubstituted benzyl, or monosubstituted or unsubstituted monocyclic heteroaryl.

- 24 040704

In some embodiments, R ¹⁴ is C ₁ -C ₄ alkyl, C 1 -C ₄ deuteroalkyl, C 1 -C ₄ fluoroalkyl, C 1 -C ₄ heteroalkyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, unsubstituted or unsubstituted cyclohexyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted morpholinyl unsubstituted thiomorpholinyl or substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R ¹⁰ is -CH2OH, C ₁ -C6 heteroalkyl, -CO2H, -C(=O)R ¹⁴ , -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -OC(= O)OR ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2,

-NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2 or -NR ¹⁵ C(=O)N(R ¹² )2; or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ; L ² is absent or is -CH2-;

L ³ is absent or is -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)NH- or -NHC(=O)O-;

L ⁴ is -CH2-, -CH2CH2-, -CH(CH ₂ OH)CH ₂ -, -CH ₂ CH ₂ CH ₂ - or -CH ₂ CH(OH)CH ₂ -;

R ¹⁴ is C1- _C4 alkyl, C1- _C4 deuteroalkyl, C1- _C4 fluoroalkyl, C1- _C4 heteroalkyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

In some embodiments, R ¹⁴ is C1- _C4 alkyl, C1- _C4 deuteroalkyl, C1- _C4 fluoroalkyl, C1- _C4 heteroalkyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperidinyl.

In some embodiments, R ¹³ is H, -CN, -OH, -N(R ¹² ) ₂ , -CH ₃ , -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2 , -C(CH3)3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CO2H, -C(=O)NHCH3, -OC(=O)NHCH3, NHC(=O)CH3, NHC(=O)OCH3, NHS(=O)2CH3, SO2CH3, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl , substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R ¹⁰ is -CH2OH, C ₁ -C6 heteroalkyl, -CO2H, -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O )OR ¹⁴ or -OC(=O)N(R ¹² )2.

In some embodiments, R ¹⁰ is -CH2OH, -CH2CH2OH,

C ₁ -C ₆ heteroalkyl, -CO2H,

-C(=O)R ¹⁴ , -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -NR ¹⁵ S(=O)2R ¹⁴ , -CH2N(R ¹² )2,

-NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2, -NR ¹⁵ C(=O)N(R ¹² )2, -S(=O)2OH or -OP(=O)(OR ¹⁵ ) ₂ or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is -CH2-, -CH2CH2-, -CH2OCH2-, -CH2SCH2- or -CH2NHCH2-;

L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -C(=O)-, -C(=O)NH -, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NH-, -NHC(=O)NH-, -NHC(=O) )O-, -OP(=O)(OR ¹⁵ )O- or -(OCH2CH2X-, r is 1 or 2;

L ⁴ is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2SCH2-, -CH2SCH2CH2-, -CH2NHCH2- or -CH2NHCH2CH2-.

In some embodiments, R ¹⁰ is -CH2OH, C ₁ -C ₆ heteroalkyl, -CO2H, -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C( =O)OR ¹⁴ or -OC(=O)N(R ¹² )2 or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ;

L ² is absent or is -CH ₂ -; L ³ is absent or is -O-, -NH-, -C(=O)NH-, -NHC(=O)-, -OC(=O)NH- or -NHC(=O)O-;

L ⁴ is -CH2-, -CH2CH2- or -CH2CH2CH2-.

In some embodiments, R ¹³ is H, -CN, -OH, -N(R ¹² ) ₂ , -CH ₃ , -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2 , -C(CH3)3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R ¹⁰ is -CH2OH, C ₁ -C ₆ heteroalkyl,

- 25 040704

-CO2H, -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ or -OC(=O)N(R ¹² )2 .

In some embodiments, no more than two X ² , X ³ , X ⁴ , X ⁴ are

N.

In some embodiments, if both X ⁴ are N then X ² is CR ² and X ³ is CR ³ or if one X ⁴ is N and the other X ⁴ is CH then only one of X ² and X ³ is N.

In some embodiments, a 6-membered ring containing X ² , X ³ , X ⁴ , X ⁴ contains no more than two N atoms in the ring.

In some embodiments, X ² is CR ² ; X ³ is CR ³ or N; each X ⁴ is CH or each X ⁴ is N or one X ⁴ is N and the other X ⁴ is CH.

In some embodiments, X ² is CR ² ; X ³ is CR ³ ; each X ⁴ is CH or each X ⁴ is N; or one X ⁴ is N and the other X ⁴ is CH.

In some embodiments, X ² is CR ² ; X ³ is CR ³ ; each X ⁴ is CH.

In some embodiments, X ² is CR ² ; X ³ is CR ³ ; each X ⁴ is N or one X ⁴ is N and the other X ⁴ is CH.

In some embodiments, X ² is CR ² ; X ³ is N; each X ⁴ is CH or each X ⁴ is N; or one X ⁴ is N and the other X ⁴ is CH.

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH ₃ ), -N(CH ₃ )2, -NHS(=O)2CH3, -OC (=O)CH3, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3 )3, -OCH3, -OCH2CH3, -OCH(CH3)2, -SCH3, -SCH2CH3, -SCH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O )CH(CH3)2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2;

R ² is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -OC(=O)(CH3 , -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3 , -OCH2CH3, -OCH(CH3)2, -SCH3, -SCH2CH3, -SCH(CH3)2, -S(=O)CH3, -S(=O)CH2CH3, -S(=O)CH(CH3) 2, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2CH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F , -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2; or

R ¹ and R ² are taken together with intermediate atoms to form a substituted or unsubstituted fused 5- or 6-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring, which is a substituted or unsubstituted dihydrofuranyl, substituted or unsubstituted dioxolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted dihydropyrrolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyridazinyl, or substituted or unsubstituted dioxynyl;

R ³ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -OC(=O)(CH3 , -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3 , -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2.

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH ₂ , -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -OC( =O)CH3, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3) 3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3 , -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2;

R ² is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -OC(=O)(CH3 , -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -OCH3 , -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2, or

R ¹ and R ² are taken together with intermediate atoms to form a substituted or unsubstituted fused 5-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring, which is a substituted or unsubstituted dihydrofuranyl substituted or unsubstituted dioxolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted isoxazolyl or substituted or unsubstituted isothiazolyl;

R ³ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -NHS(=O) ₂ CH ₃ , -OC(= O) (CH3, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3) 3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3 ,-CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH ₂ N(CH ₃ ) ₂ .

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -SCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

R ² is H, D, F, Cl, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -SCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

R ³ is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2 or -OCF3.

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

R ² is H, D, F, Cl, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3 ; R ³ is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2 or -OCF3.

In some embodiments, R ¹ is -OH, -NH ₂ , -NH(CH ₃ ), -N(CH3)2, -CH3, -OCH3, -SCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3;

R ² is H, D, F, Cl, -CH ₃ , -CD ₃ , -CH ₂ F, -CHF ₂ or -CF ₃ ;

R ³ is H.

In some embodiments, R ¹ is -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -OCH2F , -OCHF2, -OCF3 or -OCH2CF3;

R ² is H, D, F, Cl, -CH3, -CD3, -CH2F, -CHF2 or -CF3;

R ³ is H.

In some embodiments, X ⁴ x ² ' % Λ JR ¹ X ³ is rX^n^^J rI^AX^ ₅ XI R ¹ N . In some embodiments, x is II II In some embodiments, _x X ⁴ X ² H Λ J R ¹ X ³ is I / In some embodiments, 4 \ Х'ЧА УУ XT , R ¹ N , R ¹ or with ⁴ \ ^r Ia ⁿ \I\ XI or R ¹ . '4

- 27 040704 is

In some embodiments, is

In some embodiments, is

In some embodiments, X ² is N;

X ³ is N;

each X ⁴ is CH.

In some embodiments, is

In some embodiments, the compound contains the following structure of formula (IX) or a pharmaceutically acceptable salt or solvate thereof

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH ₂ , -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -OC( =O)CH3, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3) 3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2OCH3 , -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2.

In some embodiments, R ¹ is H, D, F, Cl, -CN, -OH, -NH ₂ , -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3 , -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3.

In some embodiments, R ¹ is -OH, -NH2, -NH(CH3), -N(CH ₃ ) ₂ , -CH ₃ , -OCH ₃ , -CD ₃ , -OCD ₃ , -CH ₂ F, - CHF ₂ , -CF ₃ , -OCH2F, -OCHF2, -OCF ₃ or -OCH ₂ CF ₃ .

In some embodiments, R ⁸ is H, D, -CH ₃ , -CH ₂ CH ₃ , -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, - C (CH3) 3, -CD3, -CH2F, -CHF2, -CF3, -CH2CF3, -CHFCH3, -CH2CH2F, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2NH2, -CH2CH2NHCH3, -CH ₂ CH ₂ N (CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)CH ₂ CH ₃ , -C(=O)CH(CH ₃ ) ₂ , -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , -CO ₂ CH(CH ₃ ) ₂ , -C(=O)NHCH ₃ , -S(=O) ₂ CH ₃ , -S(=O) ₂ NHCH ₃ , substituted or unsubstituted cyclopropyl, substituted

- 28 040704 or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl or substituted or unsubstituted tetrahydrothiopyranyl.

In some embodiments, R ⁸ is H, -CH ₃ , -CH2CH ₃ , -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, _-CH2 CH( _CH3 ) ₂ , -C (CH3)z, -CD3, -CH2F, -CHF2, -CF ₃ , -CH ₂ CF ₃ , -CHFCH ₃ , -CH2CH2F, -CH2CH2OH, -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ NHCH ₃ , -CH ₂ CH ₂ N(CH ₃ ) ₂ , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydropyranyl.

According to some embodiments, R ⁸ is H, -CH3, -CH2CH3, -CH ₂ CH ₂ CH ₃ , -CH( _{CH 3} ) ₂ , -C(CH 3 _{) 3} , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

In some embodiments, each R ¹² is independently H, C1-C4 alkyl, C1-C4 deuteroalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3C6 cycloalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R ¹² is independently H, C1-C4 alkyl, C1- _C4 heteroalkyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C2 - _C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R ¹² is independently H, C1-C4 alkyl, C1-C4 heteroalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, each R ¹² is independently H, C1-C4 alkyl, or substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl. In some embodiments, each R ¹² is independently H or C 1 -C ₄ alkyl.

In some embodiments, when two R ^12s are attached to the N atom, one R ¹² is independently H or C1-C4 alkyl and the other R ¹² is H, C1-C4 alkyl, C1- _C4 deuteroalkyl, C1- _C4 fluoroalkyl, C1 -C ₄ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, when two R ¹² are attached to the N atom, one R ¹² is independently H or C 1 -C 4 alkyl and the other R ¹² is H, C 1 -C 4 alkyl, C 1 -C ₄ heteroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, when two R ¹² are attached to the N atom, one R ¹² is H or C 1 -C 4 alkyl and the other R ¹² is H, C 1 -C 4 alkyl, C 1 -C ₄ heteroalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted monocyclic heteroaryl. In some embodiments, when two R ¹² are attached to the N atom, one R ¹² is independently H or C1C4 alkyl and the other R ¹² is H, C1-C4 alkyl, C1- _C4 heteroalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, when two R ¹² are attached to the N atom, one R ¹² is independently H or C 1 -C 4 alkyl and the other R ¹² is H, C 1 -C 4 alkyl, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted C ₂ - C ₆ heterocycloalkyl.

In some embodiments, R ¹⁴ is C 1 -C ₄ alkyl, C 1 -C ₄ deuteroalkyl, C 1 -C _{4 fluoroalkyl, C 1 -C 4 heteroalkyl} , substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl.

In some embodiments, R ¹⁴ is C1-C4 alkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R ¹⁴ is C1-C4 alkyl, C1-C4 heteroalkyl, substituted or unsubstituted C3C6 cycloalkyl, substituted or unsubstituted C2-C6 heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R ¹⁴ is C1-C4 alkyl.

In some embodiments, each R ¹⁶ is independently H, D, F,

- 29 040704

Cl, -CN, -OH, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -NHS(=O)2CH ₃ , -S(=O) ₂ CH ₃ , -C(= O)CH ₃ , -OC(=O)CH ₃ , -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH( CH3)2, -C(CH3)3, -CH=CH2, -CH=CHCH3, -C^CH, -C COb, -C CCH2CH:, -OCH3, -OCH2CH3, -OCH(CH3)2, -CD3 , -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, _-OCH2CF3 , -CH2OH, -CH2CH2OH, -CH ₂ OCH 3 , -CH ₂ OCH ₂ CH ₃ , -CH ₂ NH ₂ ,-CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ , substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted tetrahydrothiopyranyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl; or substituted or unsubstituted piperazinyl.

In some embodiments, each R ¹⁶ is independently H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -NHS(=O)2CH3, -S (=O)2CH3, -C(=O)CH3, -OC(=O)CH3, -CO2H, -CO2CH3, -NHC(=O)CH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3) 2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH=CH2, -CH=CHCH3, -C CH, -C CCH3, -C CCH2CH:, -OCH3, -OCH2CH3, -OCH (CH3)2, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2NH2, -CH2NHCH3 or -CH2N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl or piperazinyl.

In some embodiments, each R ¹⁶ is independently H, D, F, Cl, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2 , -SCH3, -SCH2CH3, -SCH(CH3)2, -CD3, -CH2F, -CHF2, -CF3, -CH2CF3, substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, each R ¹⁶ is independently H, D, F, Cl, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -OCH(CH3)2 , -CD3, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, each R ¹⁶ is independently H, D, F, Cl, -CH3, -CH2CH3, -CD3, -CH2F, -CHF2, -CF3, or -CH2CF3.

In some embodiments, the compound contains the following structure of formula (X), or a pharmaceutically acceptable salt or solvate thereof:

O

Formula (X).

In some embodiments, the compound contains the following structure of formula (XI) or formula (XII), or a pharmaceutically acceptable salt or solvate thereof:

oh oh

Formula (XI) Formula (XII).

This document considers any combination of the groups described above for various variables. Throughout the description, the groups and their substituents are chosen by those skilled in the art to provide stable moieties and compounds.

In some embodiments, the compounds described herein include, without limitation, those described in Table. 1 and 2.

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Table 1

No. connections Structure Chemical name 1 Z— / trans-4-((3 -(2-cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 1.01 · IZ\ trans-4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 1.02 Z— / 4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4(6-(d-imethylamino)pyride in-3 - yl)bicycle o [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 1.03 0 N trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(3 -fluoro-1 -methyl- 1Nindazol-5- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 1.04 ABOUT trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 1.05 ABOUT 4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 1.06 About χτθ trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylcarbamate 1.07 Ο Ο ^o= C^C / trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate

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1.08 °5 7 p p / 4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-transcarbamate 1.09 q O 1 °u IZ trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(3-fluoro-1-methyl-1Hind azol-5- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 1.10 Q>° l o z \__/ ABOUT IZ\ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 2 II J [1 J h S~N trans-4-((3 -(3-cyclopropylisothiazol-5 yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 2.01 -L trans-4-(((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 2.02 \ zx 4v < / trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate

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2.03 °1 χ / 4-((4-(2-Cyclopropylthiazol-5-yl)pyridine- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 2.04 ZI °=< ο ω < / trans-4-(((trans-4-(4-Methoxy-3- methylphenyl)cyclohexyl)methyl)(3-(thiazole- 2- ylethynyl)phenyl)carbamoyl)cyclohexylmethylcarbamate 2.05 \ ZI O U) Ί ' . / 4-(((4-(4-Methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)(3 -(thiazol-2- ylethynyl)phenyl)carbamoyl)cyclohexyltrans-methylcarbamate 2.06 F ΐ. / trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 2.07 Chu A' . / 4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 2.08 0 Ν'γΝ o II J | l J h S~fj 4-((3-(3-Cyclopropylisothiazol-5 yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate

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3 0 4-((3 -(2-Cyclopropyloxazole-4- yl)phenyl)((4-(6-(dimethylamino)pyridin-3yl)bicycle o [2.2.2]octane-1 - yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 3.01 O trans-4-((3 -(1-Cyclopropyl-1//-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate 3.02 44 O O 3 / trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 3.03 0 Κ'Υ^Ν'τ'Ί 0 J/M 1 LJA l J [i J ^H 4 ¹ ^N 4-((3 -(1 -Cyclopropyl- W-pyrazole-4- yl)phenyl)((4-(6-(dimethylamino)pyridine-3- yl)bicycle o [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexyl-transmethylcarbamate 3.04 ZI M V l ° X < / trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 3.05 \ ZI ° ⁴ o V < z— / trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 4 0^ trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate

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4.01 O (ZI °+ V Str /° trans-4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 4.02 O ZI °+ V ΐ 4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans-carbamate 4.03 4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((4(6-(d-imethylamino)pyride in-3 - yl) bicyclo [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans-carbamate 4.04 O ΖΙ °+ y & 8 4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl )-trans-carbamate 4.05 o dU ^e bR ° ^l « ^l trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylisopropylcarbamate 4.06 O ίΑ' ^ΧΝ γ+ θ wU dCl JJ II 1 tX. +n trans-4-((3-(1-Cyclopropyl-1//-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1 carboxylate 4.07 o ΎΎθ (\θ ⁴ ° ^Λ Ο +n trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate

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4.08 zz y trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate 4.09 -ζt °5 Y (X & / trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- (dimethylamino)ethyl)carbamate 4.10 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 4.11 ςσ° trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3 - (dimethylamino) propyl) carbamate 4.12 ΐ °5 γ Ο ο °H^S z— / 4-((3 -(1-Cyclopropyl- 1H-pyrazole-4- yl)phenyl)((4-(6-(dimethylamino)pyridine-3- yl)bicycle o [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans-carbamate 4.13 G ΖΙ % γ Q & °Χπ / trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((1H-imide azol-2yl )methyl)carbamate 4.14 ο tert-Butyl-(2-((((trans-4-((3-(1cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl )oxy)carbonyl)amino)ethyl)(methyl)carbamate 4.15 0 0 (χζ '/“ΊΟ trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((1H-imide azol-4yl)methyl)carbamate 4.16 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-aminoethyl)carbamate 4.17 ^°'άθ'ν ^ν tert-butyl-3 -((((trans-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)amino)azetidine -1-carboxylate 4.18 ν/οΧοΛΊ trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylase etidin-3-ylcarbamate 4.19 ^Xqa^ II J (ΐ J η trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate

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4.20 4'y % trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(4- (dimethylamino)butyl)carbamate 4.21 ςσ° a'ug trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(5- (dimethylamino)pentyl)carbamate 4.22 _Ν ^Ο lP ₀ Ay ^m trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 4.23 ..0%¾% ^~O 4-((3 -(2-Cyclopropyloxazole-4- yl)phenyl)((4-(6-(dimethylamino)pyridine-3- yl)bicycle o [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexyl-trans-(2hydroxyethyl)carbamate 4.24 % 1 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 4.25 Ch u -. ' O / trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate

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4.26 L J C J sA ^Oh trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 4.27 /° N γ < 1 trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1 carboxylate 4.28 & λ Co i ω / trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((methylthio)methyl) Azetidine 1-carboxylate 5 ./ o >° IZ trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylethylcarbamate 5.01 Ή A ίι / trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.02 ./ Ho IZ \ trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.03 °Cv < / O / trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate

- 38 040704

5.04 0 _n A^ \/ * ₀ Α _ν χ n trans-4-((4-(2-Isopropylthiazol-5 yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.05 trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.06 chTslH trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.07 -. z' trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.08 \ ZI °< % / trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.09 / -z \=z v? Oy° ύ o L % zz\ trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate

- 39 040704

5.10 0 II JHI . h trans-4-((3 -(1-Isopropyl-1H- and irazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.11 Op ίί Q 1 °>o IZ\ trans-4-(((trans-4 -(5-Chloro-6methoxypyride in-3 yl)cyclohexyl)methyl)(3-(1-cyclopropyl1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.12 0 7'' ^χ N'γX o ₄ 1 J Ϊ LJ X N % \^'O N' JI J h 1 . H trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.13 0 XP'^M' ^{A p /} p 0 Pr ^N ^r^ J J η 1 h trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.14 O /\.^ _N A/4 O Vr° A°'A' II J |l n trans-4-(((trans-4 -(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3 -(1 cyclopropyl- 1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.15 zx °A < % trans-4-(((trans-4 -(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3 -(1Isopropyl-1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate

- 40 040704

5.16 AA trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(6-methoxy-5methylpyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.17 λV IZ\ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1cyclopropyl-1//-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.18 o ^jO a^O a A V'O ^A n ^z II J η 1 h ^X °^ / ⁴ trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.19 O a _n A ^o ^a n ^z II J h J , H ⁴ cis-4-(((4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-177-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.20 ZI °A Az o \ O o ^o= Cf\ < / trans-4-((3-(1 -(tert-butyl)- 1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.21 Qy° A o M IZ\ trans-4-((3 -(1-Cyclobutyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.22 % o o / trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyldimethylcarbamate

- 41 040704

5.23 Υ Oh Oh / Oh trans-4-(((trans-4-(6-cyano-5methoxypyridine-2- yl)cyclohexyl)methyl)(3-(1-cyclopropyl1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.24 ZI °=< / trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.25 l L° >° ZZ) trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate 5.26 _v /.7a.x II D 1 n ^x ° J trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-\Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.27 0 _ν /Χθ.Λ JI J Ν 1 n >Ν trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.28 ΖΧ ° < ,/ р Oh o ° % / /ABOUT trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(3 -(1 -isopropyl- 1H- pyrazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate

- 42 040704

5.29 .. ¹ Lo >° IZ trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylethylcarbamate 5.30 ZI A / trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.31 0 trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.32 < A°>o IZ\ trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.33 // A % IZ\ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.34 ZI °5 v AA % / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate

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5.35 Δ%ο ΙΖ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.36 ζζ\ Ο Ζ— Ο С/ / trans-4-((3 -(b-(Dimethylamino)pyride in-3 yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.37 • o o J o < >o ZZ\ trans-4-((3 -(6-Cyclopropylpyridin-3 yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.38 ZZ °h \ About Z < / trans-4-((3 -(2-(Dimethylamino)pyrimidin-5 yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.39 °Ay < Z' trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.40 O and Ο^'θ Δ ° Ul / N N 1 trans-4-((6-(Dimethylamino)-[3,4’ bipyridine] -2’-yl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexylmethylcarbamate 5.41 _ν /ΤΧΌ,1.. II Ί [1 J n ° . NN 1 trans-4-((3 -(b-(Dimethylamino)pyride in-3 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate

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5.42 p △ %o IZ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.43 zx4. / trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.44 E- A °>o xz trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.45 >°xz trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 5.46 zx trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2isopropyloxazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarb amate 5.47 4 # A % trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate

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5.48 Sv -I / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylcarbamate 5.49 • But oh \ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate 5.50 - / A N IZ \ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(6-methoxy-5methylpyridin-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.51 \ZI A / ⁷ o / trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 5.52 0 haoin tj o \ tt h trans-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)1-methylcyclohexylmethylcarbamate 5.53 O Ji O. / GT Ϊ ιΤ Ά ^νη cis-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)1-methylcyclohexylmethylcarbamate 6 0 °0 A /< / trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate

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6.01 O(ZI°%V A - Z— / 4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3 yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)-trans-carbamate 6.02 trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.03 ABOUT L Ay Y 4 trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.04 4&Λ° iz (o trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.05 4 & iz about trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 6.06 0 ., ί'Υ'Ν'Ύ'ΐ 0 trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate

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6.07 trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.08 l J IL Λ ^H trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.09 ^s ? ZI °4 0 trans-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.10 -k %' ZA ° trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-methoxyethyl)carbamate 6.11 4 And at % Wah /° trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1,3-dihydroxypropan-2yl ) carbamate 6.12 ^CO0 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((5)-2,3dihydroxypropyl)carbamate

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6.13 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((7?)-2,3 dihydroxypropyl)carbamate 6.14 0 0 Χι (X Χ ^Α ^ ⁰ ' trans-4-((3 -(1-Isopropyl-1//-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 6.15 ΥγΟ . _ο χχ trans-4-((3 -(1-Isopropyl-1//-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.16 Α . % Αθ' ζζ τ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 6.17 ΎΎθ ν^5Ο'ό^ν—° ^{h 4} trans-4-((4-(1-Isopropyl-1//-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxyethyl)carbamate 6.18 Ο 1 J ι II and ΓΤ 1J L1 ^Η trans-4-((3-(1-Cyclopropyl-1//-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-methylazetide in- 3 yl) carbamate

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6.19 Yas.1^ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(1cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.20 trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(1isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.21 G trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1cyclopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.22 V trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.23 .A J O N [1 J H trans-4-(((trans-4-(5-Chloro-6methoxypyride in-3 yl)cyclohexyl)methyl)(3-(1-cyclopropylN-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.24 0 J 1 II u G/ ^H trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyloxetan-3-ylcarbamate

trans-4-((3-(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazine-1 carboxylate trans- 4-((3-(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2methoxyethyl)(methyl)carbamate trans-4 -((3 -(1-Cyclopropyl-N-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate trans-4-(((trans -4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1-cyclopropyl1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate trans-4-((3-(1-Cyclopropyl - N-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfonyl)azetidine-1 carboxylate trans-4-((3 -(1 -Cyclopropyl-N-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3N-τ methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylthio)azetidine-1 carboxylate

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6.31 o o _l nA F _o A _n A - LA CF / ⁿ Α' ^Χ trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate 6.32 ο ζζ Α trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-\Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylisopropylcarbam at 6.33 ./· A °' ζζ V trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylcyclopropylcarb amat 6.34 °? ΖΙ Λ Α trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-(2methoxyethyl)carbamate 6.35 ΛΑ αΛ/χ / ^Η trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylcyclopropylcarbamate 6.36 Ο=ω=ο d °Α A A trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3(methylsulfonyl)azetidine- 1-carboxylate

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6.37 0 trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmorpholine-4carboxylate 6.38 0 °0 A ¾ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-III-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-4methylpiperazine-1-carboxylate 6.39 0 /0 °* trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfonyl)azetidine-1 carboxylate 6.40 0 °0 0 / trans-4-((4-(1-Isopropyl-III-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate 6.41 0 00'^ ^N ' ^J y0 O ^γ00 trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazine-1-carboxylate 6.42 '° On trans-4-((3 -(1-Isopropyl-III-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfonyl)azetidine-1 carboxylate 6.43 6.44 6.45 6.46 6.47 0 0 0 0 0 00 00 AC 00 A ¾ 0 0 0. ' trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazin-1-carboxylate 4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-trans-(2hydroxyethyl)carbamate trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate trans-4-(( 3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.48 ΖΙ 0С 0 trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate

- 52 040704

6.49 0 trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 6.50 trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.51 ^{Vj >} 0 trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate 6.52 O ? zx °5v 1 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate 6.53 0 ^N K/\jO λΟ λχ\of ^0 trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.54 ζχ °Χ ν ¾ Ζ ' trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate

- 53 040704

6.55 trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 6.56 7 M L>o IZ / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-methoxyethyl)carbamate 6.57 i °4v o / O / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate 6.58 °5 y / O / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex or isopropylcarbamate 6.59 · A %o o trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate 6.60 A ° _>o ΙΖ h trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyloxetan-3-ylcarbamate

- 54 040704

6.61 Ο=ω=Ο P °5 v 1 trans-R-(4-(2-Cyclopropyloxazole-4- yl)pyridin-2-yl)-R-((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)-4(2-(3-(methylsulfonyl)azetide in-1-yl )-2oxoethyl)cyclohexanecarboxamide 6.62 trans-R-(4-(2-Cyclopropyloxazol-4yl)pyride in-2-yl)-4-(2-((3 hydroxypropyl)amino)-2-oxoethyl)-R((trans-4-(5- methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexanecarboxy MFA 6.63 JCy C^n i '-o trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-R-((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)-4(2-( (2-methoxyethyl)(methyl)amino)-2oxoethyl)cyclohexanecarboxamide 6.64 4 # △ % _o o / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazin-1 carboxylate 6.65 °' trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazin-1-carboxylate 6.66 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((8)-2,3-dihydroxypropyl)carbamate

- 55 040704

6.67 1 OH ABOUT trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxypropyl)(methyl)carbamate 6.68 I ^s °5 y A trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2,3-dimethylbutyl)carbamate 6.69 hDA OyN ^H OH % trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2-methylbutyl)carbamate 6.70 uyalch xTs ^N he ^0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2-methylpropyl)carbamate 6.71 A # △ >o iz about trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-hydroxypropan-2-yl)carbamate 6.72 0 Yes a\vV '-o trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxypropyl)carbamate

- 56 040704

6.73 Άγ b / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxybutan-2-yl)carbamate 6.74 △ >ο /—Z 3 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylethyl(2-hydroxyethyl)carbamate 6.75 O="=O R&1 trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfonyl)azetidine-1 carboxylate 6.76 yX Oh~ ^and oh trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2-hydroxyethoxy)azetidine-1 carboxylate 6.77 b X b / trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazin-1-carboxylate 6.78 # A °>o 0 t trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylpiperazine-1-carboxylate

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6.79 γΥΫΟΛΟ' γ^ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-methylpiperidin-4-yl)carbamate 6.80 yYaWu γ^ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((7?)-1-methylpiperide in-3-yl)carbamate 6.81 o A γ > trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-ethylpiperazine-1-carboxylate 6.82 4 # △ °>o o A trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-isopropylpiperazine-1-carboxylate 6.83 υΥ?^ YyY trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-2,2-dimethylmorpholine-4-carboxylate 6.84 4 d A % _o trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(oxetan-3-yl)azetide in-1-carboxylate

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6.85 ABOUT ZI W. / trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- hydroxyethyl) carbamate 6.86 Mind % trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2- methylpropyl)(methyl)carbamate 6.87 Y yO _N ^°> ^-o trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)(methyl)carbamate 6.88 0 △ °>o 22 O— trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypentan-2-yl)carbamate 6.89 _y y:Am% θγ%4 ^{Η he} ^0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-3-methylbutyl)carbamate 6.90 A b / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-hydroxy-2-methylpropan-2yl)carbamate

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6.91 f-C) trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2-methylpropyl)carbamate 6.92 A ZI °4 ./Af A / trans-4-((4-(1-Isopropyl-1H- and irazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy-2-methylpropyl)carbamate 6.93 2A%o IZ A trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((5)-1-hydroxypropan-2-yl)carbamate 6.94 .....r ZI % V A A ' O / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((7?)-1-hydroxypropan-2-yl)carbamate 6.95 £ Af # A / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((7?)-2-hydroxypropyl)carbamate 6.96 c °FA ^z O / o / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((5)-2-hydroxypropyl)carbamate

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7 01 ^0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.01 • .ρ Δ % £ ο τ trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.02 / ο / Μ Δ %ο £ ο τ trans-4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.03 co ⁰ trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.04 Δ &£ ο τ trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.05 At /Δ ο τ trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate

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7.06 H γ 1 trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.07 )=° trans-4-((4-(2-Isopropylthiazol-5 yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.08 vYXqa. ^Oh trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 7.09 Ύ/Λν 0^ ΥίΥί ^0Η trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.10 ^ν% ιΥ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.11 lY Υ?'° ^Λν > θ '* Hu< trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate

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7.12 o vX AUoY Τι ί 1 cx ^Oh 4-((3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-trans- 3hydroxyazetidine-1-carboxylate 7.13 0 /χ _Ν Α·/κ _ο 1 \ ϊ [I and trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.14 ο ^ΧΓ αΎΊ a Υτ^ Α ^ν λ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.15 ο Χ~ΤΎ -ΧγΥ ο y vU JL kD _o A Ύ Τ fi , W ^γ\Α ™ Μ ⁴ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.16 ο /y^A/X θ _h Α ϊ LJ ϊ ACj γγ ά ^Ν ⁴ trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1 carboxylate 7.17 Ο α°4 Ο Ο ^{ζ o=} Sae Methyl-2-((((trans-4-((3 -(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) hydroxy)carbonyl)amino)acetate

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7.18 ABOUT Ί° ΖΙ °5 Y 2-((((trans-4-((3 -(1-Cyclopropyl-1Ηpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy) carbonyl)amino)acetic acid 7.19 ..v o _g ._ _l trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.20 X °* / trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(1isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.21 °ί> γ & trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1cyclopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 7.22 6 l- P trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.23 6 Μ λ <_Ο £ ο trans-4-(((trans-4-(5-Chloro-6methoxypyride in-3 yl)cyclohexyl)methyl)(3-(1-cyclopropyl1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate

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7.24 0 4 γ 0 / trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.25 A O 1 C "0 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(6-methoxy-5methylpyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.26 . JI J|l J 4' trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methoxymethyl)azetidine-1 carboxylate 7.27 trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in -1 carboxylate 7.28 foh . JI J |l A L4ol· Πή trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetidine-1 carboxylate 7.29 40 Ay. _NX i CA _c trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate-1 oxide

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7.30 o -Xi 0a ^oA Q ⁰ o ^C trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate 1,1-dioxide 7.31 Q>° p o λ y _o d trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylazetide in-1-carboxylate 7.32 JI J |l J \Ά.ν _χ trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ((dimethylamino)methyl)azetidine-1 carboxylate 7.33 trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(3-(1-cyclopropyl1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.34 ^τν-4 o 1-(trans-4-((3-(1-Cyclopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)-3-methylazetide in -1,3 dicarboxylate 7.35 l/h 1 -(((trans-4-((3 -(1 -Cyclopropyl- lHpyrazol-4-yl)φenyl)((τpanc-4-(4-methoκci-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl )azetidine-3carboxylic acid 7.36 0 oσ° ^η _τ ν trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 -((tert- butoxycarbonyl)(methyl)amino)azetidine-1 carboxylate 7.37 M λ °Jo trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylamino)azetide in- 1 carboxylate 7.38 0 oσ° ^η ₈ ν trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((tert-butoxycarbonyl)amino) Azetidine-1 carboxylate 7.39 ΧΧθ trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-aminoazetidine-1 carboxylate 7.40 χ, ^λ trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate

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7.41 0 γΧ ό , trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2-methoxy-2oxoethyl)azetide in-1-carboxylate 7.42 υΧο a ο Υ ⁴ !^ Υ ^'° W Λ ^Ν 2-( 1 -(((trans-4-((3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) hydroxy)carbonyl)azetidine-3yl)acetic acid 7.43 °>-Ζ ο Η ο ζ \___f Υ°* ? Τ trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl) cyclohexyl) methyl) (3 - (1 -isopropyl- 1H pyrazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.44 ο Q ΎΥ''^ _Ν Υ 7Υ(Υ _ν Α II Г π 1 . η ^Χ trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex or isopropylcarbamate 7.45 z— ° < ,/ - ΐ ζ' trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyldimethylcarbamate 7.46 0 ί 1 1 IJ l ^χ ° ^^γ\ _N J ⁴ trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylazetidine-1 carboxylate

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7.47 ^mu:Lhu ^V _n 7 trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3-ethylazetidine1-carboxylate 7.48 OU trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 methoxyaz etidine-1- carboxylate 7.49 0 ⁿ % mm Yn a trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3isopropoxyazetidine-1-carboxylate 7.50 uhLhu U U trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3(dimethylamino)azetidine- 1-carboxylate 7.51 0 .. ΤΎ^ν^ΧΤ o ^N y _ 1 J i II u - AJ SU / trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3(hydroxymethyl)azetidine- 1-carboxylate 7.52 %Y% _ο < Yy / ° ^Ν ^Χ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate

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7.53 • o o x= £ -Z \ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in-1-carboxylate 7.54 trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex yl-3-ethylazetide in-1-carboxylate 7.55 About °h / trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate 7.56 —( X °A > A / trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-isopropoxyazetidine-1-carboxylate 7.57 XX X°* >° ^-Z trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-isopropylazetidine-1-carboxylate 7.58 Z—X / trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in-1-carboxylate

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7.59 aF aRAa-" A' trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetidine-1 carboxylate 7.60 Mx trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex yl-3-ethylazetide in-1-carboxylate 7.61 0 γ<ΑΑΑλ . JI J ϋ J / ΙΥχ-ΟΗ trans-4-((3-(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetidine-1 carboxylate 7.62 Μ;Ά ^οη ^<3 trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.63 ΥΑι-νΑΑ ^Oh trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.64 χσ° ifev. ^Ά7 ' trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate

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7.65 trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.66 _γ /τ:όαΛ _Ά A3 0, trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.67 ^Oh' -o trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 7.68 7σ° (¾¼ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.69 v/x/ax ° ^h trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 7.70 _ν /τ/αχ, _y ijj θγν< ^of trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate

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7.71 A y o τ trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.72 ^Oh trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 7.73 A Au P About τ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 7.74 όΆ ^Oh trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2isopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 7.75 0 R?'°A ^0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylazetidine-1-carboxylate 7.76 ~0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate

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7.77 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methoxymethyl)azetide in-1-carboxylate 7.78 / ο , Μ △ °>ο —ζ \ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyldimethylcarbamate 7.79 z— 4 γ 4 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in-1 carboxylate 7.80 Xj Λγ'° ^Λν ιΧ.οη 'O trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetide in-1 carboxylate 7.81 O .tt ³ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in- 1 carboxylate 7.82 d° M 1 trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate 7.83 G. / trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-isopropoxyazetidine-1-carboxylate 7.84 γΑΛUA. trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in-1 carboxylate 7.85 0 0^ ^-ο trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2-methoxy-2-oxoethyl)azetidine-1 carboxylate 7.86 Yr λ %ο D 2-(1-(((trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)carbonyl)azetidin-3-yl)acetic acid 7.87 όΡ'° ^Λ Ά trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-ethoxyazetidine-1-carboxylate

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7.88 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-cyanoazetidine-1-carboxylate 7.89 O H.U/ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methylazetidine-1-carboxylate 7.90 > λ%o G trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex yl-3-ethylazetide in-1-carboxylate 7.91 /Χ,.^Α/X O χΆγΑ _ν Α //·* _ο Α _ν _ , 7u ld trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-isopropoxyazetidine-1-carboxylate 7.92 o 'Ϋ\χ a % ^Z trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(6-methoxy-5methylpyridin-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetide in-1 carboxylate 7.93 ^: · ./ A %o 2 \ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(6-methoxy-5methylpyridin-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate 7.94 o _ 1 1 Ϊ II χ ^Ν η ^^ο^Ν-'λ ^Oh ^Ό trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(6-methoxy-5methylpyridin-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 7.95 γ/γ. trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2-methoxyethoxy)azetide in-1 carboxylate 7.96 'Lq'* 4-((4-(2-Cyclopropyloxazol-4-yl)pyridin2-yl)((4-(5-methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-cis-3-hydroxyazetidine-1-carboxylate 7.97 ; X L ο >°f trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetide in-1 carboxylate 7.98 4 γ X 1 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-ethynylazetidine-1-carboxylate 7.99 6 4 γ 1 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2-hydroxypropan-2-yl)azetidine-1 carboxylate

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7.100 ABOUT “Lee trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex yl-3-ethylazetide in-1-carboxylate 7.101 A IOP O _h -oCh Af trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((methylsulfonyl)methyl)azetide in-1 carboxylate 7.102 o II and I _Ν νΑχ ^O trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-isopropylazetidine-1-carboxylate 7.103 _Y 00OX xAJ I . 0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(tert-butyl)azetidine-1-carboxylate 7.104 ccT ^ol> 44 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-propoxyazetidine-1-carboxylate 7.105 _ύ ΑλΗα trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-propylazetidine-1-carboxylate

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7.106 - △ %o / ^3z— / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((dimethylamino)methyl)azetide in-1 carboxylate 7.107 b Α γ A ' O / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-2-methylmorpholine-4-carboxylate 7.108 M Y trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl) cyclohexyl) methyl) carbamoyl) cyclohex yl-3-hydroxy-[ 1,3 '-biazetide in] - Gcarboxylate 7.109 A E < A / trans-4-((4-(2-Ethyloxazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine -1 -carboxylate 8 0 1j qMu trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3((methylsulfinyl)methyl)azetidine -1 carboxylate 8.01 .χτθ 0χ^ ⁴ ° ^Λν ^ Ο Η ^Ν trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfinyl)azetidine-1 carboxylate

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9 _s trans-4-((3 -(1-cyclopropyl-1 Η-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ((methylsulfonyl)methyl)azetide in-1 carboxylate 10 0 ΊΓτ^ ό '°^Ο trans-4-((3 -(1-Cyclopropyl-1 H-p irazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-trans-4- hydroxycyclohexanecarboxylate AND 0 ΓΥ'Δ^Π ⁿ -X +p+ trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylamino)ethoxy)cyclohexanecarboxy dihydrochloride 12 Ο X Ο Ο ο ^ο= ζΧγ / 2-((trans-4-((3 -(1-Isopropyl- 1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetic acid 13 ο trans-4-(((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5 - yl)phenyl)carbamoyl)cyclohexyldimethyl rbamate 13.01 -V' trans-R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4-(2methoxyethoxy)-R-(3-(2-methox ithiazol-5yl)phenyl)cyclohexanecarboxamide

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13.02 4 Y/°° ο \ trans-R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4-(3methoxypropoxy)-R-(3-(2-methoxythiazol-5yl)phenyl)cyclohexanecarboxamide 13.03 trans-4-(2-Hydroxyethoxy)-R-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)N-(3-(2-methox ithiazol-5yl)phenyl)cyclohexanecarboxamide 13.04 0 X Ay trans-4-(3-H hydroxypropoxy)-R-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-I-(3-(2- methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide 13.05 4% z— / trans-R-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2-(dimethylamino)ethoxy)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 14 (ο A y Ο ο ° τΧ/ X /ο/ Ethyl 2-(trans-4-((3 -(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetate 15 Ρχ° L ο 1 ί τ trans-R-(3 -(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-4-(hydroxymethyl)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 15.01 0 trans-4-(Hydroxymethyl)-R-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)N-(3-(2-methoxythiazol-5 yl)phenyl)cyclohexanecarboxamide

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15.02 / trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-4-(hydroxymethyl)-L ^g -((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 15.03 ίΝ Ο I trans-4-(Hydroxymethyl)-R-(4-(1-isopropylIII-pyrazol-4-yl)pyridin-2-yl)-L-((trans-4(5-methoxy-6-methylpyridine-2 - yl)cyclohexyl)methyl)cyclohexanecarboxy MFA 15.04 ο A Ji j it L ν ^0 trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-4-(hydroxymethyl)-R((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexanecarboxy MFA 16 C ο ^ζ \ ζ— / trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17 0 trans-4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.01 0 χΑ/ξν trans-4-(((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexanecarboxylic acid

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17.02 o \=oo ^z ί / 4-(((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1 carboxylic acid 17.03 > 4' λ°4 ΔΑ ο I trans-4-(((trans-4-(3-Chloro-4- methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 17.04 ^N bCi ϊ ^0Η % trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(3 -fluoro-1 -methyl- 1Nindazol-5- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.05 M τ trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.06 Η 2 z— / trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((4-(6-(dimethylamino)pyridin-3yl)bicyclo o [2.2.2] octane-1 - yl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.07 0- M τ trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarboxylic acid

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17.08 0 vY Χθτ ^0Η trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.09 trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.10 trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.11 ΟΎχ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 17.12 0 Ύ* trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 17.13 • JY° Ο 1h ζ trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.14 ο Υ trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.15 Μ /---\ Γ ³ 'L ο /° trans-4-(((trans-4-(3-Chloro-4methoxyphenyl)cyclohexyl)methyl)(3 -(1 cyclopropyl- 1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 17.16 Μ Ο Ο °CHS 4 ^w ζ trans-4-((3-(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(3-fluoro-1-methyl-1Naindazole-5- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.17 J4>o l o Μ I trans-4-((3-(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.18 h Rcho L o 1h I trans-4-((3 -(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 17.19 I / trans-4-((4-(1-Cyclopropyl-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl )cyclohexanecarboxylic acid

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17.20 M / trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 17.21 Ο V7 Me? -A/ trans-4-((4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexancarboxylic acid 17.22 o o Μ τ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3 -(1 cyclopropyl-1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 17.23 0 χΥ Ύ ^and ' ^Long 2-(trans-4-((4-(1-Cyclopropyl-1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 17.24 iL ^x 2-(trans-4-((3 -(1-Cyclopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 17.25 Τ ο 2-(trans-4-((4-(1-Isopropyl- 1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 17.26 ο τ 2-(trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid 17.27 < ο τ 2-(trans-4-(((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid 18 Ύθ ^χ ο trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexanecarboxylic I am acid 18.01 ο ^-ο trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 18.02 ο XX _Ν -^Χχχ Ύ^ι Δ I ⁿ ^-ο trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 18.03 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarboxylic acid

-82040704

18.04 M I trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylic acid 18.05 About g—7 trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylic acid 18.06 7 L? YES o/ trans-Methyl-4-((3-(2-cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 18.07 70 ⁰ ¾ trans-Methyl-4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexanecarboxyl 18.08 trans-Methyl-4-((3-(2-cyclopropylthiazol-5yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 18.09 V M / trans-Methyl-4-(((trans-4-(6-cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexanecarboxyl

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18.10 / o %oo ^z / Methyl-4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1carboxylate 18.11 P.o°A/ trans-4-(Benzyloxy)-R-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)N-(3-(2-methox ithiazol-5yl)phenyl)cyclohexanecarboxamide 18.12 0 trans-R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4-((4methoxybenzyl)oxy)-M-(3-(2-methoxythiazol5-yl)phenyl)cyclohexanecarboxamide 18.13 O o ° mrs / trans-Methyl-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 18.14 Μ O C/ ° mCj O ^z \ z— / trans-Methyl-4-((3 -(1 -cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 18.15 0 CHUATCH o । •My tert-Butyl-(4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl )cyclohexyl)-transcarbamate 18.16 A x.zz o tert-butyl (trans-4-((3 -(1-isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate

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18.17 M / trans-Methyl-4-((4-(1-cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 18.18 O °+ y /l ' o / Ethyl 2-(trans-4-((4-(1-cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl )cyclohexyl)acetate 18.19 °x % trans-Methyl-4-((3 -(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 18.20 ( O °+ γ X / Ethyl-2-(trans-4-((4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate 18.21 ..'· Ethyl 2-(trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetate 18.22 < .A ) Ethyl 2-(trans-4-(((trans-4-(6-cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl )acetate

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18.23 0 trans-Methyl-4-((4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 18.24 0¾ trans-Methyl-4-(((trans-4-(6-cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexanecarboxylate 19 ο 4 v 0 / 2-(trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20 ο °4 v 00 0 2-(trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl)acetic acid 20.01 _Ύ Δ 0ο Ο τ 2-(trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl)acetic acid 20.02 X Ο H y 00 0 / 2-(trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid

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20.03 o °H ν AA A ⁷ o / 2-(trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.04 ίΐ 2-(trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid May 20 A Do o t 2-(trans-4-(((trans-4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid 20.06 'A y _o o X 2-(trans-4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.07 X O °H γ o ⁷ o / 2-(trans-4-((3-(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.08 0 O Ύ/th Ά trans-2-(4-((4-(1-Cyclopropyl-1H-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)cyclohexyl)acetic acid

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20.09 O A 7 Oh Oh h / 2-(trans-4-((3 -(1-Cyclopropyl-1H-pyrazol 4-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.10 O Xj' / 2-(trans-4-((4-(1-Cyclopropyl-1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.11 sn \u003d ° l O K Uo o t 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl)acetic acid 20.12 X O °h o ° χνχ Z— / 2-(trans-4-((3 -(1-Cyclopropyl- 1H-pyrazol4-yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.13 o Α ν O r ^O= CX\ - ' o / 2-(trans-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.14 O Αν ABOUT / 2-(trans-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 20.15 2-(trans-4-((4-(1-Isopropyl- 1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid

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20.16 ABOUT y y / 3 -(trans-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)propanoic acid 21 ⁷ trans-2-(4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl) cyclohexyl)acetic acid 21.01 ₀ ^_ 2-(trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.02 + J ' A Y, O 2 2-(trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.03 O °H ν h/ h / 2-(trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.04 .4 b. h 2-(trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((cis-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid May 21 %Y ^x UN % 2-(trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl)acetic acid

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21.06 / -ζ 5=2 V? d Δ Ho About Fri 2-(trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.07 .3A L About Fri 2-(trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.08 0 X A' ^0 ⁴ 2-(trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.09 - 0 about PT 2-(trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 21.10 0 VA x X 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3-(2isopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl)acetic acid 21.11 0 jol 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid

- 90 040704

21.12 0 4 1 J L IJ A XQi "^y<1 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid 21.13 O T V < % 2-(trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl)acetic acid 22 0 trans-Propyl-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 22.01 ^XT Ci ί τ trans-Isopropyl-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 22.02 XT 0¾ £ ^N trans-Butyl-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 22.03 0.XX ^e trans-Pentyl-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 22.04 0.xTXjX trans-Isobutyl-4-((3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate

- 91 040704

May 22 G o r-7 a 4 / trans-Isopentyl-4-((3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 22.06 O ΓΥ'νΑλ .Xx ύχ Υ 0 trans-Propyl-4-((4-(1-cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohex ancarboxylate 23 A . trans-A-(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)-A-(2-hydroxyethyl)-A-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexa and-1,4-dicarboxamide 24 0 RTA tr ⁿ X Ag A ⁴ trans-A-((trans-4-(4-Methoxy-3 methylφenyl)cycloheκcyl)methyl)-Λ ^fl -(3-(2methoxythiazol-5-yl)phenyl)-LHmethylcyclohexane-1,4-dicarboxamide 24.01 nY A^ Λ ^L 'A>o _x A ^x trans-I ¹ - ((trans-4- (4-Methoxy-3methylphenyl) cyclohexyl) methyl) - I ¹ - (3- (2 methoxythiazol-5-yl) phenyl) cyclohexane-1,4 dicarboxamide 24.02 0 A^r An ⁴ trans-H ¹ -((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)-H ¹ -(3-(2methoxythiazol-5-yl)φenyl)-7V ^{4,7V 4} dimethylcyclohexcan- 1,4- dicarboxamide 24.03 dA ^h Xi Λ %γ^ _0Η trans-I ¹ - (2-Hydroxyethyl) - I ⁴ - ((trans-4- (4-methoxy-3-methylphenyl) cyclohexyl) methyl) N ⁴ - (3 - (2-methoxythiazol-5 - yl) phenyl) cyclohexane- 1,4-dicarboxamide

- 92 040704

24.04 About IZ ΐ trans-I ¹ - ((trans-4- (4-Methoxy-3methylphenyl) cyclohexyl) methyl) -DC (2 methoxyethyl) - I% 3- (2-methoxythiazol-5yl) phenyl) cyclohexane-1,4-dicarboxamide May 24 I Λ ¹ ' trans-I ¹ - (2- (Dimethylamino) ethyl) -A ⁴ - ((trans-4- (4-methoxy-3 - methylphenyl) cyclohexyl) methyl) -7 \ X (3- (2 methoxythiazol-5-yl) phenyl)cyclohexane-1,4dicarboxamide 24.06 ο ίΥΥΛγ η ο X ό> τ ^< Ν ^Χ trans-I ¹ -((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)-A4-(3-(2methoxythiazol-5-yl)phenyl) ^-Lm (methylsulfonyl)cyclohexane-1,4dicarboxamide 25 0 Methyl (trans-4-((3 -(2-cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 25.01 0 ,I αθ D I ⁴ tert-butyl (trans-4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexyl)carbamate 25.02 υΧ'Λχ η Υτ^ Π υ-Αγ ⁰ ^ -i ΧΥ tert-butyl-((trans-4-(((trans-4-(4-methoxy- 3 -methylphenyl)cyclohexyl)methyl)(3 -(2methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate 25.03 Λ dXX^ γ _νθχ trans-4-(Aminomethyl)-R-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)N-(3-(2-methox ithiazol-5yl)phenyl)cyclohexanecarboxamide

- 93 040704

25.04 °H / Η 0 / trans-4-Acetamido-A-((trans-4-(4-methoxy3-methyl φ en and l) c and c o hexyl) methyl l)-A ^f -(3 -(2methoxythiazol-5yl)phenyl) cyclohexanecarboxamide May 25 '-Ν ⁴ Methyl (trans-4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)carbamate 25.06 O ⁿ .F fts '-Ν ' trans-4-(Acetamidomethyl)-R-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)A-(3-(2-methoxythiazol-5yl)phenyl)cyclohexanecarboxamide 25.07 0 ίΎ'ϊ and n Α η Methyl-((trans-4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate 25.08 0 φ ^χ trans-A-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3-(2methoxythiazol-5-yl)phenyl)-4(methylsulfonamidomethyl)cyclohexanecarb oxamide 25.09 0 N trans-4-Acetamide o-A-(3 -(2- cyclopropylthiazol-5-yl)phenyl)-A-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 25.10 ^-Ν trans-A-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(Amethylacetamido)cyclohexanecarboxamide

- 94 040704

25.11 0 ΎΎ°Χ° 4 trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4(methylsulfonamido)cyclohexanecarboxamide 25.12 0 ,χΧ άΧ'Χ trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2methoxyacetamido)cyclohexanecarboxamide 25.13 4 λ^ο ο °κ 2-((trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl acetate 25.14 Δ & Δ ^ιζ ^ο ο τ trans-R-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2-hydroxyacetamido)-L((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 25.15 2-((trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2oxoethylmethylcarbamate 25.16 trans-4-Butyramido-I-(3 -(2- cyclopropylthiazol-5-yl)phenyl)-A-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 25.17 trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4pentanamidocyclohexanecarboxamide

- 95 040704

25.18 + N trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methylbutanamido)cyclohexanecarboxamide 26 0 A M II Γ |Ι 1 η M Methyl (trans-4-((3 -(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 26.01 (_/Ο!. / trans-4-Acetamide o-N-(3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.02 ύΑλΑ 1 J ΜΙ ^{Η 0} trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4(methylsulfonamido)cyclohexanecarboxamide 26.03 Α Μ Κ4=ο ο “Γ trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-4-(2-hydroxyacetamido)-L((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.04 Α Μ λ'^ο ο ζζ / 2-((trans-4-((3-(1-Cyclopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2oxoethylmethylcarbamate

- 96 040704

May 26 o o M ^z > _o o ( o 2-Hydroxyethyl(trans-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 26.06 la O* T trans-R-(3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)-4-(trans-4- hydroxycyclohexanecarboxamido)-I- ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.07 o>° o o trans-4-Acetamide o-R-(3-(1-cyclopropyl1R-pyrazol-4-yl)phenyl)-R-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)cyclohexanecarboxamide 26.08 .^Yaol.,. AJ and oh 2-((4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl) cyclohexyl)amino)-2oxoethyl-trans-acetate 26.09 > .. ¹ /Qo o τ trans-R-(3-(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-4-(2-hydroxyacetamido)-R-((4(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)cyclohexanecarboxamide 26.10 '-ζ ζζ^γ o o ^o= CNG \ / trans-4-Acetamide o-R-(3 -(1-isopropyl- 1Hpyrazol-4-yl)phenyl)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide

- 97 040704

26.11 Y \u003d Y / - \ ^Z χ Ο &' o / 2-((trans-4-((3-(1-Isopropyl- 1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethylacetate 26.12 0 % Y ^x trans-4-(2-Hidroxyacetamide o)-7V-(3-(1isopropyl-1H-pyrazol-4-yl)phenyl)-A ^g ((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexancarboxamide 26.13 )=° Οό / trans-4-(Acetamide omethyl)-R-(3 -(1 cyclopropyl-1R-pyrazol-4-yl)phenyl)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.14 o ^Z 7 at ΐ. / Methyl-((trans-4-((3 -(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl)carbamate 26.15 CC* OSCH J trans-R-(3-(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4(methylsulfonamidomethyl)cyclohexanecarb oxamide 26.16 o °u A / trans-R-(3-(2-Cyclopropyloxazol-4yl)phenyl)-4-(2-hydroxyacetamido)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.17 y A ^IZ ^ _O °/ 2-((trans-4-((4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2 -oxoethyl acetate

- 98 040704

26.18 4 γ L 1h / trans-A-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-4-(2-hydroxyacetamido)X-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.19 0 AC* trans-4-Acetamide o-A-(3 -(2- cyclopropyloxazol-4-yl)phenyl)-A-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.20 0 _ο ΛΧ άχΧ trans-4-Acetamido-A-(4-(2- cyclopropyloxazol-4-yl)pyridin-2-yl)-A ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.21 /j- A ο \ Methyl (trans-4-((4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 26.22 < ∆\τ trans-4-(Aminomethyl)-A-(4-(2- cyclopropyloxazol-4-yl)pyridin-2-yl)-A((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexanecarboxy MFA 26.23 >= ^ο ΙΖ L 4 γ 4 trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-acetamidoethyl)carbamate

- 99 040704

26.24 XJ. ⁿ o trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- (methylsulfonamido)ethyl)carbamate 26.25 C. >7— ^H X o λ X L h / trans-4-((3 -(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylethane-1,2-diylde and carbamate 26.26 o _ν ^Xα,χ JC* y ⁴ trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-R-((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)-4(methylsulfonamidomethyl)cyclohexanecarb oxamide 26.27 o ίΎ> η ⁿ I ^N j ^Ν Λ ^U Methyl-((trans-4-((4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl)carbamate 26.28 °1 W y l L 7 Ethyl-((trans-4-((4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl ) carbamate 26.29 A > / trans-R-(4-(2-Cyclopropyloxazole-4- yl)pyridin-2-yl)-4-((2- hydroxyacetamido)methyl)-I-((trans-4-(5- methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)cyclohexanecarboxy MFA

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26.30 0 _ A 0Πι O A trans-4-Acetamido-R-(4-(1-cyclopropyl1H-pyrazol-4-yl)pyridin-2-yl)-A-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.31 αύΗ I fE AA _N 4 _Y •x L J nA ⁿ o Poof ° 2-((trans-4-((4-(1-Cyclopropyl- 1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)-2-oxoethyl acetate 26.32 0 o fchAA _N A Ή _Ν Π<» M |1 J H trans-A-(4-(1-Cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)-4-(2-hydroxyacetamido)R-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.33 °H < 0 / trans-4-Acetamide o-R-(4-(1-isopropyl- 1Hpyrazol-4-yl)pyridin-2-yl)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.34 >° η A 0 / 2-((trans-4-((4-(1-Isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)-2-oxoethyl acetate 26.35 0 ΑΑ' ^ν '] ^ζ Α ° γΑ ¹ A AA°> L J nA ⁿ / trans-4-(2-Hidroxyacetamide o)-R-(4-(1isopropyl- 1R-pyrazol-4-yl)pyridin-2-yl)- I-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 26.36 °C at A 0 / trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methylureido)cyclohexanecarboxamide

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26.37 °5γ O o . / trans-R-(3-(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methylureido)cyclohexanecarboxamide 27 A Y about τ trans-LCHZ - (2 - Cyclopropylthiazole-5 - yl)phenyl)-4-(2-hydroxy-2- methylpropanamido)-I-((trans-4-(4-methoxy3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 27.01 .ya trans-R-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2-hydroxypropanamido)-L((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 27.02 0 όγ R-(trans-4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxetane-3-carboxamide 27.03 .l/Y trans-4-(2-(1R-I midazol-1-yl)acetamido)R-(3-(2-cyclopropylthiazol-5-yl)phenyl)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 27.04 ,αΎ X ^s _n y trans-4-(2-(1H-Imidazol-2-yl)acetamido)H-(3-(2-cyclopropylthiazol-5-yl)phenyl)-H((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide

May 27 ^-Z & A / R-(trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)-1-methylazetide in-3 carboxamide 27.06 o ['''''''γ''ν γΥ o .Xj Cl ; Ύ» ⁰ YVa R-(trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)azetidine-3-carboxamide 28 ώτγ ^0Η ^>-<1 2-G hydroxyethyl (trans-4-((3-(2- cyclopropylthiazol-5-yl)phenyl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 29 ⁹ ,: °C ο τ 2-((trans-4-((3-(1-Isopropyl- 1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic acid thirty 7 Y ο\ trans-R-(3-(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methoxycyclobutanecarboxamido)cyclohexancarboxamide 30.01 0 II J |l J h v trans-4-(Cycl butanecarboxyamide o)-N- (3-(1cyclopropyl-1H-pyrazol-4-yl)phenyl)-I((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide

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30.02 / trans-4-(cyclobutanecarboxamido)-trans-(4(2-cyclopropyloxazol-4-yl)pyridin-2-yl)n-((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl) cyclohexanecarboxy MFA 30.03 o ν o ^~ο ^ζ trans-R-(4-(2-Cyclopropyloxazole-4- yl)pyridin-2-yl)-R-((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)-4(3- methoxycyclobutanecarboxamido)cyclohex ancarboxamide 30.04 -οΧυ trans-4-(Cyclobutanecarboxamidomethyl)-L(4-(2-cyclopropyloxazol-4-yl)pyridin-2yl)-R-((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxy MFA May 30 _γ χΧαΥ' ^•ο trans-R-(4-(2-Cyclopropyloxazol-4yl)pyride in-2-yl)-4-((3 - (dimethylamino)cyclobutanecarboxamido)methyl)-R-((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)cyclohexanecarboxy MFA 30.06 \ Ο=ω=ο ΙΖ Δν trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonamido)acetamido)cyclohexancarboxamide 31 0 Ο Η Η .χΔ άΔ^ν Methyl-(2-((trans-4-((3-(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)-2-oxoethyl)carbamate 31.01 Δ° ζζ Αγ < • ' ο / trans-4-(2 - Acetamide oacetamido)-R-(3-(1cyclopropyl-1R-pyrazol-4-yl)phenyl)-A((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 31.02 ,γ trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonyl)acetamido) cyclohexanecar boxamide 31.03 4 ζζ Ο=ω=Ο \ trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonamido)acetamido) cyclohexancarboxamide 31.04 0 dddX/D ο 0 ,I Dd trans-R-(3-(1-Cyclopropyl- 1R-pyrazol-4yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfinyl)acetamido) cyclohexanecar boxamide May 31 _χ χΔ (Χ'Δγ'^ο> DN Methyl-(2-((trans-4-((3 -(2cyclopropylthiazol-5-yl)phenyl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl)carbamate

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31.06 trans-A-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2-(dimethylamino)acetamido)R-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 31.07 trans-4-(2-Aminoacetamido)-А-(3-(2-cyclopropylthiazol-5-yl)phenyl)-А-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 31.08 / IZ Av A trans-A-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylamino)acetamido)cyclohexanecarboxyamide 31.09 y° IZ Av . trans-4-(2-Acetamide oacetamido)-L-(3-(2cyclopropylthiazol-5-yl)phenyl)-A-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 31.10 ^Luh N trans-LCZ -(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylthio)acetamido)cyclohexanecarboxamide 31.11 4 # A ^Iz ^o ω=ο / trans-A-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfinyl)acetamido)cyclohexanecarboxamide

- 104 040704

31.12 0 o o CCi Xa ⁰ A trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonyl)acetamido)cyclohexanecarboxamide 31.13 trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3(methylsulfinyl)propanamido)cyclohexane carboxamide 31.14 o γΜΤ γ kA See ΟγΆ ⁸ trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3(methylsulfonyl)propanamido)cyclohexane carboxamide 31.15 About xr° 7a'« ^w mm trans-4-(2-(1H-Imidazol-4-yl)acetamido)H-(3-(2-cyclopropylthiazol-5-yl)phenyl)-H((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 32 •ΙΑ b / trans-H-(3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)-4-(2-(3- hydroxypropoxy)acetamido)-I-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 32.01 7 mA“7 $° from t trans-H-(3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)-4-(2-(2- hydroxyethoxy)acetamido)-I-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide

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32.02 trans-LDZ - (2-Cyclopropylthiazol-5 yl) phenyl) -4- (2- (2- hydroxyethoxy)acetamido)-I-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 32.03 trans-I-(3 - (2-Cyclopropylthiazole-5 - yl)phenyl)-4-(2-(3- hydroxypropoxy)acetamido)-I-((trans-4- (4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 32.04 z— o °m A trans-R-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2-(2- (dimethylamino)ethoxy)acetamido)-A- ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide May 32 trans-4-(2-(2-Aminoethoxy)acetamido)-R-(3(2-cyclopropylthiazol-5-yl)phenyl)-A((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexancarboxamide 32.06 Mx'° trans-A-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2-(2(methylamino)ethoxy) acetamido)cyclohexane carboxamide 33 O n \/hA> M <Ll τι T O M ^N AM ⁿ - _n Ί trans-A-(3-(2-Cyclopropylthiazol-5yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2Yatetrazol-5-yl)cyclohexanecarboxamide 33.01 34 A A' O / O / / trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2Yatetrazol-5-yl) cyclohexanecarboxamide trans-A-(3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-4-(5-oxo4,5-dihydro-1,2,4-oxadiazol-3yl)cyclohexanecarboxamide

In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound as described in Table 1. 1.

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Structure

Chemical name

table 2

ot/?w/s-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((/lpa//s-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl )cyclohexyl(2-hydroxybutyl)(methyl)carbamate methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl(2-hydroxy-3methylbutyl)(methyl)carbamate

In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound as described in Table 1. 2.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts. In addition, active metabolites of these compounds having the same type of activity are included within the scope of the present invention. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds provided herein are also considered to be disclosed herein.

As used herein, the term pharmaceutically acceptable refers to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i. the material is administered to the individual without causing undesirable biological effects or without adversely interacting with any of the components of the composition in which it is contained.

The term pharmaceutically acceptable salt refers to the form of the therapeutically active agent which consists of the cationic form of the therapeutically active agent in combination with a suitable anion or, in alternative embodiments, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich: Wiley-VCH/VHCA, 2002. Pharmaceutical salts are generally more soluble and rapidly soluble in gastric and intestinal juices than non-ionic salts. species and thus applicable in solid dosage forms. In addition, since their solubility is often a function of pH, selective dissolution in one part of the digestive tract or another is possible, and this possibility can be manipulated as one aspect of delayed and sustained release behavior. In addition, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be controlled.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound described herein with an acid to form a pharmaceutically acceptable acid addition salt. In some embodiments, the compound described herein (ie, in free base form) is basic and reacts with an organic acid or inorganic acid. Inorganic acids include, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, without limitation, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbon dioxide; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuronic acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactic acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid - 107 040704 slot (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p) and undecylenic acid.

In some embodiments, the compound described herein is obtained as the chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt, or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound described herein with a base to form a pharmaceutically acceptable base addition salt.

In some embodiments, a compound described herein is acidic and reacts with a base. In such situations, the acidic proton of a compound described herein is replaced by a metal ion, such as lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, the compounds described herein are coordinated with an organic base such as, without limitation, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other instances, the compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Suitable inorganic bases used to form salts with compounds that include an acidic proton include, without limitation, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are obtained as the sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt, or ammonium salt.

It should be understood that reference to a pharmaceutically acceptable salt includes diluent addition forms. In some embodiments, the solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the isolation or purification of the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently obtained or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated form.

The methods and formulations described herein include the use of N-oxides (if necessary), crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity.

In some embodiments, the sites on the organic groups (eg, alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. The inclusion of appropriate substituents on organic groups will reduce, minimize, or eliminate this metabolic pathway. In particular embodiments, a suitable substituent for reducing or eliminating the susceptibility of an aromatic ring to metabolic reactions is, by way of example, only a halogen, deuterium, alkyl group, haloalkyl group, or deuteroalkyl group.

In another embodiment, the compounds described herein are labeled isotopically (eg, radioisotope) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein include isotopically labeled compounds that are identical to the compounds listed in the various formulas and structures presented herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or a mass number usually found in nature. Examples of isotopes that can be included in the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, ^for example, ² H, ³ H, 13 C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ^17O , ^35S , ^18F , ^36Cl . In one aspect, the isotopically labeled compounds described herein, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein are replaced by deuterium.

In some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter exists independently in the R or S configuration. Compounds provided herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms, as well as their respective mixtures. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their respective mixtures.

Individual stereoisomers are obtained, if desired, by methods such as stereoselective synthesis and/or separation of stereoisomers by means of chiral chromatographic columns. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a diastereomeric compound/salt pair, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separation of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation methods based on differences in solubility. In other embodiments, separation of stereoisomers is accomplished by chromatography or by formation of diastereomeric salts and separation by recrystallization or chromatography or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are prepared by stereoselective synthesis.

In some embodiments, the compounds described herein are obtained as prodrugs. A prodrug refers to an agent that is converted to the parent drug in vivo. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. They are, for example, bioavailable when administered orally, while the original agent is not. The prodrug may be a substrate for the transporter. Additionally or alternatively, the prodrug also has improved solubility in pharmaceutical compositions compared to the parent drug. In some embodiments, the prodrug design increases effective water solubility. An example, without limitation, of a prodrug is a compound described herein that is administered as an ester (prodrug) but is then metabolically hydrolyzed to produce an active agent. Another example of a prodrug is a short peptide (polyamino acid) linked to an acid group, where the peptide is metabolized to release the active moiety. In some embodiments, when administered in vivo, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized via one or more steps or processes to a biologically, pharmaceutically, or therapeutically active form of the compound.

Prodrugs of the compounds described herein include, without limitation, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, Nacyloxyalkyl derivatives, tertiary amine quaternary derivatives, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard H. Design and Application of Prodrugs in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191 and Bundgaard H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug wherein the hydroxyl group is incorporated into an acyloxyalkyl ether, alkoxycarbonyloxyalkyl ether, alkyl ester, aryl ester, phosphate ester, sugar ester, ester, and the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug in which the hydroxyl is then metabolized in vivo to form a carboxylic acid group. In some embodiments, the carboxyl group is used to form an ester or amide (ie, a prodrug), which is then metabolized in vivo to form a carboxylic acid group. In some embodiments, the compounds described herein are obtained as alkyl ester prodrugs.

Prodrugs of the compounds described herein, wherein the prodrug is metabolized in vivo to give the compound described herein as set forth herein, are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs for another derivative or

- 109 040704 active compound. In some embodiments, a prodrug of a compound disclosed herein allows targeted delivery of the compound to a specific area of the gastrointestinal tract. Formation of a pharmacologically active metabolite by drug metabolism in the colon is a widely used prodrug approach for colon-specific drug delivery systems.

In some embodiments, the prodrug is formed by forming a covalent bond between the drug and the carrier such that upon oral administration, the fragment remains intact in the stomach and small intestine. This approach involves the formation of a prodrug, which is a pharmacologically inactive derivative of the parent drug molecule that requires spontaneous or enzymatic conversion in a biological environment to release the active drug. Prodrug formation is characterized by improved delivery properties compared to the parent drug molecule. The problem of stability of some drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by the formation of a prodrug, which is converted to the parent drug molecule after entering the colon. Site-specific drug delivery via site-specific prodrug activation can be achieved by using some specific properties at the target site, such as an altered pH or high activity of certain enzymes relative to non-target tissues, to convert the prodrug into a drug.

In some embodiments, covalent bonding of the drug to the carrier forms a conjugate. Such conjugates include, without limitation, azo bond conjugates, glycosidic conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates, or amino acid conjugates.

In additional embodiments, the compounds described herein are metabolized upon administration to an organism in need of the production of a metabolite, which is then used to produce the desired effect, including the desired therapeutic effect.

A metabolite of a compound disclosed herein is a derivative of that compound which is formed during the metabolism of the compound. The term active metabolite refers to a biologically active derivative of a compound that is formed during the metabolism of the compound. As used herein, the term metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions) by which a particular substance is altered by the body. Thus, enzymes can cause specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with liver cells in vitro and analyzing the resulting compounds.

In some embodiments, the compounds described herein are rapidly metabolized after absorption from the gastrointestinal tract to metabolites that significantly reduce FXR agonist activity.

In additional embodiments, the compounds are rapidly metabolized in plasma.

In additional embodiments, the compounds are rapidly metabolized by the gut.

In additional embodiments, the compounds are rapidly metabolized by the liver.

Synthesis of compounds

The compounds described herein are synthesized using standard synthetic methods or using methods known in the art in combination with the methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used.

Compounds are prepared using standard organic chemistry techniques such as those described, for example, in March's Advanced Organic Chemistry, ^6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as variation in solvent, reaction temperature, reaction time, and various chemicals and other reaction conditions. Starting materials are available from commercial sources or are easily prepared.

Suitable reference books and treatises that detail the synthesis of reagents applicable in

- 110 040704 the preparation of the compounds described herein or provide links to articles that describe the preparation include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; S. R. Sandier et al., Organic Functional Group Preparations, 2nd Ed., Academic Press, New York, 1983; H. O. House, Modern Synthetic Reactions, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, Heterocyclic Chemistry, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., Wiley-Interscience, New York, 1992 references to articles that describe the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527 -29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. With Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 4th Edition (1992) John Wiley & Sons, ISBN: 0471-60180-2; Otera, J. (editor) Modern Carbonyl Chemistry (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Functional Groups (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. Organic Chemistry 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., Intermediate Organic Chemistry 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, in over 55 volumes and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes.

The compounds described herein are prepared by the general synthetic routes described in Schemes 1-16 below.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 1.

Scheme 1

In scheme 1, the substituents X ² , X ³ , X ⁴ , R ¹ and R ² are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine, or iodine.

In some embodiments, the boric acid ester of I-2 is reacted with the halide of I-1 under suitable metal catalyzed cross-coupling reaction conditions to form I-3. In some embodiments, suitable metal-catalyzed cross-coupling conditions involve the use of palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ with a suitable base, with a suitable solvent or mixture of solvents for a suitable time and at an appropriate temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as Na ₂ CO ₃ or Cs ₂ CO ₃ . In some embodiments, a suitable solvent or mixture of solvents is dioxane, acetonitrile, DME/EtOH, or ethanol. In some embodiments, a suitable time and a suitable temperature is from about 2 to about 18 hours (overnight) at a temperature of about 50 or about 100°C.

In some embodiments, I-3 is subjected to suitable hydrogenation conditions followed by treatment under suitable acidic conditions to produce cyclohexanone I-4. In some embodiments, suitable hydrogenation conditions involve the use of palladium. Palladium catalyzed hydrogenation conditions involve the use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent such as EtOAc, ethanol, methanol or a combination of these solvents for the appropriate amount of time at the appropriate temperature. In some embodiments, a suitable amount of time is between

- 111 040704 about 4.5 to about 18 hours (overnight) at about room temperature. In some embodiments, appropriate acidic conditions include formic acid in water and toluene for a suitable amount of time at a suitable temperature. In some embodiments, a suitable amount of time at a suitable temperature is about 4 hours at a temperature of about 120°C. In some embodiments, a suitable amount of time at a suitable temperature is approximately 18 hours (overnight) at reflux. In some embodiments, suitable acidic conditions include PPTS in acetone and water for a suitable amount of time at a suitable temperature. In some embodiments, a suitable amount of time at a suitable temperature is about 10 hours at a temperature of about 60°C. In some embodiments, suitable acidic conditions include 3 M HCl and THF for a suitable amount of time at a suitable temperature. In some embodiments, a suitable amount of time at a suitable temperature is from about 3 hours to about a night at a temperature of about 60°C.

In some embodiments, I-4 is reacted under suitable homologation conditions with one carbon atom to form I-5. In some embodiments, suitable single carbon homologation conditions involve the use of phosphonium reagents. In some embodiments, suitable single carbon homologation conditions involve pretreatment of (methoxymethyl)triphenylphosphonium chloride [Ph ₃ P ⁺ H ₂ OCH ₃ Cl ^- ] with a suitable base, a suitable solvent for a suitable amount of time at a suitable temperature prior to adding cyclohexanone I-4. In some embodiments, a suitable base is NaHMDS. In some embodiments, a suitable base is KHMDS or LiHMDS. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable amount of time before adding cyclohexanone I-4 at the appropriate temperature is from about 30 minutes to about 2 hours at about 0°C. In some embodiments, after the addition of I-4, the reaction is continued for another 30 minutes to about 3 hours at a temperature of about 0°C. In some embodiments, the reaction is allowed to warm to about room temperature overnight.

In some embodiments, I-5 is then subjected to suitable acidic conditions to produce a mixture of cis- and trans-aldehydes I-6. In some embodiments, suitable acidic conditions include formic acid in water/toluene at a temperature of about 120 to about 130° C. for about 2 to about a night. In some embodiments, suitable acidic conditions include HCl in THF at about 60° C. for about 1 or about 6 hours. In some embodiments, additional addition of aldehyde I-6 under appropriate basic conditions produces mostly trans aldehyde I-6. In some embodiments, suitable basic conditions include NaOH in a suitable solvent mixture, such as H ₂ O, EtOH, and PhMe, for a suitable amount of time at a suitable temperature. In some embodiments, THF is used instead of PhMe. In some embodiments, a suitable amount of time at a suitable temperature is from about 5.5 hours to about a night at about room temperature. In some embodiments, suitable basic conditions provide for NaOMe in a suitable solvent, such as MeOH, for a suitable amount of time at a suitable temperature. In some embodiments, a suitable amount of time at a suitable temperature is from about 4 hours to about 18 hours at about room temperature. In some embodiments, further purification by crystallization or chromatography yields pure transaldehyde I-6.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 2.

Scheme 2

- 112 040704

In scheme 2, the substituents X ² , X ³ , X ⁴ , R ¹ , R ² and m are as described herein. In some embodiments, X ² is CR ² , X ³ is CH, and each X ⁴ is CH. In some embodiments, R ⁶ is alkyl. In some embodiments, R ⁶ is methyl. In some embodiments, X is halogen. In some embodiments, X is chlorine, bromine, or iodine.

In some embodiments, II-1 is cooled to a suitable temperature, reacted under suitable metal-halogen exchange conditions with a suitable solvent for a suitable time and at a suitable temperature, and then reacted with a suitable II-2 ketone. for the right time and at the right temperature to give II-3. In some embodiments, suitable metal halide exchange conditions include an organometallic reagent. In some embodiments, a suitable solvent is THF. In some embodiments, the organometallic reagent is an alkyllithium. In some embodiments, the alkyllithium is n-butyllithium. In some embodiments, II-1 is cooled to a temperature of approximately -78° C. prior to addition of the organometallic reagent. In some embodiments, II-1 is reacted for approximately two hours at a temperature of approximately -78° C. before the corresponding II-2 ketone is added. In some embodiments, the organometallic intermediate is reacted within about 3 hours after addition of the II-2 ketone. In some embodiments, the organometallic intermediate is reacted at a temperature of approximately -78°C after addition of the ketone II-2.

In some embodiments, the II-3 alcohol is reacted under appropriate reduction conditions with a suitable solvent for a suitable time and at an appropriate temperature to form a mixture of dehydrated and reduced products. In some embodiments, the terms include the use of trifluoroacetic acid and silyl hydride. In some embodiments, the silyl hydride is triethylsilane. In some embodiments, a suitable solvent is dichloromethane. In some embodiments, the temperature is from about 0°C to about room temperature, or about 0°C. In some embodiments, a suitable time is about overnight or about 1 hour. In some embodiments, the mixture of reduced and dehydrated products is reacted under appropriate conditions with a suitable solvent for a suitable time and at a suitable temperature to form a ketone. In some embodiments, a suitable solvent is a mixture of formic acid, toluene and water. In some embodiments, a suitable temperature is about 130°C. In some embodiments, a suitable time is approximately overnight. In some embodiments, a suitable solvent is a mixture of formic acid, THF and water. In some embodiments, a suitable temperature is about 80°C. In some embodiments, a suitable time is about 18 hours. In some embodiments, this dehydrated by-product containing ketone is completely reduced under suitable reduction conditions with a suitable solvent for a suitable time and at a suitable temperature to form II-4. In some embodiments, suitable recovery conditions involve the use of hydrogen as the reducing agent. In some embodiments, the hydrogen is at a pressure of about 15 psi or about 30 psi. In some embodiments, the reduction of the alkene involves the use of a palladium catalyst. In some embodiments, the palladium catalyst is 10% palladium on carbon. In some embodiments, the solvent is ethyl acetate and concentrated HCl. In some embodiments, the solvent is ethyl acetate. In some embodiments, the temperature is approximately room temperature. In some embodiments, a suitable time is from about 30 minutes to about 18 hours.

In some embodiments, II-4 is pre-treated with an R ⁶ X electrophile in a suitable solvent and at a suitable temperature. In some embodiments, the electrophile is an alkyl halide. In some embodiments, X is chlorine, bromine, or iodine. In some embodiments, the electrophile is methyl iodide. In some embodiments, the temperature is approximately -78°C. In some embodiments, the mixture is further reacted with a base for a suitable time and at a suitable temperature to form

- 113 040704 alkylated product. In some embodiments, the base is lithium diisopropyl diamide. In some embodiments, a suitable time is about 2 hours. In some embodiments, the temperature is about -78°C. In some embodiments, the mixture is further allowed to warm to approximately room temperature for a suitable period of time. In some embodiments, a suitable amount of time is approximately overnight.

In some embodiments, the ketone II-4 is converted to the aldehyde II-7 as described in Scheme 1.

Alternatively, in some embodiments, II-4 is reacted under suitable homologation conditions with one carbon atom to produce alkene II-5. In some embodiments, suitable single carbon homologation conditions involve the use of phosphonium reagents. In some embodiments, suitable single carbon homologation conditions involve pretreatment of methyltriphenylphosphonium bromide [RI ₃ P ⁺ CH ₃ Br ^- ] with a suitable base in a suitable solvent for a suitable amount of time at a suitable temperature before adding cyclohexanone II-4. In some embodiments, a suitable base is an organic base. In some embodiments, a suitable base is an alkoxide base. In some embodiments, a suitable base is potassium tert-butoxide. In some embodiments, toluene is a suitable solvent. In some embodiments, a suitable time before adding the ketone is about 30 minutes. In some embodiments, the reaction temperature prior to addition of the ketone is approximately 100°C. In some embodiments, the II-4 ketone is added in a suitable solvent, at an appropriate temperature, and for an appropriate amount of time. In some embodiments, the reaction temperature is approximately 50° C. after the addition of the ketone. In some embodiments, the ketone is added in toluene. In some embodiments, the ketone is further reacted at a suitable temperature for a suitable period of time. In some embodiments, the ketone is further reacted at a temperature of approximately 100°C. In some embodiments, the ketone is further reacted for about 2 hours.

In some embodiments, the II-5 alkene is subjected to hydration conditions to form II-6. In some embodiments, the hydration conditions involve treatment with a reducing agent and then with an oxidizing agent. The reducing agent is reacted with II-5 in a suitable solvent, at an appropriate temperature and for the required amount of time. In some embodiments, the reducing agent is a borane. In some embodiments, the reducing agent is BH ₃ -SMe ₂ . In some embodiments, the reducing agent is reacted with II-5 in THF. In some embodiments, the reaction temperature is approximately 0°C. In some embodiments, the reaction proceeds within about one hour after the addition of the reducing agent. In some embodiments, the reaction is further continued at approximately room temperature. In some embodiments, the reaction is further continued for about 3 hours. In some embodiments, the borane intermediate is further oxidized with an oxidant to form an alcohol II-6 in an appropriate solvent, at an appropriate temperature, and for an appropriate amount of time. In some embodiments, the oxidizing agent is 30% H ₂ O ₂ . In some embodiments, the oxidation reaction is carried out in the presence of a base. In some embodiments, the base is NaOH. In some embodiments, the solvent is H ₂ O. In some embodiments, a suitable amount of time is approximately overnight. In some embodiments, a suitable temperature is approximately room temperature.

In some embodiments, the II-6 alcohol is exposed to an oxidizing agent to form the II-7 aldehyde. In some embodiments, the oxidant is a Swern oxidizer in a suitable solvent, at an appropriate temperature, and for an appropriate amount of time. In some embodiments, the Swern oxidant is formed with DMSO and oxalyl chloride. In some embodiments, a suitable solvent is dichloromethane. In some embodiments, a suitable temperature for formation of the Swern oxidizer is approximately 78°C. In some embodiments, a suitable time for formation of the Swern oxidant is 30 minutes. In some embodiments, II-6 is reacted with a Swern oxidant at a temperature of approximately 78°C. In some embodiments, II-6 is reacted with the Swern oxidant for about one hour. According to some embodiments, the basis

- 114 040704 nii is then added at the appropriate temperature for the appropriate period of time. In some embodiments, the base is an amine base. In some embodiments, the amine base is triethylamine. In some embodiments, a suitable temperature is approximately 78°C. In some embodiments, a suitable reaction time after base addition is approximately one hour. In some embodiments, oxidation produces II-7 as a mixture of cis and trans isomers.

In some embodiments, the cis/trans II-7 mixture is equilibrated to substantially trans-P-7 with the appropriate reagent, in the appropriate solvent, at the appropriate temperature, and for the appropriate time. In some embodiments, the appropriate reagent is a base. In some embodiments, the base is an inorganic base. In some embodiments, the base is sodium hydroxide. In some embodiments, a suitable solvent is a mixture such as H2O, EtOH, and PhMe. In some embodiments, a suitable time is about 3 hours. In some embodiments, a suitable temperature is about room temperature. In some embodiments, further purification by crystallization or chromatography yields pure transaldehyde II-7.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 3.

Scheme 3 _χ2 .χ* B(OH) ₂

In scheme 3, the substituents X ² , X ³ , X ⁴ , R ¹ , R ² and m are as described herein. In some embodiments, X ² is CR ² , X ³ is CH, and each X ⁴ is CH. In some embodiments, R ⁶ is alkyl. In some embodiments, R ⁶ is methyl.

In some embodiments, the ketone III-1 is treated with a base to form an enolate with a suitable base in a suitable solvent for a suitable amount of time at an appropriate temperature. In some embodiments, the base is an organic base. In some embodiments, the organic base is LiHMDS. In some embodiments, enolate formation occurs at a temperature of approximately 78°C. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable time is approximately one hour. In some embodiments, the III-1 ketone enolate is reacted with the appropriate electrophile in the appropriate solvent to form the III-2 enol ester at the appropriate temperature for the appropriate amount of time. In some embodiments, the electrophile forms a sulfate ester. In some embodiments, the electrophile is PhNTf ₂ . In some embodiments, a suitable temperature is about 78° C. and a suitable time is about 2 hours. In some embodiments, the reaction is further heated to a suitable temperature for a suitable period of time. In some embodiments, a suitable temperature is approximately room temperature overnight.

In some embodiments, boric acid III-3 is reacted with III-2 enol triflate under suitable metal catalyzed cross-coupling reaction conditions to form III-4. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions provide for Pd(dppf)Cl ₂ with a suitable base, with a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as Na ₂ CO ₃ . In some embodiments, a suitable solvent is a dioxane/water mixture. In some embodiments, a suitable time and a suitable temperature is about 6 hours at a temperature of about 30°C.

In some embodiments, III-4 is subjected to suitable olefin reduction conditions followed by treatment under suitable acidic conditions to produce cyclohexanone III-5. In some embodiments, suitable reduction conditions include palladium-catalyzed hydrogenation conditions. In some embodiments, the palladium-catalyzed hydrogenation conditions involve the use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as EtOAc, for the appropriate amount of time at the appropriate temperature. In some embodiments, a suitable amount of time is about overnight at about room temperature. In some embodiments, suitable acidic conditions involve the use of formic acid in water and toluene for a suitable amount of time at an appropriate temperature. In some embodiments, a suitable amount of time at a suitable temperature is approximately overnight at a temperature of approximately 120°C.

In some embodiments, the ketone III-5 is converted to the aldehyde I-6 or II-7 as shown in Schemes 1 and 2, respectively.

In some embodiments, the compounds described herein are prepared as shown in Scheme 4.

in this document. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, X is a halide. In some embodiments, X is iodine or bromine.

In some embodiments, the IV-1 transaldehyde is reacted with the appropriate IV-2 aniline under suitable reductive amination conditions. In some embodiments, suitable reductive amination conditions involve the use of a suitable reducing agent and acetic acid in a suitable solvent such as DCE or DCM at a suitable temperature for a suitable period of time. In some embodiments, NaBH(OAc) ₃ is used as a reducing agent. In some embodiments, a suitable temperature is approximately room temperature. In some embodiments, a suitable amount of time is from about one hour to about 2.5 hours. In some embodiments, suitable reaction conditions include acetic acid in a suitable solvent such as methanol at a suitable temperature for a suitable amount of time before adding the reducing agent. In some embodiments, a suitable temperature and time is from about 5 to about 4 hours. In some embodiments, the reaction is then further exposed to a suitable reducing agent, such as NaBH3CN, for a suitable time and at a suitable temperature. In some embodiments, a suitable amount of time is about overnight at about room temperature.

In some embodiments, acylation of the amine IV-3 with an acyl chloride provides compound IV-4. Suitable acylation conditions include, without limitation, the use of a suitable base such as TEA or pyridine in a suitable solvent such as DCM or toluene for a suitable amount of time and at a suitable temperature such as from about room temperature to about 80° C. for 1 hour to night. In some embodiments, pyridine is used both as a base and as a solvent. Other suitable conditions include the addition of DMAP.

Boric acid ester IV-5 can be obtained from IV-4 using halogen-boron exchange conditions according to some embodiments. Suitable borohalogen exchange conditions include, without limitation, the use of a suitable organometallic reagent

- 116 040704 and a suitable boron reagent. In some embodiments, suitable organometallic reagents include palladium. In some embodiments, suitable boron reagents include bis(pinacolato)diboron. In some embodiments, suitable palladium-catalyzed boron-halogen exchange conditions include Pd(dppf)Cl ₂ with a suitable base in a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is an acetate base such as KOAc. In some embodiments, toluene is a suitable solvent. In some embodiments, a suitable time and a suitable temperature are from about 4 hours to about night and from about 100 to about 115°C.

In some embodiments, the boric acid ester IV-5 is reacted with an aromatic halide under suitable metal catalyzed cross-coupling reaction conditions to form IV-6. In some embodiments, the aromatic halide is an aromatic bromide or iodide. In some embodiments, suitable metal-catalyzed cross-coupling conditions involve the use of palladium. In some embodiments, suitable conditions for a palladium-catalyzed cross-coupling reaction include Pd(dppf)Cl ₂ , Pd(PPh ₃ ) ₄ , or chloro[(du(1-αdamαntyl)-N-butylphosphine)-2-(2-αminobuphenyl)]nalαduy (II) with a suitable base, in a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as K ₂ CO ₃ , Na ₂ CO ₃ , or Cs ₂ CO ₃ . In some embodiments, the inorganic base is K ₃ PO ₄ . In some embodiments, a suitable solvent is dioxane/water or DMF/water. In some embodiments, a suitable solvent is EtOH or dioxane. In some embodiments, a suitable time and a suitable temperature are from about 10 minutes to about 4 hours at a temperature of from about 50 to about 80°C. In some embodiments, a suitable time and a suitable temperature is from about 0.5 to about 6 hours at a temperature of about 80°C. In some embodiments, a suitable time and a suitable temperature are from about 15 minutes to about 3.5 hours at a temperature of about 80°C. In some embodiments, a suitable time and a suitable temperature is about 15 hours at a temperature of about 90°C. In some embodiments, a suitable time and a suitable temperature is approximately one hour at a temperature of approximately 50°C. In some embodiments, a suitable time and a suitable temperature is about 3 hours at about 80 to about 100°C.

In some embodiments, the boric acid ester IV-5 is reacted with a nitrogen-containing heterocycle under suitable metal catalyzed cross-coupling reaction conditions to form IV-6. In some embodiments, suitable metal-catalyzed cross-coupling conditions involve the use of copper. In some embodiments, suitable conditions for a copper-catalyzed cross-coupling reaction include Cu(OAc) ₂ with a suitable ligand, a suitable oxidizing agent, in a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, a suitable ligand is N,N,N',N'tetramethylethylenediamine. In some embodiments, a suitable oxidizing agent is O2. A suitable solvent is a mixture of water and methanol. In some embodiments, a suitable time and a suitable temperature is about overnight at about room temperature.

In some embodiments, the IV-4 aryl halide is reacted with a boron reagent under suitable metal catalyzed cross-coupling reaction conditions to form IV-6. In some embodiments, the boric reagent is an aromatic boric acid. In some embodiments, the boron reagent is an aromatic ester of boric acid. In some embodiments, the boron reagent is an aromatic ester of pinacolylboron. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(dppf)Cl2 or Pd(PPh3)4 with a suitable base, with a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is

- 117 040704 is a carbonate base such as Cs ₂ CO ₃ , Na2CO ₃ or K2CO ₃ . In some embodiments, a suitable solvent is a DMF/water mixture. In some embodiments, a suitable solvent is a dioxane/water mixture. In some embodiments, a suitable time and a suitable temperature are from about 10 minutes to about 2 hours at a temperature of from about 50 to about 100°C. In some embodiments, a suitable time and a suitable temperature is from about 15 to about 30 minutes at a temperature of about 80°C.

In some embodiments, Compound IV-6 is prepared from appropriate conditions for metal catalyzed cross-coupling of IV-4 halide with a nitrogen-containing heterocycle. In some embodiments, halide IV-4 is iodide. In some embodiments, metal-catalyzed cross-couplings involve palladium-Buchwald-Hartwig catalyzed amination conditions. Suitable palladium cross-coupling catalysts include, without limitation, Pd ₂ (dba) ₃ with a suitable ligand in a suitable solvent such as dioxane with a suitable base at a suitable temperature for an appropriate amount of time. In some embodiments, a suitable ligand is a phosphine ligand. In some embodiments, a suitable phosphine is 2-(di-tert-butylphosphino)biphenyl. In some embodiments, a suitable base is an organic base. In some embodiments, a suitable organic base is sodium tert-butoxide. In some embodiments, a suitable temperature is 80°C. In some embodiments, a suitable amount of time is approximately overnight.

In some embodiments, Compound IV-6 is prepared from appropriate conditions for metal catalyzed cross-coupling of IV-4 halide with a tin reagent. In some embodiments, halide IV-4 is a bromide. In some embodiments, the tin reactant is an aromatic tin reactant. In some embodiments, metal-catalyzed cross-couplings involve Still's palladium-catalyzed cross-coupling conditions. Suitable palladium cross-coupling catalysts include, without limitation, Pd(PPh ₃ ) ₄ in a suitable solvent such as DMF or dioxane at the appropriate temperature for the appropriate amount of time. In some embodiments, a suitable temperature is 90°C. In some embodiments, a suitable amount of time is about 2 hours. In some embodiments, a suitable temperature is 100°C. In some embodiments, a suitable amount of time is approximately 4 hours.

In some embodiments, Compound IV-6 is prepared from appropriate conditions for metal catalyzed cross-coupling of IV-4 halide with an aromatic compound. In some embodiments, halide IV-4 is a bromide. In some embodiments, metal-catalyzed cross-couplings include C-H activation cross-coupling conditions. In some embodiments, C-H activation cross-coupling conditions include the use of palladium catalysts. Suitable palladium cross-coupling catalysts include, without limitation, Pd(OAc) ₂ with a suitable ligand in a suitable solvent such as dioxane with a suitable base at a suitable temperature for an appropriate amount of time. In some embodiments, a suitable ligand is a phosphine ligand. In some embodiments, a suitable phosphine is (2biphenyl)dicyclohexylphosphine. In some embodiments, a suitable base is an inorganic base. In some embodiments, a suitable inorganic base is K ₂ CO ₃ . In some embodiments, a suitable temperature is 110°C. In some embodiments, a suitable amount of time is approximately overnight.

In some embodiments, R ¹⁰ or R ¹¹ is a protected alcohol. In some embodiments, R ¹⁰ or R ¹¹ is a silyl ether protected alcohol. In some embodiments, the protecting groups are removed to provide the free alcohol using suitable deprotection conditions, including a suitable solvent, temperature, and IV-6 preparation time. In some embodiments, suitable deprotection conditions involve the use of aqueous HCl. In some embodiments, a suitable solvent is water, THF, methanol, or a combination of solvents. In some embodiments, a suitable time at an appropriate temperature is from about 1 hour at about 0° C. to about room temperature.

In some embodiments, the compounds described herein are prepared as shown in Scheme 5.

Scheme 5

In scheme 5, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and m are as described in this document. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, X is a halide. In some embodiments, X is iodine or bromine. In some embodiments, X is hydrogen. In some embodiments, M is a metal or a metalloid-containing substituent. In some embodiments, the metal or metalloids include boron, tin, or zinc.

In some embodiments, the V-1 boron reactant is reacted with the V-7 aromatic halide under suitable metal catalyzed cross-coupling reaction conditions to form V-2. In some embodiments, the aromatic halide is an aromatic bromide or an aromatic iodide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(dppf)Cl ₂ with a suitable base, with a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as Na ₂ CO ₃ . In some embodiments, a suitable solvent is a mixture of dioxane, ethanol and water. In some embodiments, a suitable time and a suitable temperature is approximately overnight at a temperature of approximately 80°C.

In some embodiments, compound V-2 is prepared from appropriate metal catalyzed cross-coupling conditions of an aromatic halide V-1 with a boron reagent V-7. In some embodiments, suitable metal catalyzed cross-coupling conditions, such as Suzuki cross-coupling conditions, are described in Schemes 4 and 5.

In some embodiments, the V-2 compound is prepared from appropriate metal catalyzed cross-coupling conditions of the V-1 halide with the nitrogen-containing V-7 heterocycle. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as Buchwald-Hartwig amination conditions, are described in Scheme 4.

In some embodiments, compound V-2 is prepared from appropriate metal catalyzed cross-coupling conditions of halide V-1 with tin reagent V-7. In some embodiments, suitable metal catalyzed cross-coupling conditions, such as Still's cross-coupling conditions, are described in Scheme 4.

In some embodiments, Compound V-2 is prepared from appropriate metal catalyzed cross-coupling conditions of V-1 tin reagent with V-7 aromatic halide. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as Still's cross-coupling conditions, are described in Scheme 4.

In some embodiments, compound V-2 is prepared from appropriate metal catalyzed cross-coupling conditions of halide V-1 with aromatic compound V-7. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as C-H activation conditions, are described in Scheme 4.

In some embodiments, the boron reactant V-3 is reacted with the aromatic halide V-8 under suitable conditions in a metal catalyzed cross-coupling reaction to form V-4. In some embodiments, Boron Reagent V-3 is

- 119 040704 boric acid or an ester of boric acid. In some embodiments, the aromatic halide is an aromatic bromide or an aromatic iodide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(dppf)Cl ₂ with a suitable base, with a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as K2CO3. In some embodiments, a suitable solvent is dioxane. In some embodiments, a suitable time and a suitable temperature is about 4 hours at a temperature of about 80°C.

In some embodiments, the V-3 aryl halide is reacted with a boron reagent V-8 under suitable metal catalyzed cross-coupling reaction conditions to form V-4. In some embodiments, the boric reagent is an aromatic boric acid. In some embodiments, the boron reagent is an aromatic ester of boric acid. In some embodiments, the aryl halide is an aryl iodide or an aryl bromide. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(dppf)Cl ₂ with a suitable base, with a suitable solvent for a suitable time and at a suitable temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as K2CO3. In some embodiments, a suitable solvent is dioxane. In some embodiments, a suitable time and a suitable temperature is about 20 minutes at a temperature of about 90°C.

In some embodiments, compound V-4 is prepared from appropriate metal catalyzed cross-coupling conditions of a V-3 halide with a nitrogen-containing V-8 heterocycle. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as Buchwald-Hartwig amination conditions, are described in Scheme 4.

In some embodiments, Compound V-4 is prepared from appropriate metal catalyzed cross-coupling conditions of a V-3 halide with a V-8 tin reagent. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as Still's cross-coupling conditions, are described in Scheme 4.

In some embodiments, Compound V-4 is prepared from appropriate metal catalyzed cross-coupling conditions of V-3 tin reagent with V-8 aromatic halide. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as Still's cross-coupling conditions, are described in Scheme 4.

In some embodiments, Compound V-4 is prepared from appropriate metal catalyzed cross-coupling conditions of halide V-3 with aromatic compound V-8. In some embodiments, suitable metal-catalyzed cross-coupling conditions, such as C-H activation conditions, are described in Scheme 4.

In some embodiments, V-2 is subjected to suitable nitro reduction conditions to produce V-4 aniline. Suitable conditions for the reduction of nitro groups involve the use of metal catalysts. Suitable metal catalyzed reductions include palladium catalyzed hydrogenation conditions. In some embodiments, suitable conditions for palladium-catalyzed hydrogenation involve the use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as methanol, for a suitable amount of time at a suitable temperature. In some embodiments, the appropriate conditions include adding HCl to the water. In some embodiments, a suitable amount of time at a suitable temperature is about 1 hour at about room temperature.

Alternatively, in some embodiments, suitable conditions for reducing the nitro groups include using a tin reducing agent in a suitable solvent for an appropriate period of time at a suitable temperature. In some embodiments, suitable tin reducing agents include SnCl ₂ -H ₂ O. In some embodiments, a suitable solvent is a mixture of water and ethanol. In some embodiments, a suitable amount of time at an appropriate temperature is from about 2 to about 16 hours at a temperature of about 80°C. According to some embodiments, a suitable amount of time at an appropriate temperature is from about two hours to about 2 hours at about room temperature.

Alternatively, in some embodiments, suitable conditions for the reduction of nitro groups include the use of a zinc reducing agent and an acid in a suitable solvent for an appropriate amount of time at an appropriate temperature. In some embodiments, the corresponding acid includes acetic acid. In some embodiments, suitable zinc reducing agents include Zn metal. In some embodiments, a suitable solvent is ACN. In some embodiments, a suitable amount of time at a suitable temperature is from about 1 hour at about 0° C. to about room temperature.

In some embodiments, the corresponding aldehyde is reacted with aniline V-4 under suitable reductive amination conditions to produce V-5. In some embodiments, suitable reductive amination conditions involve the use of a suitable reducing agent in a suitable solvent at a suitable temperature for a suitable period of time. In some embodiments, a suitable solvent is DCE or DCM. In some embodiments, a suitable solvent is DCE/acetic acid or DCM/acetic acid mixtures. In some embodiments, NaBH(OAc) ₃ is used as a reducing agent. In some embodiments, a suitable temperature is from about 0° C. to about room temperature. In some embodiments, a suitable amount of time is from about one hour to about a night. In some embodiments, suitable reaction conditions provide for acetic acid in a suitable solvent, such as methanol, at a suitable temperature for a suitable amount of time before adding the reducing agent. In some embodiments, a suitable temperature and time is room temperature and is from about 5 minutes to about 4 hours. In some embodiments, the reaction is exposed to a suitable reducing agent, such as NaBH ₃ CN, for a suitable time and at a suitable temperature. In some embodiments, a suitable amount of time at the appropriate temperature following the addition of NaBH ₃ CN is approximately overnight at approximately room temperature.

In some embodiments, acylation of the amine V-5 with an acyl chloride provides compound V-6. Suitable acylation conditions include, without limitation, the use of a suitable base such as TEA or pyridine in a suitable solvent such as DCM, toluene or pyridine for a suitable amount of time and at a suitable temperature after addition of the acyl chloride. In some embodiments, a suitable temperature and a suitable amount of time is from about room temperature to about 80° C. for about one hour to about night. Other suitable conditions include the addition of DMAP. In some embodiments, the acyl chloride is added in a suitable solvent such as toluene. In some embodiments, a suitable temperature and a suitable amount of time after the addition of the acid chloride is from about 0 to about 50°C, or from about 0 to about 80°C for about 10 minutes to about night.

In some embodiments, R ¹⁰ or R ¹¹ is a protected alcohol. In some embodiments, R ¹⁰ or R ¹¹ is a silyl ether protected alcohol. In some embodiments, the protecting groups are removed to provide the free alcohol using suitable deprotection conditions as described in Scheme 4.

In some embodiments, the compounds described herein are prepared as shown in Scheme 6.

Scheme 6

VI-1 VI-2

In Scheme 6, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and m are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X4 is C-H.

In some embodiments, compound VI-2 is obtained from the O-alkylation of VI-121 040704 with R ¹² X, a suitable base, and a suitable solvent such as THF at a suitable temperature for a suitable period of time. In some embodiments, X is a halide. In some embodiments, a suitable base is NaH. In some embodiments, Compound VI-1 is pretreated with a suitable base for a suitable amount of time at a suitable temperature, such as about 0.5 hour at about 0° C., prior to addition of the R ¹² X halide. In some embodiments, a suitable time and temperature is approximately overnight at a temperature of approximately 60°C.

In some embodiments, the compounds described herein are prepared as shown in Scheme 7.

Scheme 7

VII-1 VII-2

In scheme 7, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, each R is independently alkyl, heteroalkyl, or hydroxyalkyl, or hydrogen, or both Rs are taken together to form a substituted or unsubstituted fused 4-, 5-, or 6-membered ring with 0-3 N atoms and 0-2 O atoms or S in a ring.

In some embodiments, VII-2 is derived from VII-1 and NHR2 amine. In some embodiments, VII-1 is subjected to carbonyldiimidazole in a suitable solvent, such as ACN, at a suitable temperature, such as about 80° C., for a suitable amount of time to form the intermediate carbamoyimidazole. In some embodiments, a suitable amount of time is from about 2 hours to about 6 hours or about night. In some embodiments, the carbamoylimidazole intermediate is treated with NHR ₂ in a suitable solvent and the reaction is allowed to proceed for the appropriate amount of time at the appropriate temperature. In some embodiments, a suitable solvent is acetonitrile. In some embodiments, a suitable solvent is MeOH, THF, or DCM. In some embodiments, NHR2 is added as a solution in MeOH, THF, or DCM. In some embodiments, NHR ₂ is added neat. In some embodiments, a suitable amount of time at a suitable temperature is from about 15 minutes to about a night at about room temperature. In some embodiments, a suitable amount of time is from about 1 to about 7 days. In some embodiments, a suitable temperature is from about room temperature to about 50°C, or from about room temperature to about 100°C. In some embodiments, when NHR ₂ hydrochloride is used instead of NHR ₂ , a suitable base such as iPr ₂ NEt is added prior to addition of NHR 2 hydrochloride.

In some embodiments, the compounds described herein are prepared as shown in Scheme 8.

Scheme 8

VIII-1 VIII-2

In scheme 8, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, each R is independently alkyl, heteroalkyl, hydroxyalkyl, or hydrogen, or both Rs are taken together to form a substituted or unsubstituted fused 4-, 5-, or 6-membered ring with 0-3 N atoms and 0-2 O or S atoms in the ring.

In some embodiments, VIII-2 is prepared from VIII-1 and the amine NHR2 via an acid. In some embodiments, VIII-1 is subjected to hydrolysis conditions to form an intermediate acid in a suitable solvent at a suitable temperature for a suitable period of time. In some embodiments, the hydrolysis conditions are

- 122 040704 are the main ones. In some embodiments, hydrolysis conditions involve the use of NaOH or LiOH. In some embodiments, the solvent is a THF/methanol/water mixture or a THF/water mixture. In some embodiments, a suitable temperature is about room temperature, and a suitable time is from about 2 hours to about night. In some embodiments, the hydrolysis intermediate is the desired compound. In some embodiments, the hydrolysis intermediate and the NHR ₂ amine are reacted under amidation conditions to form VIII-2. In some embodiments, a binder, such as HATU, is added to the acid in the presence of a base for a suitable period of time, at a suitable temperature, and in a suitable solvent. In some embodiments, the base is an amine base such as N,N-diisopropylethylamine. In some embodiments, the solvent is DMF. In some embodiments, after an appropriate amount of time at a suitable temperature, such as about 10 minutes at about 0°C, NHR2 is added and the reaction is allowed to proceed for an appropriate amount of time at a suitable temperature to form VIII-2. In some embodiments, the DBU is also added. In some embodiments, a suitable amount of time at an appropriate temperature is from about 10 minutes to about 30 minutes at a temperature from about 0° C. to about room temperature.

In some embodiments, the hydrolysis intermediate is treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) hydrochloride, Et ₃ N, DMAP, and HOBt at the appropriate temperature in a suitable solvent. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature is 0°C. In some embodiments, after a suitable period of time, such as about 10 minutes, NHR ₂ is added and the reaction is allowed to proceed for an appropriate amount of time at a suitable temperature to form VIII-2. In some embodiments, a suitable amount of time at a suitable temperature is about overnight at about 0° C. to about room temperature.

In some embodiments, the compounds described herein are prepared as shown in Scheme 9.

Scheme 9

In scheme 9, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁴ and m are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H.

In some embodiments, IX-1 is exposed to appropriate acidic conditions to produce an amine. In some embodiments, appropriate acidic conditions involve the use of TFA in a suitable solvent, such as DCM, at a suitable temperature for a suitable amount of time. In some embodiments, suitable acidic conditions involve the use of HCl in a suitable solvent, such as dioxane, at a suitable temperature for a suitable period of time. In some embodiments, a suitable temperature for a suitable period of time is from about 0° C. to about room temperature for about 0.5 to about 2 hours. In some embodiments, the amine is reacted with the anhydride (R ¹⁴ CO) 2 O to form IX -2 in the presence of a suitable base and solvent at a suitable temperature for an appropriate amount of time. In some embodiments, a suitable base is TEA or pyridine. In some embodiments, a suitable solvent is ethyl acetate or DCM. In some embodiments, a suitable temperature for a suitable period of time is from about 0° C. to about room temperature for about 10 minutes to about 2 hours. Alternatively, the amine is reacted with acyl chloride R ¹⁴ COCl or chloroformate ClCO 2 R ¹⁴ to form IX-2 in the presence of a suitable base and solvent at a suitable temperature for an appropriate amount of time. In some embodiments, a suitable base is pyridine or TEA. In some embodiments, a suitable solvent is

- 123 040704

DCM or ethyl acetate. In some embodiments, a suitable temperature for a suitable period of time is from about 0° C. to about room temperature for about 10 minutes to about 2 hours. Alternatively, the amine is reacted with R ₁₄ SO ₂ Cl sulfonyl chloride to form IX-2 in the presence of suitable base and solvent at the appropriate temperature for the appropriate amount of time. In some embodiments, a suitable base is TEA or pyridine. In some embodiments, a suitable solvent is DCM or ethyl acetate. In some embodiments, a suitable temperature for a suitable period of time is from about 0° C. for about 10 minutes to about 2 hours. amount of time. In some embodiments, a suitable base is TEA. In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable temperature is approximately 0°C. In some embodiments, propylphosphonic anhydride is added after an appropriate amount of time and the reaction is allowed to proceed at an appropriate temperature for an appropriate amount of time. In some embodiments, a suitable temperature for a suitable period of time is from about 0° C. to about room temperature over about a night.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 10.

In scheme 10, the substituents X ² , X ³ , X ⁴ , R ¹ and R ² are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine, or iodine.

In some embodiments, the X-1 halide is cooled to a suitable temperature, reacted under suitable metal-halogen exchange conditions with a suitable solvent for a suitable time and at an appropriate temperature, and then reacted with a suitable X-2 ketone for a suitable time and at appropriate temperature to provide the tertiary alcohol. In some embodiments, suitable metal-halogen exchange conditions include an organometallic reagent. In some embodiments, a suitable solvent is THF. In some embodiments, the organometallic reagent is an alkyllithium. In some embodiments, the alkyllithium is n-butyllithium. In some embodiments, X-1 is cooled to a temperature of approximately -78° C. prior to addition of the organometallic reagent.

In some embodiments, X-1 is reacted for about one hour at about -78° C. before the corresponding X-2 ketone is added. In some embodiments, X-1 reacts within about 2 hours after addition of the X-2 ketone. In some embodiments, a suitable temperature for reacting X-1 and X-2 ketone is approximately -78°C. In some embodiments, the tertiary alcohol is reacted under appropriate allylation conditions which involve the use of an allylating reagent and a Lewis acid in a suitable solvent for a suitable time and at a suitable temperature to form X-3. In some embodiments, a suitable allylating reagent is allyltrimethylsilane. In some embodiments, a suitable Lewis acid is BF ₃ -OEt ₂ . In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for a suitable time is about 78° C. for about 1 hour. In some embodiments, the reaction is further heated to about room temperature for about a night. In some embodiments, a suitable temperature for

- 124 040704 a suitable time is about 0°C for about a night.

In some embodiments, X-3 is reacted under suitable oxidative cleavage conditions for an appropriate period of time, in a suitable solvent, and at an appropriate temperature to produce X-4. In some embodiments, the oxidative cleavage conditions involve the use of an osmium reagent and N-methylmorpholine N-oxide to form an intermediate diol. In some embodiments, the osmium reagent is OsO ₄ or K2OsO ₄ -2H2O. In some embodiments, a suitable solvent is an ACN/water mixture. In some embodiments, a suitable temperature for a suitable time is from about 0° C. to about room temperature for about a night. In some embodiments, the diol is cleaved to form X-4 under appropriate oxidative cleavage conditions for an appropriate period of time, in a suitable solvent, and at an appropriate temperature. In some embodiments, suitable oxidative cleavage conditions involve the use of NaIO ₄ . In some embodiments, a suitable solvent is a mixture of THF/water. In some embodiments, a suitable temperature for a suitable time is from about 0° C. to about room temperature for about a night.

In some embodiments, X-4 is reduced to a primary alcohol under suitable reduction conditions and then halogenated under suitable halogenation conditions to give X-5. In some embodiments, suitable recovery conditions involve the use of a borohydride reagent. In some embodiments, reducing conditions involve using NaBH4 in a suitable solvent at a suitable temperature for an appropriate period of time. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable temperature for a suitable time is about 0° C. for about one hour. In some embodiments, the reaction is heated to about room temperature over about a night. The alcohol reacts under suitable halogenation conditions to form an alkyl halide, in some embodiments. In some embodiments, suitable halogenation conditions are bromination conditions that involve using CBr ₄ in a suitable solvent at an appropriate starting temperature followed by PPh ₃ in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, a suitable solvent is a halogenated solvent such as DCM. In some embodiments, a suitable starting temperature is approximately 0°C. In some embodiments, a suitable temperature and time after PPh ₃ addition is about 0° C. for about 1 hour. In some embodiments, a suitable solvent for adding PPh ₃ is THF. In some embodiments, the reaction is further heated to about room temperature over about a night.

In some embodiments, X-5 is subjected to intramolecular alkylation conditions to form X-6. In some embodiments, intramolecular alkylation conditions provide for a suitable base. In some embodiments, a suitable base is lithium diisopropylamide in a suitable solvent at a suitable temperature for a suitable period of time. In some embodiments, a suitable solvent is a mixture of HMPA and THF. In some embodiments, a suitable temperature for an appropriate period of time is about 78°C for about 3 hours, or from about 78°C to room temperature for about a night.

The X-6 ester is reduced to an alcohol under suitable reduction conditions, followed by oxidation to an aldehyde X-7 under suitable oxidation conditions, in some embodiments. In some embodiments, suitable recovery conditions involve the use of DIBALH in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for a suitable time is about 78° C. for about one hour. In some embodiments, the reaction is further heated to about room temperature for about 2 hours to produce an alcohol. In some embodiments, suitable oxidation conditions are chromium-based oxidations. In some embodiments, suitable oxidizing conditions involve the use of PCC in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, silica gel is added. According to some options

- 125 040704 the suitable solvent is DCM. In some embodiments, a suitable temperature is approximately 2 hours. Alternatively, in some embodiments, the oxidation conditions involve the use of oxalyl chloride and amine base DMSO in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, a suitable amine base is TEA. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable temperature for an appropriate period of time is about 78°C for about 1 hour.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 11.

Scheme 11

In some embodiments, XI-1 is subjected to alcohol protection conditions to form the bis-silyl intermediate, followed by hydrolysis conditions to form XI-2. In some embodiments, alcohol protection conditions include the use of TBSCl and a suitable base at an appropriate temperature, in a suitable solvent, and for a suitable period of time. In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable base is an imidazole. In some embodiments, a suitable temperature for a suitable time is about 2 hours. In some embodiments, the silyl ester intermediate is subjected to hydrolysis conditions to form XI-2. In some embodiments, hydrolysis conditions include treatment with a base at an appropriate temperature, in a suitable solvent, and for a suitable period of time. In some embodiments, a suitable solvent is a mixture of EtOH, H ₂ O, THF. In some embodiments, a suitable base is K ₂ CO ₃ . In some embodiments, a suitable temperature for a suitable time is about 3 hours.

Compound XI-2 is converted to acid chloride XI-3, in some embodiments, under chlorination conditions. In some embodiments, the chlorination conditions involve the use of (chloromethylene)dimethyliminium chloride and a base at a suitable temperature in a suitable solvent. In some embodiments, a suitable base is anhydrous K2CO3. In some embodiments, a suitable temperature is approximately 0°C. In some embodiments, a suitable solvent is toluene. In some embodiments, XI-2 is added and the mixture is stirred at the appropriate temperature for the appropriate time to produce XI-3. In some embodiments, a suitable temperature for a suitable time is from about room temperature for about 0.5 to about 1 hour.

In some embodiments, the compounds described herein are prepared as shown in Scheme 12.

Scheme 12

In scheme 12, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and m are as described herein. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H.

The alcohol XII-1 reacts under suitable halogenation conditions to form an alkyl halide XII-2 according to some embodiments. According to some embodiments

- 126 040704 suitable halogenation conditions are bromination conditions using CBr ₄ in a suitable solvent at a suitable starting temperature and then PPh 3 in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, a suitable solvent is a halogenated solvent such as DCM. In some embodiments, a suitable starting temperature is approximately 0°C. In some embodiments, a suitable temperature and time after adding PPh3 is about 0°C for about one hour. In some embodiments, the reaction is further heated to about room temperature over about a night.

In some embodiments, acylation of the amine XII-3 with an acyl chloride provides compound XII-4. Suitable acylation conditions include, without limitation, the use of a suitable base, such as pyridine, in a suitable solvent, such as DCM or toluene, at a suitable temperature, such as about 0°C. In some embodiments, the acyl chloride is added in a suitable solvent at a suitable temperature for a suitable period of time. In some embodiments, a suitable solvent is toluene. In some embodiments, a suitable temperature is approximately 0° C., then warmed to room temperature over approximately overnight.

In some embodiments, compound XII-5 is prepared from N-alkylation of XII-4 with XII-2 bromide and a suitable base in a suitable solvent, such as DMF, at a suitable temperature for a suitable amount of time. Suitable bases include NaH. In some embodiments, Compound XII-4 is pretreated with a suitable base for an appropriate amount of time at a suitable temperature, such as about two hours at about 0° C. to about room temperature, before XII-2 bromide is added. In some embodiments, a suitable time and temperature following the addition of XII-2 bromide is about room temperature for about a night. In some embodiments, R ¹⁰ or R ¹¹ is a protected alcohol. In some embodiments, R ¹⁰ or R ¹¹ is an alcohol protected with silyl ether. In some embodiments, the protecting groups are removed to obtain the free alcohol using suitable deprotection conditions, including the appropriate solvent, temperature, and time to obtain XII-5. In some embodiments, suitable deprotection conditions involve the use of fluoride reagents. In some embodiments, the fluoride reactant is NH4F. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable time at an appropriate temperature is approximately overnight at a temperature of approximately 60°C.

In some embodiments, the compounds described herein are prepared as shown in Scheme 13.

Scheme 13

In scheme 13, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and m are as described in this document. In some embodiments, X ² is CR ² , X ³ is C-H, and each X ⁴ is C-H. In some embodiments, X is a suitable cross-coupling substituent. In some embodiments, X is a halide. In some embodiments, X is chlorine, bromine, or iodine.

In some embodiments, compound XIII-1 is reacted with a suitable source of acetylene under suitable metal-catalyzed cross-coupling reaction conditions to form XIII-2. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, a suitable source of acetylene is trimethylsilylacetylene. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(PPh ₃ ) ₂ Cl ₂ , a copper catalyst with a suitable base, for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, the base is an amine base such as TEA. According to some

- 127 040704 embodiments, a suitable time and a suitable temperature are about 6 hours at a temperature of about 90°C. In some embodiments, the TMS group is removed after cross-coupling under suitable deprotection conditions, providing a suitable solvent, temperature, and time to produce XIII-2. In some embodiments, suitable deprotection conditions involve the use of fluoride reagents. In some embodiments, the fluoride reactant is NH4F. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable time is approximately one hour at a temperature of approximately 60°C.

In some embodiments, acetylene XIII-2 is reacted with a suitable aromatic halide under suitable conditions for a metal-catalyzed cross-coupling reaction to form XIII-3. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, the aromatic halide is an aromatic iodide. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(PPh ₃ ) ₂ Cl ₂ , a copper catalyst with a suitable base, for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, the base is an amine base such as TEA. In some embodiments, a suitable time and a suitable temperature is about one hour at a temperature of from about 80°C to about 90°C, or from about 70°C to about 90°C.

In some embodiments, R ¹⁰ or R ¹¹ is a protected alcohol. In some embodiments, R ¹⁰ or R ¹¹ is a silyl ether protected alcohol. In some embodiments, the protecting groups are removed to obtain the free alcohol using suitable deprotection conditions, including a suitable solvent, temperature, and preparation time for XIII-3. In some embodiments, suitable deprotection conditions involve the use of aqueous HCl. In some embodiments, a suitable solvent is water, THF, methanol, or a combination of solvents. In some embodiments, a suitable time at an appropriate temperature is from about 30 minutes to about 1 hour at a temperature from about 0° C. to about room temperature.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 14.

Scheme 14

XIV-1 XIV-2 XIV-3

In scheme 14, substituents X ¹ and R ⁸ are as described herein.

In some embodiments, XIV-3 is prepared from the reaction of XIV-2 amide and XIV-1 bromide under appropriate addition/cyclization conditions. In some embodiments, the addition/cyclization conditions provide for a suitable solvent at a suitable temperature for an appropriate period of time. In some embodiments, a suitable solvent is toluene. In some embodiments, a suitable temperature for a suitable time is about 110° C. for about a night.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 15.

Scheme 15

In scheme 15, substituents X ¹ and R ⁸ are as described herein.

In some embodiments, XV-2 chloride is reacted with XV-1 acetylene under suitable metal catalyzed cross-coupling reaction conditions to form XV-3. In some embodiments, suitable metal catalyzed crossover conditions

- 128 040704 palladium. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(PPh3)2Cl2, a copper catalyst with a suitable base, in a suitable solvent, for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, the base is an amine base such as TEA. In some embodiments, a suitable solvent is THF. In some embodiments, a suitable time and a suitable temperature is about 1 hour at about room temperature.

In some embodiments, acetylene XV-3 is reacted with a suitable aromatic halide XV-4 under suitable conditions in a metal catalyzed cross-coupling reaction in the presence of TBAF to form XV-5. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, the aromatic halide is an aromatic iodide. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction include Pd(PPh3)2Cl2, ligand, copper catalyst, in a suitable solvent, with a suitable base, for a suitable time and at a suitable temperature. In some embodiments, the copper catalyst is CuI. In some embodiments, a suitable ligand is a phosphine ligand. In some embodiments, a suitable ligand is PPh3. In some embodiments, the base is an amine base such as TEA. In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable temperature is 60°C. In some embodiments, TBAF is added and the reaction is maintained at 60° C. for an appropriate period of time. In some embodiments, a suitable time is approximately 3 hours.

In some embodiments, Compound XV-6 is prepared from the reaction of XV-5 and thiocyanate under conjugate addition conditions. In some embodiments, the conditions for adding the conjugate include the use of the appropriate thiocyanate salt in the appropriate solvent for the appropriate time at the appropriate temperature. In some embodiments, a suitable thiocyanate salt is NH4SCN. In some embodiments, a suitable solvent is methyl tert-butyl ether. In some embodiments, a suitable time is approximately overnight. In some embodiments, a suitable temperature is 60°C.

In some embodiments, Compound XV-7 is prepared from the reaction of XV-6 and a source of ammonia for the appropriate time at the appropriate temperature. In some embodiments, a suitable source of ammonia is NH ₃ . In some embodiments, a suitable temperature is -78°C. In some embodiments, a suitable time is about 2 hours. In some embodiments, the reaction is further heated to a suitable temperature, such as about room temperature.

In some embodiments, intermediates used in the preparation of the compounds described herein are prepared as shown in Scheme 16.

Scheme 16

In scheme 16, substituents X ¹ and R ⁸ are as described herein. In some embodiments, X is a halogen such as bromine or chlorine.

In some embodiments, when X is bromine, the α-bromo ketone XVI-2 is obtained by subjecting the ketone XVI-1 to bromination under suitable conditions. In some embodiments, suitable bromination conditions include bromine, HBr, and acetic acid for the appropriate time at the appropriate temperature. In some embodiments, a suitable time is approximately overnight. According to some options

- 129 040704 implementation a suitable temperature is approximately room temperature.

Alternatively, in some embodiments, the α-haloketone XVI-2 is derived from the acid XVI-5. In some embodiments, XVI-5 is treated with (COCl) ₂ in a suitable solvent for a suitable time at a suitable temperature to provide an intermediate acid chloride. In some embodiments, a suitable solvent is DMF and DCM. In some embodiments, a suitable time is about 2.5 hours. In some embodiments, a suitable temperature is from about 0° C. to about room temperature. In some embodiments, the acid chloride intermediate is treated with TMSCHN2 in a suitable solvent for a suitable time at a suitable temperature to provide α-diazocarbonyl XVI-6. In some embodiments, a suitable solvent is THF/ACN. In some embodiments, a suitable time is about 1 hour. In some embodiments, a suitable temperature is from about 0° C. to about room temperature.

In some embodiments, when X is bromine, α-diazocarbonyl XVI-6 is treated with HBr/H ₂ O in a suitable solvent for a suitable time at a suitable temperature to obtain α-bromoketone XVI-2. In some embodiments, a suitable solvent is THF/ACN. In some embodiments, a suitable time is approximately 30 minutes. In some embodiments, a suitable temperature is from about 0° C. to about room temperature.

In some embodiments, when X is chlorine, the α-diazocarbonyl XVI-6 is treated with concentrated HCl in a suitable solvent for the appropriate time at the appropriate temperature to provide α-chloroketone XVI-2. In some embodiments, a suitable solvent is THF/ACN. In some embodiments, a suitable time is approximately 30 minutes. In some embodiments, a suitable temperature is from about 0° C. to about room temperature.

In some embodiments, the α-haloketone XVI-2 is treated with amide XVI-3 and AgOTf in a suitable solvent for a suitable time at a suitable temperature to obtain XVI-4. In some embodiments, a suitable solvent is EtOAc or dioxane. In some embodiments, a suitable time is approximately overnight. In some embodiments, a suitable temperature is about 70°C or about 100°C.

In some embodiments, XVI-4 is subjected to a palladium-catalyzed cross-coupling reaction in the presence of a suitable source of ammonia to form XVI-7. In some embodiments, a suitable ammonia source is LiHMDS. In some embodiments, suitable conditions for the palladium-catalyzed cross-coupling reaction provide for Pd ₂ (dba) ₃ with a suitable ligand in a suitable solvent for a suitable time at a suitable temperature. In some embodiments, a suitable ligand is X-Phos. In some embodiments, a suitable solvent is dioxane or THF. In some embodiments, a suitable time and a suitable temperature is from about 2 hours to about night at a temperature of about 100°C. In some embodiments, a suitable time and a suitable temperature is around the night at a temperature of approximately 60°C.

Additional procedures for obtaining alternative groups of ring A, not shown in the previous schemes, are known and are described in: Gangloff A. R., et al. Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles using tetrabutylammonium fluoride as a mild and efficient catalyst, Tetrahedron Letters (2001), 42(8), 14411443; Ramanathan, Mani, et al. One-Pot Reactions for Synthesis of 2,5-Substituted Tetrazoles from Aryldiazonium Salts and Amidines, Organic Letters (2015), 17(23), 5886-5889; Vallin, Karl S. A. et al., Efficient Chemoenzymatic Dynamic Kinetic Resolution of 1-Heteroaryl Ethanols, Journal of Organic Chemistry (2009), 74(24), 9328-9336; Shen, Lan et al, Synthesis and structure-activity relationships of thiadiazole-derivatives as potent and orally active peroxisome proliferator-activated receptors ?/? dual agonists, Bioorganic & Medicinal Chemistry, 16(6), 3321-3341; 2008; Genin, Michael J. et al., Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H- indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia, Journal of Medicinal Chemistry (2015) 58(24), 9768-9772; Li, Xiaobing et al, PCT Int. Appl., 2005113522, 01 Dec 2005 (Preparation of azole carboxamides as inhibitors of bacterial type III protein secretion systems); Hamada, Nagwa Mohamed Mahrous et al, Synthesis and antimicrobial evaluation of some heterocyclic chalcone derivatives, Molecules, 16, 2304-2312; 2011; Mokale, Santosh N. et al Synthesis and in-vivo hypolipidemic activity of some novel substituted phenyl isoxazol phenoxy acetic acid derivatives, Bioorganic & Medicinal Chemistry Letters, 24(9), 2155-2158; 2014; Jursic, Branko S. et. al. Prepa- 130 040704 ratio of 5-substituted 2-methyl-1,3,4-oxadiazoles from 5-substituted tetrazoles and acetic anhydride, Synthetic

Communications (1994), 24(11), 1575-82.

In some embodiments, the compounds are prepared as described in the examples.

Certain terminology

Unless otherwise indicated, the following terms used in this application are characterized by the definitions below. The use of the term including, as well as other forms such as includes and included, is not limiting. The section headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter of the description.

As used herein, C1-C _x includes C ₁ -C ₂ , C1-C ₃ . . . C ₁ -C _x . By way of example only, the group denoted as C1-C4 indicates that the fragment contains from one to four carbon atoms, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, C1-C4 alkyl indicates that the alkyl group contains from one to four carbon atoms, i. the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

An alkyl group refers to an aliphatic hydrocarbon group. A branched or straight chain alkyl group. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms, i.e. C ₁ -C ₁₀ αkil. Whenever it appears herein, a numeric range, such as 1 to 10, refers to every integer in that range; for example, 1 to 10 carbons means that the alkyl group is composed of 1 carbon, 2 carbons, 3 carbons, 4 carbons, 5 carbons, 6 carbons, etc. up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term alkyl where no numerical range is indicated. In some embodiments, alkyl is C ₁ -C ₆ alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Typical alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, or hexyl.

The term alkylene group refers to a divalent alkyl group. Any of the above monovalent alkyl groups may be alkylene by separating the second hydrogen atom from the alkyl. In some embodiments, the alkylene is C ₁ -C ₆ alkylene. In other embodiments, the alkylene is C1- _C4 alkylene. In certain embodiments, the alkylene contains from one to four carbon atoms (eg, C1-C4 alkylene). In other embodiments, the alkylene contains from one to three carbon atoms (eg, C1-C3 alkylene). In other embodiments, the alkylene contains from one to two carbon atoms (eg, C1-C2 alkylene). In other embodiments, the alkylene contains one carbon atom (eg, C1 alkylene). In other embodiments, the alkylene contains two carbon atoms (eg, C2 alkylene). In other embodiments, the alkylene contains two to four carbon atoms (eg, C2-C4 alkylene). Typical alkylene groups include, without limitation, -CH2-, -CH(CH ₃ )-, -C(CH ₃ )2-, -CH2CH2-, -CH2CH(CH ₃ )-, -CH2C(CH ₃ )2 -, -CH2CH2CH2-, -CH2CH2CH2CH2- and the like.

Deuteroalkyl refers to an alkyl group in which 1 or more hydrogen atoms of the alkyl have been replaced by deuterium.

The term alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group is characterized by the formula -C(R)=CR2, where R refers to the remaining moieties of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, the alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of the alkenyl group include -CH=CH2, -C(CH ₃ )=CH2, -CH=CHCH ₃ , -C(CH ₃ )=CHCH ₃ and -CH2CH=CH2.

The term alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, the alkenyl group is characterized by the formula -C^C-R, where R refers to the rest of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of the alkynyl group include -CAH, -CACH3 -C^CCH2CH3, -CH2C AN.

An alkoxy group refers to an (alkyl)O-group, where alkyl is as defined herein.

The term alkylamine refers to the group -N(αkyl) _xHy , where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

The term aromatic refers to a planar ring having a delocalized π- 131 040704 electron system containing 4n + 2 π electrons, where n is an integer. The term aromatic includes both carbocyclic aryl (aryl, eg phenyl) and heterocyclic aryl (or heteroaryl or heteroaromatic) groups (eg pyridine). The term includes monocyclic or polycyclic groups with fused rings (ie rings that share a common pair of carbon or nitrogen atoms).

The term carbocyclic or carbocycle refers to a ring or ring system where all of the atoms forming the backbone of the ring are carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings or heterocycles in which the ring chain contains at least one atom other than carbon. In some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In some embodiments, both rings of the bicyclic carbocycle are aromatic. The carbocycle includes cycloalkyl and aryl.

As used herein, the term aryl refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C ₆ Syuaryl. Depending on the structure, the aryl group is monoradical or biradical (ie, an arylene group).

The term cycloalkyl refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each of the ring-forming atoms (ie, backbone atoms) is a carbon atom. In some embodiments, the cycloalkyls are spirocyclic or bridged compounds. In some embodiments, the cycloalkyls are optionally fused to an aromatic ring and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups containing 3 to 10 ring atoms. In some embodiments, the cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, cycloalkyl is C ₃ C ₆ cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like.

The term halo or alternatively halogen or halide means fluorine, chlorine, bromine or iodine. In some embodiments, the halogen is fluorine, chlorine, or bromine.

The term haloalkyl refers to alkyl in which one or more hydrogen atoms have been replaced by a halogen atom. In one aspect, the fluoroalkyl is DS^toroalkyl.

The term fluoroalkyl refers to alkyl in which one or more hydrogen atoms have been replaced by a fluorine atom. In one aspect, the fluoroalkyl is C ₁ -C ₆ fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl, 2-fluoroethyl, and the like.

The term heteroalkyl refers to an alkyl group in which one or more alkyl skeletal atoms are selected from an atom other than carbon, such as oxygen, nitrogen (eg, -NH-, N(αkyl)-), sulfur, or combinations thereof. The heteroalkyl is attached to the rest of the molecule at the carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C ₁ -C 6 heteroalkyl.

The term heteroalkylene refers to a divalent heteroalkyl group.

The term heterocycle or heterocyclic refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, where each heterocyclic group has 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, or bridged connections. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings with 3-10 atoms in their ring system, and aromatic heterocyclic groups include rings with 5-10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Примеры неароматических гетероциклических групп представляют собой пирролидинил, тетрагидрофуранил, дигидрофуранил, тетрагидротиенил, оксазолидинонил, тетрагидропиранил, дигидропиранил, тетрагидротиопиранил, пиперидинил, морфолинил, тиоморфолинил, тиоксанил, пиперазинил, азиридинил, азетидинил, оксетанил, тиетанил, гомопиперидинил, оксепанил, тиепанил, оксазепинил, диазепинил, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl,

- 132 040704 dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1onyl, isoindole 1, 3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(III)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl , 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazole 2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthitiphenyl. The above groups are either C-linked (or C-linked) or N-linked where possible. For example, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) and pyrrol-3-yl (C-attached). In addition, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C attached ). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

The terms heteroaryl or alternatively heteroaromatic refer to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, thiazidiazole, oxadiaz. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 ring N atoms. In some embodiments, the heteroaryl contains 1-4 ring N atoms. In some embodiments, heteroaryl contains 0-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl is C1- _C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is C1C ₅ heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is C ₆ -C ₉ heteroaryl.

A heterocycloalkyl or heteroalicyclic group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl is fused to aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2,5dithionyl, pyrrolidin-2,5-dionyl, pyrrolidinonyl, imidazolidinyl , imidazolidin-2-onyl or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl is C ₂ -C ₁₀ heterocycloalkyl. In another aspect, heterocycloalkyl is C ₄ -C ₁₀ heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

The term bond or single bond refers to a chemical bond between two atoms or two fragments where the atoms linked by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, said group is absent, allowing a bond to be formed between the remaining identified groups.

The term fragment refers to a particular segment or functional group of a molecule. Chemical moieties are often chemical entities embedded in or attached to a molecule.

The term optionally substituted or substituted means that said group is optionally substituted with one or more additional groups. In some other embodiments, the optional substituents are individually and independently selected from the following: D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl) ₂ , -OH, -CO ₂ H, -CO ₂ alkyl, -C(=O)NH ₂ , -C(=O)NH(alkyl), -C(=O)N(alkyl) ₂ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NH (alkyl), -S (= O) ₂ N (alkyl) ₂ , -CH ₂ Co ₂ H,

- 133 040704

-OD^alkyl, -CH2C(=O)NH2, -CH _: C(O)\I(alkyl)n -CH2C(=O)N(alkyl)2, -CH2S(=O)2NH2, CH ₂ S( \u003d O) ₂ NH (alkyl), -CH ₂ S (= O) ₂ N (alkyl) ₂ , alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and arylsulfone. The term optionally substituted or substituted means that said group is optionally substituted with one or more additional groups individually and independently selected from the following: D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl) ₂ , -OH , -СО2Н, -СО ₂ alkyl, -C(=O)NH ₂ , -С(=О)NH(alkyl), -С(=О)N(alkyl) ₂ , -S(=O)2NH2, - S(=O) ₂ NH(alkyl), -S(=O) ₂ N(alkyl) ₂ , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In some other embodiments, the optional substituents are independently selected from the following: D, halogen, -CN, -NH2, -NH(CH ₃ ), -N(CH ₃ )2, -one, -CO2H, -CO2(C1- _C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O) ₂ NH ₂ , -S (= O) ₂ NH (C ₁ -C ₄ alkyl), -S (= O) ₂ N (C ₁ -C ₄ alkyl) ₂ , C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C 1 -C ₄ fluoroalkyl, C1-C ₄ heteroalkyl, C1-C ₄ alkoxy, C1-C ₄ fluoroalkoxy, -SC ₁ -C ₄ alkyl, -S(=O)C ₁ -C ₄ alkyl and -S(=O) ₂ CiC ₄ alkyl. In some embodiments, the optional substituents are independently selected from D, halo, -CN, -NH2, -OH, -NH(CH ₃ ), -N(CH ₃ )2, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ . In some embodiments, the substituted groups are substituted with one or two of the preceding groups. In some embodiments, the substituted groups are substituted with one of the preceding groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

As used herein, the term "acceptable" in relation to a composition, composition, or ingredient means that there is no permanent adverse effect on the general health of the subject being treated.

As used herein, the term modulate means interacting with a target, directly or indirectly, to change the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to prolong the activity of the target.

As used herein, the term modulator refers to a molecule that interacts directly or indirectly with a target. Interactions include, without limitation, interactions of an agonist, partial agonist, inverse agonist, antagonist, degrading compound, or combinations thereof. In some embodiments, the modulator is an agonist.

As used herein, the term introduction and the like. refers to methods that can be used to enable the delivery of compounds or compositions to the desired site of biological action. These methods include, without limitation, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

As used herein, the term co-administration or the like. is intended to cover the administration of selected therapeutic agents to a single patient and is intended to include treatment regimens in which the agents are administered by the same or different route of administration, or at the same or different times.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of an agent or compound administered that will relieve to some extent one or more symptoms of the disease or condition being treated. The result includes the reduction and/or mitigation of the signs, symptoms, or causes of a disease or any other desired change in a biological system. For example, an effective amount for therapeutic use is the amount of a composition containing a compound described herein necessary to provide a clinically meaningful reduction in the symptoms of a disease. The appropriate effective amount in any particular case is optionally determined using methods such as a dose escalation study.

As used herein, the terms enhance or amplify means to increase or prolong the action or duration of a desired effect. Thus, with regard to enhancing the effect of therapeutic agents, the term enhancement refers to the ability to enhance or prolong, in terms of effectiveness or duration, the effect of other therapeutic agents on the system. An effectively enhancing amount, as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term pharmaceutical combination means a product that is obtained by mixing or combining more than one active ingredient.

- 134 040704 and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, for example, a compound described herein or a pharmaceutically acceptable salt thereof and an agent for co-administration, are both administered to the patient simultaneously in the form of a single object or dosage. The term non-fixed combination means that the active ingredients, for example, a compound described herein or a pharmaceutically acceptable salt thereof and an agent for co-administration, are administered to a patient as separate substances simultaneously, in parallel or sequentially without any specific intermediate time restrictions, and such administration provides effective the content of the two compounds in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

The terms kit and product are used interchangeably.

The term subject or patient encompasses mammals. Examples of mammals include, without limitation, any member of the class of mammals: humans, non-human primates such as chimpanzees, and other monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, the terms treat or treat include alleviating, alleviating, or lessening the intensity of at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g. disease or condition, amelioration of a condition caused by the disease or condition, or cessation of symptoms of the disease or condition, either prophylactically and/or therapeutically.

Pharmaceutical compositions

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are prepared in a conventional manner using one or more pharmaceutically acceptable inactive ingredients which facilitate the processing of the active compounds into formulations for pharmaceutical use. The correct composition depends on the chosen route of administration. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980 and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for such disclosure.

In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be influenced by any method that delivers the compounds to the site of action. These methods include, without limitation, delivery via the enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (including epithelial, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as creams or ointments, injection, catheter or implant. The introduction can also be carried out by direct injection into the area of the affected tissue or organ.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; in the form of powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

Pharmaceutical compositions that can be used orally include tablets, hard capsules made from gelatin, as well as soft, sealed capsules made from gelatin, and a plasticizer such as glycerol or sorbitol. Tablets can be made

- 135 040704 by pressing or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the active ingredient in free flowing form such as powder or granules, optionally mixed with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be made by molding in a suitable apparatus a mixture of a powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or formulated with a break line and formulated to provide slow or controlled release of the active ingredient. All formulations for oral administration should be in dosages suitable for such administration. Hard capsules may contain the active ingredients in admixture with an excipient such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as fixed oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, stabilizers are added. The dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings for identification or to characterize various combinations of active compound doses.

In some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Compositions for injection may be presented in unit dosage form, for example in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain adjuvants such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in single or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or under lyophilized conditions requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, immediately prior to use. Injectable solutions and suspensions for immediate administration may be prepared from sterile powders, granules and tablets of the type previously described.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injectable solutions of the active compounds, which may contain antioxidants, buffers, bacteriostats, and solutes that render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.

Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds, thereby allowing highly concentrated solutions to be obtained.

Pharmaceutical compositions may also be formulated as a depot formulation. Such long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated from suitable polymeric or hydrophobic materials (eg as an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, lozenges or gels formulated in the conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may also be formulated into rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

Pharmaceutical compositions may be administered topically, ie. by non-systemic administration. This involves applying the compound of the present invention externally to the epidermis or oral cavity and instilling such a compound into the ear, eye and nose so that the compound does not enter the bloodstream significantly. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration include liquid or

- 136 040704 semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes and drops suitable for administration to the eye, ear or nose. The active ingredient may contain for topical application from 0.001 to 10 wt.%, for example from 1 to 2 wt.% of the formulation.

Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, pressurized spray packs, or other convenient aerosol spray delivery methods. Pressurized packages may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may take the form of a dry powder composition, for example a powder mixture of a compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs, from which the powder may be administered using an inhaler or insufflator.

In some embodiments, a compound disclosed herein is formulated such that delivery of the compound to a specific area of the gastrointestinal tract is achieved. For example, the compound disclosed herein is formulated for oral delivery with bioadhesive polymers, pH-sensitive time-dependent coatings, biodegradable polymers, microflora-activated systems, and the like to deliver the compound to a specific area of the gastrointestinal tract.

In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of a compound described herein from the dosage form in which it is included in accordance with the desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, sustained release, pulsatile release, and sustained release profiles. In contrast to immediate release formulations, controlled release formulations allow the agent to be delivered to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of the agent over an extended period of time and thus provide a longer pharmacological response time while minimizing side effects compared to conventional immediate release dosage forms. Such longer reaction times provide many inherent advantages that are not achieved with the corresponding short acting immediate release formulations.

Approaches for delivering an intact therapeutic compound to specific areas of the gastrointestinal tract (eg, such as the colon) include:

(i) Polymer Coating: An intact molecule can be delivered to the colon without absorption in the upper intestine by coating the drug molecule with suitable polymers that are only degraded in the colon.

(ii) Coating with pH sensitive polymers. Most of the delivery systems for the small and large intestines are based on the coating of tablets or granules, which are placed in conventional hard gelatin capsules. The most commonly used pH dependent coating polymers are methacrylic acid copolymers commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

(iii) Coated with biodegradable polymers;

(iv) Diving into matrices;

(v) Immersion in biodegradable matrices and hydrogels;

(vi) Immersion in pH sensitive matrices;

(vii) Time release systems;

(viii) Redox polymers;

(ix) Bioadhesive systems;

(x) Coating with microparticles;

(xi) Osmotically controlled drug delivery.

Another approach to colon-targeted drug delivery or controlled release systems involves incorporating the drug into polymeric matrices to trap and release it in the colon. These matrices can be pH sensitive or biodegradable. Matrix-based systems, such as multi-matrix delayed-release tablets (MMX), provide for drug release in the colon.

- 137 040704

Additional pharmaceutical approaches are known for targeted delivery of therapeutic agents to specific areas of the gastrointestinal tract. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Pharm Sci. 2003 Jan-Apr; 6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007; 24(2): 147-202. Kumar P, Mishra B. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jun; 5(3): 186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan; 3(1): 11125. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug; 16(4): 731-741.

In one aspect, a pharmaceutical composition is described herein comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous, subcutaneous, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule. Articles are provided that include a packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof within the packaging material, and a leaflet that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or its a pharmaceutically acceptable solvate is used to treat, prevent, or ameliorate one or more symptoms of a disease or condition that would benefit from FXR agonism.

It should be understood that in addition to the ingredients, especially those mentioned above, the compounds and compositions described herein may include other means conventional in the present technical field with respect to the type of composition in question, for example, those suitable for oral administration may include fragrances.

Dosing methods and treatment regimens

In another aspect, provided herein is a method of treating a disease or condition in a mammal that will benefit from FXR agonism, comprising administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof. In some embodiments, the disease or condition is a metabolic condition. In some embodiments, the disease or condition is a liver condition.

In some embodiments, the compound is administered to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.

In one aspect, the present document describes a method of treating or preventing any of the diseases or conditions described herein, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof.

In one aspect, a method for treating or preventing a metabolic or hepatic condition in a mammal is described herein, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof. In other embodiments, the metabolic or liver condition is treatable with an FXR agonist. In some embodiments, the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, this document describes a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the liver disease or condition is an alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the alcoholic liver disease or condition is fatty liver disease (steatosis), cirrhosis, or alcoholic hepatitis. According to some variations

- 138 040704 Antam implementation non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) without liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis.

In one aspect, the present document describes a method for treating or preventing liver fibrosis in a mammal, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and liver cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH).

In one aspect, this document describes a method for treating or preventing inflammation of the liver in a mammal, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and liver cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). In some embodiments, inflammation of the liver is associated with inflammation in the gastrointestinal tract. In some embodiments, the mammal is diagnosed with inflammatory bowel disease.

In one aspect, this document describes a method of treating or preventing a gastrointestinal disease or condition in a mammal, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD). ), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, graft versus host disease, or any combination thereof. In some embodiments, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unsubtyped IBS (IBS-U) or hologenic diarrhea (BAD)

In one aspect, this document describes a method of treating or preventing a disease or condition in a mammal that would benefit from treatment with an FXR agonist, comprising administering to the mammal a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods described herein further comprise administering at least one additional therapeutic agent in addition to the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

According to any of the above aspects, there are further embodiments wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof: (a) is administered systemically to a mammal and/or (b) is administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; and/or (f) administered to a mammal by injection; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to a mammal; and/or (j) administered to the mammal non-systemically or locally.

In any of the above aspects, further embodiments are provided providing for a single administration of an effective amount of the compound, including further embodiments wherein the compound is administered to the mammal once a day, or the compound is administered to the mammal several times over the course of one day. In some embodiments, the compound is administered. in continuous dosing mode. According to some

- 139 040704 embodiments, the compound is administered in a continuous daily dosing regimen.

In any of the above aspects involving the treatment of a disease or condition, further embodiments provide for the administration of at least one additional agent in addition to the administration of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof. In various embodiments, each agent is administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal or subject is a human.

In some embodiments, the compounds provided herein are administered to a human.

In some embodiments, the compounds provided herein are administered orally.

In some embodiments, provided herein is a method of treating or preventing a metabolic disorder in a subject, comprising administering to the subject's gastrointestinal tract a therapeutically effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, thereby activating farnesoid X receptors ( FXR) in the gut and treating or preventing a metabolic disorder in the subject. In some embodiments, the absorption of the compound is predominantly limited within the intestine. In some embodiments, the method substantially enhances the expression of the target FXR gene in the intestine while not significantly enhancing the expression of the target FXR gene in the liver or kidney. In some embodiments, the method substantially enhances intestinal expression of the target FXR gene while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method substantially enhances gut and liver expression of the target FXR gene while minimizing systemic plasma levels of the delivered compound. In some embodiments, the method significantly enhances intestinal expression of the target FXR gene while not significantly increasing liver or kidney expression of the target FXR gene, and also minimizes systemic plasma levels. In some embodiments, the method substantially enhances gut and liver expression of the target FXR gene and provides a stable systemic plasma level of the delivered compound. In some embodiments, the method reduces or prevents diet-induced weight gain. In some embodiments, the method increases the metabolic rate of a subject. In some embodiments, an increase in metabolic rate involves an increase in oxidative phosphorylation in a subject. In some embodiments, the method further comprises improving glucose and/or lipid homeostasis in the subject. In some embodiments, the method does not result in a significant change in food intake and/or fat intake in the subject. In some embodiments, the method does not result in a significant change in the subject's appetite. In some embodiments, the metabolic disorder is selected from obesity, diabetes mellitus, insulin resistance, dyslipidemia, or any combination thereof. In some embodiments, the metabolic disorder is non-insulin-dependent diabetes mellitus. In some embodiments, the method protects against diet-induced weight gain, reduces inflammation, enhances thermogenesis, increases hepatic insulin sensitivity, reduces hepatic steatosis, promotes BAT activation, reduces blood glucose, increases weight loss, or any combination thereof. In some embodiments, the method increases insulin sensitivity in the liver and promotes brown adipose tissue (BAT) activation. In some embodiments, the method further comprises administering to the subject an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a glucagon-like peptide (GLP) agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, nicotinamide ribonucleoside, a nicotinamide ribonucleoside analog, or their combinations.

In some embodiments, provided herein is a method for treating or preventing inflammation in the intestinal region of a subject, comprising: administering to the subject's gastrointestinal tract a therapeutically effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof, thereby activating receptors FXR in the intestine and thus treating or preventing inflammation in the intestinal region of the subject. In some embodiments, absorption of the compound is predominantly restricted within the gut. In some embodiments, the method substantially enhances the expression of the target FXR gene in the intestine while not significantly enhancing the expression of the target FXR gene in the liver or kidney. In some embodiments, inflammation is associated with a clinical condition selected from necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), gastric ulcer, non-ulcerative dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, or any combination thereof. In some embodiments, the one or more target FXR genes include IBABP, OST, Perl, FGF15, FGF19, SHP, or combinations thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of antibiotic therapy to a subject, wherein the method treats or prevents inflammation associated with pseudomembranous colitis in the subject. In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of an oral corticosteroid, other anti-inflammatory or immunomodulatory therapy, nicotinamide ribonucleoside, nicotinamide ribonucleoside analog, or combinations thereof. In some embodiments, the method increases HSL phosphorylation and β3-adrenergic receptor expression. In some embodiments, the serum concentration of the compound in the subject remains below its EC ₅₀ after administration of the compound.

In some embodiments, provided herein is a method for treating or preventing a cell proliferating disease in a subject, comprising administering to the subject's gastrointestinal tract a therapeutically effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the cell proliferation disease is an adenocarcinoma. In some embodiments, the adenocarcinoma is colon cancer. In some embodiments, treatment of the adenocarcinoma reduces the size of the adenocarcinoma, the volume of the adenocarcinoma, the number of adenocarcinomas, the adenocarcinoma-induced cachexia, delays the progression of the adenocarcinoma, increases the survival of the subject, or a combination thereof. In some embodiments, the method further comprises administering to the subject an additional therapeutic compound selected from the group consisting of a chemotherapeutic, biological, radiotherapeutic, or combinations thereof.

In some embodiments, provided herein is a method of treating or preventing a liver disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of one or more of the compounds described herein, or pharmaceutically acceptable salts or solvates thereof. In some embodiments, the liver disease or condition is an alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the alcoholic liver disease or condition is fatty liver disease (steatosis), cirrhosis, or alcoholic hepatitis. In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis.

In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from the administration of an FXR agonist. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment comprise administering pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate, in therapeutically effective amounts for the specified mammal.

Disclosed herein are methods of administering an FXR agonist in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes a therapeutic agent for the treatment of diabetes mellitus or diabetes mellitus-related disorders or conditions, alcoholic or non-alcoholic liver disease, inflammation-related intestinal diseases, or cell proliferative disorders.

In certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially stop at least one of the symptoms of the disease or condition. Amounts effective for this use will depend upon the severity and course of the disease or condition, prior therapy, the health of the patient, weight and drug response, and the judgment of the attending physician. Therapeutically effective amounts are optionally determined by methods including, without limitation, dose escalation and/or dose range clinical trials.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of developing a particular disease, disorder or condition. Such an amount is defined as a prophylactically effective amount or dose. In this application, the exact amounts also depend on the patient's health, weight, and the like. When used in patients, effective amounts for this application will depend on the severity and course of the disease, disorder or condition prior to therapy, the patient's medical condition and response to the drug, and the judgment of the attending physician. In one aspect, prophylactic treatment comprises administering to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to prevent relapse. symptoms of a disease or condition.

In certain embodiments in which the patient's condition does not improve, the compounds are administered chronically, at the physician's discretion, i. over an extended period of time, including throughout the life of the patient, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

In certain embodiments, in which the patient's condition actually improves, the dose of the administered drug is temporarily reduced or temporarily suspended for a certain period of time (ie, drug rest). In specific embodiments, the duration of drug rest is from 2 days to 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days or more than 28 days. The dose reduction during drug rest is, for example, only 10-100%, including, for example, only 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100%.

After improvement of the patient's condition, if necessary, a maintenance dose is administered. Subsequently, according to specific embodiments, the dose or frequency of administration, or both, is reduced depending on the symptoms to a level at which an improved disease, disorder, or condition is maintained. In some embodiments, however, the patient requires intermittent treatment for an extended period of time for any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount varies depending on such factors as the particular compound, the disease state and its severity, the individuality (e.g., weight, sex) of the subject or host in need of treatment, but, nevertheless, is determined according to with the specific circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

However, in general, doses used for the treatment of an adult, as a rule, are in the range from 0.01 to 5000 mg per day. In one aspect, the doses used to treat an adult human are from about 1 to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or divided doses administered simultaneously or at appropriate intervals, such as two, three, four or more sub-doses per day.

In one embodiment, suitable daily doses for a compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In some embodiments, the daily dosage or amount of the active substance in the dosage form is lower or higher than the ranges specified herein, based on a number of variables in relation to the individual treatment regimen. In various embodiments, daily and unit dosages vary depending on a number of variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the route of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the attending physician.

The toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, without limitation, the determination of LD ₅₀ and ED ₅₀ . The dose ratio between toxic and therapeutic effects is the therapeutic index and is expressed as the ratio between LD ₅₀ and ED ₅₀ . In some embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dose range and/or a therapeutically effective dosage unit amount for use in mammals, including humans. In some embodiments, the daily dosage of the amount of the compounds described herein is in a range of circulating concentrations that include the ED ₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and/or dosage unit varies within this range depending on the dosage form used and

- 142 040704 the route of administration used.

In any of the above aspects, there are additional embodiments wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to a mammal and/or (b) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered to a mammal by injection; and/or (e) administered topically to the mammal; and/or (f) administered to the mammal non-systemically or locally.

In any of the above aspects, further embodiments are provided providing for a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once per day, or (ii) the compound is administered to the mammal several times over the course of one day.

According to any of the above aspects, additional embodiments are provided, providing for multiple administration of an effective amount of the compound, including additional embodiments, in which (i) the compound is administered continuously or intermittently: as a single dose; (ii) the time between multiple injections is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In other or alternative embodiments, the method comprises a drug rest in which administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; at the end of the rest from drugs, the dosage of the drug is resumed. In one embodiment, the duration of drug rest ranges from 2 days to 1 year.

In certain instances, it is expedient to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjunct drug (i.e., the drug itself has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also includes a treatment regimen) that also has a therapeutic benefit.

In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administering either therapeutic agent alone.

In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

In some embodiments, various therapeutically effective doses of the compounds disclosed herein will be used in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agents, such as an additional therapeutically effective drug, an auxiliary drug substance; or the like. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth above for the active substances themselves. In addition, the prevention/treatment methods described herein encompass the use of metronomic dosing, i. providing more frequent, lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen provides treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, begins before, during, or after treatment with a second agent described herein, and continues until some time during treatment with a second agent. agent or after cessation of treatment with a second agent. It also provides for treatment in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further provides for intermittent treatment that starts and stops at different times to assist in the clinical management of the patient.

It is understood that a dosing regimen for the treatment, prevention, or amelioration of the condition(s)

- 143 040704 which require relief varies according to various factors (for example, the disease, disorder or condition from which the subject suffers, age, weight, sex, diet and health of the subject). Thus, in some cases, the dosage regimen actually used varies and, in some embodiments, deviates from the dosage regimens set forth herein.

For the combination therapy described herein, the dosages of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, and so on. In additional embodiments, when co-administered with one or more other therapeutic agents, a compound provided herein is administered either simultaneously with one or more other therapeutic agents or sequentially.

In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If the administration is simultaneous, multiple therapeutic agents, by way of example only, are provided in a single, unified form or in multiple forms (eg, as a single tablet or as two separate tablets).

The compounds described herein, or their pharmaceutically acceptable salts, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic agent and are administered continuously to subjects prone to developing conditions or diseases to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In specific embodiments, a compound described herein is administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period of time necessary to treat the disease. In some embodiments, the duration required for treatment varies and the duration of treatment is adjusted according to the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing a compound is administered for at least 2 weeks, from about 1 month to about 5 years.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of diabetes mellitus or diabetes-related disorders or conditions.

In some cases, the additional therapeutic agent includes a statin, an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin , gemiglptin or dutoglpitin), catecholamine (such as epinephrine, norepinephrine, or dopamine), proliferator agonist, peroxisome proliferator-activated receptor (PPAR)-gamma agonist (such as thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone], aleglitazar , farglitazar, muraglitazar, or tesaglitazar) or combinations thereof. In some cases, a statin is an inhibitor of HMG-CoA reductase. In other instances, additional therapeutic agents include fish oil, fibrate, vitamins such as niacin, retinoic acid (eg, 9-cis-retinoic acid), nicotinamide ribonucleoside, or analogs or combinations thereof. In some cases, nicotinamide ribonucleoside or analogs thereof that promote NAD+ production are substrates for many enzymatic reactions, including p450s, which is a target for FXR (for example, see Yang et al., J. Med. Chem. 50:6458- 61, 2007).

In some embodiments, an FXR agonist is administered in combination with an additional therapeutic agent such as a statin, an insulin sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin , anagliptin, teneligliptin, alogliptin, gemiglptin, or dutogliptin), catecholamine (such as epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist (such as thiazolidinedione (TZD) [such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone ], aleglitazar, farglitazar, muraglitazar, or tesaglitazar), or combinations thereof, for the treatment of diabetes mellitus or diabetes-related disorders or conditions. In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent such as fish oil, fibrate, vitamins such as niacin, retinoic acid (e.g., 9-cis-retinoic acid), nicotinamide ribonucleoside, or analogs or combinations thereof to treat diabetes mellitus or diabetes-related disorders or conditions.

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In some embodiments, an FXR agonist is administered in combination with a statin, such as an HMG-CoA reductase inhibitor, fish oil, fibrate, niacin, or a combination thereof, to treat dyslipidemia.

In further embodiments, an FXR agonist is administered in combination with a vitamin, such as retinoic acid, for the treatment of diabetes mellitus and diabetes-related disorders or conditions such as weight loss and/or reduction of elevated blood glucose from meals.

In some embodiments, the farnesoid X receptor agonist is administered with at least one additional therapy. In some embodiments, the at least one additional therapy is a glucose lowering agent. In some embodiments, the at least one additional therapy is an anti-obesity agent. In some embodiments, the at least one additional therapy is selected from a peroxisome proliferator-activating receptor (PPAR) agonist (gamma, dual, or pan), a dipeptidyl peptidase (IV) inhibitor, a glucagon-like peptide-1 analog (GLP-). I), insulin or insulin analog, insulin secretagogue, sodium glucose cotransporter 2 (SGLT2) inhibitor, glucophage, human amylin analog, biguanide, alpha-glucosidase inhibitor, meglitinide, thiazolidinedione and sulfonylurea. In some embodiments, at least one additional therapy is metformin, sitagliptin, saxagliptin, repaglinide, nateglinide, exenatide, liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, and glucagon-like peptide 1, or any combination thereof. In some embodiments, at least one additional therapy is a lipid-lowering agent. In certain embodiments, at least one additional therapy is administered concurrently with the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered less frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered more frequently than the farnesoid X receptor agonist. In some embodiments, at least one additional therapy is administered prior to administration of the farnesoid X receptor agonist. In certain embodiments, at least one additional therapy is administered following administration of the farnesoid X receptor agonist.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with chemotherapy, anti-inflammatory agents, radiation therapy, monoclonal antibodies, or combinations thereof.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of alcoholic or non-alcoholic liver disease. In some embodiments, the additional therapeutic agent includes an antioxidant, a corticosteroid, antineoplastic necrosis factor (TNF), or a combination thereof.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent, such as an antioxidant, corticosteroid, antitumor necrosis factor (TNF), or a combination thereof, to treat alcoholic or non-alcoholic liver disease. In some embodiments, an FXR agonist is administered in combination with an antioxidant, a vitamin precursor, a corticosteroid, antitumor necrosis factor (TNF), or a combination thereof, to treat alcoholic or non-alcoholic liver disease.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent to treat inflammation-related intestinal conditions. In some cases, the additional therapeutic agent includes an antibiotic (such as metronidazole, vancomycin and/or fidaxomicin), a corticosteroid, or additional anti-inflammatory or immunomodulatory therapy.

In some cases, the FXR agonist is administered in combination with an additional therapeutic agent, such as an antibiotic, corticosteroid, or additional anti-inflammatory or immunomodulatory therapy, to treat inflammation-related intestinal conditions. In some instances, an FXR agonist is administered in combination with metronidazole, vancomycin, fidaxomycin, a corticosteroid, or combinations thereof for the treatment of inflammatory bowel disease.

As discussed above, inflammation is sometimes associated with pseudomembranous colitis. In some cases, pseudomembranous colitis is associated with bacterial overgrowth (eg, C. dificile overgrowth). In some embodiments, an FXR agonist is administered in combination with an antibiotic, such as metronidazole, vancomycin, fidaxomicin, or a combination thereof, to treat inflammation associated with bacterial overgrowth (eg, pseudomembranous colitis).

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of cell proliferative disorders. In some embodiments, the additional therapeutic agent includes a chemotherapeutic agent, a biological agent (e.g., an antibody, e.g., bevacizumab, cetuximab, or panitumumab), a radiotherapy agent (e.g., FOLFOX, FOLFIRI, CapeOX, 5-FU, leucovorin, regorafenib , irinotecan, or oxaliplatin) or combinations thereof.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent for the treatment of primary biliary cirrhosis. In some embodiments, the additional therapeutic agent includes ursodeoxycholic acid (UDCA).

In some embodiments, an FXR agonist is administered in combination with an additional therapeutic agent, such as a chemotherapeutic, biological, radiotherapeutic, or combinations thereof, to treat a cell proliferative disorder. In some instances, an FXR agonist is administered in combination with an antibody (eg, bevacizumab, cetuximab, or panitumumab), a chemotherapeutic agent, FOLFOX, FOLFIRI, CapeOX, 5-FU, leucovorin, regorafenib, irinotecan, oxaliplatin, or combinations thereof to treat a cell proliferative disorder.

Examples

The following examples are provided for illustrative purposes only and not to limit the scope of the claims of the present invention presented herein.

As used above and throughout the description of the present invention, the following abbreviations, unless otherwise indicated, shall have the following meanings:

ACN or MeCN - acetonitrile

AcOH - acetic acid

Ac-acetyl

BINAP - 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene

Vp - benzyl

BOC or Boc - tert-butylcarbamate t-Bu - tert-butyl

Su - cyclohexyl

DBA or dba - dibenzylideneacetone

CDI - 1,1-carbonyldiimidazole

DCE - dichloroethane (ClCH ₂ CH ₂ Cl)

DCM - dichloromethane (CH ₂ Cl ₂ )

DIPEA or DIEA - diisopropylethylamine

DMAP - 4-(N,N-dimethylamino)pyridine

DME - 1,2-dimethoxyethane

DMF - N,N-dimethylformamide

DMA - N,N-dimethylacetamide

DMSO dimethyl sulfoxide

Dppf or dppf - 1,1'-bis(diphenylphosphino)ferrocene

EDC or EDCI - N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

EEDQ - 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq - equivalent(s)

Et - ethyl

Et2O - diethyl ether

EtOH - ethanol

EtOAc - ethyl acetate

HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate

HMPA - hexamethylphosphoramide

HOBt - 1-hydroxybenzotriazole

HPLC - high performance liquid chromatography

KHMDS - potassium bis(trimethylsilyl)amide

NaHMDS - sodium bis(trimethylsilyl)amide

LiHMDS - lithium bis(trimethylsilyl)amide

LAH - lithium aluminum anhydride

LCMS - Liquid Chromatography Mass Spectrometry

Me - methyl

MeOH - methanol

MS - mass spectrometry

Ms - methylsulfonyl

MTBE - methyl tert-butyl ether

NBS - N-bromosuccinimide

NMM - N-methylmorpholine

NMP - N-methylpyrrolidin-2-one

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NMR - nuclear magnetic resonance

OTf - trifluoromethanesulfonate

PCC - pyridinium chlorochromate

PE - petroleum ether

Ph - phenyl

PPTS - pyridinium p-toluenesulfonate iPr/i-Pr - isopropyl

TBS - tert-butyldimethylsilyl

TBAF - tetra-n-butylammonium fluoride

TBAI - tetra-n-butylammonium iodide

RP-HPLC - High Pressure Reversed Phase Liquid Chromatography

TFA - trifluoroacetic acid

TEA - triethylamine

THF - tetrahydrofuran

TLC - thin layer chromatography

TMEDA - N,N,N',N'-tetramethylethylenediamine

Intermediate 1. 6-Chloro-3-methoxypicolinonitrile

Stage 1. 2-Cyano-3-methoxypyridine-1-oxide

3-Chloroperbenzoic acid (90.8 g, 447 mmol, 85% purity) was added to a solution of 3-methoxypicolinonitrile (50 g, 373 mmol) in DCE (500 ml) at rt. The reaction mixture was heated at 65° C. overnight and then allowed to cool to rt. The mixture was washed with NaHCO ₃ (5x300 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then triturated in petroleum ether/EtOAc = 5/1 (300 ml) to give 2-cyano-3-methoxypyridine-1-oxide (50 g, 89%) as a yellow solid.

1H NMR (400 MHz, CDCf): δ 7.95 (d, 1H), 7.37 (t, 1H), 6.90 (d, 1H), 4.03 (s, 3H);

LCMS: 151.0 [M+H]+.

Stage 2. 6-Chloro-3-methoxypicolinonitrile

A mixture of 2-cyano-3-methoxypyridine-1-oxide (30 g, 200 mmol) and POCl ₃ (333 g, 2.17 mol) was heated to 100° C. for 2 h under N ₂ atmosphere. The mixture was concentrated to dryness, diluted with NaHCO ₃ (300 ml), extracted with EtOAc (2x100 ml). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=2/1) to give 6-chloro-3-methoxypicolinonitrile (20 g, 59%) as yellow solid.

1H NMR (400 MHz, CDCl3): δ 7.51 (d, 1H), 7.38 (d, 1H), 3.99 (s, 3H);

LCMS: 169.0 [M+H] ⁺ .

Intermediate 2. 5-Bromo-3-fluoro-1-methyl-1H-indazole

1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diyl tetrafluoroborate (16.11 g, 45.48 mmol) was added to a solution of 5-bromo-1-methyl- 1H-indazole (8.00 g, 37.90 mmol) in CH3CN (80 mL) at rt. The mixture was stirred at 80°C overnight, quenched by adding H2O (50 ml) at rt. and then diluted with EtOAc (50 ml). The mixture was extracted with EtOAc (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether/EtOAc = 50 to 5:1) to give 5-bromo-3-fluoro-1-methyl-1H-indazole (3.95 g, 46%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.53-7.65 (m, 2H), 3.90 (s, 3H).

Intermediate 3: trans-4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde

Step 1: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene

Mixture of 1,4-dioxaspiro[4.5]dec-7-ene-8-boronic acid pinacol ester (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol), Pd(dppf)Cl ₂ (1.38 g, 1.89 mmol), dioxane (470 ml) and 1 M Na ₂ CO ₃ (282 ml, 282 mmol) were degassed with 3 vacuum/N ₂ cycles, stirred at 50°C for 2.5 h and then allowed to cool to rt. The mixture was diluted with EtOAc (500 ml) and washed with saturated NaHCO ₃ solution (2x500 ml). The aqueous layers were back extracted with EtOAc (200 ml). The combined EtOAc extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4dioxaspiro [4.5]dec-7-ene (19.9 g, 81%).

1 H NMR (400 MHz, DMSO-d6): δ 7.21-7.16 (m, 2H), 6.85 (d, 1H), 5.89-5.84 (m, 1H), 3.90 (s, 4H), 3.76 (s,

3H), 2.52-2.47 (m, 2H), 2.32 (br s, 2H), 2.13 (s, 3H), 1.77 (t, 2H);

LCMS: 261.1 [M+H]+.

Step 2: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane

Palladium on carbon (10 wt.%, 8.08 g, 7.59 mmol) at r.t. under N2 was added to a solution of 8-(4methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (19.8 g, 76.1 mmol) in EtOAc (300 mL). The N2 inlet was replaced with an H ₂ balloon. The reaction mixture was stirred for 4.5 hours, filtered through celite with EtOAc and then concentrated to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (18.2 g; contains 13% ketone) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.00-6.95 (m, 2H), 6.81 (d, 1H), 3.91-3.84 (m, 4H), 3 .73 (s, 3H), 2.492.42 (m, 1H), 2.11 (s, 3H), 1.76-1.68 (m, 4H), 1.67-1.55 (m, 4H );

LCMS: 263.1 [M+H] ⁺ .

Step 3: 4-(4-Methoxy-3-methylphenyl)cyclohexanone

Formic acid (96%, 14 ml, 356 mmol) followed by H2O (2.20 ml, 122 mmol) at rt. under N ₂ was added to a solution of 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (18.2 g) in toluene (60 ml). The reaction mixture was heated at 120°C for 4 h, allowed to cool to rt. and then poured into H2O (200 ml) and toluene (200 ml). The toluene layer was washed (200 ml H2O and then 200 ml saturated NaHCO ₃ solution). The aqueous layers were back-extracted with the addition of toluene (100 ml). The combined toluene extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-(4methoxy-3-methylphenyl)cyclohexanone (15.5 g, 88% in 2 steps) as a white solid.

1 H NMR (400 MHz, DMSO-d6): δ 7.08-7.03 (m, 2H), 6.84 (d, 1H), 3.74 (s, 3H), 3.00-2.91 (m, 1H), 2.612.51 (m, 2H), 2.28-2.20 (m, 2H), 2.12 (s, 3H), 2.06-1.98 (m, 2H), 1.88-1.76 (m, 2H);

LCMS: 219.0 [M+H] ⁺ .

Step 4: 1-Methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene

A mixture of (methoxymethyl)triphenylphosphonium chloride (35.74 g, 104.3 mmol) and THF (260 mL) under N2 was cooled to -2.2° C. in an ice/brine bath. A solution of sodium bis(trimethylsilyl)amide (2M in THF, 50 ml, 100 mmol) was added dropwise via an addition funnel over 12 min (int. temp. < 0.6° C.) with a THF (5 ml) wash. The reaction mixture was stirred for 30 min and then 4-(4-methoxy-3-methylphenyl)cyclohexanone (14.5 g, 66.6 mmol) was added portionwise over 5 min (heat development to 7.3°C). The residual cyclohexanone was poured into the reaction mixture with THF (20 ml). The reaction mixture was stirred at 0°C for 25 min and then poured into H ₂ O (400 ml) and toluene (400 ml). The toluene layer was washed (400 ml H2O), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 1-methoxy-4-(4-(methoxymethylene)cyclohexyl )-2-methylbenzene (15.6 g, 95%) as a pale golden oil.

1H NMR (400 MHz, DMSO-d6): δ 6.99-6.94 (m, 2H), 6.80 (d, 1H), 5.87 (s, 1H), 3.73 (s, 3H ), 3.48 (s, 3H), 2.78-2.71 (m, 1H), 2.56-2.44 (m, 1H), 2.10 (s, 3H), 2.17- 2.09 (m, 1H), 2.01-1.91 (m, 1H), 1.83-1.73 (m, 2H), 1.72-1.63 (m, 1H), 1, 38-1.23 (m, 2H); LCMS: 247.1 [M+H] ⁺ .

Step 5: 4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde

Formic acid (96%, 12.5 ml, 331 mmol) and then water (2.5 ml, 139 mmol) were added to a solution of 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene (16, 05 g, 65.15 mmol) in toluene (130 ml) under N2 atmosphere. The reaction mixture was heated at 120°C for 2 h, allowed to cool to rt. and then poured into 350 ml EtOAc and 350 ml H ₂ O. The organic layer was washed with 350 ml H ₂ O, dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde (15 05 g) as a 1:1 mixture of stereoisomers.

Stage 6: trans-4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde

An aqueous solution of sodium hydroxide (3.2 M, 31 ml, 99 mmol) was added to the crude mixture from step 5 (14.68 g, 63.19 mmol), toluene (60 ml) and ethanol (250 ml) at rt . The reaction mixture was stirred for 5.5 h (equilibrium monitored by NMR) and then poured into 350 ml H2O and 350 ml EtOAc. The organic layer was washed with 350 ml H2O and the aqueous layers were back-extracted with 150 ml EtOAc. The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give trans-4-(4-methoxy-3methylphenyl)cyclohexanecarbaldehyde (10.17 g, 69% ) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.01-6.97 (m, 2H), 6.82 (d, 1H), 3.74 (s, 3H ), 2.41-2.27 (m, 2H), 2.12 (s, 3H), 2.03-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.51-1.39 (m, 2H), 1.35-1.23 (m, 2H);

LCMS: 233.0 [M+H] ⁺ .

The following intermediates were synthesized from the appropriate aryl halide (IV or intermediate) according to the procedures described for Intermediate 3.

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ID No. Structure Name [M+N] ⁺ 3.01 77'% A J 1 trans-4-(6- (Dimethylamino) pyridin-3 yl) cyclohexanecarbaldehyde 233.0 3.02 ^10,11,12 77% trans-4-(5-Methoxy-6methylpyridin-2yl)cyclohexanecarbaldehyde 234.1 3 039MP ⁰ trans-4-(6-Methoxy-5 methylpyridin-3 yl)cyclohexanecarbaldehyde 234.1 ^{Z.O4 3.7'10} 77'% O N trans-4-(5-Chloro-6methoxypyride in-3 yl)cyclohexanecarbaldehyde 254.4 3.05 TS · 5-(trans-4-Formylcyclohexyl)-2methoxybenzonitrile 244.0 3 0 ₆ E8D0D1D2 I y 6-(trans-4-formylcyclohexyl)-3methoxypicolinonitrile 245.1 3 07 ⁶ D° F / trans-4-(3-Fluoro-1-methyl-\Nindazole-5- yl)cyclohexanecarbaldehyde 261.2

Alternative terms:

Stage 1: 1EtOH, DME, 100°C, 5 h; ² EtOH, dioxane, 100°C, overnight; ³ Cs2CO3, dioxane, 100°С, 6 h; ⁴ Pd(PPh3)4, 100°С, 5 h; ⁵ Pd(PPh ₃ )4, CH ₃ CN/H ₂ O, reflux, overnight;

Stage 2: ⁶ CH ₃ OH; ^7HCl , EtOAc;

Stage 3: 8PPTS, acetone, H ₂ O, 60°C 10 h; ⁹ 3 M HCl, THF, 60°C, 3 h overnight;

Stage 4: ¹⁰ LiHMDS (1 M THF), 0° C. or rt, 0.5-2 h;

Stage 5: 113 M HCl, THF, rt or 60°C, 1-6 hours;

Step 6: ¹² NaOMe, CH ₃ OH, rt, 4 h overnight.

Intermediate 4: trans-4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde

Step 1: 8-(3-Chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decan-8-ol

To a three-necked round bottom flask was added 4-bromo-2-chloro-1-methoxy-benzene (45.00 g, 203.18 mmol) and THF (450 mL), n-butyl lithium (2.5 M in hexanes, 90.21 ml, 1.11 eq.) was added at -78°C. The mixture was stirred for 2 hours at -78°C. A solution of 1,4-dioxaspiro[4.5]decan-8-one (34.91 g, 223.50 mmol) in THF (90 ml) was added dropwise to the reaction mixture. The resulting mixture was stirred for 3 hours at -78°C. The reaction was quenched by adding an aqueous solution of NH ₄ Cl (100 ml) and was extracted by adding EtOAc (500 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was washed with hexanes (350 ml), filtered and dried under high vacuum. The solid was triturated with hexanes (15 mL), filtered and dried under high vacuum to give 8-(3chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (37 g, 61%) in form of a white solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.31 (d, 1H), 7.29 (dd, 1H), 7.10 (d, 1H), 3.90-3.92 (m, 4H) , 3.89 (s, 3H), 1.99-2.02 (m, 4H), 1.70-1.73 (m, 4H); LCMS: 281.2 [M-OH] ⁺ .

Step 2: 8-(3-Chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane

A solution of triethylsilane (19.26 g, 165.6 mmol), TFA (25.18 g, 220.8 mmol) and CH ₂ Cl ₂ (100 ml) was added dropwise to a solution of 8-(3-chloro-4-methoxyphenyl )-1,4-dioxaspiro[4.5]decan-8-ol (31.0 g, 110.4 mmol) and CH ₂ Cl ₂ (200 ml) at 0°C. The reaction mixture was stirred at rt. overnight and then cooled to 0°C. The pH was adjusted to -8 with an aqueous solution of NaHCO ₃ and the mixture was extracted by adding CH ₂ Cl ₂ (2x100 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give 8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane containing a small amount of 8-(3-chloro-4- methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene, (38 g, crude) as a yellow oil. LCMS: 283.1 [M+H] ⁺ .

Step 3: 4-(3-Chloro-4-methoxyphenyl)cyclohexanone

8-(3-chloro-4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane (38.0 g, 134 mmol), formic acid (32.3 g, 672 mmol), H ₂ O (4.84 g, 269 mmol) and toluene (400 ml) were degassed in 3 vacuum/N ₂ cycles, then

- 149 040704 stirred at 130°C overnight and then washed with H2O (200 ml) and saturated NaHCO ₃ solution (200 ml). The combined aqueous layers were extracted by adding toluene (300 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was triturated (petroleum ether: EtOAc=10:1, 80 ml) to give 4-(3-chloro-4-methoxyphenyl)cyclohexanone containing a small amount of 3'-chloro-4'-methoxy-5,6-dihydro-[ 1,1'-biphenyl]-4(3H)-one, (20 g, 54%) as a light yellow solid. This solid (5.00 g, 21.12 mmol) was added to a mixture of Pd/C (10 wt%, 820 mg, 0.77 mmol), HCl (12 M, 1.00 ml) and EtOAc (100 ml ). The resulting mixture was degassed in 3 vacuum/H ₂ cycles, stirred at rt. for 30 min in an atmosphere of H ₂ (15 psi), filtered and then diluted with EtOAc (50 ml). The mixture was washed with water (100 ml) and washed with saturated NaHCO ₃ solution (100 ml). The aqueous phase was extracted with EtOAc (100 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give 4-(3-chloro-4methoxyphenyl)cyclohexanone (4.60 g, 84%) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ): δ 7.24 (d, 1H), 7.09 (dd, 1H), 6.88 (d, 1H), 3.90 (s, 3H), 2.88 -3.05 (m, 1H), 2.44-2.54 (m, 4H), 2.12-2.25 (m, 2H), 1.79-1.96 (m, 2H);

LCMS: 239.1 [M+H]+.

Step 4: 2-Chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene

Lithium bis(trimethylsilyl)amide (1 M, 36 ml) was added dropwise to a mixture of methoxymethyl(triphenyl)phosphonium chloride (12.24 g, 35.71 mmol) and THF (80 ml) at 0°C. The mixture was stirred for 2 h at 0°C. A solution of 4-(3-chloro-4-methoxyphenyl)cyclohexanone (5.50 g, 23.04 mmol) in THF (20 ml) was added dropwise at 0°C. The resulting mixture was stirred for 3 hours at 0°C. The reaction mixture was quenched with H2O (100 ml) and extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (200 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (petroleum ether: EtOAc=20:1) to give 2-chloro-1-methoxy-4 -(4-(methoxymethylene)cyclohexyl)benzene (5 g, 77%) as a yellow oil.

LCMS: 267.1 [M+H] ⁺ .

Step 5: 4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde

A mixture of 2-chloro-1-methoxy-4-(4-(methoxymethylene)cyclohexyl)benzene (5.00 g, 18.74 mmol), formic acid (4.50 g, 93.7 mmol), H ₂ O ( 675.5 mg, 37.48 mmol) and toluene (100 ml) were degassed in 3 vacuum/N ₂ cycles, stirred at 130° C. overnight, allowed to cool to rt. and then washed with H2O (200 ml) and washed with saturated NaHCO ₃ solution (200 ml). The combined aqueous layers were extracted by adding toluene (300 ml). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give 4-(3-chloro-4-methoxyphenyl)cyclohexanecarbaldehyde (5.60 g, crude), a mixture of cis/trans isomers, as a yellow oil.

Step 6: trans-4-(3-Chloro-4-methoxyphenyl)cyclohexanecarbaldehyde

A solution of NaOH (992.6 mg, 24.82 mmol) in H ₂ O (12 ml) was added to the crude mixture from step 5 (5.60 g, 15.51 mmol), EtOH (90 ml) and toluene (15 ml ). The mixture was stirred at rt. overnight, quenched with H ₂ O (100 ml) and then extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (200 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give a residue. The residue was purified by silica gel chromatography (petroleum ether:EtOAc = 20:1) and then triturated with MTBE (20 ml) to give trans-4-(3-chloro4-methoxyphenyl)cyclohexanecarbaldehyde (1.96 g, 49%) as white solid.

1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.27 (d, 1H), 7.16 (dd, 1H), 7.05 (d, 1H), 3, 81 (s, 3H), 2.43 (m, 1H), 2.27-2.37 (m, 1H), 1.95-2.05 (m, 2H), 1.84 (m, 2H) , 1.45 (m, 2H), 1.21-1.35 (m, 2H);

LCMS: 253.1 [M+H] ⁺ . The following intermediate was synthesized from 4-bromo-1-methoxy-2-methylbenzene according to the procedures described for intermediate 4.

ID No. Structure Name [M+N] ⁺ 3 τσ°'° trans-4-(4-Methoxy-3 - methylphenyl)cyclohexanecarbaldehyde 233.0

Alternative conditions: Stage 1: -60°C; Stage 2: 0°C, 1 h; Stage 3a: THF instead of PhMe, 80°C, 18 hours; Step 3b: no HC1, 30 psi H2, 18 hours; Stage 4: 15 h; Stage 5: 3 N HCl, THF, 60°C, 1 h; Stage 6: THF instead of PhMe.

Intermediate 5: 4-(4-Methoxy-3-methylphenyl)pyridine[2.2.2]octane-1-carbaldehyde

OOO

Stage 1: Ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate n-Butyllithium (2.5M in hexanes, 60 ml, 150.0 mmol) was added dropwise to a solution of 4-bromo-1

- 150 040704 methoxy-2-methylbenzene (27.78 g, 138.2 mmol) in THF (300 ml) at -78°C. The mixture was stirred at -78°C for 1 h and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) and THF (300 ml) at -78°C. The reaction mixture was stirred at -78°C for 2 h, added to a saturated solution of NH ₄ Cl (600 ml) and then was extracted with the addition of EtOAc (2x600 ml). The combined organic extracts were washed (400 ml water and then 400 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give ethyl 4-hydroxy-4(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.9 g, 45%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d6): δ 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H ), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H), 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS: 275.2 [M-OH] ⁺ .

Step 2: Ethyl 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate

Boron trifluoride diethyl etherate (24.85 g, 84.03 mmol) was added to a solution of ethyl 4-hydroxy4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (18.90 g, 64.64 mmol), allyltrimethylsilane (11, 82 g, 103.42 mmol) and CH ₂ Cl ₂ (400 ml) at -78°C. The mixture was stirred at -78°C for 1 h, stirred at rt. overnight and then added to brine (200 ml) and CH ₂ Cl ₂ (200 ml). The organic layer was separated, washed (2x200 ml saturated NaHCO ₃ solution and then 200 ml brine), dried (Na2SO4), filtered and then concentrated. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give ethyl 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (15 g, 71%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.00-7.10 (m, 2H), 6.76 (d, 1H), 5.26-5.50 (m, 1H), 4.81 -4.98 (m, 2H), 4.15 (q, 0.5H), 4.03 (q, 1.5H), 3.81 (s, 3H), 2.26-2.42 (m , 3H), 2.21 (s, 3H), 2.15 (d, 1.5H), 1.98 (d, 0.5H), 1.75-1.88 (m, 2.5H), 1.60-1.72 (m, 0.5H), 1.33-1.55 (m, 3H), 1.27 (t, 0.8H), 1.18 (t, 2.2H); LCMS: 339.3 [M+Na] ⁺ .

Step 3: Ethyl 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate

Osmium tetroxide (0.1 M in t-butanol, 7.6 ml, 0.76 mmol) was added to a solution of ethyl 4-allyl-4(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (4.81 g, 15 2 mmol), 4-methylmorpholine-I-oxide (2.67 g, 22.8 mmol), CH3CN (100 ml) and H2O (25 ml) at 0°C. The reaction mixture was stirred at rt. overnight and a saturated solution of Na ₂ SO ₃ (50 ml) was added. The mixture was stirred at rt. over 30 min, concentrated, dissolved in water (80 ml) and then extracted with EtOAc (2x100 ml). The organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to give ethyl 4-(2,3dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (5.23 g, 94%) in yellow oil.

1 H NMR (400 MHz, CDCl ₃ ): δ 7.05-7.16 (m, 2H), 6.78 (d, 1H), 4.06-4.17 (m, 0.5H), 3, 95-4.05 (m, 1.5H), 3.80 (s, 3H), 3.48-3.66 (m, 1H), 3.18-3.32 (m, 2H), 2, 40-2.53 (m, 2H), 2.27-2.37 (m, 1H), 2.19 (s, 3H), 1.80 (t, 3H), 1.32-1.68 ( m, 7H), 1.24 (td, 0.8H), 1.17 (t, 2.2H); LCMS: 373.3 [M+Na] ⁺ .

Step 4: Ethyl 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate

Sodium periodate (3.83 g, 17.90 mmol) was added to a solution of ethyl 4-(2,3-dihydroxypropyl)-4-(4methoxy-3-methylphenyl)cyclohexanecarboxylate (5.23 g, 14.9 mmol), THF (70 ml) and H2O (35 ml) at 0°C. The mixture was stirred at rt. overnight and added to water (50 ml) and EtOAc (2x100 ml). The organic layer was separated, washed (80 ml water and then 80 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give ethyl 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarboxylate (3.95 g, 82%) in yellow oil.

1H NMR (400 MHz, CDCl3): δ 9.28-9.42 (m, 1H), 7.07-7.19 (m, 2H), 6.79 (d, 1H), 4.15 (q , 0.5H), 4.04 (q, 1.5H), 3.82 (s, 3H), 2.41-2.52 (m, 3H), 2.33 (s, 1H), 2. 21 (s, 3H), 1.75-1.92 (m, 3H), 1.46-1.63 (m, 4H), 1.231.31 (t, 0.5H), 1.19 (t, 2.5H); LCMS: 341.3 [M+Na] ⁺ .

Step 5: Ethyl 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate

Sodium borohydride (704 mg, 18.6 mmol) was added to a solution of ethyl 4-(4-methoxy-3-methylphenyl)-4(2-oxoethyl)cyclohexanecarboxylate (3.95 g, 12.41 mmol) and THF (100 ml) at 0°C. The mixture was stirred at 0° C. for 1 h, stirred at rt. overnight and then diluted with water (100 ml). The organic solvent was removed under reduced pressure and the aqueous layer was extracted with CH ₂ Cl ₂ (2x300 ml). The organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give ethyl 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (3.11 g, 67%) in yellow oil.

1 H NMR (400 MHz, CDCl ₃ ): δ 6.96-7.04 (m, 2H), 6.71 (d, 1H), 4.03-4.12 (q, 0.4H), 3, 97 (q, 1.6H), 3.74 (s, 3H), 3.28-3.38 (m, 2H), 2.19-2.39 (m, 3H), 2.14 (s , 3H), 1.71-1.80 (m, 2H), 1.60-1.70 (m, 2H), 1.28-1.50 (m, 4H), 1.17-1.24 (t, 1H), 1.12 (t, 2H); LCMS: 343.2 [M+Na] ⁺ .

Stage 6: Ethyl 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate

- 151 040704

A solution of triphenylphosphine (4.60 g, 17.54 mmol) and CH2C12 (20 ml) was added dropwise to a solution of ethyl 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (2.81 g, 8.77 mmol), CBr ₄ (4.36 g, 13.16 mmol) and CH ₂ Cl ₂ (40 ml) at 0°C. The mixture was stirred at 0° C. for 1 h, stirred at rt. overnight and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give ethyl 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (2.62 g, 77%) in yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.96-7.08 (m, 2H), 6.77 (d, 1H), 4.15 (q, 0.3H), 4.03 (q , 1.7H), 3.81 (s, 3H), 2.91-3.06 (m, 2H), 2.24-2.41 (m, 3H), 2.15-2.24 (s , 3H), 1.95-2.06 (m, 2H), 1.77-1.87 (m, 2H), 1.34-1.53 (m, 4H), 1.27 (t, 1H ), 1.18 (t, 2H); LCMS: 405.1 [M+Na]+.

Step 7: Ethyl 4-(4-methoxy-3-methylphenyl)pyridine[2.2.2]octane-1-carboxylate Lithium diisopropylamide (2M in THF, 4.8 ml, 9.60 mmol) was added dropwise to a solution of ethyl -4-(2-bromoethyl)-4-(4-methoxy3-methylphenyl)cyclohexanecarboxylate (1.81 g, 4.72 mmol), HMPA (4.23 g, 23.61 mmol) and THF (90 ml) at -78°C. The mixture was stirred at -78°C for 3 h, added to a saturated solution of NH ₄ Cl (90 ml) and then was extracted with the addition of EtOAc (2x150 ml). The combined organic layers were washed (100 ml H2O and then 100 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 30/1) to give ethyl 4-(4-methoxy-3-methylphenyl)pyridine[2.2.2]octane-1-carboxylate (1.17 g, 82% ) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.98-7.05 (m, 2H), 6.69 (d, 1H), 4.05 (q, 2H), 3.73 (s, 3H ), 2.14 (s, 3H), 1.70-1.87 (m, 12H), 1.18 (t, 3H); LCMS: 303.3 [M+H] ⁺ .

Stage 8: (4-(4-Methoxy-3-methylphenyl)pyridine[2.2.2]octan-1-yl)methanol

Diisobutylaluminum hydride (1M in toluene, 14 mL, 14.0 mmol) was added to a solution of ethyl 4-(4methoxy-3-methylphenyl)pyridine[2.2.2]octane-1-carboxylate (1.64 g, 5.42 mmol ) and CH ₂ Cl ₂ (100 ml) at -78°C. The mixture was stirred at -78°C for 1 h, stirred at rt. for 2 h and then added to ice-cold H2O (80 ml). The pH was adjusted (pH=6) with 1 N HCl and the mixture was filtered. The layers were separated and the aqueous layer was extracted with the addition of CH ₂ Cl ₂ (2x200 ml). The combined organic layers were washed (100 ml water and then 100 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give (4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methanol (1.22 g, 82 %) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.99-7.07 (m, 2H), 6.64-6.72 (m, 1H), 3.73 (s, 3H), 3.25 (s, 2H), 2.14 (s, 3H), 1.69-1.81 (m, 6H), 1.40-1.50 (m, 6H); LCMS: 261.2 [M+H]+.

Step 9: 4-(4-Methoxy-3-methylphenyl)pyridine[2.2.2]octane-1-carbaldehyde

Pyridinium chlorochromate (1.03 g, 4.78 mmol) was added to a mixture of (4-(4-methoxy-3-methylphenyl)pyridin[2.2.2]octan-1-yl)methanol (621 mg, 2.39 mmol) , SiO ₂ (1.93 g, 32.19 mmol) and CH ₂ Cl ₂ (120 ml). The mixture was stirred at rt. for 2 h, filtered through a pad of neutral alumina and then concentrated to give Intermediate 3 (601 mg, 93%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ): δ 9.48-9.56 (s, 1H), 7.06-7.11 (m, 2H), 6.72-6.78 (m, 1H), 3.81 (s, 3H), 2.22 (s, 3H), 1.83-1.91 (m, 6H), 1.71-1.80 (m, 6H); LCMS: 259.3 [M+H]+.

The following intermediate was synthesized from 5-bromo-N,N-dimethylpyridin-2amine according to the procedures described for Intermediate 5.

ID No. Structure Name [M+N] ⁺ 5.01 And Λ J 1 trans-4-(6- (Dimethylamino) pyride in-3 yl) cyclohexanecarbaldehyde 259.2

Alternative conditions: Stage 2: 0°C; during the night; Stage 3: K ₂ OsO ₄ -2H2O; Stage 7: -78°C, 1 hour then rt, overnight; Step 9: oxalyl chloride, DMSO, Et ₃ N, -78°C.

Intermediate 6: 3-(2-Cyclopropylthiazol-5-yl)aniline

A mixture of 3-aminophenylboronic acid (2.02 g, 14.7 mmol), Pd(dppf)Cl ₂ (363 mg, 0.50 mmol), K ₂ CO ₃ aqueous solution (2.2 M, 13.5 ml, 29.7 mmol) and dioxane (17.5 ml) were degassed in 3 vacuum/N ₂ cycles. 5-Bromo-2-cyclopropylthiazole (2.01 g, 9.85 mmol) was added and the reaction mixture was heated at 80° C. for 4.25 hours. The reaction mixture was allowed to cool to rt. and then poured into 100 ml of water. The mixture was extracted with 100 ml EtOAc and the organic phases were washed with 75 ml brine. The combined aqueous washes were back-extracted with 50 ml of EtOAc. The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by chromatography.

- 152 040704 on silica gel (10-40% EtOAc in hexanes) to give 3-(2-cyclopropylthiazol-5-yl)aniline (1.84 g,

87%) as a yellow solid.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 7.79 (s, 1H), 7.04 (t, 1H), 6.76-6.71 (m, 2H), 6.55-6, 49 (m, 1H), 5.23 (s, 2H), 2.41-2.33 (m, 1H), 1.14-1.08 (m, 2H), 1.00-0.94 ( m, 2H); LCMS: 217.4 [M+H]+.

The following intermediates were synthesized from the appropriate boronic acid and the appropriate heteroaryl bromide according to the procedure described for Intermediate 6.

ID No. Structure Name [M+N] ⁺ 6.01 nh ₂ Λ. 3 - (2 - Methoxythiazol-5 -yl) aniline 207.4 6.02 ¹ νη ₂ xd 4-(2-Cyclopropylthiazol-5yl)pyridine-2-amine 218.0 6.03 ² νη ₂ Δη 3-(2-Isopropylthiazol-5 yl)aniline 219.3 6.04 ² νη ₂ Λ 4-(2-Isopropylthiazol-5yl)pyridine-2-amine 220.3

Alternative terms:

¹ Cs ₂ CO ₃ , dioxane/H ₂ O (4:1), 80°C, overnight;

² Heated at 90°C.

Intermediate 7: 3-(1-Cyclopropyl-1H-pyrazol-4-yl)aniline

A mixture of 3-iodaniline (63.36 g, 289.9 mmol), Pd(dppf)Cl ₂ (7.05 g, 9.63 mmol), K ₂ CO ₃ (2.2 M, 265 ml, 583.0 mmol) and dioxane (340 ml) were degassed with vacuum/N ₂ cycles (3x). 1-Cyclopropyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-pyrazole (-90%, 50.09 g, 192.6 mmol) was added and a mixture heated in a preheated oil bath (90° C.) for 20 minutes (internal temp. at 20 minutes was 72° C.). The reaction mixture was allowed to cool to rt, diluted with EtOAc (800 ml) and H ₂ O (800 ml) and then filtered through celite while washing with EtOAc (-400 ml). The layers were separated and the organic layer was washed (800 ml H ₂ O), dried (Na ₂ SO ₄ ), filtered and concentrated (73.88 g). The residue was dry loaded onto silica gel and purified by silica gel chromatography (20-60% EtOAc in hexanes) to give 3-(1-cyclopropyl-1H-pyrazol-4-yl)aniline (31.5 g, 82%) as a beige solid.

1H NMR (400 MHz, DMSO-d6): δ 8.03 (s, 1H), 7.66 (d, 1H), 6.97 (t, 1H), 6.73-6.72 (m, 1H ), 6.71-6.68 (m, 1H), 6.42-6.38 (m, 1H), 5.00 (s, 2H), 3.75-3.68 (m, 1H), 1.08-1.00 (m, 2H), 1.00-0.92 (m, 2H); LCMS: 200.3 [M+H] ⁺ .

The following intermediates were synthesized from the appropriate boronic acid/ester and the appropriate aryl halide according to the procedure described for Intermediate 7.

- 153 040704

ID No. Structure Name [M+N] ⁺ 7.01 ¹ nh ₂ ώ Ν 4-(1-Cyclopropyl-1 H-pyrazol-4yl)pyridine-2-amine 201.3 7.02 ¹ νη ₂ Ν Υ / 1 - ^Ν \ ^Χ 4-(1-Isopropyl-1H-pyrazol-4yl)pyridine-2-amine 203.0 7.03 νη ₂ Υ , \ , ^Ν \ ^Χ 3-(1-Isopropyl-1H-pyrazol-4yl)aniline 202.0 7.04 νη ₂ άν / 1 , ^Ν \ ^Χ 3-(1-(tert-butyl)- 1H-pyrazol-4yl)aniline 216.4 7.05 νη ₂ Υλ τ ν—chu 3-(1-Cyclobutyl-1H-pyrazol-4yl)aniline 214.4 7.06 ² Υ ζ 4-(1-Cyclopropyl-1H-pyrazol-4yl)-6-methylpyridin-2-amine 215.1

1 used 4-bromopyridine-2-amine.

² used 4-bromo-6-methylpyridine-2-amine.

Intermediate 8: 3-(2-Isopropyloxazol-4-yl)aniline

Step 1: 2-Isopropyl-4-(3-nitrophenyl)oxazole

Isobutyramide (44.62 g, 512.2 mmol) was added to a solution of 2-bromo-1-(3-nitrophenyl)ethanone (50 g, 205 mmol) in toluene (100 ml) at rt. The mixture was heated at reflux for 4 hours, allowed to cool to rt. and then filtered through filter paper. The filtrate was diluted with diethyl ether (80 ml). The organic phases were washed successively with H ₂ O (50 ml), aq. NaOH solution (0.5 M, 50 ml), aq. HCl solution (0.5 M, 50 ml) and brine (100 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 1/0 to 10/ 1) to give 2-isopropyl-4-(3-nitrophenyl)oxazole (28 g, 59%) as a white solid.

'H NMR (400 MHz, DMSO-d ₆ ): δ 8.76 (s, 1H), 8.54 (s, 1H), 8.19-8.13 (m, 2H), 7.71 (t , 1H), 3.20-3.09 (m, 1H), 1.33 (d, 6H); LCMS: 233.1 [M+H]+.

Step 2: 3-(2-Isopropyloxazol-4-yl)aniline

A mixture of palladium on carbon (10 wt%, 3 g, 2.8 mmol), 2-isopropyl-4-(3-nitrophenyl)oxazole (27 g, 116 mmol) and CH ₃ OH (80 ml) was degassed with vacuum/ H ₂ (3x). The mixture was stirred under H ₂ atmosphere at rt. for 4 h and then filtered through celite. The filtrate was concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=30/1 - 10/1) to give 3-(2isopropyloxazol-4-yl)aniline (15 g, 64%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6): δ 7.77 (s, 1H), 7.19-7.09 (m, 3H), 6.64-6.62 (m, 1H), 3.72 (s, 2H), 3.183.11 (m, 1H), 1.38 (d, 6H); LCMS: 203.1 [M+H]+.

The following intermediate was synthesized from cyclopropanecarboxamide according to the procedure described for intermediate 8.

ID No. Structure Name [M+N] ⁺ 8.01 nh ₂ X ^0 3-(2-Cyclopropyloxazol4-yl)aniline 201.1

Intermediate 9: 3-Cyclopropyl-5-(3-nitrophenyl)isothiazole

Step 1: 1-Cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one

Mixture of ethynyltrimethylsilane (1.00 g, 10.18 mmol), cyclopropanecarbonyl chloride (1.06 g, 10.18 mmol), Et3N (1.03 g, 10.18 mmol), CuI (78 mg, 0.407 mmol), Pd (PPh3)2Cl2 (143 mg, 0.204 mmol) and THF (20

- 154 040704 ml) were degassed with cycles vacuum / ^ (3x), stirred at rt. for 1 h, quenched by adding

NH ₄ Cl (20 ml) and then extracted with EtOAc (3x20 ml). The combined organic layers were washed (2×25 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 50/1) to give 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one (350 mg, 21%) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 1.76-1.89 (m, 1H), 0.95-1.10 (m, 2H), 0.79-0.82 (m, 2H), 0 .00 (s, 9H); LCMS: 167.1 [M+H]+.

Step 2: 1-Cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one

A mixture of 1-cyclopropyl-3-(trimethylsilyl)prop-2-in-1-one (50 mg, 0.301 mmol), 1-iodo-3-nitrobenzene (115 mg, 0.460 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (27 mg, 0.039 mmol), PPh ₃ (21 mg, 0.081 mmol), Et ₃ N (107.4 mg, 1.06 mmol), CuI (4 mg, 0.021 mmol) and DMF (4 ml) were degassed with vacuum/N cycles ₂ (3x) and heated to 60°C. TBAF (1 M, 300 µl, 0.3 mmol) was added to the mixture over 30 min and the reaction mixture was stirred at 60°C for 3 h. The solution was concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 20/1 - 5/1) to obtain 1-cyclopropyl-3-(3nitrophenyl)prop-2-yn-1-one (40 mg, 62%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38-8.47 (m, 1H), 8.26-8.35 (m, 1H), 7.82-7.91 (m, 1H) , 7.56-7.66(m, 1H), 2.18-2.27(m, 1H), 1.33-1.38(m, 2H), 1.15-1.19(m, 2H).

Step 3: 1-Cyclopropyl-3-(3-nitrophenyl)prop-2-yn-1-one

A mixture of 1-cyclopropyl-3-(3-nitrophenyl)prop-2-in-1-one (800 mg, 3.72 mmol), NH ₄ SCN (314 mg, 4.13 mmol) and 2-methoxy-2- methylpropane (10 ml) was degassed with vacuum/N ₂ cycles (3x), stirred at 60° C. overnight and quenched with H ₂ O (10 ml). The layers were separated and the aqueous phase was extracted with 2-methoxy-2-methylpropane (10 ml). The combined organic extracts were washed (5 ml H2O), dried (K2CO3), filtered and concentrated. The crude (Z)-1-cyclopropyl3-(3-nitrophenyl)-3-thiocyanatoprop-2-en-1-one (800 mg) was used in the next step without further purification.

LCMS: 248.0 [M-CN] ⁺ .

Stage 4: 3-Cyclopropyl-5-(3-nitrophenyl)isothiazole

A mixture of (Z)-1-cyclopropyl-3-(3-nitrophenyl)-3-thiocyanatoprop-2-en-1-one (800 mg, 2.92 mmol) and NH ₃ (50 ml) at -78°C was left slowly heat up to rt. for 2 hours. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 3-cyclopropyl-5-(3-nitrophenyl)isothiazole (200 mg, 28%) as a white solid.

1 H NMR (400 MHz, CDCl ₃ ): δ 8.35 (s, 1H), 8.17 (d, 1H), 7.80 (d, 1H), 7.55 (t, 1H), 7.15 (s, 1H), 2.08-2.22 (m, 1H), 0.95-1.01 (m, 4H); LCMS: 247.1 [M+H] ⁺ .

Step 6: 3-(3-Cyclopropylisothiazol-5-yl)aniline

A mixture of 3-cyclopropyl-5-(3-nitrophenyl)isothiazole (300 mg, 1.22 mmol), SnCl ₂ -2H ₂ O (1.10 g, 4.87 mmol), EtOH (5 ml) and H2O (500 μl) was degassed with vacuum/N ₂ cycles (3x), stirred at 78° C. for 2 h, poured into CH ₂ Cl ₂ (10 ml) and then filtered. The filtrate was diluted with H ₂ O (10 ml), extracted with CH ₂ Cl ₂ (3x10 ml), washed (15 ml brine), concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to obtain 3-(3-cyclopropylisothiazol-5-yl)aniline (140 mg, 53%) as a white solid.

1H NMR (400 MHz, CDCl3): δ 7.20 (t, 1H), 7.06 (s, 1H), 6.98 (d, 1H), 6.87 (t, 1H), 6.68- 6.73 (m, 1H), 3.78 (s, 2H), 2.11-2.27 (m, 1H), 0.93-1.14 (m, 4H); LCMS: 217.2 [M+H] ⁺ .

Intermediate 10: 4-(2-Cyclopropyloxazol-4-yl)pyridine-2-amine

Step 1: 2-Bromo-1-(2-chloropyridin-4-yl)ethanone

Bromine (12.94 g, 80.99 mmol) and HBr (19.5 ml, 108.0 mmol, 30% in AcOH) were added to a mixture of 1-(2chloropyridin-4-yl)ethanone (14 g, 90 mmol) and AcOH (280 ml) at rt. The mixture was stirred at rt. overnight, diluted with MTBE (400 ml) and filtered. The filter cake was washed (400 ml MTBE), added to a mixture of saturated NaHCO ₃ solution (300 ml) and EtOAc (500 ml) and then stirred for 1 h. The organic layer was separated and washed (300 ml saturated NaHCO ₃ solution). The combined aqueous layers were extracted with EtOAc (2 x 300 ml). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give 2-bromo-1-(2-chloropyridin-4yl)ethanone (15 g, crude) as a red solid.

1 H NMR (400 MHz, CDCl3): δ 8.65 (d, 1H), 7.80 (s, 1H), 7.70 (d, 1H), 4.40 (s, 2H); LCMS 234.0 [M+H] ⁺ .

Step 2: 4-(2-Chloropyridin-4-yl)-2-cyclopropyloxazole

Mixture of 2-bromo-1-(2-chloropyridin-4-yl)ethanone (20 g, 85 mmol), cyclopropanecarboxamide (9.07 g, 106 mmol), AgOTf (43.83 g, 170.6 mmol) and EtOAc (300 ml) was stirred at 70°C overnight in

- 155 040704 in the dark under N2 and then allowed to cool to rt. Saturated brine (300 ml) was added to the mixture and the mixture was stirred for 3 hours and filtered. The aqueous layer was separated and extracted with EtOAc (3x300 ml). The combined organic layers were washed (2x300 ml saturated NaHCO ₃ solution and then 200 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 9/1) to give 4-(2-chloropyridin-4-yl)-2-cyclopropyloxazole (13.2 g, 70%) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ): δ 8.38 (d, 1H), 7.92 (s, 1H), 7.66 (d, 1H), 7.49 (d, 1H), 2.17 -2.09 (m, 1H), 1.18-1.07 (m, 4H); LCMS 220.9 [M+H]+.

Step 3: 4-(2-Cyclopropyloxazol-4-yl)pyridine-2-amine

Lithium bis(trimethylsilyl)amide (126 ml, 126 mmol, 1M in THF) was added to a mixture of 4-(2-chloro-4pyridyl)-2-cyclopropyloxazole (13.2 g, 59.8 mmol), XPhos (2.28 g, 4.80 mmol), Pd ₂ (dba) ₃ (2.19 g, 2.394 mmol) and THF (150 ml) at r.t. in an N2 atmosphere. The reaction mixture was heated at 60° C. overnight, allowed to cool to rt, added to ice-cold HCl (200 ml, 1 M) and then stirred for 2 h. Sodium hydroxide (1 M) was added to the mixture (pH = 11) and the mixture was extracted with EtOAc (3x300 ml). The combined organic layers were washed (200 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc/EtOH = 36/3/1) and then triturated (petroleum ether/EtOAc/EtOH = 36/3/1) to give 4-(2-cyclopropyloxazol-4-yl) pyridine-2-amine (3.53 g, 29%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.46 (s, 1H), 7.88 (d, 1H), 6.80 (s, 1H), 6.77 (d, 1H), 5.96 (s, 2H), 2.252.05 (m, 1H), 1.09-1.03 (m, 2H), 1.02-0.96 (m, 2H); LCMS 202.1 [M+H] ⁺ .

The following intermediate was synthesized from isobutyramide according to the procedure described for Intermediate 10.

ID No. Structure Name [M+N] ⁺ 10.01 hh ₂ 4-(2-Isopropyloxazol-4yl)pyridine-2-amine 204.2

Intermediate 11: 4-(2-Ethyloxazol-4-yl)pyridine-2-amine

Step 1: 2-Chlorisonicotinoyl chloride

Oxalyl chloride (96.67 g, 761.64 mmol) was added to a solution of 2-chloropyridine-4-carboxylic acid (75 g, 476.03 mmol), DMF (3.48 g, 47.60 mmol) and CH ₂ Cl ₂ (850 ml) at 0°C under N2. The reaction mixture was stirred at rt. for 2.5 hours and then concentrated to dryness to give 2-chloroisonicotinoyl chloride (85 g, crude) as a black-brown oil.

Step 2: 1-(2-Chloropyridin-4-yl)-2-diazoethanone

A suspension of 2-chloropyridine-4-carbonyl chloride (85 g, crude) in CH3CN (50 ml) and THF (50 ml) was added to a solution of diazomethyl(trimethyl)silane (2M in n-hexane, 483 ml, 966 mmol), CH3CN (400 ml) and THF (400 ml) at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at rt. for 1 hour and then concentrated to dryness to give 1-(2-chloropyridin-4-yl)-2-diazoethanone (90 g, crude) as a black-brown oil. LCMS: 182.2 [M+H]+.

Step 3: 2-Chloro-1-(2-chloropyridin-4-yl)ethanone

Hydrochloric acid (12 M, 85.4 mL, 1025 mmol) was added to a solution of 1-(2-chloro-4-pyridyl)-2-diazoethanone (60 g, crude), THF (200 mL) and CH3CN (200 mL) at 0°С in N2 atmosphere. The reaction mixture was stirred at rt. within 30 min, extinguished by adding NaHCO ₃ (100 g) and then filtered. The filtrate was diluted with H2O (1000 ml) and extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (2x150 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 2-chloro-1-(2-chloropyridin-4-yl)ethanone (36 g) as a green solid.

1 H NMR (400 MHz, CDCl ₃ ): δ 8.63 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H), 4.65 (s, 2H);

LCMS: 189.8 [M+H] ⁺ .

Step 4: 4-(2-Chloropyridin-4-yl)-2-ethyloxazole

Silver trifluoromethanesulfonate (59.5 g, 231.55 mmol) was added to a solution of 2-chloro-1-(2chloropyridin-4-yl)ethanone (22 g, 115.77 mmol), propanamide (11.00 g, 150.51 mmol) and dioxane (250 ml) at rt. in N ₂ atmosphere. The mixture was heated at reflux overnight in the dark, allowed to cool to rt, poured into a mixture of saturated NaHCO ₃ solution (800 ml) and EtOAc (1000 ml) and then

- 156 040704 filtered. The filtrate was extracted with EtOAc (2x1000 ml) and the combined organic phase was washed (800 ml brine), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give 4-(2-chloropyridin-4-yl)-2-ethyloxazole (15.1 g, 60%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 8.31 (d, 1H), 7.92 (s, 1H), 7.60 (s, 1H), 7.53-7.37 (m, 1H ), 2.79 (q, 2H), 1.32 (t, 3H); LCMS: 209.1 [M+H]+.

Step 5: 4-(2-Ethyloxazol-4-yl)pyridine-2-amine

Lithium bis(trimethylsilyl)amide (1M in THF, 76 mL, 76 mmol) was added to a solution of 4-(2chloropyridin-4-yl)-2-ethyloxazole (16 g, 76.69 mmol), XPhos (3.66 g, 7.67 mmol), Pd(dba) ₃ (3.51 g, 3.83 mmol) and dioxane (320 ml) at rt. The mixture was heated to 100° C. under N2 for 2 h, allowed to cool to rt, poured into water (500 ml) and then extracted with EtOAc (2x600 ml). The combined organic layers were washed (300 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 3/1-1/1) and then triturated (100 ml 1:1 petroleum ether:MTBE) to give 4-(2ethyloxazol-4-yl)pyridin-2-amine (8.02 g, 55%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.51 (s, 1H), 7.87 (d, 1H), 6.82 (s, 1H), 6.77 (d, 1H), 5.95 (s, 2H), 2.78 (q, 2H), 1.25 (t, 3H); LCMS: 190.1 [M+H] ⁺ .

Intermediate 12: 5-(3-Aminophenyl)-N,N-dimethylpyridin-2-amine

I

A mixture of 3-iodaniline (3.96 g, 18.08 mmol), (6-(dimethylamino) pyridin-3-yl) boronic acid (2.04 g, 12.26 mmol), 2.2 M K ₂ CO ₃ (16 ml, 35 mmol), Pd(dppf)Cl ₂ (443 mg, 0.61 mmol) and dioxane (21 ml) were degassed with vacuum/nitrogen cycles (3x), heated at 90°C for 60 min and then cooled to k.t. The reaction mixture was diluted with EtOAc (100 ml), washed (2x100 ml H2O and then 100 ml brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc in hexanes) to give 5-(3-aminophenyl)-N,N-dimethylpyridine-2-amine as a beige solid (2.18 g, 84%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.30 (d, 1H), 7.68 (dd, 1H), 7.05 (t, 1H), 6.75 (t, 1H), 6 .72-6.66 (m, 2H), 6.49 (dd, 1H), 5.08 (s, 2H), 3.04 (s, 6H); LCMS 214.4 [M+H] ⁺ .

Intermediate 13: 3-Iodo-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline

Sodium triacetoxyborohydride (3.74 g, 17.6 mmol) was added to a solution of intermediate 3 (2.56 g, 11.0 mmol), 3-iodoaniline (2.56 g, 11.7 mmol), acetic acid (1 .3 ml, 23 mmol) and dichloroethane (45 ml) at rt. in an N2 atmosphere. The reaction mixture was stirred for 80 min, poured into 50 ml saturated NaHCO ₃ solution and extracted with 50 ml EtOAc. The EtOAc layer was washed with 50 ml saturated NaHCO3 solution and washed with 50 ml brine. The aqueous layers were combined and back extracted with 25 ml EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 3-iodo-N-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)aniline (4.43 g, 88%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d6): δ 7.01-6.95 (m, 2H), 6.91 (s, 1H), 6.86-6.77 (m, 3H), 6, 57 (d, 1H), 5.92 (t, 1H), 3.73 (s, 3H), 2.85 (t, 2H), 2.42-2.31 (m, 1H), 2.11 (s, 3H), 1.94-1.85 (m, 2H), 1.82-1.73 (m, 2H), 1.63-1.50 (m, 1H), 1.45-1 .31 (m, 2H), 1.14-1.00 (m, 2H); LCMS: 436.4 [M+H] ⁺ .

Intermediate 14: 3-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)aniline

Dichloroethane was cooled in an ice/water bath under N2. Intermediate 5 (151 mg, 0.58 mmol), intermediate 7 (118 mg, 0.59 mmol) and then sodium triacetoxyborohydride (198 mg, 0.93 mmol) were added to the reaction mixture at 0°C. The reaction mixture was allowed to warm to rt, stirred at rt. over 85 min, poured into 20 ml saturated NaHCO ₃ solution and then extracted with 20 ml EtOAc. The organic layer was washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give 3-(1-cyclopropyl-1H-pyrazole-4- yl)-N-((4-(4-methoxy-3- 157 040704 methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)aniline (233 mg, 90%) as a white foam.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 8.09 (s, 1H), 7.71 (s, 1H), 7.11-7.05 (m, 2H), 7.00 (t, 1H), 6.84-6.76 (m, 2H), 6.68 (d, 1H), 6.47 (d, 1H), 5.32 (t, 1H), 3.75-3.68 (m, 4H), 2.83 (d, 2H), 2.12 (s, 3H), 1.78-1.69 (m, 6H), 1.62-1.52 (m, 6H), 1.10-1.04 (m, 2H), 1.00-0.93 (m, 2H); LCMS: 442.3 [M+H]+.

The following intermediates were synthesized from the appropriate amine (IV or intermediate) and the appropriate aldehyde intermediate according to the procedures described for Intermediate 14

ID No. Structure Name [M+N] ⁺ 14.01 ¹ 5-(trans-4-(((3- Iodophenyl)amino)methyl)cyclohexyl) -2-methoxybenzonitrile 447.1 14.02 ¹ A 4-Bromo-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)pyridine-2-amine 389.1 14.03 3 -Yod-I-((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)aniline 462.0 14.04 A %^Br 4-Bromo-A-((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)pyridine-2-amine 415.2 14.05 Η /О' ώγγ R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-3(2-methoxythiazol-5-yl)aniline 423.2 14.06 3-(2-Cyclopropylthiazol-5-yl)-I ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)anil in 433.3 14.07 χχ A-((trans-4-(3-Chloro-4methoxyphenyl)cyclohexyl)methyl)-3(2-cyclopropylthiazol-5-yl)aniline 453.3 14.08 Δ z— / 5-(trans-4-(((3-(2- Cyclopropylthiazole-5- yl)phenyl)amino)methyl)cyclohexyl)- R,7U-dimethylpyridine-2-amine 433.4

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14.09 l Λ 3-(2-Cyclopropylthiazol-5-yl)-I((trans-4-(3-fluoro-1-methyl-\Nindazol-5- yl)cyclohexyl)methyl)aniline 461.2 14.10 J% 5-(trans-4-(((3-(2- Cyclopropylthiazole-5- yl)phenyl)amino)methyl)cyclohexyl)- 2-methoxybenzonitrile 444.3 14.11 ² ΓΎΎ AA 5-(trans-4-(((4-(2- Cyclopropylthiazol-5-yl)pyridin-2yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 445.9 14.12 .. ΑΑΆη Ag. A 6-(trans-4-(((3 -(2- Cyclopropylthiazole-5- yl)phenyl)amino)methyl)cyclohexyl)- 3-methoxypicolinonitrile 445.3 14.13 ² X / ^2=/ / O 6-(trans-4-(((4-(2- Cyclopropylthiazol-5-yl)pyridin-2yl)amino)methyl)cyclohexyl)-3 methoxypicolinonitrile 446.6 14.14 X' o/ 3-(2-Cyclopropylthiazol-5-yl)-I((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)aniline 434.1 14.15 ΑΧ An 4-(2-Cyclopropylthiazol-5-yl)-I ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)pyridine-2-amine 434.3 14.16 ΑυΆη A ³ a^ A 4-(2-Cyclopropylthiazol-5-yl)-I((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)pyridine-2amine 435.3

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14.17 / 3-(2-Isopropylthiazol-5-yl)-I((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)aniline 436.2 14.18 ² /z=/ A / 4-(2-Isopropylthiazol-5-yl)-I ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)pyridine-2-amine 436.6 14.19 ¹ /z=/ > ' O / 4-(2-Isopropylthiazol-5-yl)-R((/agy5-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)pyridine-2amine 437.5 14.20 M/M ^NH 3-(2-Cyclopropylthiazol-5-yl)-^-((4(4-meτoκci-3- methyl phenyl) bicyclo [2.2.2] octan-1 yl) methyl) aniline 459.3 14.21 5-(4-(((3-(2-Cyclopropylthiazol-5yl)phenyl)amino)methyl)bicyclo[2.2.2]octan-1-yl)-N,N-dimethylpyridin-2amine 459.4 14.22 . ; zλ 3 - (1 -Cyclopropyl- 1H-pyrazol-4-yl) R - ((trans-4- (4-methoxy-3 - methylphenyl)cyclohexyl)methyl)anil in 416.3 14.23 ..; zλ R-((trans-4-(3-Chloro-4methoxyphenyl)cyclohexyl)methyl)-3(1-cyclopropyl-1R-pyrazol-4yl)aniline 436.6 14.24 7 A z— / 5 - (trans-4- (((3 - (1 -Cyclopropyl-\Hpyrazole-4- yl)phenyl)amino)methyl)cyclohexyl)N,N-dimethylpyridin-2-amine 416.3

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14.25 F ΔΎΎ 3 - (1 -Cyclopropyl- 1H-pyrazol-4-yl) R - ((trans-4- (3 -fluoro-1 -methyl-\Nindazol-5- yl)cyclohexyl)methyl)aniline 444.6 14.26 1 4-(1-Cyclopropyl- 1H-pyrazol-4-yl)- I-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)pyridine-2-amine 417.1 14.27 ³ 7 θ' X / ⁼ \ Οχ / 4-(1-Cyclopropyl- 1H-pyrazol-4-yl)n-((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-6methylpyridin-2-amine 431.6 14.28 Well/ 1 3 -(1-Cyclopropyl- 1H-pyrazol-4-yl)H-((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)aniline 417.1 14.29 < Ο 1 4-(1-Cyclopropyl- 1H-pyrazol-4-yl)H-((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)pyridine-2amine 418.3 14.30 3 -(1-Cyclopropyl- 1H-pyrazol-4-yl)H-((trans-4-(6-methoxy-5methylpyridine-3 - yl)cyclohexyl)methyl)aniline 417.3 14.31 R-((trans-4-(5-Chloro-6methoxypyr idin-3 yl)cyclohexyl)methyl)-3-(1 cyclopropyl-1R-pyrazol-4yl)aniline 437.4

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14.32 Adu 5 -(trans-4-(((3 -(1 -Cyclopropyl-\Hpyrazole-4- yl)phenyl)amino)methyl)cyclohexyl)2-methoxybenzonitrile 427.3 14.33 v. PA YQj CX 5-(trans-4-(((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 428.3 14.34 02 L z λ 6-(trans-4-(((3 -(1 -Cyclopropyl-\Hpyrazole-4- yl)phenyl)amino)methyl)cyclohexyl)3-methoxypicolinonitrile 428.3 14.35 CW l z λ 6-(trans-4-(((4-(1-Cyclopropyl-\Hpyrazol-4-yl)pyridin-2yl)amino)methyl)cyclohexyl)-3 methoxypicolinonitrile 429.4 14.36 \_/ I zλ 4-(1-Cyclopropyl- 1H-pyrazol-4-yl)- I-((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)pyridine-2-amine 443.1 14.37 1 5 - (4- (((3 - (1 -Cyclopropyl- 1Hpyrazole-4- yl)phenyl)amino)methyl)bicyclo[2.2.2]octan-1-yl)-H,H-dimethylpyridine-2amine 442.4 14.38 /anh 3 - (1 -Isopropyl- 1H-pyrazol-4-yl) -R ((trans-4- (4-methoxy-3 - methylphenyl)cyclohexyl)methyl)anil in 418.3 14.39 /Anh ⁿ uV / 4-(1-Isopropyl- 1H-pyrazol-4-yl)-H((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)pyridine-2-amine 419.3

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14.40 3 - (1 -Isopropyl-1 Η- π irazol-4-yl ) -Ν ((trans-4- (5-methoxy-6methylpyridin-2yl) cyclohexyl) methyl) aniline 419.7 14.41 ³ ό , 4-(1-Isopropyl-1 Η- π irazol-4-yl)-Ν((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)pyridine-2amine 420.3 14.42 ν ₄ ΠΎ ^Ν ά / 5-(trans-4-(((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 430.4 14.43 ^2,3,4 \_/ X 5-(4-(((4-(1-Isopropyl- 1H-pyrazol-4yl)pyridine-2- yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 430.3 14.44 ² J1 6-(trans-4-(((3 -(1 -Isopropyl- 1Yapyrazole-4- yl)phenyl)amino)methyl)cyclohexyl)3-methoxypicolinonitrile 430.4 14.45 \_/ X 6-(trans-4-(((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2yl)amino)methyl)cyclohexyl)-3 methoxypicolinonitrile 431.4 14.46 ζ^ ¹ '% /ο/ 3 - (1 - (tert-butyl) - 1H-pyrazol-4-yl) R - ((trans-4- (5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)aniline 433.4 14.47 - . - ζ ά 3 -(1-Cyclobutyl- 1H-pyrazol-4-yl)-R((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)aniline 431.8

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14.48 X eiX / 3 - (2 -Cyclopropyl oxazol-4-yl) -L ((trans-4- (4-methoxy-3 - methylphenyl)cyclohexyl)methyl)anil in 417.3 14.49 ² O 4-(2-Cyclopropyloxazol-4-yl)-I((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)pyridine-2-amine 418.6 14.50 ³ /== / HH 4-(2-Cyclopropyloxazol-4-yl)-I((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)pyridine-2amine 419.5 14.51 ¹ 4 5-(4-(((3-(2-Cyclopropyloxazol-4yl)phenyl)amino)methyl)bicyclo[2.2.2]octan-1-yl)-N,N-dimethylpyridin-2amine 443.3 14.52 ² X E^) 5-(trans-4-(((4-(2- Cyclopropyloxazol-4-yl)pyridin2-yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 429.3 14.53 ² AND 5-(trans-4-(((4-(2-Isopropyloxazol4-yl)pyridin-2yl)amino)methyl)cyclohexyl)-2methoxybenzonitrile 431.4 14.54 ² X E-L 0 / /° 6-(trans-4-(((4-(2- Cyclopropyloxazol-4-yl)pyridin2-yl)amino)methyl)cyclohexyl)-3methoxypicolinonitrile 430.4 14.55 ³ X EnGL ⁷ 2— ⁷ 0 ⁷ o / 4-(2-Ethyloxazol-4-yl)-R-((trans-4(5-methoxy-6-methylpyride in-2yl)cyclohexyl)methyl)pyridine-2amine 407.4

Alternative terms:

1 Method used for intermediate 13;

² Heated at 40°C.

³ The solvent was CH ₂ Cl ₂ ;

⁴ Synthesized from an isomeric mixture of intermediate 3.05.

Intermediate 15: trans-4-(cyanomethyl)cyclohexanecarboxylic acid

Step 1: trans-Ethyl 4-((tosyloxy)methyl)cyclohexanecarboxylate p-Toluenesulfonyl chloride (1.54 g, 8.05 mmol) was added to a solution of trans-ethyl 4-(hydroxymethyl)cyclohexanecarboxylate (1 g, 5.37 mmol), Et ₃ N (1.63 g, 16.11 mmol), DMAP (131.19 mg, 1.07 mmol) and CH ₂ Cl ₂ (60 ml) at 0°C. The mixture was allowed to warm to rt. during the night. Water (10 ml) was added and the layers were separated. The aqueous layer was extracted by adding CH ₂ Cl ₂ (20 ml). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=20/1) to give trans-ethyl 4-((tosyloxy)methyl)cyclohexanecarboxylate (1, 49 g, 82%) as a yellow oil.

1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H), 7.37 (d, 2H), 4.19-4.06 (m, 2H), 3.85 (d, 2H), 2.47 (s, 3H), 2.20 (t, 1H), 2.05-1.96 (m, 2H), 1.86-1.77 (m, 2H), 1.73-1, 61 (m, 1H), 1.43-1.39 (m, 2H), 1.27 (t, 3H), 1.08-0.91 (m, 2H); LCMS: 341.2 [M+H]+.

Stage 2: trans-Ethyl-4-(cyanomethyl)cyclohexanecarboxylate

Potassium cyanide (903.8 mg, 13.88 mmol) was added to a solution of trans-ethyl-4((tosyloxy)methyl)cyclohexanecarboxylate (1.89 g, 5.55 mmol) in DMSO (30 mL) at rt.

The mixture was heated to 50°C during the night. Water (50 ml) was added and then the mixture was extracted with EtOAc (2x100 ml). The organic layers were combined, washed with water (50 ml), dried (Na2SO4), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give trans-ethyl 4-(cyanomethyl)cyclohexanecarboxylate (807 mg, 74.45%) as a yellow oil.

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1H NMR (400 MHz, CDC13): δ 4.05 (q, 2H), 2.27-2.09 (m, 3H), 2.04-1.93 (m, 2H), 1.91-1 .80 (m, 2H),

1.68-1.55 (m, 1H), 1.46-1.32 (m, 2H), 1.18 (t, 3H), 1.14-1.00 (m, 2H).

Step 3: trans-4-(cyanomethyl)cyclohexanecarboxylic acid

Lithium hydroxide monohydrate (2.60 g, 62.00 mmol) was added to a solution of trans-ethyl-4(cyanomethyl)cyclohexanecarboxylate (807 mg, 4.13 mmol), THF (15 ml) and H ₂ O (15 ml) at k.t. The mixture was stirred at rt. overnight and then the organic layer was removed. The aqueous layer was adjusted to pH=1 with 1N HCl and extracted with CH ₂ Cl ₂ (5x20 ml). The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-4-(cyanomethyl)cyclohexanecarboxylic acid (500 mg, crude) as a yellow oil.

'H NMR (400 MHz, CDC13): δ 2.37-2.22 (m, 3H), 2.12-2.06 (m, 2H), 2.00-1.91 (m, 2H), 1.75-1.63 (m, 1H), 1.50-1.45 (m, 2H), 1.24-1.09 (m, 2H).

Intermediate 16: tert-Butyl 2-(trans-4-(chlorocarbonyl)cyclohexyl)acetate

Stage 1: trans-Methyl-4-(chlorocarbonyl)cyclohexanecarboxylate

Oxalyl chloride (47.72 g, 375.9 mmol) was added dropwise to a solution of trans-4(methoxycarbonyl)cyclohexanecarboxylic acid (35 g, 188 mmol) and DMF (1.37 g, 18.8 mmol) and CH ₂ Cl ₂ (700 ml) at r.t. The mixture was stirred for 2 hours and concentrated to dryness to give trans-methyl-4-(chlorocarbonyl)cyclohexanecarboxylate (38.5 g, crude) as a yellow oil.

Step 2: trans-Methyl 4-(2-diazoacetyl)cyclohexanecarboxylate (Trimethylsilyl)diazomethane (2M in hexanes, 385 mL, 770 mmol) was added to a solution of trans-methyl 4-(chlorocarbonyl)cyclohexanecarboxylate (38.5 g, 188.1 mmol), CH3CN (700 ml) and THF (700 ml) at 0°C. The reaction mixture was allowed to warm to rt, stirred overnight, concentrated and then dissolved in EtOAc (1000 ml). The organic phase was washed with water (300 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 40/1) to give trans-methyl 4-(2-diazoacetyl)cyclohexanecarboxylate (35 g, 166 mmol, 89%) as a yellow oil.

'H NMR (400 MHz, CDC13): δ 5.27 (s, 1H), 3.66 (s, 3H), 2.33-2.12 (m, 2H), 2.11-2.00 ( m, 2H), 1.98-1.85 (m, 2H), 1.53-1.35 (m, 4H).

Stage 3: trans-Methyl-4-(2-(tert-butoxy)-2-oxoethyl)cyclohexanecarboxylate

Silver benzoate (8.17 g, 35.7 mmol) was added to a solution of methyl 4-(2diazoacetyl)cyclohexanecarboxylate (25 g, 119 mmol), dioxane (300 ml) and t-BuOH (300 ml) at rt. in N ₂ atmosphere. The mixture was stirred for 15 h, poured into water (500 ml), filtered and extracted with EtOAc (2x1000 ml). The combined organic layers were washed with water (2x300 ml), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (pe. oils.

'H NMR (400 MHz, CDCI3): δ 3.65 (s, 3H), 2.28-2.13 (m, 1H), 2.09 (d, 2H), 1.97 (d, 2H) , 1.87-1.78 (m, 2H), 1.75-1.66 (m, 1H), 1.55-1.43 (d, 11H), 1.07-0.90 (m, 2H).

Step 4: trans-4-(2-(tert-Butoxy)-2-oxoethyl)cyclohexanecarboxylic acid

Lithium hydroxide monohydrate (65.48 g, 1.56 mol) was added to a solution of methyl 4-(2-tert-butoxy-2oxoethyl)cyclohexanecarboxylate (20 g, 78 mmol), THF (400 ml) and water (400 ml) at k.t. The mixture was stirred overnight and concentrated to remove the organic solvent. Hydrochloric acid (3M) was added to the mixture (pH=4) and the resulting precipitate was collected by filtration and dried in vacuo to give trans-4-(2-(tert-butoxy)-2-oxoethyl)cyclohexanecarboxylic acid (7.2 g , crude) as a yellow solid.

'H NMR (400 MHz, CDC13): δ 2.29-2.21 (m, 1H), 2.10 (d, 2H), 2.0-1.97 (m, 2H), 1.87- 1.80 (m, 2H), 1.781.66 (m, 1H), 1.53-1.39 (m, 11H), 1.05-0.95 (m, 2H).

Intermediate 17: trans-4-(3-(tert-Butoxy)-3-oxopropyl)cyclohexanecarboxylic acid o o

Step 1: 2-(trans-4-(Methoxycarbonyl)cyclohexyl)acetic acid

A mixture of intermediate 16, Step 3 (2 g, 7.80 mmol) and hydrochloric acid (4M in dioxane, 50 ml) was stirred at rt. over 1 hour. The mixture was concentrated to dryness to give 2-(trans-4-(methoxycarbonyl)cyclohexyl)acetic acid (1.56 g, crude) as a yellow oil.

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1 H NMR (400 MHz, CDCl ₃ ): δ 3.67 (s, 3H), 2.32-2.19 (m, 3H), 2.05-1.95 (m, 2H), 1.93- 1.84(m, 2H),

1.84-1.72(m, 1H), 1.55-1.39(m, 2H), 1.11-0.97(m, 2H).

Stage 2: trans-Methyl-4-(2-chloro-2-oxoethyl)cyclohexanecarboxylate

Oxalyl chloride (1.98 g, 15.58 mmol) was added to a solution of 2-(trans-4(methoxycarbonyl)cyclohexyl)acetic acid (1.56 g, 7.79 mmol), DMF (57.0 mg, 0.779 mmol) and CH ₂ Cl ₂ (20 ml) at rt. The mixture was stirred at rt. for 2 hours and then concentrated to dryness to give trans-methyl-4-(2-chloro-2-oxoethyl)cyclohexanecarboxylate (1.7 g, crude) as a yellow oil.

Stage 3: trans-Methyl-4-(3-diazo-2-oxopropyl)cyclohexanecarboxylate (Trimethylsilyl)diazomethane (2M in hexanes, 11.6 ml) was added to a solution of trans-methyl-4-(2-chloro-2oxoethyl)cyclohexanecarboxylate (1.7 g, 7.77 mmol), CH3CN (10 ml) and THF (10 ml) at 0°C. The mixture was allowed to warm to rt. overnight, concentrated to dryness and then purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give trans-methyl 4-(3-diazo-2oxopropyl)cyclohexanecarboxylate (1.2 g, 62%) as yellow oil.

1H NMR (400 MHz, CDCl3): δ 5.06 (s, 1H), 3.50 (s, 3H), 2.14-1.99 (m, 3H), 1.88-1.78 (m , 2H), 1.73-1.58 (m, 3H), 1.32-1.29 (m, 2H), 0.93-0.75 (m, 2H).

Stage 4: trans-Methyl-4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate

Silver benzoate (367.5 mg, 1.61 mmol) was added to a solution of trans-methyl-4-(3-diazo-2oxopropyl)cyclohexanecarboxylate (1.2 g, 5.35 mmol), dioxane (10 ml) and t- BuOH (10 ml) at RT The mixture was stirred at rt. overnight, poured into water (50 ml) and then filtered. The filtrate was extracted with EtOAc (2x50 ml). The organic layers were combined, washed with water (30 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=40/1) to give trans-methyl-4-(3- (tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate (730 mg, 50%) as a yellow oil.

1 H NMR (400 MHz, CDCl ₃ ): δ 3.59 (s, 3H), 2.22-2.09 (m, 3H), 1.95-1.85 (m, 2H), 1.79- 1.69 (m, 2H), 1.48-1.25 (m, 13H), 1.22-1.10 (m, 1H), 0.94-0.78 (m, 2H).

Step 5: trans-4-(3-(tert-Butoxy)-3-oxopropyl)cyclohexanecarboxylic acid

Lithium hydroxide monohydrate (113.3 mg, 2.70 mmol) was added to a solution of trans-methyl-4-(3-(tert-butoxy)-3-oxopropyl)cyclohexanecarboxylate (730 mg, 2.70 mmol), THF (10 ml) and H ₂ O (10 ml). The mixture was stirred at 30° C. overnight, concentrated to remove THF, adjusted to pH=5 with 3 M HCl and then filtered. The precipitate was dried in vacuo to give trans-4-(3-(tert-butoxy)-3oxopropyl)cyclohexanecarboxylic acid (330 mg, crude) as a white solid.

¹ H NMR (400 MHz, CDCl3): δ 2.27-2.08 (m, 3H), 1.95 (d, 2H), 1.76 (d, 2H), 1.49-1.27 ( m, 13H), 1.261.10 (m, 1H), 0.97-0.76 (m, 2H).

Intermediate 18: trans-4-(Benzyloxy)cyclohexanecarbonyl chloride

Stage 1: trans-Methyl-4-(benzyloxy)cyclohexanecarboxylate

Benzyl bromide (4.76 g, 27.81 mmol) was added in one portion to a mixture of trans-methyl-4hydroxycyclohexanecarboxylate (4.00 g, 25.28 mmol) and iPr ₂ NEt (7.40 g, 57.26 mmol) under atmosphere N2. The mixture was stirred at 150° C. for 8 h in a sealed tube and then allowed to cool to rt. Aqueous hydrochloric acid (1 N, 40 ml) was added to the resulting heterogeneous mixture. The mixture was extracted with EtOAc (3x20 ml). The combined organic phases were dried (MgSO ₄ ) and concentrated to give trans-methyl-4-(benzyloxy)cyclohexanecarboxylate (6.00 g, crude) as a yellow oil.

Step 2: trans-4-(Benzyloxy)cyclohexanecarboxylic acid

An aqueous solution of sodium hydroxide (5 M, 10 ml) was added in one portion to a mixture of trans-methyl-4(benzyloxy)cyclohexanecarboxylate (6.00 g, 24.16 mmol), CH3OH (20 ml) and THF (20 ml) at .T. in N ₂ atmosphere. The mixture was stirred at rt. overnight, neutralized to pH=1 with 5 N HCl and then concentrated. The mixture was partitioned between EtOAc (30 ml) and water (30 ml). The layers were separated. The aqueous layer was extracted with EtOAc (2x15 ml). The combined organic phases were concentrated to give trans-4-(benzyloxy)cyclohexanecarboxylic acid (4.00 g, 71%) as a yellow solid.

1H NMR (400 MHz, CDCl3): δ 7.32-7.36 (m, 4H), 7.23-7.29 (m, 1H), 4.56 (s, 2H) 3.26-3, 41 (m, 1H), 2.272.37 (m, 1H), 2.13-2.18 (m, 2H), 2.04-2.08 (m, 2H), 1.42-1.55 ( m, 2H), 1.26-1.40 (m, 2H); LCMS: 233.1 [MN] ⁺ .

Step 3: trans-4-(Benzyloxy)cyclohexanecarbonyl chloride trans-4-(Benzyloxy)cyclohexanecarboxylic acid (600.3 mg, 2.56 mmol) was added in one portion to a mixture of N-(chloromethylene)-N-methylmethanaminium chloride (655.6 mg, 5.12 mmol), K2CO3 (1.06 g, 7.68 mmol) and toluene (10.0 ml) under N2 atmosphere. The mixture was stirred at rt. for 1 hour and then filtered to give trans-4-(benzyloxy)cyclohexanecarbonyl chloride as a clear solution. The solution was used directly without purification.

The following intermediate was synthesized using 4-methoxybenzyl bromide according to the procedures described for Intermediate 18.

ID No. Structure Name 18.01 ‘Ύγι trans-4-((4- Methoxybenzyl)oxy)cyclohexanecarbonyl chloride

Intermediate 19: trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride

Stage 1: trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate tert-Butyldimethylsilyl chloride (31.47 g, 208.8 mmol) was added to a mixture of trans-4hydroxycyclohexanecarboxylic acid (10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol) and DMF (140 ml) at rt. in an N2 atmosphere (the reaction gave off heat up to 32°C). The reaction mixture was stirred at rt. for 2 h and then diluted with diethyl ether (300 ml). The organic layer was washed (2x300 ml 1 N HCl and then 300 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31 .5 g) as a clear oil.

1H NMR (400 MHz, DMSO-d6): δ 3.61-3.53 (m, 1H), 2.26-2.18 (m, 1H), 2.04-1.96 (m, 2H) , 1.92-1.85 (m, 2H), 1.51-1.39 (m, 2H), 1.39-1.27 (m, 2H), 0.94 (s, 9H), 0 .89 (s, 9H), 0.26 (s, 6H), 0.06 (s, 6H).

Stage 2: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid

Potassium carbonate (58.01 g, 419.7 mmol) in H ₂ O (300 mL) was added to a mixture of trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g crude, 69.6 mmol), ethanol (1000 ml) and THF (300 ml) at rt. in an N2 atmosphere. The reaction mixture was stirred at rt. over 3 h, concentrated to a residue of 300 ml, diluted with brine (600 ml) and then acidified to pH 2-3 with 20% NaHSO ₄ (550 ml). The aqueous layer was extracted with diethyl ether (800 ml). The organic layer was washed (800 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-4((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (17.3 g, 96% in 2 steps) in form of a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 12.30 (br s, 1H), 3.59-3.51 (m, 1H), 2.15-2.05 (m, 1H), 1 .88-1.74 (m, 4H), 1.41-1.29 (m, 2H), 1.28-1.16 (m, 2H), 0.84 (s, 9H), 0.02 (s, 6H).

Stage 3: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride

(Chloromethylene)dimethyliminium chloride (34.02 g, 265.78 mmol) was weighed into a 1000 ml round bottom flask (three necked) and degassed with vacuum/N ₂ cycles (3x). Toluene (240 ml) was added to the flask and the mixture was cooled (1.3° C.) in an ice bath. Anhydrous potassium carbonate* (68.71 g, 497.14 mmol) and trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (34.29 g, 132.69 mmol) were added successively to the reaction mixture. The ice bath was removed and the mixture was stirred for 35 minutes. Celite (7 g) was added to the reaction mixture and then the reaction mixture was filtered through celite (70 g, 465 ml Chemglass porous funnel) with washes with toluene (3x100 ml). This solution (451 g, 8.5% acid chloride, 100% yield, 72 mg/ml) was used directly in the acylation reaction.

1H NMR (400 MHz, CDCl3): δ 3.77-3.68 (m, 1H), 2.83-2.74 (m, 1H), 2.31-2.22 (m, 2H), 2 .09-1.99 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.42 (m, 2H), 1.02 (s, 9H), 0.20 (s, 6H). *Potassium carbonate was dried in vacuo by heating with a hair dryer for ~5 min and then left to cool overnight.

The following intermediates were synthesized from the appropriate starting material or intermediate according to the procedures described for Intermediate 19.

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ID No. Structure Name 19.01 ABOUT οιΡύ \ / cis-4-((tert- butyldimethylsilyl)oxy)cyclohex sancarbonyl chloride 19.02 ¹ ABOUT CI o I Hahk n tert-butyl(trans-4- (chlorocarbonyl)cyclohexyl)carba mat 19.03 ¹ about ^s| Arn t > o ¹ tert-butyl-((trans-4- (chlorocarbonyl)cyclohexyl)methyl) carbamate 19.04 ¹ ABOUT οιΥγ ΜγΧ ABOUT trans-methyl-4- (Chlorocarbonyl)cyclohexanecarboc silat 19.05 ¹ O Ethyl-2-(trans-4- (chlorocarbonyl)cyclohexyl)acetate 19.Ob ¹ tert-butyl-2-(trans-4- (chlorocarbonyl)cyclohexyl)acetate 19.07 ¹ About ciP^A About 1 tert-butyl-3-(trans-4(chlorocarbonyl)cyclohexyl)propa noat 19.08 ¹ O % trans-4- Cyanocyclohexanecarbonyl chloride 19.09 ^{1 s, l} ah trans-4- (cyanomethyl)cyclohexanecarbonyl chloride 19.10 ² Αγ 4-((tert-butyldimethylsilyl)oxy)- 4- methylcyclohexanecarbonyl chloride

1 Stage 3 only;

² Step 1: Ethyl 4-oxocyclohexanecarboxylate, AlMe ₃ , toluene, 0° C., 1 h afforded ethyl 4-hydroxy-4-methylcyclohexanecarboxylate as a cis/trans mixture;

Step 2: TBSOTf, 2,6-lutidine, DCM, 0°C-rt, overnight; Stage 3: LiOH-H ₂ O, H ₂ O, THF;

Step 4: Step 3 for Intermediate 19.

Intermediate 20: 2-Hydroxyethyl-(4-nitrophenyl) carbonate

4-Nitrophenylcarbonochloridate was added to a solution of ethane-1,2-diol (230 mg, 3.70 mmol) and pyridine (293 mg, 3.70 mmol) in CH ₂ Cl ₂ (10 ml) at 0° C. under N ₂ . The mixture was allowed to warm to rt. and stirred at room temperature. within 3 hours. The reaction mixture was used in the next step without purification.

Intermediate 21: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-iodophenyl)-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Intermediate 19 (74 mg/ml in toluene, 43 ml, 11.49 mmol) was added to a solution of intermediate 13 (3.32 g, 7.63 mmol), pyridine (2.5 ml, 31 mmol) and toluene ( 15 ml). The mixture was stirred at rt. for 90 min, diluted with EtOAc (50 ml) and washed (50 ml H ₂ O, 50 ml saturated NaHCO ₃ solution and then 50 ml brine). The organic layer was dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-iodophenyl) -N-((trans-4(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (4.05 g, 79%) as a white foam.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.76 (d, 1H), 7.72 (s, 1H), 7.31 (d, 1H), 7.27 (t, 1H), 6 .97-6.92 (m, 2H), 6.80-6.76 (m, 1H), 3.72 (s, 3H), 3.60-3.40 (m, 3H), 2.37 -2.27(m, 1H), 2.09(s, 3H), 2.01-1.91(m, 1H), 1.781.67(m, 6H), 1.65-1.56(m , 2H), 1.49-1.21 (m, 5H), 1.10-0.94 (m, 2H), 0.92-0.76 (m, 11H), -0.01 (s, 6H); LCMS: 676.6 [M+H]+. The following intermediates were synthesized from the appropriate

- 168 040704 intermediate according to the procedure described for the intermediate

21.

ID No. Structure Name [M+N] ⁺ 21.01 O th ω trans-4-((tert- butyldimethylsilyl)oxy)-L-((trans4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)-N(3-iodophenyl)cyclohexanecarboxamide 687.5 21.02 ¹ o XX ν y ⁴ ] Δ V g trans-L-(4-Bromopyridin-2-yl)-4((tert-butyldimethylsilyl)oxy)-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 629.2 21.OZ ² .χχX, trans-4-((tert- butylde and methylsilyl)oxy)-L-(3-iodphenyl)-A-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide 702.2 21.04 ¹ γγθΫθ Χργχ/ Ν^Ι ^^^OTBS ^χ _ο ΧΔ χΧ _ΒΓ trans-N-(4-Bromopyridin-2-yl)-4((tert-butyldimethylsilyl)oxy)-R((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide 655.2 21.05 ¹ αΧ trans-Methyl-4-((4-bromopyridin-2yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 557.1

- 169 040704

21.06 ¹ 0 trans-Methyl-4-((4-bromopyridin-2yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarb oxylate 583.1 21.07 ⁴ tert-butyl-((1K,4g)-4-((4bromopyridin-2-yl)((( 1 r,4R)-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamyl)cyclohexyl)carbamate 614.0 21.08 ² g Μ / trans-Methyl-4-(((trans-4-(3-chloro-4methoxyphenyl)cyclohexyl)methyl)(3(2-cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexanecarb oxylate 621.6 21.09 ² - M / trans-Methyl-4-((3-(2cyclopropylthiazol-5 yl)phenyl)((trans-4-(3-fluoro-1-methylIII-indazol-5yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 629.4 21.10 ² 0 . - And trans-Methyl-4-((3 -(2- cyclopropylthiazol-5-yl)phenyl)((4(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarb oxylate 627.5 21.11 ² Su A ζ— / trans-Methyl-4-((3-(2cyclopropylthiazol-5-yl)phenyl)((4(b-(dimethylamino)pyridine-Zyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarb oxylate 627.8

- 170040704

21.12 ⁴ O J A A lx Μ** Αγχ trans-Methyl-4-((3 -(2cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 602.2 21.13 ³ ΜΧθΊΛ Mm trans-Methyl-4-((4-(2- cyclopropylthiazol-5-yl)pyridin-2yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 603.4 21.14 ² ..' And trans-Methyl-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(2-cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexanecarb oxylate 612.4 21.15 ² i JM° l o M / trans-Methyl-4-(((trans-4-(3-chloro-4methoxyphenyl)cyclohexyl)methyl)(3(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexanecarb oxylate 604.7 21.16 ² f mF Mi MM trans-Methyl-4-((3-(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(3fluoro-1-methyl-1H-indazol-5yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate 612.4 21.17 ² H JY> ° l about M, / trans-Methyl-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((4-(4methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarb oxylate 610.4

- 171 040704

21.18 ⁴ °i O o ύ / trans-Methyl-4-((3-(1-cyclopropylN-pyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 585.4 21.19 ² / O V7 o o ° lHya Δ Z' trans-Methyl-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexanecarb oxylate 595.4 21.20 ⁵ o Ύ Υ ?ι ί _ο trans-Methyl-4-((4-(1-isopropyl-\Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyride in-2yl)cyclohexyl)methyl)carbamoyl )cyclohexanecarboxylate 588.7 21.21 ² I trans-4-Cyano-R-(3-(2cyclopropylthiazol-5-yl)phenyl)-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 568.4 21.22 ² 0 αΛΑ trans-4-(Cyanomethyl)-L-(3-(2cyclopropylthiazol-5-yl)phenyl)-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 582.4 21.23 ² /7οο°vyC/ trans-4-Cyano-L-(3-(1-cyclopropyl1H-pyrazol-4-yl)phenyl)-H-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 551.4

Alternative terms:

1Et ₃ N, CH2C12, rt, overnight;

2Solvent was CH2Cl2;

³ Amine in pyridine only (no toluene);

4DMAP, pyridine, 80°C, overnight;

5DMAP, Et ₃ N, toluene, 80°C, 90 min.

Intermediate 22: trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide o

Step 1: N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline

Mixture of intermediate 13 (824 mg, 1.89 mmol), bis(pinacolato)diboron (727 mg, 2.86 mmol), potassium acetate (373 mg, 3.80 mmol), Pd(dppf)Cl ₂ (141 mg , 0.19 mmol) and DMF (12 ml) were degassed in 3 vacuum/N ₂ cycles, heated at 80° C. for 24 h and then allowed to cool to rt. The mixture was filtered through Celite with an EtOAc wash. The filtrate was washed with 50 ml water, washed with 50 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-10% EtOAc in hexanes) to give N-((trans-4-( 4-Methoxy-3methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (563 mg, ~90% purity, ~60% yield ) as a green sticky foam.

1H NMR (400 MHz, DMSC-d6): δ 7.07 (t, 1H), 7.01-6.95 (m, 2H), 6.95-6.91 (m, 1H), 6.84 -6.79 (m, 2H), 6.70-6.65 (m, 1H), 5.63 (t, 1H), 3.73 (s, 3H), 2.90-2.85 (m , 2H), 2.43-2.33(m, 1H), 2.11(s, 3H), 1.96-1.88(m, 2H), 1.82-1.75(m, 2H ), 1.63-1.52 (m, 1H), 1.44-1.33 (m, 2H), 1.27 (s, 12H), 1.13-1.03 (m, 2H); LCMS: 436.0 [M+H]+.

Step 2: N-((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(2-methoxythiazol-5yl)aniline

- 172 040704

A mixture of N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ( 532 mg, 1.22 mmol), 5-bromo-2-methoxythiazole (363 mg, 1.87 mmol), Cs ₂ CO ₃ (1.23 g, 3.77 mmol), Pd (PPh ₃ ) ₄ (284 mg, 0.246 mmol) and DMF (6 ml) were degassed in 3 vacuum/N ₂ cycles. Water (60 μl, 1 vol%) was added and the reaction mixture was heated at 80° C. for 4.5 h then allowed to cool to rt. The mixture was poured into 40 ml saturated NaHCO ₃ solution and extracted with EtOAc (2x40 ml). Each extract was washed with 40 ml of brine. The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (5-20% EtOAc in hexanes) to give N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl )-3-(2-Methoxythiazol-5-yl)aniline (351 mg, 68%).

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.50-7.48 (m, 1H), 7.08 (t, 1H), 7.01-6.96 (m, 2H), 6, 82-6.79 (m, 1H), 6.69-6.65 (m, 2H), 6.54-6.49 (m, 1H), 5.83 (t, 1H), 4.03 ( s, 3H), 3.73 (s, 3H), 2.92 (t, 2H), 2.43-2.34 (m, 1H), 2.11 (s, 3H), 1.98-1 .89 (m, 2H), 1.84-1.74 (m, 2H), 1.65-1.52 (m, 1H), 1.46-1.32 (m, 2H), 1.17 -1.04 (m, 2H); LCMS: 423.4 [M+H]+.

Step 3: trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide

A solution of intermediate 19 (0.1 ml, 0.36 mmol) was added to a solution of N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)-3-(2-methoxythiazol-5-yl)aniline (148 mg, 0.35 mmol), pyridine (0.11 ml, 1.4 mmol) and CH ₂ Cl ₂ (3.5 ml) at rt.

The reaction mixture was stirred for 10 min, poured into 20 ml of saturated NaHCO3 solution and then extracted with CH ₂ Cl ₂ . The organic phases were washed with 20 ml brine, dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (10-30% EtOAc in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N(( trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide (181 mg, ~86% purity, 67% yield) as white foam.

¹ H NMR (400 MHz, DMSC-d6): δ 7.75 (s, 1H), 7.56-7.46 (m, 3H), 7.26-7.20 (m, 1H), 6, 98-6.92 (m, 2H), 6.81-6.76 (m, 1H), 4.06 (s, 3H), 3.72 (s, 3H), 3.60-3.44 ( m, 3H), 2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.07-1.99 (m, 1H), 1.79-1.68 (m, 6H), 1.68-1.60 (m, 2H), 1.50-1.37 (m, 3H), 1.36-1.23 (m, 2H), 1.12-0.98 ( m, 2H), 0.91-0.76 (m, 11H), -0.02 (s, 6H); LCMS: 663.5 [M+H]+.

Step 4: trans-4-Hidroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (6 N, 0.35 ml, 2.1 mmol) was added to a solution of trans-4((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)-N-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide (176 mg, 0.265 mmol), CH3OH (1 ml) and THF (1 ml) at r.t. The reaction mixture was stirred for 1 min, poured into 20 ml saturated NaHCO3 solution and then extracted with EtOAc (2x20 ml). The combined extracts were washed with 20 ml saturated NaHCO ₃ , washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (40-90% EtOAc in hexanes) to give trans-4-hydroxy -N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide (68 mg, 93% purity, 50% yield ) as a whitish foam.

1 H NMR (400 MHz, DMSO-d6): δ 7.76 (s, 1H), 7.57-7.47 (m, 3H), 7.27-7.21 (m, 1H), 6.98 -6.92 (m, 2H), 6.81-6.75 (m, 1H), 4.41 (br s, 1H), 4.06 (s, 3H), 3.71 (s, 3H) , 3.63-3.50 (m, 2H), 3.31-3.21 (m, 1H), 2.38-2.28 (m, 1H), 2.09 (s, 3H), 2 .03-2.00 (m, 1H), 1.81-1.68 (m, 6H), 1.68-1.58 (m, 2H), 1.49-1.35 (m, 3H) , 1.35-1.22 (m, 2H), 1.13-1.00 (m, 2H), 0.83-0.69 (m, 2H); LCMS: 549.4 [M+H]+.

Intermediate 23: trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)cyclohexanecarboxamide

Step 1: trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)-N-((trans-4-(4- methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide Mixture of intermediate 21.02 (800 mg, 1.27 mmol), 2-yl)pyrazole (297.4 mg, 1.27 mmol), Cs ₂ CO ₃ (827.8 mg, 2.54 mmol), Pd(PPh ₃ ) ₄ (146.8 mg, 0.127 mmol), DMF (10 ml) and H ₂ O (0.2 ml) were degassed in 3 vacuum/N ₂ cycles. The mixture was stirred at 50° C. under N2 for 1 h, allowed to cool to rt, poured into water (50 ml) and then extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 80/20) to give trans-4-((tert-butyldimethylsilyl)oxy )-N-(4-(1-cyclopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)-N-((trans-4-(4-methoxy- 173 040704

3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (720 mg, 86%) as a yellow oil.

'H NMR (400 MHz, CDCl ₃ ): δ 8.46 (d, 1H), 7.86 (d, 2H), 7.29 (d, 1H), 7.22 (s, 1H), 6, 97-6.92 (m, 2H), 6.73 (d, 1H), 3.79 (s, 3H), 3.76 (d, 2H), 3.72-3.65 (m, 1H) , 3.60-3.50(m, 1H), 2.41-2.31(m, 1H), 2.27-2.16(m, 4H), 1.90-1.79(m, 8H), 1.67-1.57 (m, 3H), 1.41-1.30 (m, 2H), 1.23-1.05 (m, 8H), 0.84 (s, 9H) 0.02 (s, 6H); LCMS: 657.5 [M+H]+.

Step 2: trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (1 M, 1.7 mL, 1.7 mmol) was added to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridine -2-yl)-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (720 mg, 1.10 mmol), CH ₃ OH (10 ml) and THF (10 ml) at 0°C. The mixture was allowed to warm to rt. and stirred for 1 h. Saturated aq. was added. NaHCO ₃ solution (40 ml) and the mixture was extracted with EtOAc (3x40 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=60/40) to give trans-N-(4-( 1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (395.8mg, 66 %) as a white solid.

'H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.44 (d, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7 .57 (d, 1H), 6.976.89 (m, 2H), 6.80-6.72 (m, 1H), 4.41 (d, 1H), 3.81-3.73 (m, 1H ), 3.71 (s, 3H), 3.67 (d, 2H), 3.31-3.21 (m, 1H), 2.33-2.26 (m, 1H), 2.19- 2.10 (m, 1H), 2.08 (s, 3H), 1.81-1.67 (m, 8H), 1.47-1.35 (m, 3H), 1.30-1, 20 (m, 2H), 1.12-1.06 (m, 2H), 1.06-0.94 (m, 4H), 0.88-0.74 (m, 2H); LCMS: 543.3 [M+H] ⁺ .

The following intermediates were synthesized from intermediate 21.02 or intermediate 21.04 and the appropriate boronic acid/ester according to the procedures described for intermediate 23.

ID No. Structure

Name

[M+N] ⁺

23.01

trans-R-(4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)-4-hydroxy-7U((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

560.4

23.02

trans-R-(4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)-4-hydroxy-R-((4(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) cyclohexanecarboxamide

586.3

23.03

trans-R-(6-(Dimethylamino)-[3,4' bipyridine] -2'-yl)-4-hydroxy-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

The following intermediates were synthesized from the appropriate intermediate and the appropriate boronic acid/ester according to the procedure described for Intermediate 23, Step 1.

- 174 040704

ID No. Structure Name [M+N] ⁺ 23.04 / Oh Mr. 7 X / trans-Methyl-4-((4-(2- cyclopropylthiazol-5-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexane rboxylate 628.4 May 23 / About V7 / trans-Methyl-4-((4-(2- cyclopropylthiazol-5-yl)pyridine2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 602.2 23.06 ¹ Eat / trans-Methyl-4-((4-(1-cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 585.2 23.07 A o o λ tert-butyl (trans-4-((4-(1cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 642.9 23.08 O II J N 1 n tert-butyl (trans-4-((4-(1isopropyl-1H-pyrazol-4yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 644.6

Alternative conditions: ¹ Pd(PPh ₃ ) ₄ , K2CO ₃ , dioxane, water (10%), 100°С, 2 h.

Intermediate 24: trans-N-(3-(6-(Dimethylamino)pyridin-3-yl)phenyl)-4-hydroxy-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide η o

Step 1: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(6-(dimethylamino)pyridin-3-yl)phenyl)N-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Mixture of intermediate 21 (130 mg, 0.192 mmol), (6-(dimethylamino)pyridin-3yl)boronic acid (50 mg, 0.301 mmol), K ₂ CO ₃ (85 mg, 0.615 mmol), Pd(dppf)Cl ₂ (15 mg, 0.021 mmol), dioxane (1.8 ml) and H2O (1.3 ml) were degassed with vacuum/nitrogen (3x) cycles, heated at 80°C for 25 min and then cooled to rt. The reaction mixture was diluted with EtOAc (20 ml), washed (2x20 ml H ₂ O), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(6(dimethylamino)pyridin-3-yl)phenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide as a white foam (93 mg, 72%).

¹ H NMR (400 MHz, DMSO-d6): δ 8.47 (d, 1H), 7.87 (dd, 1H), 7.64 (d, 1H), 7.54-7.48 (m, 2H), 7.19 (d, 1H), 6.96-6.92 (m, 2H), 6.79-6.76 (m, 1H), 6.74 (d, 1H), 3.71 (s, 3H), 3.61-3.54 (m, 2H), 3.53-3.43 (m, 1H), 3.07 (s, 6H), 2.39-2.28 (m , 1H), 2.11-2.00 (m, 4H), 1.81-1.60 (m, 8H), 1.51-1.38 (m, 3H), 1.35-1.21 (m, 2H), 1.12-0.99 (m, 2H), 0.90-0.73 (m, 11H), -0.03 (s, 6H); LCMS: 670.6 [M+H]+.

Step 2: trans-N-(3-(6-(Dimethylamino)pyridin-3-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (1 N, 0.25 ml, 0.25 mmol) was added to a solution of trans-4((tert-butyldimethylsilyl)oxy)-N-(3-(6-(dimethylamino)pyridin-3-yl)phenyl )-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (85 mg, 0.127 mmol), CH ₃ OH (0.5 ml) and THF (0.5 ml) at 0 ° WITH. The ice bath was removed and the mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc (20 ml), washed (20 ml saturated NaHCO ₃ solution and then 20 ml brine), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on

- 175 040704 silica gel (0-5% CH ₃ OH in CH2C12) to give trans-N-(3-(6-(dimethylamino)pyridin-3-yl)phenyl)-4hydroxy-K-((trans-4-( 4-Methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide as a white foam (61 mg, 86%). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (d, 1H), 7.87 (dd, 1H), 7.64 (d, 1H), 7.547.48 (m, 2H), 7, 19 (d, 1H), 6.96-6.92 (m, 2H), 6.79-6.76 (m, 1H), 6.74 (d, 1H), 4.39 (d, 1H) , 3.71 (s, 3H), 3.633.51 (m, 2H), 3.31-3.20 (m, 1H), 3.07 (s, 6H), 2.39-2.28 (m , 1H), 2.15-2.00 (m, 4H), 1.84-1.69 (m, 6H), 1.681.56 (m, 2H), 1.51-1.36 (m, 3H ), 1.35-1.22 (m, 2H), 1.13-0.98 (m, 2H), 0.85-0.69 (m, 2H); LCMS: 556.5 [M+H]+.

The following intermediates were synthesized from the appropriate iodide intermediate and the appropriate boronic acid/ester according to the procedure described for Intermediate 24.

ID No. Structure 24.01 p L Υ*ι A o-on ° LL ^Ν \7 24.02 I\ 24.03 b O Λ o / x 24.04 A r r ° 2'

Name [M+N] ⁺ trans-I-(3-(6- Cyclopropylpyridin-3-yl)phenyl)4-hydroxy-7U-((trans-4-(4-methoxy- methylphenyl)cyclohexyl)methyl)ci clohexanecarboxamide 553.5 trans-I-(3-(2- (Dimethylamino)pyrimidin-5 yl)phenyl)-4-hydroxy-R-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)ci clohexanecarboxamide 557.3 trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)4-hydroxy-R-(3-(1-isopropyl-\Hpyrazole-4- yl)phenyl)cyclohexanecarboxamide 555.5 trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)R-(3-(1-cyclopropyl-1R-pyrazol-4yl)phenyl)-4hydroxycyclohexanecarboxamide 553.5

Intermediate 25: trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-N-(3-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanecarboxamide

A mixture of bis (pinacolato) diboron (1.42 g, 5.59 mmol), potassium acetate (1.45 g, 14.8 mmol), Pd (dppf) Cl ₂ (135 mg, 0.18 mmol) and toluene ( 23 ml) was degassed in 3 vacuum/N ₂ cycles. Intermediate 21 (2.50 g, 3.70 mmol) was added to the mixture and the reaction mixture was degassed with 2 vacuum/N ₂ cycles, heated at 115°C for 3.5 h and then allowed to cool to rt. The mixture was diluted with 75 ml EtOAc. The organic phases were washed with saturated NaHCO ₃ (2x75 mL), dried (Na ₂ SO ₄ ), filtered, concentrated and dried under high vacuum overnight to give trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans -4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanecarboxamide (2 .99 g, 120% crude) as a brown solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.82-7.78 (m, 1H), 7.61-7.57 (m, 1H), 7.43 (t, 1H), 7.27- 7.24 (m, 1H), 6.996.94 (m, 2H), 6.74 (d, 1H), 3.80 (s, 3H), 3.72-3.45 (m, 3H), 2 .44-2.33 (m, 1H), 2.20 (s, 3H), 2.11-2.01 (m, 1H), 1.90-1.76 (m, 6H), 1.75 -1.65 (m, 3H), 1.58-1.47 (m, 2H), 1.42-1.32 (m, 14H), 1.24-1.10 (m, 2H), 1 .06-0.92 (m, 2H), 0.84 (s, 9H), 0.01 (s, 6H); LCMS: 676.6 [M+H]+. Note: Intermediate 25 was also synthesized from a bromine-containing version of intermediate 21.

Intermediate 26: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-hydroxy-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

- 176 040704

Step 1: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexanecarboxamide

Mixture of 5-bromo-2-cyclopropylthiazole (93 mg, 0.45 mmol), intermediate 25 (204 mg, 0.302 mmol), Pd(dppf)Cl ₂ (23 mg, 0.031 mmol), Cs ₂ CO ₃ (290 mg , 0.89 mmol), DMF (3 ml) and water (30 μl, 1 vol%) were degassed in 3 vacuum/N ₂ cycles, stirred at 80° C. for 25 min and then allowed to cool to rt. The reaction mixture was poured into 20 ml saturated NaHCO ₃ solution and then extracted with 20 ml EtOA^ The organic layer was washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (520% EtOAc in hexanes ) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide (179 mg, 88%) as a white foam.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 8.09 (s, 1H), 7.63-7.55 (m, 2H), 7.52 (t, 1H), 7.29-7, 22 (m, 1H), 6.986.91 (m, 2H), 6.82-6.75 (m, 1H), 3.71 (s, 3H), 3.62-3.44 (m, 3H) , 2.47-2.38 (m, 1H), 1.38-2.28 (m, 1H), 2.09 (s, 3H), 2.07-1.99 (m, 1H), 1 .79-1.68 (m, 6H), 1.68-1.60 (m, 2H), 1.51-1.37 (m, 3H), 1.36-1.23 (m, 2H) , 1.18-1.11 (m, 2H), 1.11-0.96 (m, 4H), 0.91-0.72 (m, 11H), -0.03 (s, 6H); LCMS: 673.4 [M+H]+.

Step 2: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (6 N, 0.35 ml, 2.1 mmol) was added to a solution of trans-4((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (174 mg, 0.26 mmol), CH ₃ OH (0.7 ml) and THF (0.7 ml) at 0 °C. The reaction mixture was allowed to warm to rt, stirred at rt. for 30 min and then poured into 20 ml of cold saturated NaHCO ₃ solution. The mixture was extracted with 20 ml of EtOAc. The organic layer was washed with 20 ml of saturated NaHCO ₃ solution and washed with 20 ml of brine. The first aqueous wash was back extracted with 10 ml of EtOAc. The combined EtOAc extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-N-(3-(2-cyclopropylthiazol-5-yl) phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (131 mg, 90%) as a white foam.

1 H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.63-7.55 (m, 2H), 7.53 (t, 1H), 7.30-7.23 (m, 1H), 6.986.91 (m, 2H), 6.82-6.75 (m, 1H), 4.40 (d, 1H), 3.71 (s, 3H), 3.62- 3.50 (m, 2H), 3.31-3.20 (m, 1H), 2.48-2.39 (m, 1H), 2.38-2.27 (m, 1H), 2, 09 (s, 3H), 2.06-1.96 (m, 1H), 1.80-1.68 (m, 6H), 1.68-1.58 (m, 2H), 1.49- 1.35 (m, 3H), 1.35-1.22 (m, 2H), 1.18-1.11 (m, 2H), 1.11-0.97 (m, 4H), 0. 83-0.69 (m, 2H); LCMS: 559.9 [M+H]+.

Intermediate 27: trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxαamide

Step 1: 5-Bromo-2-((trimethylsilyl)ethynyl)thiazole n-Butyllithium (2.5 M in hexanes, 4.50 mL) was added to a solution of 2-((trimethylsilyl)ethynyl)thiazole (2.00 g, 11.03 mmol) in THF (50 ml) at -78°C. The mixture was stirred for 1 hour at -78°C. Bromine (1.59 g, 9.93 mmol) was added to the mixture. The mixture was stirred for 1 h at -78°C, poured into saturated water. NH ₄ Cl solution (100 ml) and then extracted with EtOAc (2x100 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 600/1 - 300/1) to give 5-bromo-2-((trimethylsilyl)ethynyl)thiazole ( 1.80 g, 62% yield) as a red oil.

'H NMR (400 MHz, CDCI3): δ 7.77 (s, 1H), 0.36 (s, 9H); LCMS: 260.0 [M+H]+.

Step 2: trans-4-((tert-Butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-((5-(trimethylsilyl) thiazol-2-yl)ethynyl)phenyl)cyclohexancarboxamide

To a solution of intermediate 25 (900 mg, 1.33 mmol), 5-bromo-2((trimethylsilyl)ethynyl)thiazole (693 mg, 2.66 mmol), dioxane (12 ml) and H ₂ O (2 ml) Pd(dppf)Cl ₂ (195 mg, 0.266 mmol) and Na ₂ CO ₃ (285.9 mg, 2.70 mmol) were added. The mixture was degassed with 3 vacuum/N ₂ cycles, stirred for 2 h at 80° C. and then allowed to cool to rt. The reaction mixture was diluted with H ₂ O (30 ml) and then extracted with EtOAc (2x50 ml). The combined organic phases were dried over Na2SO4, filtered, concentrated and then purified by silica gel column chromatography (elution with petroleum ether/EtOAc = 30/1 - 10/1) to give trans-4-((tert-177 040704 butyldimethylsilyl)oxy)- N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-((5-(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamide (230 mg, 24 % yield) as a yellow oil.

1 H NMR (400 MHz, CDCl ₃ ) δ: 7.86 (s, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.41 (s, 1H), 7.21 (d, 1H), 6.97-6.95 (m, 2H), 6.73 (d, 1H), 3.78 (s, 3H), 3.60 (d, 2H), 3.55- 3.51 (m, 1H), 2.43-2.34 (m, 1H), 2.18 (s, 3H), 2.08-2.03 (m, 1H), 1.88-1, 78 (m, 6H), 1.67-1.58 (m, 4H), 1.44-1.37 (m, 3H), 1.21-1.17 (m, 2H), 1.07- 1.03 (m, 2H), 0.83 (s, 9H), 0.38 (s, 9H), 0.00 (s, 6H); LCMS: 729.3 [M+H]+.

Step 3: trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-((5(trimethylsilyl)thiazol-2-yl)ethynyl )phenyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (1 M, 1 ml) was added to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3 -((5-(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamide (230 mg, 0.315 mmol) in CH ₃ OH (6 ml) at 0°C. The mixture was stirred for 1 h at RT. and concentrated under reduced pressure. The reaction mixture was diluted with saturated aqueous solution. NaHCO ₃ solution (10 ml) and then extracted with CH ₂ Cl ₂ (2x10 ml). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give trans-4-hydroxy-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-N-(3-((5- (trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamide (180 mg, crude) as a yellow oil. LCMS: 615.5 [M+H] ⁺ .

Step 4: trans-4-Hidroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide

Potassium fluoride (68.7 mg, 1.18 mmol) was added to a solution of trans-4-hydroxy-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)-N-(3-((5 -(trimethylsilyl)thiazol-2-yl)ethynyl)phenyl)cyclohexanecarboxamide (180 mg, 0.293 mmol) in CH ₃ CN (10 ml). The mixture was stirred overnight at 70°C. The resulting mixture was filtered through filter paper to remove excess potassium fluoride. The filtrate was concentrated and then purified by reverse phase HPLC (water (10 mM NH4HCO3)MeCN) to give trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N- (3(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide (82.4 mg, 51% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ: 7.98 (d, 1H), 7.95 (d, 1H), 7.68-7.64 (m, 2H), 7.57 (t, 1H ), 7.44 (d, 1H), 6.92 (s, 2H), 6.76 (d, 1H), 4.40 (d, 1H), 3.69 (s, 3H), 3.53 (d, 2H), 3.27-3.25 (m, 1H), 2.33-2.28 (m, 1H), 2.07 (s, 3H), 1.96 (t, 1H), 1.71-1.59 (m, 8H), 1.42-1.26 (m, 5H), 1.03-1.00 (m, 2H), 0.77-0.74 (m, 2H ); LCMS: 543.2 [M+H] ⁺ .

Intermediate 28: trans-4-Hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(thiazole-2- ylethynyl)phenyl)cyclohexanecarboxyamide

Step 1: trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3 -((trimethylsilyl)ethynyl)phenyl)cyclohexanecarboxyamide

Mixture of Intermediate 21.03 (2.75 g, 3.92 mmol), ethynyl(trimethyl)silane (384.9 mg, 3.92 mmol), CuI (74.6 mg, 0.392 mmol), Pd(dppf)Cl ₂ (286.7 mg, 0.392 mmol) and dry Et ₃ N (30 ml) were degassed in 3 vacuum/N ₂ cycles, stirred at 90° C. under N 2 for 2 h and then allowed to cool to rt. The reaction mixture was poured into 100 ml water and extracted with EtOAc (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 95/5) to give trans-4((tert-butyldimethylsilyl)oxy)-N-((4- (4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3((trimethylsilyl)ethynyl)phenyl)cyclohexanecarboxamide (2.12 g, 81%) as white solid substances.

1H NMR (400 MHz, CDCl ₃ ): δ 7.43-7.39 (m, 1H), 7.35-7.30 (m, 2H), 7.20 (d, 1H), 7.07- 7.02 (m, 2H), 6.73 (d, 1H), 3.79 (s, 3H), 3.73-3.39 (m, 3H), 2.23-2.17 (m, 4H), 1.84-1.79 (m, 2H), 1.76-1.63 (m, 10H), 1.50-1.43 (m, 6H), 1.09-0.99 ( m, 2H), 0.93-0.82 (m, 9H), 0.29 (s, 9H), 0.02 (s, 6H); LCMS: 672.3 [M+H]+.

Step 2: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl )methyl)cyclohexanecarboxamide

Ammonium fluoride (688.8 mg, 18.60 mmol) was added to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1-yl)methyl)-N-(3-((trimethylsilyl)ethynyl)phenyl)cyclohexanecarboxamide (2.5 g, 3.72 mmol) in CH ₃ OH (50 ml) at r.t. The reaction mixture was heated to 60° C., stirred for 3 h and then allowed to cool to rt. The reaction mixture was concentrated to dryness and purified by silica gel chromatography (petroleum ether/EtOAc=95/5) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N((4-(4 -methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (1.6 g, 72%) in

- 178 040704 as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ): δ 7.47-7.42 (m, 1H), 7.40-7.34 (m, 2H), 7.24 (d, 1H), 7.08- 7.02 (m, 2H), 6.74 (d, 1H), 3.79 (s, 3H), 3.62 (s, 2H), 3.57-3.50 (m, 1H), 3 .16 (s, 1H), 2.24-2.12 (m, 4H), 1.86-1.78 (m, 2H), 1.771.57 (m, 10H), 1.50-1.43 (m, 6H), 1.10-0.97 (m, 2H), 0.85 (s, 9H), 0.02 (s, 6H); LCMS: 600.5 [M+H]+.

Step 3: trans-4-((tert-Butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3 -(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide

A mixture of trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-ethynylphenyl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl )cyclohexanecarboxamide (1.4 g, 2.33 mmol), 2-bromothiazole (765.6 mg, 4.67 mmol), CuI (44.4 mg, 0.233 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (163 .8 mg, 0.233 mmol) and dry Et ₃ N (15 ml) were degassed in 3 vacuum/X ₂ cycles, stirred at 90° C. under N ₂ for 1 h and then allowed to cool to rt. The reaction mixture was poured into 90 ml of water and then extracted with EtOAc (3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc=95/5) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-((4 -(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide (1.36 g) as a yellow solid substances.

1 H NMR (400 MHz, CDCl ₃ ): δ 7.91 (d, 1H), 7.49 (d, 1H), 7.46 (d, 1H), 7.43-7.39 (m, 2H) , 7.29 (s, 1H), 7.07-7.03 (m, 2H), 6.76-6.72 (m, 1H), 3.79 (s, 3H), 3.62 (s , 2H), 3.57-3.50 (m, 1H), 2.21-2.13 (m, 4H), 1.871.79 (m, 2H), 1.77-1.56 (m, 10H ), 1.50-1.43 (m, 6H), 1.10-0.97 (m, 2H), 0.85 (s, 9H), 0.02 (s, 6H).

Stage 4: trans-4-Hydroxy-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-N-(3(thiazol-2-ylethynyl) phenyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (1 M, 3 ml, 3.0 mmol) was added to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)-N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide (1.36 g) in CH3OH (10 ml) and THF (10 ml) at 0°C. The reaction mixture was allowed to warm to rt. and stirred for 1 h. Saturated aq. NaHCO ₃ solution (40 ml) was added and the mixture was extracted with EtOAc (3x40 ml). The combined organic layers were washed with brine (20 ml), dried over Na2SO4, filtered, concentrated and then purified by silica gel chromatography (CH ₂ C1 ₂ /CH ₃ OH=97/3). The crude material was further purified by reverse phase prep. HPLC (water (10 mmol NH ₄ HCO ₃ )/MeCN) to give trans-4-hydroxy-N-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)- N-(3-(thiazol-2-ylethynyl)phenyl)cyclohexanecarboxamide (47.3 mg, 13%) as a white solid.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 7.98 (d, 2H), 7.73 (s, 1H), 7.62 (s, 1H), 7.58-7.50 (m, 2H), 7.05-6.97 (m, 2H), 6.76 (d, 1H), 4.45-4.41 (m, 1H), 3.70 (s, 3H), 3.65 -3.45(m, 2H), 3.30-3.21(m, 1H), 2.15-2.05(m, 4H), 1.75(d, 2H), 1.70-1 .55 (m, 8H), 1.45-1.32 (m, 8H), 0.90-0.70 (m, 2H); LCMS: 569.3 [M+H] ⁺ .

Intermediate 29: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4(3-fluoro-1-methyl-1H-indazol-5 - yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide

Step 1: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)N-((trans-4-(3-fluoro-1 -methyl-1H-indazol-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide

Intermediate 19 (75 mg/ml solution in toluene, 1.7 ml, 0.461 mmol) was added to a solution of Intermediate 14.25 (130 mg, 0.293 mmol), pyridine (95 μl, 1.17 mmol) and toluene (2.5 ml) in H ₂ O bath at r.t. The mixture was stirred at rt. for 2 h, diluted with EtOAc (20 ml), washed (20 ml saturated NaHCO ₃ solution and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (040% EtOAc in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)-N-( (trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide (184 mg, 90%) as a white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7, 50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (d, 1H), 7.10 (d, 1H), 3.86 (s, 3H), 3.77 -3.70 (m, 1H), 3.68-3.42 (m, 3H), 2.61-2.52 (m, 1H), 2.13-2.02 (m, 1H), 1 .84-1.75 (m, 4H), 1.75-1.68 (m, 2H), 1.68-1.59 (m, 2H), 1.54-1.33 (m, 5H) , 1.14-1.03 (m, 4H), 1.02-0.92 (m, 2H), 0.90-0.72 (m, 11H), -0.03 (s, 6H); LCMS: 684.2 [M+H] ⁺ .

Step 2: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl) cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide

Aqueous hydrochloric acid (1 N, 0.5 ml, 0.5 mmol) was added to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl )-N-((trans-4-(3-fluoro-1-methyl1H-indazol-5-yl)cyclohexyl)methyl)cyclohexanecarboxamide (180 mg, 0.263 mmol), THF (1 ml) and CH3OH (1 ml) at 0°C. The ice bath was removed after 10 minutes and the reaction mixture was stirred for 50 minutes. The mixture was diluted with EtOAc (20 ml), washed (2x20 ml saturated NaHCO ₃ solution and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans- 4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)-4-hydroxycyclohexanecarboxamide (150 mg, 100%, 95% pure) as a white foam.

¹ H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7 .50 (dd, 1H), 7.48-7.41 (m, 2H), 7.36 (dd, 1H), 7.10 (d, 1H), 4.38 (d, 1H), 3, 86 (s, 3H), 3.77-3.70 (m, 1H), 3.68-3.43 (m, 2H), 3.31-3.20 (m, 1H), 2.61- 2.52 (m, 1H), 2.16-2.00 (m, 1H), 1.84-1.68 (m, 6H), 1.68-1.59 (m, 2H), 1, 52-1.33 (m, 5H), 1.15-1.04 (m, 4H), 1.02-0.96 (m, 2H), 0.81-0.67 (m, 2H); LCMS: 570.4 [M+H]+.

The following intermediates were synthesized from the appropriate secondary amine intermediate and intermediate 19 according to the procedures described for intermediate 29.

ID No. Structure Name [M+N] ⁺ 29.01 A' to 4 trans-A-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-A-((trans-4-(6(d imethylamino)pyridin-3 yl)cyclohexyl)methyl)-4hydroxycyclohexanecarboxamide 542.4 29.02 About r 1 trans-A-(3 -(1-cyclopropyl-\Hpyrazol-4-yl)phenyl)-4-hydroxy-I((trans-4-(5-methoxy-6-methylpyridine- 2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 543.5 29.03 ¹ ABOUT χ°Χ trans-A-((trans-4-(6-cyano-5- methoxypyridine-2- yl) cyclohexyl)methyl)-A-(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)-4- hydroxycyclohexanecarboxamide 554.5

- 180 040704

29.04 ¹ _YA° o o A g trans-4-Γ hydroxy-L-(3-(1-isopropyl1H-pyrazol-4-yl)phenyl)-H-((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexanecarboxamide 545.5 May 29 ¹ a J3'''aX ^c 'XJj όγ' ^he trans-R-((trans-4-(5-chloro-6methoxypyr idin-3 yl)cyclohexyl)methyl)-R-(3 -(1 cyclopropyl- 1R-pyrazol-4yl)phenyl)-4- hydroxycyclohexanecarboxamide 563.5 29.06 ¹ Ρ7=° Λ O λ ί trans-R-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-hydroxy-R((trans-4-(6-methoxy-5-methylpyridine- 3- yl)cyclohexyl)methyl)cyclohexanecarboxamide 543.4 29.07 ¹ 0 jA'Aj Ύ ^ν *ι Λ ^' ^0Η μ _ν trans-R-(3 -(1 -(tert-butyl)- 1Hypyrazol-4-yl)phenyl)-4-hydroxy-R((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 559.5 29.08 ¹ ο ο °4ZpC > ⁷ ο / trans-R-(3-(1-Cyclobutyl-1Hpyrazol-4-yl)phenyl)-4-hydroxy-R((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 557.5

- 181 040704

29.09 ^1.2 If / trans-4-Γ hydroxy-R-(4-(1-isopropyl1R-pyrazol-4-yl)pyridin-2-yl)-R((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 546.5 29.10 ¹ /=\ / J%>° A o z \__/ θ / I trans-I-((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)-4-hydroxy-R(3-(1-isopropyl-1H-pyrazol-4yl)phenyl)cyclohexanecarboxamide 556.5 29.11 % p p 7 / trans-LCZ - (1-Cyclopropyl- 1Hpyrazol-4-yl) phenyl) -4-hydroxy-R ((trans-4- (4-methoxy-3- methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 542.5 29.12 0 hard ^X trans-4-Γ hydroxy-R-(3 -(1-isopropyl1R-pyrazol-4-yl)phenyl)-R-((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cycle hexanecarboxamide 544.4 29.13 ¹ 0 trans-R-(3 -(1-cyclopropyl- 1Hpyrazol-4-yl)phenyl)-4-hydroxy-R((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)cyclohexanecarboxamide 568.4 29.14 0 % trans-R-(3-(2-cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(3-fluoro-1 methyl- 1R-indazol-5 yl)cyclohexyl)methyl)-4hydroxycyclohexanecarboxamide 587.9

- 182 040704

29.15 o Υ ^χ νΑυ ά s ^{OH 1} trans-A-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-I-((trans-4-(6- (d imethylamino) pyridine-3 - yl)cyclohexyl)methyl)-4hydroxycyclohexanecarboxamide 559.4 29.16 ¹ A trans-R-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-hydroxy-R-((4-(4methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)cyclohexanecarboxamide 585.4 29.17 ^1.2 υΎ trans-L-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-4-hydroxy-R-((trans-4-(5methoxy-6-methylpyridin-2 yl)cyclohexyl)methyl)cyclohexanecarboxamide 560.3 29.18 ^1.2 0 trans-R-(4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)-4-hydroxy-R((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 561.4 29.19 ¹ 0 trans-R-((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)-R-(3-(2cyclopropylthiazol-5-yl)phenyl)-4hydroxycyclohexanecarboxamide 571.3 29.20 ¹ 0 4¾ trans-4-Hydroxy-R-(3-(2isopropylthiazol-5-yl)phenyl)-R((trans-4-(5-methoxy-6-methylpyridine2- yl)cyclohexyl)methyl)cyclohexanecarboxamide 562.4

(1 g, 4 g)-4-Hydro roxy-L-(3-(1-isopropyl1H-pyrazol-4-yl)phenyl)-R-((trans-4(4-methoxy-3-558.3 methylphenyl )cyclohexyl)methyl)-4methylcyclohexanecarboxamide (1s,4s)-4-T hydroxy-L-(3-(1-isopropyl1H-pyrazol-4-yl)phenyl)-R-((trans-4(4-methoxy- 3-558.3 methylphenyl)cyclohexyl)methyl)-4methylcyclohexanecarboxamide

Alternative terms:

Step 1: 1 The solvent was CH2C12;

2 The base was Et ₃ N; Stage 2:

M HCl, THF, MeOH, 45°C, overnight.

⁴ Isolated during purification of intermediate 29.21.

Intermediate 30: (M1125, 050-102/106) trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans- 4-(5-Methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide

- 183 040704

Step 1: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)-N-((trans-4-(5- methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide

Intermediate 19 (1.6 ml, 0.42 mmol, 73 mg/ml in toluene) was added to a mixture of intermediate 14.29 (87 mg, 0.21 mmol), DMAP (26 mg, 0.21 mmol) and pyridine (1.5 ml) at rt. The reaction mixture was heated at 80°C for 75 min, allowed to cool to rt. and then diluted with EtOAc (20 ml). The organic layer was washed with saturated NaHCO ₃ solution (20 ml), washed with water (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (30-60 % EtOAc in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1 H-pyrazol-4-yl)pyridin-2yl)-N-((trans- 4-(5-Methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide (114 mg, 82% yield) as an off-white foam. ¹ H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.43 (d, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7 .57 (d, 1H), 7.18 (d, 1H), 6.97 (d, 1H), 3.81-3.72 (m, 4H), 3.67 (d, 2H), 3. 57-3.47(m, 1H), 2.512.42(m, 1H), 2.28(s, 3H), 2.25-2.11(m, 1H), 1.84-1.69( m, 8H), 1.50-1.26 (m, 5H), 1.12-0.84 (m, 8H), 0.80 (s, 9H), -0.02 (s, 6H); LCMS: 658.6 [M+H]+.

Step 2: trans-N-(4-(1-Cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(5methoxy-6-methylpyridin-2 -yl)cyclohexyl)methyl)cyclohexanecarboxamide

A solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-(4-(1-cyclopropyl-1 H-pyrazol-4-yl)pyridin2-yl)-N-((trans-4-(5-methoxy -6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide (107 mg, 0.16 mmol) in THF (1 ml) and CH ₃ OH (1 ml) was cooled in an ice/water bath. Aqueous hydrochloric acid (1 N, 0.22 ml, 0.22 mmol) was added at 0°C. The reaction mixture was allowed to warm to rt, stirred for 20 min and then diluted with chilled saturated NaHCO ₃ (20 ml) and EtOAc (20 ml). The organic layer was washed with saturated NaHCO ₃ solution (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-7% methanol in dichloromethane) to obtain trans-N(4-(1-cyclopropyl-1H-n-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl )methyl)cyclohexanecarboxamide (79 mg, 89% yield) as a white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.44 (d, 1H), 8.13 (s, 1H), 7.64 (s, 1H), 7, 57 (dd, 1H), 7.19 (d, 1H), 6.98 (d, 1H), 4.41 (d, 1H), 3.81-3.72 (m, 4H), 3.67 (d, 2H), 3.31-3.22 (m, 1H), 2.51-2.42 (m, 1H), 2.28 (s, 3H), 2.19-2.09 (m , 1H), 1.83-1.67 (m, 8H), 1.48-1.26 (m, 5H), 1.12-0.94 (m, 6H), 0.88-0.75 (m, 2H); LCMS: 544.5 [M+H]+.

The following intermediates were synthesized from the appropriate secondary amine intermediate and intermediate 19 according to the procedures described for intermediate 30.

- 184 040704

30.02 0 dX Xy _N / ^X trans-4-Γhydroxy-R-(4-( 1 isopropyl- 1R-pyrazol-4yl)pyridin-2-yl)-R-((trans-4-(4methoxy-3- methylphenyl)cycle ohexyl)methyl)ci clohexanecarboxamide 545.5 30.03 ¹ 0 I>» _he >Ν trans-H-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)7/-(4-(1-cyclopropyl-1H-pyrazol4-yl)pyridin-2-yl)-4hydroxycyclohexanecarboxamide 554.4 30.04 ¹ 0 Αχ^Ο'Ύ Λ SL ^Χ trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)4-hydroxy-R-(4-(1-isopropyl-\Hpyrazol-4-yl)pyridin-2yl)cyclohexanecarboxamide 556.4 30.05 ¹ ϊ $Ϋ>° ο Ο Ζ \--/ ι cis-I-((4-(3-cyano-4- methoxyphenyl)cyclohexyl)methyl)4-hydroxy-M-(4-(1-isopropyl-Spyrazol-4-yl)pyridin-2yl)cyclohexanecarboxamide 556.4 30.06 ¹ < ί' Υ ί' trans-I-((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)-4-hydroxy/V-(4-(l-isopropyl- 1H-pyrazol-4yl)pyridine-2- yl)cyclohexanecarboxamide 557.4 30.07 ^{1 2} 0 λλΥ -„AN Άγ- _Β- .1 ¹ trans-R-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-R-((4-(6(dimethylamino)pyridin-3yl)bicyclo[2.2.2]octan-1yl)methyl )-4- hydroxycyclohexanecarboxamide 568.5

- 185 040704

30.08 ¹ 0 ^.yXc,. A' trans-R-((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)-R-(4-(1 cyclopropyl-1R-pyrazol-4yl)pyridin-2-yl)-4- hydroxycyclohexanecarboxamide 555.5 30.09 p y / /° trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)R-(4-(2-cyclopropylthiazol-5yl)pyridin-2-yl)-4hydroxycyclohexanecarboxamide 571.4 30.10 ¹ p y / /° trans-R-((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)-T4-(4-(2cyclopropylthiazol-5-yl)pyridin2-yl)-4hydroxycyclohexanecarboxamide 572.4 30.11 /s/ trans-4-Hydroxy-R-(4-(2isopropylthiazol-5-yl)pyridin-2yl)-R-((trans-4-(4-methoxy-3 methyl phenyl)cycle ohexyl)methyl)ci clohexanecarboxamide 562.5 30.12 ¹ 3 / trans-4-Hydroxy-R-(4-(2isopropylthiazol-5-yl)pyridin-2yl)-R-((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)cyclohexane carboxamide 563.4 30.13 Oh ta A trans-N-(3-(2-Cyclopropylthiazol5-yl)phenyl)-N-((4-(6(dimethylamino)pyridin-3yl)bicyclo[2.2.2]octan-1yl)methyl)-4hydroxycyclohexanecarboxamide 585.5

- 186 040704

30.14 ² '-O 30.15 ¹ ABOUT M* 30.16 ΡίΑ -A- 30.17 0 ^0 30.18 ³ ΜΑ /

trans-I-(3-(2- Cyclopropyloxazol-4-yl)phenyl)R-((4-(6-(dimethylamino)pyridin3-yl)pyride in[2.2.2]octan-1yl)methyl)-4hydroxycyclohexanecarboxamide 569.5 trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)-R-(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)-4hydroxycyclohexanecarboxamide 555.5 trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)-R-(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)-4hydroxycyclohexanecarboxamide 557.4 trans-R-((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)-R-(4-(2cyclopropyloxazol-4yl)pyridin-2-yl)-4hydroxycyclohexanecarboxamide 556.4 trans-R-(4-(2-Ethyloxazol-4yl)pyridin-2-yl)-4-hydroxy-R((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)cyclohexane carboxamide 533.4

Alternative terms:

Step 1: 1 Additional acid chloride required, total 2.5-3.5 eq.;

² Heated at 50°C;

³ DMAP, Et ₃ N, toluene, 80°C, 20 min.

Intermediate 31: trans-N-(3-(3-Cyclopropylisothiazol-5-yl)phenyl)-4-hydroxy-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Step 1: 3-(3-Cyclopropylisothiazol-5-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline

Mixture of Intermediate 9 (140 mg, 0.647 mmol), Intermediate 3 (165 mg,

0.712 mmol), AcOH (117 mg, 1.94 mmol) and CH ₃ OH (10 ml) were degassed with vacuum/N ₂ cycles (3x) and stirred at RT. over 2 h. NaBH ₃ CN (81 mg, 1.29 mmol) was added to the mixture and the reaction mixture was stirred at rt. during the night. The solution was concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give 3-(3-cyclopropylisothiazol-5-yl)-N-((trans4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl )aniline (200 mg, 71%) as a yellow solid.

1H NMR (400 MHz, CDCl3): δ 7.22 (t, 1H), 7.07 (s, 1H), 7.00-7.05(m, 2H), 6.86-6.93 (m , 1H), 6.77 (d, 2H), 6.65-6.67 (m, 1H), 3.86-3.93 (m, 1H), 3.82 (s, 3H), 3, 06 (d, 2H), 2.35-2.52 (m, 1H), 2.22 (s, 3H), 2.13-2.20 (m, 1H), 1.89-2.03 ( m, 4H), 1.61-1.75 (m, 1H), 1.43-1.53 (m, 2H), 1.17-1.25 (m, 2H), 0.98-1, 08 (m, 4H); LCMS: 433.2 [M+H]+.

Step 2: trans-4-((tert-Butyldimethylsilyl)oxy)-N-(3-(3-cyclopropylisothiazol-5-yl)phenyl)-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexanecarboxamide

Pyridine (110 mg, 1.39 mmol) was added to a solution of 3-(3-cyclopropylisothiazol-5-yl)-N-((trans-4(4-methoxy-3-methylphenyl)cyclohexyl)methyl)aniline (200 mg, 0.462 mmol) and CH ₂ Cl ₂ (10.0 ml) at rt. The solution was stirred at rt. for 30 min and intermediate 19 (384 mg, 1.39 mmol) was added. The mixture was stirred overnight, concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give trans-4-((tert-butyldimethylsilyl)oxy)N-(3-(3-cyclopropylisothiazol-5-yl )phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (250 mg, 80%) as a colorless oil. LCMS: 673.5 [M+H]+.

- 187 040704

Step 3: trans-N-(3-(3-Cyclopropylisothiazol-5-yl)phenyl)-4-hydroxy-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (2 M, 450 μl, 0.9 mmol) was added slowly to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(3-cyclopropylisothiazol-5-yl)phenyl)-N -((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (250 mg, 0.371 mmol) and CH ₃ OH (10 ml). The solution was stirred at rt. for 1 h, concentrated and then purified by SPHPLC (H ₂ O (10 mm NH ₄ HCO ₃ )/CH ₃ CN) to obtain trans-X-(3-(3-cyclopropylisothiazol-5-yl)phenyl)4- hydroxy-X-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (112 mg, 54%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 7.67-7.71 (m, 2H), 7.65 (s, 1H), 7.58 (t, 1H), 7.38 (d, 1H ), 6.91-6.97 (m, 2H), 6.75-6.81 (m, 1H), 3.71 (s, 3H), 3.53-3.64 (m, 2H), 3.20-3.29 (m, 1H), 2.33 (t, 1H), 2.17-2.25 (m, 1H), 2.09 (s, 3H), 2.01-2, 07 (m, 1H), 1.62-1.81 (m, 8H), 1.23-1.48 (m, 5H), 0.92-1.11 (m, 6H), 0.69- 0.84 (m, 2H); LCMS: 559.6 [M+H]+.

Intermediate 32: trans-N-(3-(2-Cyclopropyloxazol-4-yl)phenyl)-4-hydroxy-N-((4(4-methoxy-3-methylphenyl)pyridine[2.2.2]octane-1 -yl)methyl)cyclohexanecarboxamide

Step 1: 3-(2-Cyclopropyloxazol-4-yl)-X-((4-(4-methoxy-3-methylphenyl)pyridine[2.2.2]octan-1yl)methyl)aniline

Sodium triacetoxyborohydride (496 mg, 2.34 mmol) was added to a solution of intermediate 5 (302 mg, 1.17 mmol), intermediate 8.01 (236 mg, 1.18 mmol) and DCE (6 ml) at 0° WITH. The ice bath was removed and the reaction mixture was stirred at RT. for 1 h. The mixture was diluted with EtOAc (50 ml), washed (2x50 ml saturated NaHCO ₃ solution and then 50 ml brine), dried (Na ₂ SO ₄ ), filtered and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20:1 - 5:1) to give 3-(2-cyclopropyloxazol-4-yl)-X-((4-(4-methoxy-3-methylphenyl)pyridine[2.2 .2]octan-1-yl)methyl)aniline (471 mg, 90%) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.14-7.21 (m, 1H), 7.08-7.14 (m, 2H), 7.02 (s , 1H), 6.96 (d, 1H), 6.77 (d, 1H), 6.52-6.59 (m, 1H), 3.81 (s, 3H), 3.72 (br s , 1H), 2.95-2.96 (m, 2H), 2.22 (s, 3H), 2.11-2.16 (m, 1H), 1.80-1.91 (m, 6H ), 1.58-1.68 (m, 6H), 1.00-1.20 (m, 4H); LCMS: 443.3 [M+H]+.

Step 2: trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-N-((4(4-methoxy-3-methylphenyl)pyridine [2.2 .2]octan-1-yl)methyl)cyclohexanecarboxamide

Intermediate 19 (20 ml, 2.79 mmol, 4.3 wt% solution in toluene) was added to a solution of 3-(2-cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3- methylphenyl)pyridine[2.2.2]octan-1-yl)methyl)aniline (471 mg, 1.06 mmol), pyridine (337 mg, 4.26 mmol) and toluene (8 ml) at 0°C. The ice bath was removed and the reaction mixture was stirred at rt. for 1 h. The mixture was diluted with H ₂ O (50 ml) and was extracted with the addition of EtOAc (3x50 ml). The combined organic extracts were washed (100 ml brine), dried (Na ₂ SO ₄ ), filtered and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1 - 5/1) to give trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-yl)phenyl )-N-((4-(4-methoxy-3methylphenyl)pyridine[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (533 mg, 74%) as a colorless oil.

1H NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 7.63-7.69 (m, 2H), 7.45 (t, 1H), 7.28 (d, 1H ), 6.95-7.02 (m, 2H), 6.74 (d, 1H), 3.68 (s, 3H), 3.42-3.61 (m, 3H), 2.10- 2.18 (m, 2H) 2.06 (s, 3H), 1.67-1.85 (m, 4H), 1.55-1.63 (m, 7H), 1.29-1.46 (m, 9H), 0.93-1.10 (m, 4H), 0.76 (s, 9H), -0.05 (s, 6H); LCMS: 683.5 [M+H]+.

Step 3: trans-N-(3-(2-Cyclopropyloxazol-4-yl)phenyl)-4-hydroxy-N-((4-(4-methoxy-3methylphenyl)pyridine[2.2.2]octan-1-yl )methyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (1 N, 1.2 ml, 1.2 mmol) was added slowly to a solution of trans-4-((tert-butyldimethylsilyl)oxy)-N-(3-(2-cyclopropyloxazol-4-yl)phenyl) -N-((4-(4-methoxy-3methylphenyl)pyridine[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (533 mg, 0.780 mmol), THF (4 ml) and CH ₃ OH (4 ml) at 0°C. The ice bath was removed and the reaction mixture was stirred at rt. for 1 h. The mixture was diluted with H2O (50 ml) and extracted with EtOAc (3x50 ml). The combined organic extracts were washed (100 ml brine), dried (Na2SO4), filtered and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1 - 2/1 and then CH ₂ Cl ₂ /CH ₃ OH = 10/1) to give trans-N-(3-(2-cyclopropyloxazol4-yl) phenyl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl)pyridine[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide (364 mg, 82%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.73-7.76 (m, 2H), 7.48 (t, 1H), 7.31 (d, 1H ), 6.95-7.07 (m, 2H), 6.77 (d, 1H), 4.41 (d, 1H), 3.52-3.70 (m, 5H), 3.19- 3.30 (m, 1H), 2.11-2.22 (m, 2H), 2.08 (s, 3H), 1.71-1.75

- 188 040704 (m, 2H), 1.54-1.67 (m, 8H), 1.32-1.47 (m, 8H), 0.96-1.11 (m, 4H), 0, 68-0.82 (m, 2H); LCMS: 569.3 [M+H]+.

The following intermediates were synthesized from the appropriate amine and aldehyde intermediates according to the procedures described for the intermediate

32.

ID No. Structure Name [M+N] ⁺ 32.01 ² Ύ R k o trans-I-(3-(3- Cyclopropylisothiazol-5yl)phenyl)-4-hydroxy-R-((4-(4methoxy-3methylphenyl)pyridine[2.2.2]octan-1 yl)methyl)cyclohexanecarboxamide 585.4 32.02 ² (X trans-R-(3-(2-Cyclopropyloxazol4-yl)phenyl)-4-hydroxy-A-(trans-4(4-methoxy-3- methyl phenyl)cycle ohexyl)methyl)ci clohexanecarboxamide 543.3 32.03 ² l ° A= trans-R-(3-(2-Cyclopropyloxazol4-yl)phenyl)-A-((trans-4-(6(dimethylamino)pyridin-3 yl)cyclohexyl)methyl)-4hydroxycyclohexanecarboxamide 543.5 32.04 χΧ XX trans-4-Γ hydroxy-7U-(3 -(2- isopropyloxazol-4-yl)phenyl)-A((trans-4-(4-methoxy-3 - methyl phenyl)cycle ohexyl)methyl)ci clohexanecarboxamide 545.4 32.05 ² / trans-4-Γ hydroxy-R-(3 -(2isopropyloxazol-4-yl)phenyl)-A((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)cyclohexane carboxamide 546.5

- 189 040704

32.Ob ² O trans-R-(3-(2-Cyclopropyloxazol4-yl)phenyl)-4-hydroxy-R-((trans4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexane carboxamide 544.4 32.07 ABOUT trans-R-(4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)-4-hydroxy-R((trans-4-(4-methoxy-3 - methyl phenyl)cycle ohexyl)methyl)ci clohexanecarboxamide 544.4 32.08 ⁴ A / trans-R-(4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)-4-hydroxy-R((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)cyclohexane carboxamide 545.9 ^{32.09 1'4'6 _} ABOUT cis-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-4-hydroxy-R-((4(5-methoxy-6-methylpyride in-2yl)cyclohexyl)methyl)cyclohexane carboxamide 545.3 32.10 ² - A § trans-R-((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)R-(3-(2-cyclopropyloxazol-4yl)phenyl)-4hydroxycyclohexanecarboxamide 554.5 32.11 ² TUI '-o trans-R-((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)-R-(3-(2cyclopropyloxazol-4-yl)phenyl)4- hydroxycyclohexanecarboxamide 555.5 32.12 ⁵ Oh y'h 1 trans-I-(3-(6- (Dimethylamino) pyride in-3 - yl)phenyl)-4-hydroxy-R-((trans-4(5-methoxy-6-methylpyride in-2yl)cyclohexyl)methyl)cyclohexane carboxamide 557.5 ^{32.13 2'3} 7 :/ trans-4-Γ hydroxy-R-(4-(2isopropyloxazol-4-yl)pyridin-2yl)-R-((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)cyclohexane carboxamide 547.4 32.14 ² ABOUT trans-I-((trans-4-(6-cyano-5- methoxypyridine-2- yl)cyclohexyl)methyl)-4-hydroxyR-(3-(2-isopropyl oxazol-4yl)phenyl)cyclohexanecarboxamide 557.5

Alternative Conditions: Step 1: 1 Solvent was CH2C12;

Stage 2: ² The solvent was CH ₂ Cl ₂ ;

³ Base was Et ₃ N;

4DMAP, Et ₃ N, toluene, 80°C;

⁵ trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid,

1-propylphosphonic acid, cyclic anhydride (50 wt% in CH ₂ Cl ₂ ), pyridine, rt, 200 min.

⁶ Synthesized from an isomeric mixture of intermediate 3.02.

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Compound 1: trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate o o

A mixture of intermediate 29.15 (101 mg, 0.181 mmol), CDI (59 mg, 0.364 mmol) and CH3CN (2 mL) was heated at 80°C for 130 min, cooled to rt. and concentrated. Methylamine (40% in CH ₃ OH, 1.5 ml) was added to the reaction mixture.

The mixture was stirred for 15 min, diluted with EtOAc (20 ml), washed (20 ml H ₂ O and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered and then concentrated. The residue was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give trans-4((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridine-3 -yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate (103 mg, 93%) as a white foam.

1H NMR (400 MHz, CDCl ₃ ): δ 8.00 (d, 1H), 7.78 (d, 1H), 7.55-7.50 (m, 1H), 7.46 (t, 1H) , 7.30-7.27(m, 3H), 7.15-7.09(m, 1H), 6.47(d, 1H), 4.65-4.51(m, 1H), 4 .49-4.37(m, 1H), 3.61(d, 2H), 3.03(s, 6H), 2.75(d, 3H), 2.41-2.30(m, 2H ), 2.20-2.07 (m, 1H), 2.04-1.94 (m, 2H), 1.91-1.69 (m, 8H), 1.60-1.50 (m , 1H), 1.39-1.28 (m, 2H), 1.23-1.10 (m, 5H), 1.11-0.96 (m, 2H); LCMS: 616.5 [M+H]+.

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 1.

I Comm. I Structure I Name I [M+H] ⁺ 1

1.01 A AI A trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 616.5 1.02 O ΧΑ ^Ν 14 ⁰ - LA 6.A L La 4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((4-(6(dimethylamino)pyridin-3yl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-methylcarbamate 642.4 1.03 \ ΖΤ And L 1 trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(3-fluoro-1-methyl1H-indazol-5- yl)cyclohexyl)methyl)carbamoyl)cycle ohexylmethylcarbamate 644.3 1.04 ..A Ru A trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 599.5

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1.05 O ya ci %% 4-((3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-methylcarbamate 625.6 1.06 ¹ Oh,Ά όΡ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamyl)cyclohexylcarbamate 585.5 1.07 ³ ABOUT trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate 600.1 1.08 ^{2 0} 7A|^ [fS a 4-((3-(1-Cyclopropyl-III-pyrazol-4yl)phenyl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-carbamate 611.4 1.09 □ \ jX a^O a <17^ Cl ° and trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(3-fluoro1-methyl-1H-indazol-5- yl)cyclohexyl)methyl)carbamoyl)cycle ohexylmethylcarbamate 627.6 1.10 Oh A' trans-4-((3 -(1-Isopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cycle ohexylmethylcarbamate 602.4

Alternative terms:

Μθ% ammonia in CH ₃ OH;

² 0.4 M ammonia in THF, then 40% ammonia in CH ₃ OH;

³ Isolated during purification of compound 1.06.

Compound 2: trans-4-((3-(3-Cyclopropylisothiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate o o

CDI (44.1 mg, 0.272 mmol) was added to a solution of intermediate 31 (101.3 mg, 0.181 mmol) in CH ₃ CN (5 ml). The reaction mixture was heated at 80° C. overnight, allowed to cool to rt. and then concentrated to give a colorless oil. This oil was dissolved in CH2CI2 (3 ml). Methylamine (2M in THF, 1.10 ml) was added to the solution and the reaction mixture was stirred at rt. during the night. The reaction mixture was concentrated and purified by reverse phase HPLC [water (10 mM NH ₄ HCO ₃ )-CH ₃ CN] to give trans-4-((3-(3-cyclopropylisothiazol-5-yl)phenyl)((trans- 4(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate (70 mg, 63% yield) as a white solid.

Ή NMR (400 MHz, CDC1 ₃ ): δ 7.61-7.55 (m, IH), 7.52 (t, IH), 7.38 (s, IH), 7.22 (d, IH) , 7.15 (s, IH), 6.99-6.93 (m, 2H), 6.74 (d, IH), 4.57 (br s, IH), 4.42 (s, IH) , 3.80 (s, 3H), 3.64 (d, 2H), 2.74 (d, 3H), 2.39 (t, IH), 2.24-2.17 (m, 4H), 2.16-2.09 (m, IH), 1.97-2.02 (m, 2H), 1.88 (d, 2H), 1.83-1.70 (m, 6H), 1, 60-1.58 (m, IH), 1.42-1.29 (m, 2H), 1.27-1.12 (m, 2H), 1.10-0.95 (m, 6H); LCMS: 616.3 [M+H] ⁺ .

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 2.

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Comm.

Structure

Name

[m+n] ⁺ 1

2.01 0 trans-4-(((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)(3(2-methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 606.3 2.02 Chu A ' O / trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 617.4 2.03 About ifh • ₀ XJ 4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-methylcarbamate 643.5 2.04 About yAJ a II J HI H V trans-4-(((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)(3(thiazole-2- ylethynyl)phenyl)carbamoyl)cyclohexylmethylcarbamate 600.2 2.05 O ΧτΧδγ A' 4-(((4-(4-Methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl) methyl) (3 - (thiazol-2 - ylethynyl)phenyl)carbamoyl)cyclohexyl-trans-methylcarbamate 626.3 2.06 PP A A IZ\ trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 600.3 2.07 A X A' / 4-((3 -(2-Cyclopropyloxazol-4yl)phenyl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-methylcarbamate 626.5 2.08 i V Q Δ >o IZ\ 4-((3-(3-Cyclopropylisothiazol-5yl)phenyl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-methylcarbamate 642.3

Compound 3: 4-((3-(2-Cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl-trans-methylcarbamate

A mixture of Intermediate 30.14 (81 mg, 0.14 mmol), CDI (46 mg, 0.29 mmol) and CH ₃ CN (1.5 ml) was heated at 80°C for 2 h, allowed to cool to RT . and then concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 ml). A portion of this solution (1.5 ml, 0.071 mmol) was concentrated and then diluted with methylamine (40% in CH ₃ OH, 1.5 ml). The mixture was stirred at rt. for 2 h, diluted with EtOAc (20 ml), washed (20 ml H ₂ O and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-5 % CH ₃ OH in CH ₂ Cl ₂ ) to give 4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2 ]octan-1-yl)methyl)carbamoyl)cyclohexyl-trans-methylcarbamate (39 mg, 89%) as a white foam.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.53 (s, 1H), 7.96-7.94 (m, 1H), 7.74-7.67 (m, 2H), 7 .48 (t, 1H), 7.40 (dd, 1H), 7.33 (d, 1H), 6.84-6.77 (m, 1H), 6.52 (d, 1H), 4, 39-4.28 (m, 1H), 3.78-3.44 (m, 2H), 2.94 (s, 6H), 2.272.12 (m, 2H), 1.89-1.79 ( m, 2H), 1.74-1.58 (m, 8H), 1.53-1.32 (m, 8H), 1.11-1.02 (m, 2H), 1.02-0, 97 (m, 2H),

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0.97-0.82 (m, 2H), NHCH ₃ with DMSO; LCMS: 626.5 [M+H]+.

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 3.

Comm. Structure Name [M+N] ⁺ 3.01 ¹ ( zx °5 7 O h / trans-4-((3 -(1-Cyclopropyl- 1Ηpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate 613.5 3.02 7 ΙΖ\ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 600.4 3.03 0 .MX ⁰ '-'···' λ J 1Л ^{Η 1} 4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(6(dimethylamino)pyridin-3yl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl )cyclohexyltrans- methyl carbamate 625.6 3.04 trans-4-((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(4-metho xi-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 600.5 3.05 kv z— / trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cy clohexylmethylcarbamate 600.4

M ethylamine in THF.

Compound 4: trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-( 2-hydroxyethyl) carbamate o o

A mixture of intermediate 29.11 (130 mg, 0.240 mmol), CDI (59 mg, 0.364 mmol) and CH3CN (2 mL) was heated at 80°C for 2 h, allowed to cool to rt. and concentrated. The residue was dissolved in CH ₂ Cl ₂ (2 ml). Ethanolamine (149 mg, 2.44 mmol) was added to the reaction mixture and the mixture was stirred for 40 min, diluted with EtOAc (20 ml), washed (20 ml H ₂ O and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-4-((3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-( 4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate (131 mg, 87%) as a white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.55 (s, 1H), 7, 44 (t, 1H), 7.10 (d, 1H), 6.98-6.92 (m, 2H), 6.85 (t, 0.87H), 6.80-6.45 (m, 1H), 6.60-6.45(m, 0.13H), 4.55(t, 1H), 4.40-4.26(m, 1H), 3.80-3.69(m, 4H), 3.66-3.40(m, 2H), 3.35-3.25(m, 2H), 3.03-2.82(m, 2H), 2.38-2.27( m, 1H), 2.18-2.03 (m, 4H), 1.90-1.80 (m, 2H), 1.80-1.63 (m, 6H), 1.56-1, 38 (m, 3H), 1.35-1.21 (m, 2H), 1.12-0.95 (m, 6H), 0.950.82 (m, 2H); LCMS: 629.6 [M+H]+.

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 4.

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Comm. I Structure I Name I [M+H] ⁺

4.01 Τ °? ΖΙ 4 γ 4 / trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 646.4 4.02 Yr An 4-((3-(2-Cyclopropylthiazol-5 yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans -carbamate 672.5 4.03 z o t Y 4 z— / 4-((3 -(2-Cyclopropylthiazol-5 yl)phenyl)((4-(6- (dimethylamino)pyridin-3 yl)bicyclo [2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans-carbamate 672.6 4.04 about t °5 γ γ R/ 4-((3-(1-Cyclopropyl-1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl )-trans-carbamate 655.7 4.05 4.06 4.07 4.08 4.09 vYpT II J Al h A' 0 TtY όγ ⁰ n / A ⁰ A o Αΐ^ΝΤ ⁴ ! O γγΟ lKhDlr A yppOJA II J [1 J h A trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylisopropylcarb mat trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine-1-carboxylate trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4carboxylate trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2(dimethylamino)ethyl)carbamate 627.6 655.4 655.5 625.6 656.5

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4.10 0 trans-4-((3 -(1-Cyclopropyl- 1Ηpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3 hydroxypropyl)carbamate 643.7 4.11 πτΑ ¹ ____ II τ κι η ι trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3 - (dimethylamino) propyl) carbamate 670.5 4.12 4-((3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)((4-(6- (dimethylamino)pyridin-3 yl)bicyclo [2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)-trans-carbamate 655.5 4.13 0 at ⁰ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((1H-imidazol2-yl)methyl)carbamate 665.6 4.14 \ JA>° η ο 1 °0ο ΙΖ 4 tert-Butyl-(2-((((trans-4-((3 -(1 cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)oxy)carbonyl)amino)ethyl)(methyl)carbamate 742.9

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4.15 ¹ O l IT O ° n X/n >N trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((1H-imidazol4-yl)methyl)carbamate 665.7 4.16 \ o>° o o 1 i IZ Z I trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2aminoethyl)carbamate 628.4 4.17 dYa’D tert-Butyl-3 -((((trans-4-((3 -(1 cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)oxy)carbonyl)amino)azetidine-1-carboxylate 740.6 4.18 ⁴ 0 ΛΎ ιΥ ί γνη II J [I J h I^^ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylazetidine-3 ylcarbamate 640.5 4.19 XaY° II J h J h I'^ I' trans-4-((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 630.5

- 197040704

4.20 ABOUT II J [11 n 'N trans-4-((3 -(1-Cyclopropyl- 1/7pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(4(dimethylamino)butyl)carbamate 684.6 4.21 trans-4-((3 -(1-Cyclopropyl- 1/7pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(5 - (dimethylamino)pentyl)carbamate 698.7 4.22 . U'' trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(6- (d imethylamino) pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)carbamate 630.4 4.23 χΧρ 4-((3 -(2-Cyclopropyloxazol-4yl)phenyl)((4-(6- (dimethylamino)pyridin-3 yl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyltrans-(2-hydroxyethyl)carbamate 656.5 4.24 ιΧύ?'°Χ ^0Η trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl) carbamate 632.6 4.25 ² x+eX -0¾ ^0Η trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 641.2

Getting carbamate:

trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine- 1 carboxylate trans-4-((4-(1-Cyclopropyl-177pyrazol-4-yl)pyridin-2-yl)((trans4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 hydroxyazetidine- 1-carboxylate trans-4-((3-(1-Cyclopropyl-1/7pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3(( methylthio)methyl)azetide in-1 carboxylate

CH3OH was added to increase solubility;

¹ iPriNEt was added as the amine was the HCl salt;

¹ Et ₃ N was added as the amine was the HCl salt.

^d Deprotection of compound 4.17 (20% TFA in CH ₂ Cl ₂ ).

Compound 5: trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl- 198 040704

N-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylethylcarbamate

A mixture of intermediate 30.04 (520 mg, 0.936 mmol), CDI (232 mg, 1.44 mmol) and CH ₃ CN (13 ml) was heated at 80°C for 165 min. Additional CDI (16 mg, 0.099 mmol) was added to the mixture and the reaction mixture was heated for 30 min and then allowed to cool to rt. A portion of this solution (1 ml, 0.072 mmol) was added to ethylamine (2M in THF, 1 ml, 2.0 mmol). The mixture was stirred overnight, diluted with EtOAc (15 ml), washed (15 ml H ₂ O and then 15 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (0-5% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4-( 1 - isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylethylcarbamate (41 mg, 91%) as a white foam.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.55 (s, 1H), 8.43 (d, 1H), 8.14 (s, 1H), 7.66 (s, 1H), 7 .56 (dd, 1H), 7.51 (d, 1H), 7.49 (dd, 1H), 7.11 (d, 1H), 6.92 (t, 0.87H), 6.70- 6.55(m, 0.13H), 4.52(sept, 1H), 4.41-4.27(m, 1H),

3.85 (s, 3H), 3.68 (d, 2H), 3.00-2.82 (m, 2H), 2.47-2.36 (m, 1H), 2.30-2, 14 (m, 1H), 1.91-1.65 (m, 8H), 1.551.37 (m, 9H), 1.36-1.22 (m, 2H), 1.08-0.85 ( m, 7H); LCMS: 627.5 [M+H]+.

The following compounds were synthesized using the appropriate intermediate and the appropriate amine according to the procedure described for compound 5.

Comm. I Structure I Name I [M+H] ⁺

5.01 ³ Cn 5.02 ³ O DM 5.03 ³ A /

trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 617.5 trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 619.5 trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 618.5

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5.04 ² and γ° Υ τζ \ trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 620.5 5.05 ² 0 ΥΥ Yy^ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropylthiazol-5-yl)pyridine2- yl)carbamoyl)cyclohexylmethylcarbamate 628.4 5.06 ² < H: X s τζ \ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 628.5 5.07 ² 0 vATsOjy ΥΥ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 629.6 5.08 ³ \ ΖΙ Y γ A / trans-4-((3-(2-Isopropylthiazol-5yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 619.5 5.09 ^1.3 Υ Οyj Ί Z— / trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 599.5

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5.10 ³ · /=\ /l o O >° IZ\ trans-4-((3-(1-Isopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 601.6 5.11 ³ - /A / L ν o 1 /o IZ\ trans-4-(((trans-4-(5-Chloro-6methoxypyridine-3yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 620.4 5.12 ³ ATZ \ trans-4-((4-(1-Isopropyl-1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 602.5 5.13 ³ 0 II J n 1 n trans-4-((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 601.5 5.14 ³ L 7 O o ^{o \u003d} SDS% / / ° trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cycle ohexyl)methyl)(3(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 610.5 5.15 ³ _Rl l o Z \__/ Yes. ABOUT IZ\ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cycle ohexyl)methyl)(3(1-Isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 612.3

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5.16 ³ /=\ / uncle Δ o 1I ΤΖ \ trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(6methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 600.5 5.17 ³ 0 ΎζΎΟ Oh ah Il J n 1 n I' trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-cyclopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylmethylcarbamate 611.5 5.18 ³ o' ft • L o IZ \ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylmethylcarbamate 613.5 5.19 ² \ zx ° \ p -γ (j Y ^o= wX ³ / /° cis-4-(((4-(3-Cyano-4- methoxyphenyl)cyclohexyl)methyl)(4- (1-isopropyl- 1H-pyrazole-4- yl)pyridine-2- yl)carbamoyl)cyclohexylmethylcarbamate 613.7 5.20 ² and o Λ- ° xz \ trans-4-((3 -(1 -(tert-butyl)- 1Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 616.6 5.21 ² 0 δ Δ ³ / Λ trans-4-((3 -(1-Cyclobutyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 614.5

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5.22 ² ν Yaa l o I -Z\ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyldimethylcarbamate 613.5 5.23 ² Ra o o A °> o IZ\ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 611.5 5.24 ² LJ nA / ^{n x} ° trans-4-((4-(1-Isopropyl-1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 603.5 5.25 T A. o >° ΙΣ ) trans-4-((4-(1-Isopropyl-1H-pyrazol4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate 617.6 5.26 ² 0 ALh JI J [1 1 , n ^X ° 4/^4/ A ⁴ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridine2- yl)carbamoyl)cyclohexylmethylcarbamate 614.5

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5.27 ² 0 νγΟΑχυ II J n 1 n v' trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1 cyclopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylmethylcarbamate 612.5 5.28 ² ο ^λ / -· /=\ / J7>o П Ο A °' τζ \ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 613.6 5.29 ^{5 Χ} ° trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridine2- yl)carbamoyl)cyclohexylethylcarbamate 628.5 5.30 ³ 0 ^-Οί' trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 602.5 5.31 ³ \ ζτ °7A / trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 603.3 5.32 ³ Ru “8? ΐ. / trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 601.5

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5.33 ³ 0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 601.5 5.34 ³ Τ χ A ' O / trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5 methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 602.5 5.35 ^{3 oz} / .. . Η. IZ\ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 611.5 5.36 ² 0 J J |l J h ° 4%_ N N 1 trans-4-((3-(6- (Dimethylamino)pyride in-3 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 613.6 5.37 ² Λ J LT ^H C._ n% trans-4-((3-(6-Cyclopropylpyridine- 3-yl)phenyl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 610.5 5.38 ² 0 X?'° ^A C 1 trans-4-((3-(2- (Dimethylamino)pyrimidin-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 614.6

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5.39 ² M* 0γ trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropyloxazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylmethylcarbamate 612.5 5.40 ² • .Γ —ΖΟ \ >ο ΙΖ \ trans-4-((6-(Dimethylamino)- [3,4 'bipyridine] -2 '-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 614.5 5.41 ² \ ΖΙ °C \ Ρ z— Ο ξΧ 'ο / trans-4-((3-(6- (Dimethylamino)pyride in-3 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 614.5 5.42 ² Doo trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl) phenyl) carbamoyl) cycle oxyl methyl carbamate 612.7 5.43 ² \ ΖΙ M trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 604.5 5.44 ² Μ* C£n ⁿ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 613.5

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5.45 ² O trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexylmethylcarbamate 614.5 5.46 ² O 70° Air trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2isopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexylmethylcarbamate 614.4 5.47 O trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate 616.5 5.48 ⁴ 0 A trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylcarbamate 588.4 5.49 ⁶ 0 trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate 603.4 5.50 ² 0 .ppyUA, AJ ⁿ trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(6methoxy-5-methylpyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 602.4 5.51 ² \ ZT 1 trans-4-((4-(2-Ethyloxazol-4yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate 590.5 5.52 ² Q>° o z 5__< θγ° trans-4-((3-(1-Isopropyl-1H-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)-1- methylcyclohexylmethylcarbamate 615.4 5.53 ² ^Z O^O About / cis-4-((3 -(1-Isopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl) cyclohexyl) methyl) carba moyl) -1- methylcyclohexylmethylcarbamate 615.5

Acylimidazole preparation:

1DMF as solvent. Getting carbamate:

M methylamine in THF;

³ 40% methylamine in CH ₃ OH;

M ammonia in CH ₃ OH;

⁵ Stirred at rt. for 4 h, heated at 80°C for 1 h and then stirred at RT. within 1 hour

⁶ Isolated during purification of compound 5.48.

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Compound 6:

trans-4-((4-(2-Isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4- carboxylate

Intermediate 32.13 (98 mg, 0.18 mmol) and CDI (45 mg, 0.28 mmol) were dissolved in CH3CN (2 mL). The reaction mixture was heated at 80° C. for 15.5 h. Additional CDI (11 mg, 0.068 mmol) was added at rt. The reaction mixture was heated at 80° C. for 1 h and then allowed to cool to rt. Part of the reaction mixture (1 ml, 0.090 mmol) was added to morpholine (80 μl, 0.915 mmol). The reaction mixture was stirred at rt. for 72 h and then diluted with EtOAc (20 ml). The organic phases were washed with water (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-5% CH ₃ OH in CH ₂ Cl ₂ ) to obtain trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine -4-carboxylate (52 mg, 88% yield) as an off-white foam.

¹ H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.55 (d, 1H), 7.71 (s, 1H), 7.70 (d, 1H), 7 .18 (d, 1H), 6.97 (d, 1H), 4.48-4.38 (m, 1H), 3.80 (s, 3H), 3.73-3.65 (m, 2H ), 3.58-3.42 (m, 4H), 3.30-3.22 (m, 4H), 3.22-3.12 (m, 1H), 2.50-2.42 (m , 1H), 2.28 (s, 3H), 2.28-2.20 (m, 1H), 1.96-1.85 (m, 2H), 1.85-1.72 (m, 6H ), 1.58-1.42 (m, 3H), 1.41-1.26 (m, 8H), 1.12-0.96 (m, 4H); LCMS: 660.6 [M+H]+.

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 6.

Comm. Structure Name [M+N] ⁺ 6.01 ¹ ABOUT ZI H ν • Z— / 4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)-transcarbamate 646.5 6.02 o ^H trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 647.5 6.03 T about ZI I A / trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 649.6

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6.04 Τ about ( ΖΙ 4 / trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)carbamate 649.6 6.05 trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(3- hydroxypropyl)carbamate 663.5 6.06 ζ ο ζζ Αγ 4 trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 658.6 6.07 0 trans-4-((3 -(2-Cycle opropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)carbamate 647.5 6.08 ¹ 0 ρϊαν λ J l L ⁿ χ Ya trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(6(d-imethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- hydroxyethyl) carbamate 629.5 6.09 0 trans-4-((3 -(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 631.5

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6.10 ² o xx trans-4-((3 -(1-Cyclopropyl- 1Ηpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2methoxyethyl)carbamate 643.5 6.11 trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1,3dihydroxypropan-2-yl)carbamate 659.5 6.12 0 ,γΧ άΔ'Ρχ' ⁰ trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(($)-2,3dihydroxypropyl)carbamate 659.5 6.13 0 Χι'Χ uX Ο . X UX ⁿ he X' trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((7?)-2,3 dihydroxypropyl)carbamate 659.7 6.14 0 ο„ II J [1 1 . η trans-4-((3 -(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-(3 hydroxypropyl) carbamate 645.4

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6.15 dL DΔA trans-4-((3-(1-Isopropyl- lHpyrazol-4-yl)φenyl)((τpanc-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl) carbamate 632.5 6.16 trans-4-((3 -(1 -Isopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3- hydroxypropyl)carbamate 646.5 6.17 ⁰ \N-4 trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 632.5 6.18 A/A A trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-methylazetidin-3-yl)carbamate 654.5 6.19 γ/χάλΑ 11 J (J n A trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 662.5 M+Na 6.20 O ., rA'A o A sta trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(1-isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 642.6

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6.21 O 11 D n J n I' trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 641.5 6.22 Ζ About ζζ °Р ____ζ Р : trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 643.5 6.23 c τγΟ Δθγ _Ν —θΗ YJ UY ^H —n trans-4-(((trans-4-(5-Chloro-6methoxypyridin-3 yl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 650.3 6.24 0 -D- aU _o a, H II D | l J n trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl oxetan-3 ylcarbamate 641.6 6.25 / O I Υ ρ ρ ^{o \u003d} СлС >' ο / trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-4methylpiperazine-1-carboxylate 668.5

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6.26 O trans-4-((3 -(1-Cyclopropyl- 1Ηpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoil)cyclohexyl-(2methoxyethyl)(methyl)carbamate 679.6 M+Na 6.27 0 4 Υ ρ ρ °AAC / trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexylthiomorpholine-4carboxylate 671.5 6.28 ο % ^ν /7 A Uo ^a »^° ^h 11 J ΚΙ η 'Ύ'νΑ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 641.7 6.29 04 4 ο λ ρ A Ο=ω=ο \ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 - (methylsulfonyl)azetide in-1 carboxylate 703.6 6.30 0 Ρ> ^Χ νΥ ^/ \ Q AC pAv trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 - (methylthio)azetidine-1-carboxylate 671.5

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6.31 _ν Α'Χα _ο Α II J h J , h trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate 629.6 6.32 4:4L II J nJ . h \4-yi\ _N / trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridine2- yl)carbamoyl)cyclohexylisopropyl carbamate 642.6 6.33 - Τ' A°' >° IZ 1> trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridine2- yl)carbamoyl)cyclohexylcyclopropylcarbamate 640.6 6.34 / o L Ά A 1 trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-(2methoxyethyl)carbamate 657.5 6.35 0 A^ _N 4 4' ^X trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylcyclopropylcarbamate 639.6

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6.36 x YES ΙΛ/Χ / ° o trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3(methylsulfonyl)azetidine-1 carboxylate 717.5 6.37 0 M/MO dxo D _n As V-. _o x _n a \„YES HELL^\ / Μ ^X trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexylmorpholine4-carboxylate 669.6 6.38 E ^L A o / trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-4methylpiperazine-1-carboxylate 682.5 6.39 0 /X^A/X 0 Λ χ DA M/s / ⁰ ^ιΤΜ o trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3(methylsulfonyl)azetidine-1 carboxylate 707.5 6.40 A ss a 0 trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine- 4-carboxylate 659.5

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6.41 / 0 A 4 / trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 4-methylpiperazine-1 carboxylate 672.5 6.42 Ο=ω=ο trans-4-((3-(1-Isopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3(methylsulfonyl )azetidine-1 carboxylate 706.3 6.43 0 °C . / A 4. / trans-4-((3-(1-Isopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate 658.4 6.44 0 0 Ζ \--f /A o 0° 0 / trans-4-((3 -(1 -Isopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(5 methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazine-1 carboxylate 671.4 6.45 0fe 4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-(2-hydroxyethyl)carbamate 656.7 6.46 ¹ .p fey trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 630.7

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6.47 .A 4% trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 632.4 6.48 ΑΫ trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)carbamate 633.6 6.49 Ac" ⁴ trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(3- hydroxypropyl)carbamate 647.6 6.50 A trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxyethyl)carbamate 631.5 6.51 14 9 trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(3- hydroxypropyl)carbamate 645.5 6.52 _o a° SpY ^-(3 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 631.6

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6.53 X A ΑΧ A / /° trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(2-cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 641.6 6.54 A % χζ ί X trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropyloxazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 642.6 6.55 ^-ο trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-(2hydroxyethyl)carbamate 642.4 6.56 /ο ? ζχ °5v A / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-methoxyethyl ) carbamate 646.5 6.57 ACf Aum % trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylcyclopropylcarbamate 628.5 6.58 Ατ A 'ο / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylisopropylcarbamate 630.6

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6.59 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylmorpholine-4-carboxylate 658.6 6.60 λ %o IZ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyloxetan-3-ylcarbamate 644.6 6.61 ιΧΔ° ^Χ Νγ _ο Г ^-0 trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-R-((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-(2-(3 (methylsulfonyl)azetidin-1-yl)-2oxoethyl)cyclohexanecarboxamide 706.6 6.62 O -oG' Δχ ^Η '-o trans-R-(4-(2-Cyclopropyloxazol-4yl)pyride in-2-yl)-4-(2-((3 hydroxypropyl)amino)-2-oxoethyl)R-((trans-4-(5- methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)cyclohexane rboxamide 646.5 6.63 ..U Ϋχ·· X) trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-R-((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-(2-(( 2methoxyethyl)(methyl)amino)-2oxoethyl)cyclohexanecarboxamide 660.4

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6.64 4 △ %o 0 / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-4methylpiperazine-1-carboxylate 670.6 6.65 'Α* ΟγΥ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-4-methylpiperazin- 1 carboxylate 671.6 6.66 # λ %o ζζ ζ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((8) -2,3 dihydroxypropyl) carbamate 662.5 6.67 0 _Υ γΟ AJ ArU-<1 ° Υ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2hydroxypropyl)( methyl) carbamate 660.4 6.68 4 ^s ZT °5 γ Ά 4 / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxy -2,3 dimethylbutyl) carbamate 688.6

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6.69 Δ F Δ °>ο ζζ 4 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxy -2methylbutyl)carbamate 674.5 6.70 YAHU θγγ ^{Η 0Η} trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2-hydroxy -2methylpropyl)carbamate 660.5 6.71 τ ο ΖΙ °Χ= γ ο / ο / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(1-hydroxypropane -2yl)carbamate 646.6 6.72 Δ W Δ °Up to ΙΖ Ο ζ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2hydroxypropyl)carbamate 646.7 6.73 ο Ρ''* ⁴ Ν'γ ⁴ | 0 * -οΑΔ C^N ^Η trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(3-hydroxybutane -2yl)carbamate 660.5

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6.74 z about L H y A / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylethyl(2hydroxyethyl)carbamate 660.6 6.75 4¾¼ 1 _o ^ ⁰ trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(methylsulfonyl )azetidine-1 carboxylate 708.3 6.76 That Ch u / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-(2hydroxyethoxy )azetidine-1 carboxylate 688.5 6.77 A but o / trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-4-methylpiperazine -1 carboxylate 673.5 6.78 ³ 0 th Ήν< - ^ΝΗ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylpiperazin-1-carboxylate 657.3

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6.79 uuLA ^{4 0} γ'Ά aUa-C a* a-a ^-0 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(1-methylpiperide in-4yl)carbamate 685.3 6.80 / about zx 0 Υ b/ y / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((7? )-1-methylpiperidin-3 yl)carbamate 685.5 6.81 O Well / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-4-ethylpiperazin- 1 carboxylate 685.5 6.82 l o n u l / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-4-isopropylpiperazin- 1 carboxylate 699.5 6.83 γΡ'/ΟΛγ Δα 'ABOUT trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-2,2- dimethylmorpholine-4carboxylate 686.8

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6.84 0 UATT yl 44 R|U .y C <h, A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-(oxetane -3 -yl)azetide in1 -carboxylate 684.6 6.85 Χτθ '''19 ^ζ α ^η α^υ trans-4-((4-(2-Ethyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-(2- hydroxyethyl) carbamate 620.4 6.86 0 0 ,ιγ ΥΎ A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy -2methylpropyl)(methyl)carbamate 674.6 6.87 0 Ζ\'''νΑ ^/ \ q ± YyA _N ^ ^0H aX9 1 A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)( methyl) carbamate 646.5 6.88 4 # △ °>o IZ P trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypentane -2yl)carbamate 674.5

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6.89 A λ p TZ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy -3 methylbutyl)carbamate 674.5 6.90 O γγΝ Υγ about . , ΥΥ Υμ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-hydroxy -2-methylpropan2-yl)carbamate 660.7 6.91 Υ ζχ °C -7 / trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxy- 2methylpropyl)carbamate 662.4 6.92 Υ ζχ °C / trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (2-hydroxy-2methylpropyl)carbamate 661.5 6.93 X / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((5) -1-hydroxypropan-2yl)carbamate 646.7 6.94 .....A °γ / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((7? )-1-hydroxypropan-2 yl)carbamate 646.7 6.95 Η γ Υ 1 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((7? )-2hydroxypropyl)carbamate 646.7 6.96 /· Α °>ο τζ οΑ τ \ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-((5) -2hydroxypropyl)carbamate 646.6

Acylimidazole preparation:

YMF as a solvent. Obtaining carbamate: Reactions that proceeded at rt. slowly, or left to mix for many days, or heated (50-80°C);

The reaction mixture was diluted with CH ₂ C1 ₂ before adding the amine.

³ Deprotected from N-Boc-piperazine (20% TFA in CH ₂ C1 ₂ ).

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Compound 7:

trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - hydroxyazetidine-1-carboxylate

A mixture of intermediate 32.08 (510 mg, 0.937 mmol), CDI (233 mg, 1.44 mmol) and CH3CN (8 mL) was heated at 80°C for 16 h and allowed to cool to rt.

Diisopropylethylamine (1.5 ml, 8.6 mmol) and then azetidin-3-ol hydrochloride (465 mg, 4.24 mmol) were added to the reaction mixture at rt. The mixture was stirred for 70 min, diluted with EtOAc (50 ml), washed (50 ml H2O and then 50 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (0-7% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4 -(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate (567 mg, 92%) as a white foam.

¹ H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 8.54 (d, 2H), 7.71 (s, 1H), 7.67 (d, 1H), 7 .19 (d, 1H), 6.97 (d, 1H), 5.63 (d, 1H), 4.41-4.31 (m, 2H), 4.01-3.94 (m, 2H ), 3.74 (s, 3H), 3.73-3.67 (m, 2H), 3.60-3.53 (m, 2H), 2.50-2.42 (m, 1H), 2.28 (s, 3H), 2.26-2.17 (m, 1H), 1.90-1.72 (m, 8H), 1.55-1.40 (m, 3H), 1, 40-1.27 (m, 2H), 1.13-0.94 (m, 8H); LCMS: 644.6 [M+H]+.

The following compounds were synthesized from the appropriate intermediate and the appropriate amine according to the procedure described for compound 7.

Comm. Structure Name [M+N] ⁺ 7.01 △ %o I trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(6(dimethylamino)pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 658.5 7.02 ^{1 He} trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 658.4 7.03 4 d A % P O I trans-4-((4-(2-Cyclopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 hydroxyazetidine-1-carboxylate 659.5

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7.04 fXX Nn trans-4-((4-(2-Isopropylthiazol-5yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 hydroxyazetidine-1-carboxylate 661.6 7.05 O °h A /, / trans-4-((3 -(2-Isopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 661.4 7.06 _V HX°JL ^he trans-4-((4-(2-Cyclopropylthiazol-5yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine -1 carboxylate 660.6 7.07 0 & >° £ o I trans-4-((4-(2-Isopropylthiazol-5yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine -1 carboxylate 662.5 7.08 0 hehe trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropylthiazol-5-yl)pyridin2-yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 670.5

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7.09 -/Δ °γ _ο / o ζ trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 670.5 7.10 M ^he trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropylthiazol-5-yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 671.5 7.11 T o d °H 7 A / trans-4-((3-(2-Cyclopropylthiazol-5yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 659.5 7.12 ¹ MM MM ^0N 4-((3-(1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyltrans-3 - hydroxyazetidine-1 carboxylate 667.3 7.13 0 /a-'^nA^a o nMJ Μ αΑ ₀ Δ -νΜ ^{oh 1} trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3 yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1 carboxylate 641.5

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7.14 %%° ⁴ trans-4-((3 -(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 hydroxyazetidine-1-carboxylate 643.4 7.15 T o d p O o / trans-4-((3 -(1-Isopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(5 methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 644.5 7.16 0 II4 / ^OH ^X trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(4-methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 - hydroxyazetidine-1-carboxylate 644.5 7.17 0 0 ^xh Methyl-2-((((trans-4-((3 -(1 cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carb amoyyl)cyclohexyl) hydroxy)carbonyl)am ino)acetate 657.7 7.18 ⁵ 2-((((trans-4-((3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)oxy)carbonyl)am ino)acetic acid 643.5

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7.19 .. ¹ λ °% ο ζ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 674.4 M+Na 7.20 0 ν.__0X00 I X Χρ ^οη trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3(1-isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 654.5 7.21 A to χ X ο ζ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 653.5 7.22 0 ... 0 X _Λ 1 J 1 and I XX trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 655.5 7.23 0 °Χ d W ^0Η trans-4-(((trans-4-(5-Chloro-6methoxypyridine-3 yl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 662.4 7.24 0 Z\.χΑζ\ 0 Χχ 022 trans-4-((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyride in-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -3-hydroxyazetidine-1 carboxylate 643.6

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7.25 0 γχθ άθΑ trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(6methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1 carboxylate 642.6 7.26 . II J ϋ J Al trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3 (methoxymethyl)azetidine-1 carboxylate 669.6 7.27 ³ \ z— ύ °5 v A ^f 4 / trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3(dimethylamino)azetidine-1 carboxylate 668.6 7.28 I J 4 γ A 4 trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3 (hydroxymethyl)azetidine-1 carboxylate 655.6 7.29 4 λ p p o' trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexylthiomorpholine-4carboxylate-1-oxide 687.7

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7.30 _YU° o o _o 0 ° and o trans-4-((3 -(1-Cyclopropyl-\Ηpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexylthiomorpholine-4carboxylate-1,1-dioxide 703.6 7.31 λ i ύ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexylazetidine-1 carboxylate 625.6 7.32 o υύΥΧί l γγ A ° ΥΔ ^VnA trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 - ((dimethylamino)methyl)azetidine-1 carboxylate 682.5 7.33 I ABOUT / H γ l Δ / /O trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 653.4 7.34 D'gal- . II \ ϋ J ν- Ο^ D 1 -(trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)-3 methylazetidine-1,3-dicarboxylate 683.4

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7.35 ⁵ O γΡΡ Pl PPpr ⁰ A 1 -(((trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)oxy)carbonyl)az etidine-3-carboxylic acid 669.5 7.36 X A λ $O y —Ζ o l trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3-((tert-butoxycarbonyl)(methyl)amino)azeti din-1-carboxylate 754.1 7.37 ⁶ 0 xP τΡυ A trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 - (methylamino)azetide in-1-carboxylate 654.7 7.38 y Gu j * Ay th ° ^X A trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3-((tert-butoxycarbonyl)amino)azetidine-1 carboxylate 762.6 M+Na 7.39 ⁶ 0 xP ίρρ trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3-aminoazetidine 1-carboxylate 640.6

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7.40 O '-oAy J ^OH °\N-X trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4-yl)pyridin2-yl)carbamoyl)cyclohexyl-3 hydroxyazetidine- 1-carboxylate 656.5 7.41 ² 7Id Xf 4 / trans-4-((3 -(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3-(2-methoxy-2oxoethyl)azetide in-1-carboxylate 697.8 7.42 ⁵ 7 4 y ' O / 2-( 1 -(((trans-4-((3 -(1-Cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)oxy)carbonyl)az etidin-3-yl)acetic acid 683.8 7.43 X about M./ ABOUT About ij 4 / /° trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(1isopropyl- 1H-pyrazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 655.7 7.44 o ΥλΥα Λ J ζΛ/χ / ⁿ trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylisopropylcarbamate 631.6

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7.45 E 1 * /to >° -Z\ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyldimethyl rbamate 627.6 7.46 0 % hdLo I trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexylazetidine 1-carboxylate 639.5 7.47 Ρ L° trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3 ethylazetidine-1-carboxylate 667.6 7.48 0 l ΥΑγΑ _Ν Α \/* ₀ ^Λ _Ν η 1 J y J , A / ⁰ A ⁴ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3 methoxyaz etidine-1-carboxylate 669.5 7.49 ¾ A A _ trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyl-3 isopropoxyazetidine-1-carboxylate 697.6

- 235 040704

7.50 \ z- y I trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-\H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3(dimethylamino)azetidine- 1 carboxylate 682.8 7.51 II J ii J , wV-oh trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(1-isopropyl-\H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3(hydroxymethyl)azetidine- 1 carboxylate 669.8 7.52 \ ABOUT A°4 I V About if < / trans-4-((3-(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine- 1 carboxylate 658.5 7.53 /=\ / S^y° o z \__/ i -z\ trans-4-((3 -(1-Isopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(5 methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino)azetidine1-carboxylate 671.6 7.54 trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-ethylazetidine-1 carboxylate 657.5

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7.55 0 A £ο\ trans-4-((4-(1-Isopropyl-\Ηpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -3-methoxyazetidine-1 carboxylate 659.5 7.56 0 Α Α Ο P trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-isopropoxyazetidine-1 carboxylate 687.5 7.57 ο γγπ'γ' ⁴ 0 Υφ 04 “Λφ trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-isopropylazetide in-1 carboxylate 671.5 7.58 ³ \ ζ— d Μ η 0 / trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-(dimethylamino)azetidine1-carboxylate 672.6 7.59 ο XX ν η^Χ ο ΆφΑ nA II 1 ϋ J . ΙΑ, οη ^Χ trans-4-((4-(1-Isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-(hydroxymethyl)azetidine1-carboxylate 659.5

- 237 040704

7.60 A A / trans-4-((3-(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-ethylazetidine- 1 carboxylate 656.3 7.61 _YXl -pCl,! II \ |l \ , V—P.OH a-ay D ^b N ^X trans-4-((3 -(1-Isopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(5 methoxy-6-methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl)azetidine1-carboxylate 658.4 7.62 ¹ 0 Mf ^N M ^0H '-o trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 642.4 7.63 MaW MrH^ ^{oh 1} %' trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3 yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 642.5 7.64 T o d M X/ A / trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 644.5 7.65 A p o I trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 645.5

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7.66 / o / O Δ °>ο ο I trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine-1 carboxylate 643.3 7.67 0 hrDN _ν Α ΗΑ ₀ Η _ν -, ^0Η % trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) carb amoyl) cyclohexyl-3 hydroxyazetidine-1-carboxylate 643.5 7.68 0 Ύ λ ⁰ -ν '—ο trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cycle ohexyl)methyl)(3(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 653.8 7.69 ^ΟΗ' -ο trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropyloxazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate 654.6 7.70 γθΛ _Υ i^ Υ ^ν λ ^οη '-ο trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 654.2

- 239 040704

7.71 Τ o d °% T / o / trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine -1 carboxylate 646.6 7.72 TVn. Oh trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(2cyclopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 655.7 7.73 0 D Ua %rV ^ ^0H trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1-carboxylate 656.5 7.74 < Ho X o X trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3 -(2isopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl-3hydroxyazetidine-1-carboxylate 656.6 7.75 £3 Up to V Αχ A / O / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexylazetidine-1-carboxylate 628.6 7.76 o o Puk I \Α% ₀ Α _Ν γ -οΉ ° o trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-methoxyazetidine- 1 carboxylate 658.5

- 240 040704

7.77 / O H V 4 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-(methoxymethyl )azetidine1-carboxylate) 672.6 7.78 -Z \ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyldimethylcarbamate 616.4 7.79 \ Z— H γ 4 / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(dimethylamino) Azetidine-1 carboxylate 671.5 7.80 _γ γΛγ _x JI J i A m αΑ,οη trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(hydroxymethyl) Azetidine-1 carboxylate 658.6 7.81 νΑοΧ ^[ ^ ^Ν γ f'-o trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl-3(dimethylamino)azetidine-1 carboxylate 670.5

- 241 040704

7.82 \ o d °=( Δ / trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-methoxyazetidine -1 carboxylate 660.6 7.83 / O / Ο trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-isopropoxyazetidine -1 carboxylate 688.8 7.84 \ z - d XX¾ / trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(dimethylamino )azetidine-1 carboxylate 673.6 7.85 ² ο trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3 -(2 -methoxy-2oxoethyl)azetidine-1-carboxylate 700.6 7.86 ⁵ _γ ^;?α _ο χ "-0¾ Hu '-ο 2-(1-(((trans-4-((4-(2- Cyclopropyloxazol-4-yl)pyridine2-yl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl)oxy)carbonyl)azetidine-3yl)acetic acid 686.6

- 242 040704

7.87 4 •if 4 / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-ethoxyazetidine- 1 carboxylate 672.6 7.88 λ ° _>ο ζ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-cyanoazetidine- 1 carboxylate 653.6 7.89 Αοχ SU at A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-methylazetidine- 1 carboxylate 642.5 7.90 9 4 γ 4 / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-ethylazetidine- 1 carboxylate 656.5 7.91 4 # Δ % _o £ o g trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-isopropoxyazetidine- 1 carboxylate 686.6

- 243 040704

7.92 A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(6methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(dimethylamino )azetidine-1 carboxylate 671.6 7.93 AA ΑγΝ^ trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(6methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-methoxyazetidine -1 carboxylate 658.6 7.94 χτθ όΡ'° A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(6methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine -1 carboxylate 644.5 7.95 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-(2methoxyethoxy )azetidine-1 carboxylate 702.6 7.96 •yyOpQA^ And he 4-((4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)((4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-cis-3-hydroxyazetidine-1 carboxylate 644.5

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7.97 si trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3(hydroxymethyl )azetidine-1 carboxylate 660.4 7.98 0 0 \/ ^Ν ΥΥ _Ν Υ \Υ ₀ Υ^ Α+,-< A trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-ethinylazetide in -1 carboxylate 652.6 7.99 γϊοχ uu ρ° ^Η Re trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-(2 -hydroxypropan-2yl)azetide in-1-carboxylate 686.6 7.100 0 γ _ζ γ ' ο / trans-4-((4-(2-Isopropyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-ethylazetidine -1 carboxylate 658.5 7.101 °Α γ Υ b / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3- ((methylsulfonyl)methyl)azetide in-1 carboxylate 720.5

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7.102 D zQ / o / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5methoxy-6-methyl pyride in-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3 -isopropylazetidine-1 carboxylate 670.5 7.103 A D △ To g trans-4-((4-(2-Cyclopropyloxazol4-yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methyl pyride in-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl -3 -(tert-butyl)azetide in-1 carboxylate 684.5 7.104 trans-4-((4-(2-Cyclopropyloxazol4-yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methyl pyride in-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl -3-propoxyazetidine-1 carboxylate 686.5 7.105 / O / O d A Before G trans-4-((4-(2-Cyclopropyloxazol4-yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methyl pyride in-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl -3-propylazetide in-1 carboxylate 670.7 7.106 O ..L Yeah ^-o trans-4-((4-(2-Cyclopropyloxazol4-yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methyl pyride in-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl -3 - ((dimethylamino)methyl)azetidine-1carboxylate 685.5

7.107 b zQ / o / trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-2-methylmorpholine- 4carboxylate 672.8 7.108 ⁴ mi » _Lohn trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5 methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxy-[1,3' biazetidine]-1'-carboxylate 699.4 7.109 t o d °5 g zQ / o / trans-4-((4-(2-Ethyloxazol-4yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl-3-hydroxyazetidine -1 carboxylate 632.3

Acylimidazole preparation:

1DMF as solvent. Preparation of carbamate: Reactions that proceeded slowly at RT were either left stirring for many days or heated (50-80°C);

² Amine was the TFA salt;

³ Amine was dihydrochloride;

4Amin was an oxalate.

⁵ From the corresponding methyl ester (1 M NaOH, THF, MeOH, rt).

⁶ From the appropriate Boc-protected amine (20% TFA in CH ₂ Cl ₂ ).

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Compound 8: trans-4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 -((methylsulfinyl)methyl)azetidine-1-carboxylate

Sodium periodate (0.12 ml, 0.438 mmol, 3.5 M in H2O) was added to a mixture of compound 4.28 (200 mg, 0.292 mmol) in THF (1 ml) at 0°C. The mixture was stirred at rt. overnight and then diluted with EtOAc (10 ml). The organic layer was washed with sat. aq. NaHCO ₃ solution (2x5 ml) and brine (5 ml), dried over Na ₂ SO ₄ , filtered, concentrated and purified by reverse phase prep. HPLC (water(0.04% NH4OH+10 mM NH ₄ HCO ₃ )/CH ₃ CN) to give trans-4-((3(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans- 4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((methylsulfinyl)methyl)azetidine-1-carboxylate (105 mg, 51%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 7.94 (s, 1H), 7.61 (d, 1H), 7.55 (s, 1H), 7, 44 (t, 1H), 7.10 (d, 1H), 6.99-6.91 (m, 2H), 6.82-6.71 (m, 1H), 4.38-4.26 ( m, 1H), 4.01-3.90 (m, 2H), 3.83-3.43 (m, 8H), 3.132.82 (m, 3H), 2.51 (s, 3H), 2 .38-2.29 (t, 1H), 2.19-2.02 (m, 4H), 1.89-1.63 (m, 8H), 1.55-1.36 (m, 3H) , 1.36-1.20 (m, 2H), 1.18-0.83 (m, 8H); LCMS: 701.5 [M+H] ⁺ .

The following compound was synthesized from compound 6.30 according to the procedure described for compound 8.

Comm.

Structure

Name

[M+N]·

trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3(methylsulfinyl)az etidine-1carboxylate

¹ NaIO ₄ (0.15 M in CH ₃ OH); CH ₃ OH instead of THF as solvent.

Compound 9:

trans-4-((3 -(1-Cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 -( (methylsulfonyl)methyl)azetidine-1-carboxylate

meta-Chloroperoxybenzoic acid (118.5 mg, 0.584 mmol, 85%) was added to a solution of compound 4.28 (200.0 mg, 0.292 mmol) in CH ₂ Cl ₂ (10 ml) at 0°C. The reaction mixture was stirred for 1 h at rt. and then diluted with EtOAc (10 ml). The organic layer was washed with sat. water. NaHCO ₃ solution (2x5 ml), washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by reverse phase prep. HPLC (water (0.04% NH ₄ OH+10 mM NH ₄ HCO ₃ )/CH ₃ CN) to give trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)( (trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-((methylsulfonyl)methyl)azetidine-1-carboxylate (80.1 mg, 38%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.95 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.45 (t, 1H), 7.11 (d, 1H), 6.99-6.92 (m, 2H), 6.84-6.73 (m, 1H), 4.40-4.26 (m , 1H), 4.01-3.90 (m, 2H), 3.80-3.49 (m, 8H), 3.45 (d, 2H), 3.07-2.96 (m, 1H ), 2.92 (s, 3H), 2.39-2.28 (m, 1H), 2.19-2.04 (m, 4H), 1.89-1.65 (m, 8H), 1.57-1.38 (m, 3H), 1.38-1.22 (m, 2H), 1.14-0.82 (m, 8H); LCMS: 717.5 [M+H] ⁺ .

Compound 10:

trans-4-((3 -(1-Cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-trans-4 -hydroxycyclohexanecarboxylate

The title compound was isolated during the purification of intermediate 29.11.

1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.61 (d, 1H), 7.55 (s, 1H), 7, 44 (t, 1H), 7.10 (d, 1H), 6.94 (s, 2H), 6.78 (d, 1H), 4.55-4.44 (m, 2H), 3.78 -3.69 (m, 4H), 3.63-3.49 (m, 2H), 3.30-3.25 (m, 1H), 2.39-2.28 (m, 1H), 2 .19-2.01 (m, 5H), 1.86-1.66 (m, 12H), 1.56-1.39 (m, 3H), 1.37-1.20 (m, 4H) , 1.14-0.87 (m,

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10N); LCMS: 668.5 [M+H]+.

Compound 11:

trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methocCi-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy )cyclohexanecarboxamide

Step 1: trans-4-(Allyloxy)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Sodium hydride (178.9 mg, 4.47 mmol, 60% pure) was added to a solution of intermediate 26 (500 mg, 0.894 mmol) in THF (25 ml) at 0°C. The reaction mixture was stirred at 0° C. for 1 h under N ₂ and then 3-bromoprop-1-ene (649.5 mg, 5.37 mmol) was added. The reaction mixture was stirred at 70° C. overnight and then more 3-bromoprop-1-ene (649.5 mg, 5.37 mmol) was added. The reaction mixture was stirred at 70° C. overnight, water (30 ml) was added and the mixture was extracted with EtOAc (2x50 ml). The organic layers were combined, washed with water (30 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give trans-4-(allyloxy)-N -(3-(2-cyclopropylthiazol-5yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (420 mg, 78%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.69 (s, 1H), 7.47-7.41 (m, 1H), 7.40-7.32 (m, 1H), 7.21 ( t, 1H), 7.04 (d, 1H), 6.91-6.86 (m, 2H), 6.66 (d, 1H), 5.86-5.72 (m, 1H), 5 .16(d, 1H), 5.05(d, 1H), 3.88(d, 2H), 3.72(s, 3H), 3.55(d, 2H), 3.25-3, 13 (m, 1H), 2.36-2.22 (m, 2H), 2.14-2.01 (m, 4H), 1.98-1.89 (m, 2H), 1.85- 1.63 (m, 6H), 1.61-1.44 (m, 3H), 1.39-1.26 (m, 2H), 1.16-1.01 (m, 6H), 0. 96-0.84 (m, 2H); LCMS: 599.4 [M+H] ⁺ .

Step 2: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-oxoethoxy )cyclohexanecarboxamide

Potassium osmate(VI) dihydrate (153.8 mg, 0.417 mmol) and 18-crown-6 (441.3 mg, 1.67 mmol) were added to a solution of trans-4-(allyloxy)-N-(3-(2 -cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (500 mg, 0.834 mmol), NaIO ₄ (535.7 mg, 2, 50 mmol), THF (16 ml) and H2O (10 ml) at rt. The reaction mixture was stirred at rt. overnight, poured into water (20 ml) and extracted with EtOAc (2x50 ml). The combined organic layers were washed with water (10 ml), washed with brine (10 ml), dried (Na2SO4), filtered, concentrated and then purified by prep. TLC (petroleum ether/EtOAc=1/1) to give trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)-4-(2-oxoethoxy)cyclohexanecarboxamide (130 mg, 26%) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ): δ 9.67 (s, 1H), 7.79 (s, 1H), 7.56-7.40 (m, 2H), 7.29-7.26 ( m, 1H), 7.12 (d, 1H), 6.99-6.93 (m, 2H), 6.74 (d, 1H), 4.05 (s, 2H), 3.80 (s , 3H), 3.63 (d, 2H), 3.29 (t, 1H), 2.46-2.29 (m, 2H), 2.23-2.10 (m, 4H), 2, 09-1.97 (m, 2H), 1.93-1.72 (m, 5H), 1.71-1.58 (m, 2H), 1.44-1.11 (m, 10H), 1.10-0.94 (m, 2H); LCMS: 601.4 [M+H] ⁺ .

Step 3: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-( methylamino)ethoxy)cyclohexanecarboxamide hydrochloride

Acetic acid (10.9 mg, 0.183 mmol) was added to a solution of trans-N-(3-(2-cyclopropylthiazol5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) methyl)-4-(2-oxoethoxy)cyclohexanecarboxamide (110 mg, 183.09 µmol) and methanamine (2M in THF, 1.83 ml, 3.66 mmol) in DCE (5 ml) at rt. The reaction mixture was stirred at rt. over 3 hours. Sodium triacetoxyborohydride (116.4 mg, 0.549 mmol) was added. The reaction mixture was stirred at rt. during the night, poured into sat. water. NaHCO3 solution (20 ml) and extracted with CH2Cl2 (5x20 ml). The organic layers were combined, dried (Na2SO4), filtered, concentrated and then purified by reverse phase HPLC (water (0.05% HCl)/CH ₃ CN) to give trans-N-(3-(2-cyclopropylthiazole-5- yl)phenyl)-N((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy)cyclohexanecarboxamide hydrochloride (25.6 mg, 21%) as a yellow solid substances.

1 H NMR (400 MHz, DMSO-d6): δ 8.89-8.78 (m, 2H), 8.14 (s, 1H), 7.64-7.58 (m, 2H), 7.58 -7.47(m, 1H), 7.28(d, 1H), 6.98-6.90(m, 2H), 6.80-6.76(m, 1H), 3.72(s , 3H), 3.64-3.51 (m, 4H), 3.22 (t, 1H), 2.99-2.62 (m, 2H), 2.49-2.42 (m, 4H ), 2.33 (t, 1H), 2.12-2.07 (m, 4H), 1.95 (d, 2H), 1.80-1.63 (m, 6H), 1.51- 1.36 (m, 3H), 1.35-1.21 (m, 2H), 1.21-1.13 (m, 2H), 1.12-0.97 (m, 4H), 0. 87-0.73 (m, 2H); LCMS: 616.4 [M+H] ⁺ .

Compound 12: 2 -((trans-4-((3 -(1-Isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)oxy)acetic acid

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Stage 1: tert-Butyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)oxy)acetate

tert-Butylammonium bromide (29.6 mg, 0.092 mmol) was added to a mixture of intermediate 29.12 (500 mg, 0.92 mmol), tert-butyl-2-bromoacetate (896.8 mg, 4.6 mmol), NaOH ( 4 ml, 50% in H ₂ O) and toluene (10 ml) at rt. The reaction mixture was heated to 90° C., stirred overnight, poured into H2O (20 ml) and then extracted with CH ₂ Cl ₂ (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 50/50) to give t-butyl-2-((trans -4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetate (400 mg, 65%) as a yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.94 (s, 1H), 7.64-7.58 (m, 1H), 7.55 (s, 1H ), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.89 (m, 2H), 6.82-6.74 (m, 1H), 4.58- 4.42 (m, 1H), 3.94-3.86 (m, 2H), 3.71 (s, 3H), 3.653.45 (m, 2H), 3.23-3.10 (m, 1H), 2.40-2.30 (m, 1H), 2.14-2.02 (m, 4H), 1.96-1.85 (m, 2H), 1.80-1.63 ( m, 6H), 1.47-1.41(m, 9H), 1.38(s, 9H), 1.32-1.23(m, 2H), 1.08-0.96(m, 2H), 0.84-0.67 (m, 2H); LCMS: 658.5 [M+H]+.

Step 2: 2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)oxy)acetic acid

tert-Butyl-2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)oxy)acetate (400 mg, 0.61 mmol) and HCl in dioxane (4 M, 20 mL) were stirred at rt. over 1 hour. The reaction mixture was concentrated and then purified by reverse phase HPLC (water (0.05% HCl)-MeCN) to give a white solid. The solid was dissolved in H2O (3 ml), adjusted to pH=9 with NaOH (1 M), adjusted to pH=6 with HCl (1 M) at rt, stirred at rt. for 10 min, filtered and then dried in vacuo to give 2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy3 -methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxy)acetic acid (200 mg, 55%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 13.44-12.25 (m, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.61 (d, 1H) , 7.55 (s, 1H), 7.44 (t, 1H), 7.09 (d, 1H), 7.00-6.91 (m, 2H), 6.84-6.74 (m , 1H), 4.58-4.42 (m, 1H), 3.88 (s, 2H), 3.71 (s, 3H), 3.65-3.42 (m, 2H), 3, 25-3.13 (m, 1H), 2.40-2.24 (m, 1H), 2.17-2.05 (m, 4H), 1.97-1.85 (m, 2H), 1.81-1.60 (m, 6H), 1.48-1.24 (m, 11H), 1.13-0.96 (m, 2H), 0.85-0.66 (m, 2H ); LCMS: 602.4 [M+H] ⁺ .

Compound 13: trans-4-(((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyldimethylcarbamate o o

Intermediate 22 (200 mg, 0.364 mmol) was dissolved in THF (5.0 ml) at 0°C. Sodium hydride (60% pure, 43.7 mg, 1.09 mmol) was added at 0°C. The solution was stirred at 0° C. for 0.5 h. Dimethylcarbamic acid chloride (47.0 mg, 0.437 mmol) in THF (5.0 ml) was added slowly. The solution was stirred at 60° C. overnight, quenched with saturated NH ₄ Cl solution (10 ml) and then extracted with EtOAc (3x15 ml). The organic phases were washed with brine (2x15 ml), concentrated and purified first by RP-HPLC [water (10mM NH ₄ CO ₃ )-MeCN] and then prep. TLC (petroleum ether: EtOAc=1:1) to give trans-4(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl) carbamoyl)cyclohexyldimethylcarbamate (31.1 mg) as a white solid.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 7.74 (s, 1H), 7.44-7.54 (m, 3H), 7.23 (d, 1H), 6.91-6, 93 (m, 2H), 6.76 (d, 1H), 4.32-4.33 (m, 1H), 4.04 (s, 3H), 3.69 (s, 3H), 3.54 (s, 2H), 2.71 (s, 6H), 2.30-2.31 (m, 1H), 2.06-2.08 (m, 4H), 1.82-1.83 (m , 2H), 1.71-1.73 (m, 6H), 1.40-1.53 (m, 3H), 1.20-1.32 (m, 2H), 0.90-1.08 (m, 4H); LCMS: 531.3 [M-OC(O)N(CH3)2] ⁺ .

The following compounds were synthesized from the appropriate intermediate and the appropriate alkyl halide according to the procedure described for compound 13

Comm. Structure Name [M+N] ⁺ 13.01 about AP Ή ⁴ trans-U-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4-(2methoxyethoxy)-U-(3-(2methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide 607.3

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13.02 0 A ⁴ trans-R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4-(3methoxypropoxy)-L'-(3-(2methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide 621.3 ^{13.03 2'3} A ύΑ trans-4-(2-Hydroxyethoxy)-I-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-I-(3(2-methoxythiazole-5 - yl)phenyl)cyclohexanecarboxamide 593.4 13.04 ⁴ nA y %y A ⁴ trans-4-(3-Hydroxypropoxy)-K- ((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-I-(3(2-methoxythiazole-5 - yl)phenyl)cyclohexanecarboxamide 607.3 13.05 ¹ 4 A g 2— / trans-R-(3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2- (dimethylamino)ethoxy)-I-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 630.5

1Heated at 65°C;

² Heated at 70°C;

³ From alcohol protected with THP bromine, deprotection (p-TsOH-H ₂ O, CH ₂ Cl ₂ , CH ₃ OH, rt, 3 h);

⁴ 2-(3-bromopropoxy)tetrahydro-2H-pyran, nBu ₄ NBr, KOH, toluene, rt, overnight; then additional KOH, rt, overnight; then deprotection (p-TsOH-H ₂ O, CH ₂ Cl ₂ , CH ₃ OH, rt, 3 h).

Compound 14:

Ethyl 2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)carbamoyl )cyclohexyl)acetate

Intermediate 14.28 (50 mg, 0.12 mmol) and trans-4-(2-ethoxy-2oxoethyl)cyclohexanecarboxylic acid (40 mg, 0.19 mmol) were dissolved in CH ₂ Cl ₂ (1 ml). In the reaction mixture at room temperature pyridine (40 μl, 0.49 mmol) was added followed by 1-propylphosphonic acid cyclic anhydride (50 wt% in CH ₂ Cl ₂ ; 90 μl, 0.19 mmol). The reaction mixture was stirred at rt. overnight and then heated at 40°C for 3.5 hours Added additional amount of cyclic anhydride 1-propylphosphonic acid (50 wt.% in CH ₂ Cl ₂ ; 3 μl, 0.006 mmol). The reaction mixture was heated at 40°C for ~7 h and then diluted with EtOAc (20 ml). The organic phases were washed with water (20 ml), washed with saturated NaHCO ₃ solution (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (20-70 % EtOAc in hexanes) to give ethyl-2(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridine-2 -yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate as an off-white foam (47 mg, 64% yield).

1H NMR (400 MHz, DMSC-d6): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.59 (d, 1H), 7.53 (s, 1H), 7, 43 (t, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 6.98 (d, 1H), 3.99 (q, 2H), 3.79-3.70 (m, 4H), 3.67-3.46 (m, 2H), 2.29 (s, 3H), 2.13-2.01 (m, 3H), 1.82-1.72 (m , 4H), 1.70-1.51 (m, 5H), 1.48-1.30 (m, 5H), 1.17-0.95 (m, 10H), 0.70-0.56 (m, 2H); LCMS: 613.6 [M+H]+.

Compound 15:

trans-N-(3 -(1-Cyclopropyl-1 H-n-nirazol-4-yl)phenyl)-4-(hydroxymethyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

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Sodium borohydride (35 mg, 0.92 mmol) was added to a mixture of compound 18.13 (50 mg, 0.086 mmol), LiCl (9 mg, 0.21 mmol) and THF (2 ml). The mixture was stirred at rt. for 25 min, heated at 80°C for 2 h, allowed to cool to rt. and then diluted with EtOAc (20 ml). The organic layer was washed (2x20 ml saturated NaHCO ₃ solution and then 20 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (05% CH3OH in CH ₂ Cl ₂ ) to give trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4(hydroxymethyl)-N-(( trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (41 mg, 86%) as a white foam.

¹ H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.58 (d, 1H), 7.55-7.51 (m, 1H), 7.43 (t, 1H), 7.08 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.75 (m, 1H), 4.26 (t, 1H), 3.77-3.72 (m, 1H), 3.71 (s, 3H), 3.65-3.41 (m, 2H), 3.07 (t, 2H), 2.38-2.27 (m, 1H), 2.08 (s, 3H), 2.07-2.02 (m, 1H), 1.80-1.57 (m, 8H), 1, 47-1.18 (m, 6H), 1.11-0.95 (m, 6H), 0.62-0.46 (m, 2H); LCMS: 556.4 [M+H]+.

The following compounds were synthesized from the appropriate methyl ester according to the procedure described for compound 15.

Comm. Structure Name [M+N] ⁺ 15.OT trans-4-(Hydroxymethyl)-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)N-(3-(2-methox ithiazol-5yl)phenyl)cyclohexanecarboxamide 563.5 15.02 ² About τσ° Y trans-I-(3-(2- Cyclopropylthiazole-5- yl)phenyl)-4-(hydroxymethyl)-I((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 573.5 15.OZ ² Ο ΑΉγ trans-4-(Hydroxymethyl)-R-(4-(1isopropyl- 1R-pyrazole-4- yl)pyridin-2-yl)-R-((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexancarboxamide 560.3 15.04 ³ 4 / trans-I-(4-(2- Cyclopropyloxazol-4yl)pyridin-2-yl)-4(hydroxymethyl)-R-((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)cyclohexancarboxamide 587.6

1Heated at 60°C for 1 hour, 70°C for 4 hours and then 80°C for 1 hour;

² Heated at 80°C overnight;

³ Heated at 80°C for 5 hours, added more NaBH4 and then heated at 80°C for 1 hour.

Compound 16: trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid

An aqueous solution of sodium hydroxide (1 N, 0.3 ml, 0.3 mmol) was added to a solution of compound 18.08

- 251 040704 (37 mg, 0.061 mmol), THF (0.6 ml) and CH ₃ OH (0.3 ml) at RT The mixture was stirred for 4.5 h and then poured into a mixture of 20 ml of a saturated solution of NH ₄ Cl and 0.3 ml of 1 N HCl. This mixture was extracted with EtOAc. Additional 1 N HCl (0.2 ml) was added to the aqueous layer to adjust the pH from 5 to 3. The aqueous layer was extracted by adding first EtOAc and then EtOAc, the layer was washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The compound was found in both aqueous and organic layers. The aqueous layer was basified with 1 N

NaOH to pH ~ 6 was added to the concentrated residue and then extracted with EtOAc (2x20 ml). The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridine-3- yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid (33 mg, 94%) as an off-white foam.

1H NMR (400 MHz, DMSC-d6): δ 12.00 (br s, 1H), 8.09 (s, 1H), 7.88-7.82 (m, 1H), 7.62-7, 55 (m, 2H), 7.55-7.48 (m, 2H), 7.30-7.24 (m, 1H), 6.75-6.67 (m, 1H), 3.63- 3.53 (m, 2H), 3.02 (s, 6H), 2.47-2.41 (m, 1H), 2.41-2.31 (m, 1H), 2.17-2, 04 (m, 2H), 1.86-1.65 (m, 8H), 1.51-1.36 (m, 3H), 1.36-1.26 (m, 2H), 1.18- 1.11 (m, 2H), 1.11-0.87 (m, 6H); LCMS: 587.4 [M+H]+.

Compound 17: trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid

An aqueous solution of sodium hydroxide (1 N, 1.25 ml, 1.25 mmol) was added to a solution of compound 18.06 (153 mg, 0.25 mmol), CH ₃ OH (1.25 ml) and THF (2.50 ml) at k.t. The reaction mixture was stirred for 2 h, concentrated, diluted with 2 ml of water and then acidified at 0°C with 1.3 ml of 1 N HCl. The mixture was diluted with EtOAc. The organic phases were washed with 30 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and dried under high vacuum overnight to give trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl) ((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid (142 mg, 95%) as an off-white foam.

1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.10 (s, 1H), 7.63-7.56 (m, 2H), 7.52 (t, 1H ), 7.31-7.24 (m, 1H), 6.98-6.91 (m, 2H), 6.82-6.74 (m, 1H), 3.72 (s, 3H), 3.62-3.49(m, 2H), 2.4-2.39(m, 1H), 2.39-2.28(m, 1H), 2.17-2.03(m, 5H ), 1.86-1.64 (m, 8H), 1.50-1.36 (m, 3H), 1.36-1.24 (m, 2H), 1.18-1.11 (m , 2H), 1.11-0.87 (m, 6H); LCMS: 587.4 [M+H] ⁺ .

The following compounds were synthesized from the appropriate ester intermediates according to the procedure described for compounds 16 and 17.

Comm. Structure 17.01 ⁴ 7 A O 17.02 ⁴ ‘ί /=\ / c OO=( About I

Name [M+N] ⁺ trans-4-(((trans-4-(4-Methoxy-3methyl phenyl)cycle ohexyl)methyl)(3(2-methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexane carboxylic acid 577.3 4-(((trans-4-(4-Methoxy-3- methyl l phenyl) cycle ohexyl) methyl) (3 - (2-methoxythiazole-5- yl)phenyl)carbamoyl)bicyclo[2.2.2] octane-1-carboxylic acid 603.5

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17.03 ⁴ 0 trans-4-(((trans-4-(3-Chloro-4methoxyphenyl)cyclohexyl)methyl)( 3 -(2-cyclopropylthiazol-5 yl)phenyl)carbamoyl)cyclohexane carboxylic acid 607.3 17.04 2 •L Μ I trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((trans-4-(3-fluoro-1 methyl- 1R-indazol-5- yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 615.4 17.05 ⁴ 7 •Ar Μ I trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexane carboxylic acid 613.4 17.06 ¹ trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((4-(6(dimethylamino)pyridin-3yl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexane carboxylic acid 613.4 17.07 ^1.5 I / trans-4-((4-(2-Cyclopropylthiazol5-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexane carboxylic acid 614.4 17.08 ¹ H NX I trans-4-((3-(2-Cyclopropylthiazol5 -yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 588.4

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17.09 ¹ 0 Χι Δ Tg ^he trans-4-((4-(2-Cyclopropylthiazol5-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 588.5 17.10 ¹ Τ ο V7 Η Η 'ο / trans-4-((4-(2-Cyclopropylthiazol5-yl)pyride in-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 589.4 17.11 ² ο trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexane carboxylic acid 598.3 17.12 ² trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexane rboxonic acid 599.6 17.13 ⁶ Μ Ο ο ^{o \u003d} C-Ae / trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 570.4 17.14 ³ Μ Ο ο ^{o \u003d} SpS ζ - / trans-4-((3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 570.5

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17.15 ⁴ Μ O o ^{o \u003d} CaC 7 ^υ / trans-4-(((trans-4-(3-Chloro-4methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexane rboxonic acid 590.3 17.16 574° about bh I trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(3fluoro-1-methyl- \H-indazol-5 yl)cyclohexyl)methyl)carbamoyl) c cyclohexanecarboxylic acid 598.3 17.17 ⁴ trans-4-((3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane1- yl)methyl)carbamoyl)cyclohexane rbonic acid 596.4 17.18 Μ Ο ο ^{o \u003d} Sdr ' ο / trans-4-((3-(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 571.5 17.19 ² 4 U Μ τ trans-4-((4-( 1 -Cyclopropyl-\Hpyrazol-4-yl)pyridin-2-yl)((4-(4methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexane carboxylic acid 597.5 17.20 ο n''VYj άΑ ύάχ trans-4-((4-(1-Cyclopropyl-\Hpyrazol-4-yl)pyridin-2-yl)((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid 571.5

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^{17.21 3'6} A I / trans-4-((4-(1-Cyclopropyl-1Ηpyrazol-4-yl)pyridin-2-yl)((trans4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexanecarboxylic acid 572.5 17.22 ² ί /=\ / Dd>° L O M I trans-4-(((trans-4-(3-Cyano-4-methoxy-phenyl)-cyclohexane)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexane 581.5 17.23 ⁴ O And Λ Wu' oh / 2-(trans-4-((4-(1-Cyclopropyl-177pyrazol-4-yl)pyridin-2-yl)((trans4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexyl)acetic acid 586.4 17.24 ⁴ O °H ' O / 2-(trans-4-((3-(1-Cyclopropyl-177pyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexyl)acetic acid 585.5 17.25 ⁶ ί about X 2-(trans-4-((4-(1-Isopropyl- 177pyrazol-4-yl)pyridin-2-yl)((trans4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)c cyclohexyl)acetic acid 588.5 17.26 ³ λΎ.λ nA Ά^ _ΟΗ - AA / 2-(trans-4-(((trans-4-(3-Cyano-4methoxy phenyl) oxyl)methyl)(4-(1-isopropyl- 1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyl)acetic acid 598.5 17.27 ³ ο ^Ζ / < .. I 2-(trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyl)acetic acid 599.5

Alternative terms:

¹ THF/CH ₃ OH (1:1);

² LiOH H ₂ O, THF, 0°С-rt, 2 h. Isolation options:

3 Acidified to pH=6 before extraction;

⁴ Purified by silica gel chromatography;

⁵ Purified by reverse phase HPLC;

⁶ Was isolated as a solid by filtration of the aqueous layer after adjusting the pH.

Compound 18: trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid

Step 1: 5-(trans-4-(((3-(2-Cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-2-methoxybenzonitrile

Sodium triacetoxyborohydride (436 mg, 2.06 mmol) was added to a solution of intermediate

- 256 040704 3.05 (200 mg, 0.82 mmol), intermediate 8.01 (165 mg, 0.82 mmol) and DCE (20 ml) at 0°C under N2. The reaction mixture was stirred at rt. overnight, poured into a saturated solution of NaHCO ₃ (30 ml) and was extracted with the addition of CH ₂ Cl ₂ (3x30 ml). The combined organic layers were washed (30 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 17/3) to give 5-(trans-4-(((3-(2-cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-2- methoxybenzonitrile (250 mg, 66%) as a yellow oil.

1H NMR (400 MHz, CDCl3): δ 7.71(s, 1H), 7.42-7.35(m, 2H), 7.20-7.18(m, 1H), 7.01-6 .97 (m, 2H), 6.90 (d, 1H), 6.56 (d, 1H), 3.90 (s, 3H), 3.07 (d, 2H), 2.50-2, 43 (m, 1H), 2.15-2.11 (m, 1H), 2.05-2.00 (m, 2H), 1.991.90 (m, 2H), 1.70-1.67 ( m, 1H), 1.43-1.39 (m, 2H), 1.13-1.11 (m, 2H), 1.10-1.06 (m, 2H), 1.06-1, 04 (m, 2H); LCMS: 428.3 [M+H]+.

Stage 2: trans-Methyl-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate

Intermediate 19.04 (20 ml in toluene, 1.87 mmol) was added to a solution of 5-(trans-4(((3-(2-cyclopropyloxazol-4-yl)phenyl)amino)methyl)cyclohexyl)-2-methoxybenzonitrile ( 200 mg, 0.47 mmol), pyridine (0.76 ml, 9.36 mmol) and dry CH ₂ Cl ₂ (10 ml) at 0°C under N2 atmosphere. The reaction mixture was allowed to warm to rt, stirred overnight, poured into saturated NaHCO3 solution (30 ml) and then extracted with CH ₂ Cl ₂ (3x30 ml). The combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=4/1) to give trans-methyl-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2- cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylate (190 mg, 52%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80 (s, 1H), 7.67 (d, 1H), 7.56 (s, 1H), 7.47-7.42 (m, 1H ), 7.35-7.32 (m, 2H), 7.08 (d, 1H), 6.88 (d, 1H), 3.89 (s, 3H), 3.60 (s, 3H) , 2.48-2.40(m, 1H), 2.30-2.23(m, 1H), 2.20-2.09(m, 2H), 1.93-1.76(m, 7H), 1.66-1.56(m, 5H), 1.48-1.43(m, 1H), 1.33-1.30(m, 2H), 1.22-1.11( m, 6H), 1.11-1.04 (m, 2H); LCMS: 596.4 [M+H] ⁺ .

Step 3: trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid

Lithium hydroxide monohydrate (169 mg, 4.03 mmol) was added to a solution of trans-methyl-4-(((trans-4(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexanecarboxylate (300 mg, 0.5 mmol), THF (20 ml) and H2O (5 ml) at 0°C. The mixture was allowed to warm to rt. and stirred overnight. THF was removed under reduced pressure and the mixture was diluted with H2O (20 ml). The mixture was concentrated to remove water (5 ml) and then hydrochloric acid (1 M) was added to the solution at 0°C (pH=6). The resulting solid was collected by filtration, washed with ice-cold H2O (20 ml) and dried in vacuo. The solid was purified by reverse phase HPLC (water(0.05% HCl)/CH ₃ CN) to give trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3-( 2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid (130 mg, 44%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.52 (s, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7, 53-7.49 (m, 3H), 7.24 (d, 1H), 7.12 (d, 1H), 3.86 (s, 3H), 3.56 (d, 2H), 2.45 -2.42 (m, 1H), 2.19-2.13 (m, 1H), 2.10-2.07 (m, 2H), 1.81-1.72 (m, 6H), 1 .69-1.66 (m, 2H), 1.46-1.31 (m, 5H), 1.07-1.04 (m, 4H), 1.00-0.99 (m, 2H) , 0.98-0.88 (m, 2H); LCMS: 582.4 [M+H] ⁺ .

The following compounds were synthesized from the appropriate intermediates according to the procedures described for compound 18.

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Name

Comm.

Structure

[M+N]'

trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid trans-4-((4-( 2-Cyclopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbam oil)cyclohexanecarboxylic acid trans-4-((4-(2-Cyclopropyloxazol-4yl)pyridine -2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarboxylic acid trans-4-((3-(2-Cyclopropyloxazol-4yl)phenyl )((trans-4-(6(d-imethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid trans-4-(((trans-4-(6-Cyano-5methoxypyridine-2yl)cyclohexyl )methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylic acid

Alternative condition:

Step 2: 1 The base was Et ₃ N.

Selection options:

² Purified by silica gel chromatography;

³ Filter off the solids with an H ₂ O wash (no further purification).

The following compounds were synthesized from the appropriate intermediates according to the procedures described for compound 18, steps 1 and 2.

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18.06 ² G and trans-Methyl-4-((3-(2cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 601.4 18.07 O - -D' trans-Methyl-4-(((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)(3(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexanecarboxylate 591.4 18.08 / About g—7 A d Z— / trans-Methyl-4-((3-(2- cyclopropylthiazole-5- yl)phenyl)((trans-4-(6- (dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexanecarboxylate 601.4 18.09 0 trans-Methyl-4-(((trans-4-(6-cyano- 5-methoxypyr idin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5- yl)phenyl)carbamoyl)cyclohexanecarboxylate 613.5 ^{18.ΙΟ 2'5} O.: :......'V'-Ν ^X Methyl 4-(((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)(3(2-methoxythiazol-5yl)phenyl)carbamoyl)bicyclo[2.2.2]o ctane-1-carboxylate 617.4 18.11 d trans-4-(Benzyloxy)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-I(3-(2-methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide 639.5

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18.12 ^A4 trans-R-((trans-4-(4-Methoxy-3 methylphenyl)cyclohexyl)methyl)-4((4-methoxybenzyl)oxy)-T4-(3-(2methoxythiazole-5 - yl)phenyl)cyclohexanecarboxamide 669.4 18.13 ² M 4 / trans-methyl-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 584.5 18.14 ² 0 , λΡ όΡ С ¹ А trans-Methyl-4-((3-(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(6(d-imethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)ci clohexanecarboxylate 584.6 18.15 0 SL 1J L1 ^Η A tert-butyl-(4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((4-(4methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl)carbamoyl)cyclohexyl)trans-carbamate 667.4 18.16 °Α A /=\ / JY>° AND ζ \__/ >° tert-butyl(trans-4-((3 -(1-isopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 665.5 M+Na 18.17 ³ '3 M / trans-Methyl-4-((4-(1-cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexanecarboxylate 586.6

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18.18 ³ Ethyl 2-(trans-4-((4-(1-cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexyl)acetate 614.6 18.19 ² - b ao7 o o ' o / trans-Methyl-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(5 methoxy-6-methylpyridine-2 - yl)cyclohexyl)methyl)carbamoyl)ci clohexanecarboxylate 585.5 18.20 ⁴ 0 _ν ΑΪΌΑ Αν Mch ^X Ethyl 2-(trans-4-((4-(1-isopropyl1H-pyrazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)ci clohexyl)acetate 616.5 18.21 ³ 0 ALA ^x ° ^X Ethyl-2-(trans-4-(((trans-4-(3-cyano4- methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridine-2- yl)carbamoyl)cyclohexyl)acetate 626.5 18.22 ³ .E %° o ) Ethyl 2-(trans-4-(((trans-4-(6-cyano5-methoxypyridine-2yl)cyclohexyl)methyl)(4-(1isopropyl-1H-pyrazol-4yl)pyridin-2yl)carbamoyl)cyclohexyl )acetate 627.5 18.23 ^1.4 0 '-o trans-Methyl-4-((4-(2cyclopropyloxazol-4-yl)pyridin2-yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)ci clohexanecarboxylate 587.7 18.24 mm trans-Methyl-4-(((trans-4-(6-cyano5-methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylate 597.4

Alternative terms:

Step 1: 1 The solvent was CH2C12;

Step 2: ² The solvent was toluene;

3DMAP, pyridine 80°С;

4DMAP, Et ₃ N, toluene, 80°С, 2 h;

550°C, overnight.

Compound 19: 2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid

Step 1: Methyl 2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) acetate

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A mixture of intermediate 21.22 (450 mg, 0.773 mmol) and HCl in CH ₃ OH (4 M, 100 ml, 0.4 mol) was stirred at RT. overnight and then heated to 65°C for 10 hours the Mixture was allowed to cool to rt, concentrated under reduced pressure and then diluted with EtOAc (50 ml). The organic layer was washed with aq. sat. solution. NaHCO ₃ (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give methyl-2- (trans-4-((3-(2cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate (270.2mg, 57% ) as a yellow solid.

1 H NMR (400 MHz, CDCl ₃ ): δ 7.77 (s, 1H), 7.55-7.49 (m, 1H), 7.49-7.41 (m, 1H), 7.29 ( t, 1H), 7.11 (d, 1H), 7.01-6.91 (m, 2H), 6.74 (d, 1H), 3.80 (s, 3H), 3.68-3 .55 (m, 5H), 2.45-2.29 (m, 2H), 2.20 (s, 3H), 2.15-2.06 (m, 3H), 1.94-1.62 (m, 11H), 1.45-1.25 (m, 3H), 1.22-1.08 (m, 6H), 0.82-0.68 (m, 2H); LCMS: 615.4 [M+H]+.

Step 2: 2-(trans-4-((3-(2-Cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid

Lithium hydroxide monohydrate (273 mg, 6.51 mmol) was added to a solution of methyl 2-(trans-4-((3-(2cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate (200.2mg, 0.325mmol), THF (6mL) and H2O (6mL) at r.t. The mixture was stirred at rt. during the night. The organic solvent was removed under reduced pressure and the aqueous layer was extracted with EtOAc (10 ml). The aqueous layer was adjusted to pH=1 with 3 M HCl and then filtered. The precipitate was dried in vacuo to give 2-(trans-4-((3-(2-cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid (166.9 mg, 85%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 8.07 (s, 1H), 7.63-7.44 (m, 3H), 7.25 (d, 1H), 7.03-6.90 (m, 2H), 6.80-6.65 (m, 1H), 3.71 (s, 3H), 3.59-3.54 (m, 2H) , 2.46-2.39 (m, 1H), 2.39-2.27 (m, 1H), 2.14-2.01 (m, 4H), 1.95 (d, 2H), 1 .79-1.71 (m, 4H), 1.68-1.58 (m, 4H), 1.56-1.53 (m, 1H), 1.46-1.33 (m, 3H) , 1.31-1.21 (m, 2H), 1.18-0.93 (m, 6H), 0.71-0.52 (m, 2H); LCMS: 601.3 [M+H]+.

Compound 20:

2-(trans-4-(((trans-4-(3-Cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexyl)acetic acid

Step 1: tert-Butyl-2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl) acetate

Pyridine (1.25 g, 15.78 mmol) was added to a solution of intermediate 14.10 (200 mg, 0.451 mmol) in CH ₂ Cl ₂ (5 mL) under N2 at 0°C and then intermediate 19.06 (7, 7 ml solution in toluene, 3.83 mmol). The reaction mixture was heated to rt, stirred overnight, poured into sat. water. NaHCO3 solution (20 ml) and then extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 20/1x5/1) to give tert-butyl-2-( trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetate (150 mg, 47%) as yellow oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.77 (s, 1H), 7.51 (d, 1H), 7.45 (t, 1H), 7.37-7.34 (m, 1H) , 7.32-2.30(m, 1H), 7.28-7.27(m, 1H), 7.10(d, 1H), 6.88(d, 1H), 3.90(s , 3H), 3.63 (d, 2H), 2.49-2.38 (m, 1H), 2.37-2.30 (m, 1H), 2.17-2.07 (m, 1H ), 1.98 (d, 2H), 1.90-1.80 (m, 4H), 1.75-1.69 (m, 5H), 1.66-1.55 (m, 4H), 1.41 (s, 9H), 1.35-1.26 (m, 2H), 1.21-1.12 (m, 5H), 0.80-0.66 (m, 2H); LCMS: 668.4 [M+H]+.

Step 2: 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid

A mixture of tert-butyl-2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl) acetate (150 mg, 0.224 mmol) and HCl in dioxane (4 M, 50 mL) were stirred at RT. for 1 h, concentrated to dryness and then purified by reverse phase HPLC (water (10 mM HCl)/CH ₃ CN) to give 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl )methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid (60 mg, 43%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 12.13 (s, 1H), 8.09 (s, 1H), 7.63-7.46 (m, 5H), 7.26 (d, 1H), 7.13 (d, 1H), 3.87 (s, 3H), 3.65-3.50 (m, 3H), 2.47-2.38 (m, 2H), 2.13 -2.02 (m, 1H), 1.97 (d, 2H), 1.82-1.71 (m, 4H), 1.70-1.58 (m, 4H), 1.50-1 .27 (m, 5H), 1.19-0.96 (m, 6H), 0.73-0.55 (m, 2H); LCMS: 612.3 [M+H]+.

The following compounds were synthesized from the appropriate intermediates according to the procedures described for compound 20.

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Comm. Structure Name [M+N] ⁺ 20.01 ABOUT A* Hf 2-(trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2yl)cyclohexyl)methyl)(3-(2cyclopropylthiazole-5- yl)phenyl)carbamoyl)cyclohexyl)acetic acid 613.5

20.02 ² O -A ff 2-(trans-4-((4-(2Cyclopropylthiazol-5 yl)pyridin-2-yl)((trans-4-(4methoxy-3methylphenyl)cyclohexyl)methyl)c arbamoyl)cyclohexyl)acetic acid 602.3 20.oz ³ I About 0 / 2-(trans-4-((3-(2- Cyclopropylthiazol-5 yl)phenyl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 602.4 20.04 ¹ A A o X 2-(trans-4-((4-(2- Cyclopropylthiazol-5 yl) pyride in-2-yl) ((trans-4-(5 methoxy-6-methylpyridin-2yl) cyclohexyl) methyl) carbamoyl) cyclohexyl) acetic acid 603.5 May 20 RSX Y?^ ^he 2-(trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl) (4-(2-cyclopropylthiazol-5 yl)pyridine-2- yl)carbamoyl)cyclohexyl)acetic acid 613.3 20.Ob ⁵ About -.4 fs ¹ 2-(trans-4-((3-(2- Cyclopropylthiazol-5 yl)phenyl)((trans-4-(6(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 601.4

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20.07 X about °H γ A 4 / 2-(trans-4-((3-(2- Isopropylthiazole-5- yl)phenyl)((trans-4-(5-methoxy-6- methylpyridine-2- yl) cyclohexyl) methyl) carbamoyl) cyclohexyl) acetic acid 604.5 20.08 ¹ O °H γ A b / trans-2-(4-((4-(1-Cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane1- yl)methyl)carbamoyl)cyclohexyl)acetic acid 611.5 20.09 ⁴ O r o o o ° Adx / 2-(trans-4-((3 -(1-Cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)c arbamoyl)cyclohexyl)acetic acid 584.6 20.10 ² ...... ra l 2-(trans-4-((4-(1-Cyclopropyl1H-pyrazol-4-yl)pyridin-2yl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)c arbamoyl)cyclohexyl)acetic acid 585.5 20.11 δ p o o 4 / / O 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl) (3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl)acetic acid 595.6

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20.12 ⁵ at 4 Z— / 2-(trans-4-((3-(1-Cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4(b-(dimethylamino)pyride in-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 584.6 20.13 X about A γ 4 ' O / 2-(trans-4-((3-(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 587.5 20.14 2-(trans-4-((3-(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) to arbamoyl) cyclohexyl) acetic acid 586.6 20.15 3 E about X Acetic acid 587.5 20.16 & 4 3 -(trans-4-((3 -(1-Isopropyl-1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)c arbamoyl)cyclohexyl)propanoic acid 600.4

Alternative terms:

Step 1: The base was Et ₃ N;

² Pyridine, DMAP, 50-80°C;

³ Amine only in pyridine (without CH ₂ C1 ₂ );

Step 2: ⁴ HCl in EtOAc (4 M);

⁵ TFA in CH ₂ C1 ₂ .

Compound 21: trans-2-(4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1 -yl)methyl)carbamoyl)cyclohexyl)acetic acid o

Step 1: 4-(2-E(iclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)pyridine-2-amine

Sodium triacetoxyborohydride (658 mg, 3.11 mmol) was slowly added to a solution of Intermediate 10 (312 mg, 1.55 mmol), Intermediate 5 (401 mg, 1.55 mmol) and DCE (5 ml) at 0°C . The mixture was allowed to warm to rt, stirred for 5 h, poured into water (30 ml) and then extracted with EtOAc (3x20 ml). The combined organic layers were washed (2x20 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1->5/1) to give 4-(2-cyclopropyloxazol-4-yl)-X-((4-(4-methoxy-3-methylphenyl)bicyclo[ 2.2.2]octan-1-yl)methyl)pyridine-2amine (254 mg, 35%) as a yellow oil.

*H NMR (400 MHz, CDC1 ₃ ): δ 8.05 (d, IH), 7.82 (s, IH), 7.13-7.07 (m, 2H), 6.80 (s, IH ), 6.78-6.74 (m, 2H), 4.66-4.55 (m, IH), 3.81 (s, 3H), 3.15 (d, 2H), 2.22 ( s, 3H), 2.18-2.09 (m, IH), 1.88-1.80 (m, 6H), 1.66-1.58 (m, 6H), 1.17-1, 11 (m, 2H), 1.11-1.05 (m, 2H); LCMS: 444.1 [M+H] ⁺ .

Step 2: tert-Butyl-2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)carbamoyl)cyclohexyl)acetate

Intermediate 19.06 (5 ml in toluene, 0.701 mmol) was added to a solution of 4-(2

-265 040704 cyclopropyloxazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridine-2amine (136 mg, 0.306 mmol), Et ₃ N (155 mg, 1.53 mmol) and CH ₂ Cl ₂ (5 ml) at 0°C. The mixture was allowed to warm to rt, stirred for 1 h, poured into H ₂ O (50 ml) and then extracted with EtOAc (3x30 ml). The combined organic layers were washed (100 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1^5/1) to give tert-butyl-2-(trans-4-((4-(2cyclopropyloxazol-4-yl)pyridin-2-yl) ((4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetate (155 mg, 76%) as a colorless oil.

Ή NMR (400 MHz, CDCl3): δ 8.50 (d, 1H), 7.95 (s, 1H), 7.56 (s, 1H), 7.46 (d, 1H), 7.07- 6.99 (m, 2H), 6.76-6.69 (m, 1H), 3.88-3.73 (m, 5H), 2.40-2.25 (m, 1H), 2, 22-2.10 (m, 4H), 2.01-1.99 (m, 2H), 1.89-1.66 (m, 12H), 1.65-1.55 (m, 3H), 1.48-1.45(m, 4H), 1.42(s, 9H), 1.20-1.06(m, 4H), 0.80-0.71(m, 2H).

Stage 3: 2-(trans-4-((4-(2-Cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1- yl)methyl)carbamoyl)cyclohexyl)acetic acid

Hydrogen chloride (8M in dioxane, 100 mL, 800 mmol) was added to a solution of tert-butyl-2-(trans-4-((4(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4 -methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl)acetate (125 mg, 0.187 mmol) and dioxane (10 ml) at 5°C. The mixture was allowed to warm to rt, stirred for 1 h and then concentrated. The residue was purified by RP-HPLC (water(0.05% HCl)/CH ₃ CN) to give trans-2-(4-((4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)((4- (4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl)acetic acid (43 mg, 38%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d6): δ 12.01( s, 1H), 8.76 (s, 1H), 8.52 (d, 1H), 7.74 (s, 1H), 7 .63 (d, 1H), 7.05-6.94 (m, 2H), 6.76 (d, 1H), 3.81-3.62 (m, 5H), 2.30-2.14 (m, 2H), 2.08 (s, 3H), 1.99 (d, 2H), 1.78-1.51 (m, 11H), 1.48-1.24 (m, 8H), 1.13-1.05 (m, 2H), 1.05-0.99 (m, 2H), 0.70-0.67 (m, 2H); LCMS: 612.3[M+H] ⁺ .

The following compounds were synthesized from the appropriate intermediates according to the procedures described for compound 21.

Comm. Structure Name [M+N] + 21.01 A d A r _o o X 2-(trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 586.5 ^{21.02 1'2} A at A / 2-(trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carba moyl)cyclohexyl)acetic acid 585.5

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21.03 ^ο 7 γ and Δ / 2-(trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cycle ohexyl)acetic acid 586.5 21.04 ³ 2-(trans-4-((3-(2-Cyclopropyloxazol4-yl)phenyl)((cis-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)carbamoyl)cycle ohexyl)acetic acid 586.6 21.05 ¹ i ³ ip- 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(3(2-cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl)acetate hydroic acid 596.5 21.06 ¹ o dd'chd o A, kAA _0H 2-(trans-4-((3-(2-Cyclopropyloxazole- 4-yl)phenyl)((trans-4-(6- (d imethylamino) pyridine-3 - yl)cyclohexyl)methyl)carbamoyl)cycle ohexyl)acetic acid 585.5 21.07 ¹ # λ 4° o I 2-(trans-4-((4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)((trans-4-(5 methoxy-6-methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cycle ohexyl)acetic acid 587.5 21.08 ¹ O °H γ r ' O / 2-(trans-4-((3-(2-Isopropyloxazol-4yl)phenyl)((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 587.4

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21.09 ¹ A o I 2-(trans-4-((4-(2-Isopropyloxazol-4yl)pyridin-2-yl)((trans-4-(4-methoxy3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid 588.4 21.10 ¹ / O I 2-(trans-4-(((trans-4-(3-cyano-4methoxyphenyl)cyclohexyl)methyl)(3(2-isopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl)acetic acid 598.7 21.11 O 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-isopropyloxazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl)acetic acid 599.4 21.12 And at 2-(trans-4-(((trans-4-(3-Cyano-4methoxyphenyl)cyclohexyl)methyl)(4(2-cyclopropyloxazol-4-yl)pyridin2-yl)carbamoyl)cyclohexyl)acetic acid 597.4 21.13 ¹ Ή* Hmm 2-(trans-4-(((trans-4-(6-Cyano-5methoxypyridin-2 yl)cyclohexyl)methyl)(3-(2cyclopropyloxazole-4- yl)phenyl)carbamoyl)cyclohexyl)acetic acid 597.4

Alternative terms:

Step 2: The base was pyridine;

Stage 3: 212 M aq. HCl solution, CH ₃ CN.

^{The 3} cis isomer of compound 21.03 (Stage 2) was separated by prep. TLC (petroleum ether: EtOAc=3:2) and then hydrolyzed (4 M HCl in dioxane, rt, 1 h).

Compound 22: trans-Propyl-4-((3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate o O

A solution of compound 17.13 (35 mg, 0.061 mmol), pTsOH-H ₂ O (10 mg, 0.053 mmol) and 1-propanol (4 ml) was heated at 80°C for 4 h and then diluted with saturated NaHCO ₃ solution (20 ml ) and EtOAc (20 ml). The layers were separated and the organic phase was washed with brine (20 ml), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography (050% EtOAc in hexanes) to give trans-propyl-4-((3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3 -methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate as a white foam (30 mg, 79%).

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.38 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.54 (s, 1H), 7 .44 (t, 1H), 7.10 (d, 1H), 6.97-6.92 (m, 2H), 6.80-6.75 (m, 1H), 3.88 (t, 2H ), 3.77-3.72 (m, 1H), 3.71 (s, 3H), 3.67-3.40 (m, 2H), 2.38-2.28 (m, 1H), 2.26-2.17 (m, 1H), 2.16-2.09 (m, 1H), 2.08 (s, 3H), 1.85-1.65 (m, 8H), 1, 56-1.47 (m, 2H), 1.46-1.37 (m, 3H), 1.35-1.21 (m, 2H), 1.11-1.02 (m, 4H), 1.01-0.92 (m, 4H), 0.81 (t, 3H); LCMS: 612.6 [M+H]+. The following compounds were synthesized from compound 17.13 or compound 18.17 and the appropriate alcohol according to the procedure described for compound 22.

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Comm. Structure Name [M+N] ⁺ 22.01 o F 0CV ₀ trans-Isopropyl-4-((3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 612.6 22.02 °Lv p p °m> trans-Butyl-4-((3 -(1-cyclopropyl- Spirazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 626.5 22.03 trans-Pentyl-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 640.3 22.04 m At trans-isobutyl-4-((3 -(1-cyclopropylH-pyrazol-4-yl)φenyl)((τpanc-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 626.6 May 22 l trans-Isopentyl-4-((3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate 640.6 22.06 l / trans-Propyl-4-((4-(1-cyclopropyl^-πirazol-4-yl)πiridin-2yl)((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)carbamoyl)cycle hexanecarboxylate 614.3

Compound 23:

trans-N ¹ -(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N ⁴ -(2-hydroxyethyl)-N ¹ -((trans-4-(4-methoxy3-methylphenyl)cyclohexyl )methyl)cyclohexane-1,4-dicarboxamide

2-Aminoethanol (96.5 mg, 1.58 mmol) was added to a solution of compound 17.13 (150 mg, 0.263 mmol), EDCI (75.7 mg, 0.394 mmol), DMAP (16.1 mg, 0.131 mmol), Et ₃ N (79.8 mg, 0.790 mmol), HOBt (53.4 mg, 0.395 mmol) and CH ₂ Cl ₂ (1 ml) at 0°C. The mixture was stirred at rt. overnight, poured into water (40 ml) and extracted with EtOAc (3x50 ml).

The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by reverse phase prep. HPLC (water(10mM NH ₄ HCO ₃ )/MeCN) to give transN-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N ⁴ -(2-hydroxyethyl)-N ¹ -(( trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexane-1,4-dicarboxamide (89 mg, 55%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.93 (s, 1H), 7.66-7.57 (m, 2H), 7.57-7.53 (m, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 7.00-6.89 (m, 2H), 6.83-6.67 (m, 1H), 4.57 (t, 1H), 3.77-3.68 (m, 4H), 3.68-3.49 (m, 2H), 3.31-3.26 (m, 2H), 3. 09-3.01 (m, 2H), 2.39-2.22 (m, 1H), 2.17-1.96 (m, 5H), 1.83-1.53 (m, 8H), 1.52-1.21 (m, 5H), 1.15-0.85 (m, 8H); LCMS: 613.3 [M+H] ⁺ .

Compound 24:

trans-N ¹ -((trans-4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)-N ¹ -(3-(2-methoxythiazol-5-yl)phenyl)-N ⁴ -methylcyclohexane-1, 4-dicarboxamide

- 269 040704

HATU (44 mg, 0.116 mmol) was added to a mixture of compound 17.01 (60 mg, 0.104 mmol), iPr2NEt (36 μl, 0.207 mmol) and DMF (1 ml) at 0°C. The mixture was stirred for 10 min and then methylamine (40% in CH3OH, 0.1 ml, 0.98 mmol) was added. After stirring at 0°C for 10 min, the reaction mixture was diluted with CH ₂ Cl ₂ (20 ml), washed (20 ml H2O and then 20 ml brine), dried (Na ₂ SO ₄ ) and then concentrated. The residue was purified by silica gel chromatography (0-5% CH3OH in CH ₂ Cl ₂ ) to give trans-N ¹ -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N ¹ -(3 -(2-methoxythiazol-5-yl)phenyl)-N ⁴ -methylcyclohexane-1,4-dicarboxamide (38 mg, 62%) as a white foam.

¹ H NMR (400 MHz, DMSO-d6): δ 7.75 (s, 1H), 7.61-7.56 (m, 1H), 7.55-7.47 (m, 3H), 7, 28-7.21(m, 1H), 6.98-6.91(m, 2H), 6.81-6.76(m, 1H), 4.06(s, 3H), 3.71( s, 3H), 3.65-3.46(m, 2H), 2.47(d, 3H), 2.39-2.27(m, 1H), 2.12-1.92(m, 5H), 1.80-1.56 (m, 8H), 1.49-1.35 (m, 3H), 1.34-1.21 (m, 2H), 1.12-0.92 ( m, 4H); LCMS: 590.4 [M+H]+.

The following compounds were synthesized from the appropriate amine according to the procedure described for compound 24.

Comm. Structure Name [M+N] ⁺ 24.01 А О< _о ύ Р /0 0=4 Z □: trans-L ^r1 -((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)-U ¹ (3-(2-methoxythiazol-5yl)phenyl)cyclohexane-1,4dicarboxamide 576.3 24.02 Oh and । .¾pv trans-U ¹ - ((trans-4- (4-Methoxy-3methylphenyl) cyclohexyl) methyl) - U ¹ (3- (2-methoxythiazol-5 - and l) phenyl l) M ^-dimethylcyclohexane-! ,4dicarboxamide 604.4 24.03 ABOUT trans-L ^r1 -(2-Hydroxyethyl)-L ⁴ -((trans4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-7U ⁴ (3-(2-methoxythiazol-5yl)phenyl)cyclohexane- 1,4 dicarboxamide 620.4 24.04 Ο ^η -°GP ο trans-U ¹ -((trans-4-(4-Methoxy-3methylphenyl)cyclotexyl)methyl)-L ^r4 (2-methoxyethyl)-M -(3-(2methoxythiazol-5-yl)phenyl)cyclohexane-1,4dicarboxamide 634.6 May 24 Ο ηχ Υη ⁿ trans-L ^r1 -(2-(Dimethylamino)ethyl)-L ⁴ ((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-U ⁴ (3-(2-methoxythiazol-5yl)phenyl )cyclohexane-1,4dicarboxamide 647.5 24.Ob ¹ χχΡχ ° trans-U ¹ -((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)-U ¹ (3-(2-methoxythiazol-5-yl)phenyl)-M(methylsulfonyl)cyclohexane-1,4dicarboxamide 654.4

Option: 1 also added DBU, rt, 30 min.

Compound 25: Methyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate

Step 1: tert-Butyl(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methyl-270 040704 phenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)carbamate

Pyridine (0.17 ml, 2.10 mmol) and then intermediate 19.02 (38.6 mg/ml in toluene, 8 ml, 1.18 mmol) were added to a mixture of intermediate 14.06 (227 mg, 0.53 mmol) and toluene (2 ml) under N ₂ at room temperature. The reaction mixture was stirred for 1 h, poured into a saturated NaHCO ₃ solution (30 ml) and then extracted with EtOAc (30 ml). The organic phases were washed with brine (30 ml). The combined aqueous washes were back-extracted with EtOAc (20 ml). The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (20-50% EtOAc in hexanes) to give tert-butyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl )((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (331 mg, 96%) as an off-white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.62-7.56 (m, 2H), 7.52 (t, 1H), 7.29-7.24 (m, 1H), 6.976.92 (m, 2H), 6.81-6.76 (m, 1H), 6.54 (d, 1H), 3.72 (s, 3H), 3.61- 3.52 (m, 2H), 3.17-3.06 (m, 1H), 2.47-2.39 (m, 1H), 2.38-2.28 (m, 1H), 2. 09 (s, 3H), 2.06-1.96 (m, 1H), 1.79-1.62 (m, 8H), 1.48-1.38 (m, 3H), 1.36- 1.22 (m, 11H), 1.18-1.11 (m, 2H), 1.11-1.03 (m, 2H), 1.03-0.98 (m, 2H), 0. 86-0.72 (m, 2H); LCMS: 680.8 [M+Na]+.

Step 2: trans-4-Amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Solution of tert-butyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (326 mg, 0.50 mmol) and trifluoroacetic acid (20% in CH ₂ Cl ₂ , 5 ml) were stirred at rt. for 2 h, diluted with CH ₂ Cl ₂ (25 ml), washed with saturated NaHCO ₃ solution (2x30 ml) and then washed with brine (30 ml). The combined aqueous washes were back-extracted with CH2Cl2 (20 ml). The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and dried under high vacuum to give trans-4-amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans- 4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (256 mg, 92%) as an off-white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.62-7.49 (m, 3H), 7.30-7.23 (m, 1H), 6.98 -6.92 (m, 2H), 6.82-6.75 (m, 1H), 3.72 (s, 3H), 3.62-3.50 (m, 2H), 3.38-3 .28 (m, 1H), 2.48-2.39 (m, 1H), 2.38-2.29 (m, 1H), 2.09 (s, 3H), 2.06-1.96 (m, 1H), 1.80-1.57 (m, 10H), 1.48-1.37 (m, 3H), 1.35-1.23 (m, 2H), 1.18-1 .12 (m, 2H), 1.12-0.97 (m, 4H), 0.73-0.58 (m, 2H); LCMS: 558.5 [M+H] ⁺ .

Step 3: Methyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate

A solution of trans-4-amino-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (100 mg, 0.18 mmol) in CH ₂ Cl ₂ (2 ml) was cooled in an ice/water bath under N ₂ atmosphere. Triethylamine (0.10 ml, 0.72 mmol) and then methyl chloroformate (17 μl, 0.22 mmol) were added at 0° C. and the reaction mixture was stirred for 8 minutes. The mixture was diluted with 20 ml CH2Cl2, washed with saturated NaHCO3 solution (2x20 ml) and washed with brine (20 ml). The combined aqueous washes were back-extracted with 20 ml CH ₂ Cl ₂ . The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (20-80% EtOAc in hexanes) to give methyl(trans-4-((3-(2cyclopropylthiazol-5-yl)phenyl)( (trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (92 mg, 83%) as an off-white foam.

1H NMR (400 MHz, DMSO-de): δ 8.09 (s, 1H), 7.61-7.56 (m, 2H), 7.52 (t, 1H), 7.27 (d, 1H ), 6.97-6.92 (m, 2H), 6.87-6.75 (m, 2H), 3.71 (s, 3H), 3.62-3.51 (m, 2H), 3.45 (br s, 3H), 3.23-3.09 (m, 1H), 2.48-2.39 (m, 1H), 2.38-2.28 (m, 1H), 2 .09 (s, 3H), 2.06-1.97 (m, 1H), 1.80-1.62 (m, 8H), 1.50-1.36 (m, 3H), 1.36 -1.22 (m, 2H), 1.18-1.11 (m, 2H), 1.11-0.97 (m, 4H), 0.88-0.74 (m, 2H); LCMS: 616.4 [M+H] ⁺ .

The following compounds were synthesized from the appropriate starting materials according to the procedure described for Compound 25, Step 1.

Comm. Structure Name [M+N] ⁺ 25.01 ..XX ⁰ 7% tert-butyl (trans-4-(((trans-4-(4- methoxy-3- methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5 - yl)phenyl)carbamoyl)cyclohexyl)carb amate 670.5 M+Na 25.02 tert-butyl-((trans-4-(((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)(3-(2methoxythiazole-5 - yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate 606.4 [(MtBu+H)+H] ⁺

- 271 040704

The following compound was synthesized from compound 25.02 according to the procedure described for compound 25, Step 2.

Comm. Structure Name [M+N] ⁺ 25.03 ¹ O trans-4-(Aminomethyl)-7/-((trans4-(4-methoxy-3- methyl l phenyl l)cycle oxyl)methyl l)7/-(3-(2-methoxythiazole-5 - yl)phenyl)cyclohexanecarboxam id 562.4

Option: 10°C, 100 min.

The following compounds were synthesized from the appropriate amine and the appropriate acylating agent according to the procedure described for compound 25.

Comm. Structure Name [M+N] ⁺ 25.04 ^{1 3} ABOUT .......A trans-4-Acetamido-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-A(3-(2-methoxythiazole-5- yl)phenyl)cyclohexanecarboxamide 590.5 ^{25.05 1'3} Oh _oh Methyl (trans-4-(((trans-4-(4methoxy-3- methyl phenyl)cycle ohexyl)methyl)(3(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)carbamate 606.4

- 272 040704

25.06 ² τ .<: ¹ - /° \ ΖΙ °Γ trans-4-(Acetamidomethyl)-R((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-R(3-(2-methoxythiazol-5yl)phenyl)cyclohexanecarboxamide 604.4 25.07 π'Αο ^η γγΑ Λ A ⁴ Methyl-((trans-4-(((trans-4-(4methoxy-3- methyl phenyl) cycle ohexyl) methyl) (3 - (2-methoxythiazole-5- yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate 620.8 25.08 ^A4 trans-A-((trans-4-(4-Methoxy-3methylphenyl)cyclohexyl)methyl)-R(3-(2-methoxythiazol-5-yl)phenyl)-4(methylsulfonamidomethyl)cyclohexanecarboxamide 640.5 25.09 ^2.3 about γ A trans-4-Acetamide o-N-(3-(2cyclopropylthiazol-5-yl)phenyl)-A((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 600.4 25.10 ⁵ ../λ y _o trans-A-(3-(2-Cyclopropylthiazol-5yl)phenyl)-L-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4(N- methylacetamido)cyclohexanecarboxyamide 614.6 25.11 O A ¹ Ρυ A trans-A-(3-(2-Cyclopropylthiazol-5yl)phenyl)-L-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4(methylsulfonamido)cyclohexanecarboxamide 636.4

- 273 040704

methoxyacetamido ⁾ cyclohexanecarboxamide oxoethylacetate methylbutanamidoschiclohexanecarboxamide (2-Cyclopropylthiazol-5yl)phenyl)-L'-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-42-((trans-4-((3-(2Cyclopropylthiazol-5yl)phenyl) ((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)amino)-2trans-Am3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2-hydroxyacetamido)AM (trans- 4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

2-((trans-4-((3-(2Cyclopropylthiazol-5yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoil)cyclohexyl)amino)-2oxoethylmethylcarbamate trans-4-Butyramide o-Ah 3 -(2-cyclopropylthiazole-b-sphphenyl)-?/((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide trans-A/-(3-(2-Cyclopropylthiazol-5yl) phenyl)-Ach(trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4pentanamidocyclohexanecarboxy

Alternative terms:

Step 3: 1 The base was pyridine;

³ ] ⁴ ' Solvent was EtOAc;

^s k.t., 0.5-3 h.

¹ From Compound 25.13 (1 M NaOH, THF CH ₃ OH, rt).

'From Compound 25.09 (NaH, THF, CH ₃ I, 0°C-rt).

' From Compound 25.14 (Procedure for Compound 2).

Compound 26: Methyl(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl ) carbamate

Step 1: tert-Butyl(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3- 274 040704 methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)carbamate

Pyridine (0.17 ml, 2.10 mmol) and then intermediate 19.02 (38.6 mg/ml in toluene, 8 ml, 1.18 mmol) were added to a solution of intermediate 14.22 (223 mg, 0.537 mmol) in toluene (2 ml) at r.t. The resulting mixture was stirred at rt. within 55 min, poured into 30 ml of a saturated solution of NaHCO ₃ and then extracted with the addition of 30 ml of EtOAc. The organic layer was washed with 30 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (30-60% EtOAc in hexanes) to give t-butyl(trans-4-((3-( 1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (328 mg, 95%) as a white foam.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.57-7.52 (m, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 6.98-6.92 (m, 2H), 6.81-6.76 (m, 1H), 6.54 (d, 1H), 3.78-3.69 (m, 4H), 3.64-3.46 (m, 1H), 3.173.04 (m, 1H), 2.38-2.28 (m , 1H), 2.12-2.00 (m, 4H), 1.81-1.60 (m, 8H), 1.50-1.22 (m, 15H), 1.12-0.95 (m, 6H), 0.85-0.70 (m, 2H); LCMS: 663.7 [M+Na]+.

Step 2: trans-4-Amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Solution of tert-butyl (trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (321 mg, 0.50 mmol) and trifluoroacetic acid (20% in CH ₂ Cl ₂ , 5 ml) were stirred at RT. for 2 h, diluted with 25 ml CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution (2x30 ml) and then washed with 30 ml brine. The combined aqueous layers were back extracted with 20 ml CH ₂ Cl ₂ . The combined extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-4-amino-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4 -methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (267 mg, 98%) as an off-white foam.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.56-7.52 (m , 1H), 7.44 (t, 1H), 7.09 (d, 1H), 6.97-6.93 (m, 2H), 6.80-6.76 (m, 1H), 3, 77-3.69 (m, 4H), 3.64-3.47 (m, 2H), 3.11-2.87 (m, 1H), 2.47-2.38 (m, 1H), 2.38-2.28 (m, 1H), 2.26-2.13 (m, 1H), 2.11-2.00 (m, 4H), 1.80-1.70 (m, 4H ), 1.70-1.58 (m, 4H), 1.48-1.37 (m, 3H), 1.35-1.22 (m, 2H), 1.12-0.95 (m , 6H), 0.72-0.59 (m, 2H); LCMS: 541.6 [M+H] ⁺ .

Step 3: Methyl (trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl ) carbamate

Triethylamine (0.13 ml, 0.74 mmol) and then methyl chloroformate (17 μl, 0.22 mmol) were added to a solution of trans-4-amino-M-(3-(1-cyclopropyl-1H-pyrazole-4- yl)phenyl)-N-((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (100 mg, 0.19 mmol) in CH ₂ Cl ₂ (2 ml) at 0° C. under atmosphere N2. The reaction mixture was stirred at 0° C. for 13 min, diluted with 20 ml CH ₂ Cl ₂ , washed with saturated NaHCO 3 solution (2x20 ml) and then washed with brine (20 ml). The combined aqueous washes were back-extracted with 20 ml CH ₂ Cl ₂ . The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (40-90% EtOAc in hexanes) to give methyl (trans-4-((3-(1-cyclopropyl-1Hpyrazol-4-yl )phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (88 mg, 79%) as a white foam.

1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.57-7.53 (m, 1H ), 7.44 (t, 1H), 7.10 (d, 1H), 6.97-6.92 (m, 2H), 6.87-6.81 (m, 1H), 6.81- 6.76 (m, 1H), 3.77-3.69 (m, 4H), 3.65-3.38 (m, 5H), 3.22-3.09 (m, 1H), 2, 38-2.28 (m, 1H), 2.11-2.00 (m, 4H), 1.80-1.62 (m, 8H), 1.49-1.35 (m, 3H), 1.35-1.22 (m, 2H), 1.11-0.95 (m, 6H), 0.87-0.73 (m, 2H); LCMS: 599.4 [M+H] ⁺ .

The following compounds were synthesized from intermediate 14.22 and the appropriate acylating agent according to the procedures described for compound 26.

- 275 040704

Comm. Structure Name [M+N] ⁺ 26.01 ¹ O 03; A trans-4-Acetamido-A-(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 583.5 26.02 О О I 1 ¹ II Г |1 [ but trans-A-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-U-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-4(methylsulfonamido)cyclohexanecarb oxamide 619.5 26.OZ ^2.6 trans-A-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-(2hydroxyacetamido)-U-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 599.5 26.04 ³ • . ' to “S o ΖΙ / 2-((trans-4-((3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamyl)cyclohexyl)amino)-2oxoethylmethylcarbamate 656.6 26.05 ⁴ 2-Hydroxyethyl (trans-4-((3 -(1 cyclopropyl-1H-pyrazol-4yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate 629.3 26.Ob ⁵ 4 / m O o trans-A-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-(trans-4hydroxycyclohexanecarboxamido)4-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 667.6

Alternative terms:

Step 3: 1LS ₂ O, Et ₃ N, EtOAc, rt;

² Solvent was EtOAc.

³ From Compound 26.03 (Procedure for Compound 2).

⁴ From Intermediate 20 (Et ₃ N, CH ₂ Cl ₂ , rt, overnight).

⁵ From Intermediate 19, then desilylation (1 N HCl, THF, CH3OH, 0°C-rt, 75 min).

⁶ From acetoxyacetyl chloride, then hydrolysis (1 M NaOH, THF, CH3OH, rt).

The following compounds were synthesized from the appropriate intermediate and the appropriate acylating agents according to the procedures described for compound 26.

- 276 040704

Comm. Structure Name [M+N] ⁺ 26.07 ^1,4,6 Mol l J ID ⁿ mm trans-4-Acetamido-A-(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)-R-((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide 609.5 26.08 ^1.6 .. Up to °h° 2-((4-((3-(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane1- yl)methyl)carbamoyl)cyclohexyl)am ino)-2-oxoethyl-trans-acetate 667.6 26.09 ⁷ < .. cd o z trans-R-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-(2hydroxyacetamido)-R-((4-(4methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide 625.4 26.10 ^1,4,6 - J\IZ >° trans-4-Acetamido-R-(3 -(1 isopropyl-1R-pyrazol-4-yl)phenyl)A-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 585.5 26.11 ^1.6 A / 2-((trans-4-((3 -(1-Isopropyl- 1Hpyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carb amoyl)cyclohexyl)amino)-2- oxoethyl acetate 643.5 26.12 ⁷ _{0 N} / M ^X trans-4-(2-Hydroxyacetamido)-A(3-(1-isopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 601.5 26.13 ^1.5 Ά'Χθ-ν IFj Ca .o trans-4-(Acetamide omethyl)-A-(3-(1 cyclopropyl-1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 597.3 26.14 ^1.5 xL έ?''Μ -oM Μ γ ⁰ Methyl-((trans-4-((3 -(1-cyclopropyl1H-pyrazol-4-yl)phenyl)((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)methyl)carbamate 613.6 26.15 ^1.5 0 MD trans-A-(3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-4(methylsulfonamidomethyl)cyclohexanecarboxamide 633.5

- 277 040704 trans-A-(3-(2-Cyclopropyloxazole-

methoxy-loxoethyl acetate trans-A-(4-(2-Cyclopropyloxazol4-yl)pyridin-2-yl)-4-(2hydroxyacetamido)-Sch(trans-4-(4methoxy-3trans-4-(Aminomethyl)-A-( 4-(2cyclopropyloxazol-4-yl)pyridin2-yl)-A-((trans-4-(5-methoxy-6methylpyridin-2yl)cycle ohexyl)methyl)cycle ohexane arboxamide

4-yl)phenyl)-4-(2hydroxyacetamido)-A-((trans-4-(4lohexanecarboxamide)

2-((trans-4 -((4-(2cyclopropyloxazol-4-yl)pyridin2-yl)((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)caroamoyl)cyclohexyl)amino)-2methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide trans-4-Acetamido-A-(3 -(2((trans-4-(4-methoxy-3 loghexanecarboxamide trans-4-Acetamido-A-(4-(22-yl)- A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Methyl (trans-4-((4-(2cyclopropyloxazol-4-yl)pyridin2-yl)((trans-4-(5-methoxy-6methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cy clohexyl)methylphenylcarbamate)cyclohexyl) methyl) cyclopropyloxazol-4-yl) phenyl)-A methylphenyl) cyclohexyl) methyl) cyclo cyclopropyloxazol-4-yl) pyridine Alternative conditions:

Step 1: The solvent was CH2C12;

2DMAP, pyridine, 80°C;

³ DMAP, Et ₃ N, toluene, 80°C; Stage 3:

⁴ Ac2O;

⁵ The base was pyridine;

The solvent was EtOAc.

⁷ As a result of hydrolysis of an acetylated compound (1 M NaOH, THF CH ₃ OH, rt).

⁸ Stages 1 and 2 only.

The following compounds were synthesized from Compound 4.16 or Compound 26.22 according to the procedure described for compound 26, Step 3.

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Comm. Structure Name [M+N] ⁺ 26.23 ¹ χΔ ΔΑ Δ Υζ, _Ν -< trans-4-((3-(1-Cyclopropyl-III-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2acetamidoethyl)carbamate 670.5 26.24 ² Λ J ζ, ^Η δ trans-4-((3-(1-Cyclopropyl-III-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- (methylsulfonamido)ethyl)carbamate 706.6 26.25 / Ά t γ γ Ο ο ·. / trans-4-((3-(1-Cyclopropyl-III-pyrazol4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylethane-1,2diyldicarbamate 686.8 26.26 \ ο="=ο ί I Δ /ο/ trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-R-((trans-4-(5methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4- (methylsulfonamidomethyl)cyclohexane arboxamide 636.6 26.27 ” ϊ ο / ο / Methyl-((trans-4-((4-(2cyclopropyloxazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6-methylpyridine2- yl) cyclohexyl) methyl) carbamoyl) cyclohexyl) methyl) carbamate 616.6 26.28 °>° < Ethyl-((trans-4-((4-(2- cyclopropyloxazol-4-yl)pyridin-2yl)((trans-4-(5-methoxy-6-methylpyridin- 2- yl) cyclohexyl) methyl) carbamoyl) cyclohexyl) methyl) carbamate 630.6 26.29 ³ ΔΛΔ 'ο / trans-R-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-4-((2hydroxyacetamido)methyl)-R-((trans-4(5-methoxy-6-methylpyridin-2yl)cyclohexyl) methyl)cyclohexanecarboxyxamide 616.5

Stage 3: ¹ Ac2O, Et ₃ N, EtOAc, rt;

2Solvent was EtOAc.

³ From acetoxyacetyl chloride, then hydrolysis (1 M NaOH, THF, CH ₃ OH, rt).

The following compounds were synthesized from intermediate 23.07 or intermediate 23.08 according to the procedures described for compound 26, Steps 2 and 3.

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Comm. Structure Name [M+N] ⁺ 26.30 ¹ And at L / trans-4-Acetamido-R-(4-(1-cyclopropyl-1R-pyrazol-4yl)pyridin-2-yl)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 584.5 26.31 O 1J A ⁿ O 2-((trans-4-((4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbam oil)cyclohexyl)amino)-2- oxoethyl acetate 642.6 26.32 ² U l / y o I trans-R-(4-(1-Cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)-4-(2hydroxyacetamido)-R-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 600.4 26.ZZ ¹ About IA - DU OSx ⁿ / trans-4-Acetamido-R-(4-(1-isopropyl1R-pyrazol-4-yl)pyridin-2-yl)-A((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 586.5 26.34 U l g °h 2-((trans-4-((4-( 1 -Isopropyl- 1Hpyrazol-4-yl)pyridin-2-yl)((trans-4(4-methoxy-3- methylphenyl)cyclohexyl)methyl)carbam oil)cyclohexyl)amino)-2- oxoethyl acetate 644.6 26.35 ² h /=Ζ / D ιζ g X trans-4-(2-Hydroxyacetamide o)-R-(4-(1isopropyl-1R-pyrazol-4-yl)pyridin-2yl)-A-((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl )methyl)cyclolog exancarboxamide 602.5

Stage 3: 1Ac ₂ O, Et ₃ N, CH2C12, k.t.

² As a result of hydrolysis of an acetylated compound (1 M NaOH, THF, CH ₃ OH, rt).

The following compounds were synthesized from compound 25, Step 2 or compound 26, Step 2 according to the procedure described for compound 5 using methylamine (40% in CH ₃ OH).

Comm. Structure Name [M+N] ⁺ 26.36 O N A SA ^N A trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-R-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methylureido)cyclohexanecarboxamide 615.5 26.37 L O o ° alS / trans-A-(3-(1-Cyclopropyl-1 N-pyrazol4-yl)phenyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3methylureido)cyclohexanecarboxamide 598.5

Compound 27: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropanamido)-N-((trans-4-(4-methoxy-3-methylphenyl) )cyclohexyl)methyl)cyclohexanecarboxamide

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Hexafluorophosphate (U) ((1 H-benzo ^] [ 1,2,3] triazol-1 -yl) oxy) tri (pyrrolidin-1 -yl) phosphonium (229.9 mg, 0.442 mmol) and iPr ₂ NEt ( 0.804 mmol, 0.14 ml) was added to a solution of compound 25, Step 2 (205.4 mg, 0.368 mmol), 2-hydroxy-2-methylpropanoic acid (46.1 mg, 0.442 mmol) and DMF (2 ml) at 0°C in N ₂ atmosphere. The reaction mixture was stirred at rt. overnight, poured into water (30 ml) and then extracted with EtOAc (3x20 ml). The organic layers were combined, washed with brine (2x20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by reverse phase HPLC (water (10 mM NH ₄ CO ₃ )/CH ₃ CN) to give trans -N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropanamido)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (76.8 mg, 32%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.63-7.56 (m, 2H), 7.55-7.47 (m, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 6.98-6.91 (m, 2H), 6.78-6.76 (m, 1H), 5.17 (s, 1H), 3.71 (s, 3H), 3.55-3.49 (m, 2H), 3.42-3.40 (m, 1H), 2.47-2.39 (m, 1H), 2, 33 (t, 1H), 2.08-2.03 (m, 4H), 1.80-1.57 (m, 8H), 1.51-1.37 (m, 3H), 1.35- 1.22 (m, 2H), 1.19-1.11 (m, 8H), 1.11-0.90 (m, 6H); LCMS: 644.3 [M+H]+.

The following compounds were synthesized from compound 25, Step 2 and the appropriate acid according to the procedure described for compound 27.

Comm. Structure Name [M+N] ⁺ 27.01 % trans-R-(3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2-hydroxypropanamido)U-((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 630.4 27.02 R-(trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbam oilyl)cyclohexyl)oxetan-3 carboxamide 642.5 27.03 N trans-4-(2-( 1H-Imid azol-1 yl)acetamido)-R-(3 -(2cyclopropylthiazol-5-yl)phenyl)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 666.5 27.04 trans-4-(2-(1H-Imide azol-2yl)acetamido)-R-(3 -(2cyclopropylthiazol-5-yl)phenyl)-R((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 666.6 May 27 Ο N U- (trans-4- ((3- (2-Cyclopropylthiazol5-yl) phenyl) ((trans-4- (4-methoxy-3 methyl phenyl) cyclohexyl) methyl) carb amoil) cyclohexyl) - 1-methylazetidine-3 carboxamide 655.5 27.Ob ¹ R-(trans-4-((3-(2-Cyclopropylthiazol5-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbam oil)cyclohexyl)azetidine-3 carboxamide 641.5

From 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid after deprotection (TFA/CH2Cl2).

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Compound 28: 2-Hydroxyethyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate

Potassium carbonate (148.6 mg, 1.07 mmol) was added to a solution of compound 25, Step 2 (200 mg, 0.358 mmol) and 1,3-dioxolan-2-one (94.7 mg, 1.08 mmol) in DMF (5 ml) at RT The mixture was heated at 120° C. overnight under N ₂ , poured into water (50 ml) and extracted with EtOAc (3x50 ml). The organic layers were combined, dried over Na ₂ SO ₄ , filtered, concentrated and then purified by reverse phase HPLC (water(10 mM NH ₄ HCO ₃ )-MeCN) to give 2hydroxyethyl(trans-4-((3-(2- cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate (19 mg, 8%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.09 (s, 1H), 7.48-7.63 (m, 3H), 7.27 (d, 1H), 6.94-6, 86 (m, 3H), 6.796.738 (m, 1H), 4.69-4.63 (m, 1H), 3.89-3.83 (m, 2H), 3.72 (s, 3H), 3 .70-3.49 (m, 4H), 3.19-3.12 (m, 1H), 2.342.33 (m, 1H), 2.15-1.96 (m, 4H), 1.85 -1.55 (m, 9H), 1.48-1.38 (m, 3H), 1.37-1.27 (d, 2H), 1.18-0.97 (m, 6H), 0 .93-0.81(m, 2H); LCMS: 646.3 [M+H]+.

Compound 29:

2-((trans-4-((3 -(1-Isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl )amino)acetic acid o o

Stage 1: Ethyl-2-((trans-4-((3 -(1-isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) methyl)carbamoyl)cyclohexyl)amino)acetate

Ethyl 2-bromoacetate (257.2 mg, 1.54 mmol) was added to a solution of compound 26.10, Step 2 (380 mg, 0.7 mmol), Et ₃ N (0.22 ml, 1.54 mmol) and CH ₂ Cl ₂ (5 ml). The reaction mixture was stirred at rt. overnight, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc/EtOH = 4/3/1). The compound was further purified by reverse phase HPLC (water(0.05% HCl)/MeCN) to give ethyl 2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl )((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetate (65.5 mg, 15%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.94 (s, 1H), 7.60 (d, 1H), 7.55-7.51 (m, 1H), 7.43 (t, 1H), 7.12-7.02 (m, 1H), 6.98-6.90 (m, 2H), 6.82-6.73 (m, 1H) , 4.58-4.42(m, 1H), 4.04(q, 2H), 3.71(s, 3H), 3.643.44(m, 2H), 3.38-3.32(m , 4H), 2.40-2.21 (m, 1H), 2.15-2.00 (m, 4H), 1.83-1.58 (m, 8H), 1.48-1.41 (m, 7H), 1.40-1.22 (m, 4H), 1.11 (t, 3H), 1.07-0.96 (m, 2H), 0.70-0.51 (m , 2H); LCMS: 629.5 [M+H]+.

Step 2: 2-((trans-4-((3-(1-Isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)amino)acetic acid

Lithium hydroxide monohydrate (53.4 mg, 1.27 mmol) was added to a solution of ethyl 2-((trans-4-((3-(1isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4- (4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetate (100 mg, 0.16 mmol), THF (4 ml) and H ₂ O (1 ml) at 0°C. The reaction mixture was allowed to warm to rt. and stirred overnight. The resulting solution was concentrated at rt. to remove most of the THF, diluted with H ₂ O (10 ml) and then concentrated further to remove 5 ml of H ₂ O. The mixture was cooled to 0°C and 1 M HCl was added dropwise with vigorous stirring (to avoid clumping) to pH =6. The solid was filtered, washed with ice-cold H ₂ O (20 ml) and then dried under high vacuum to give 2-((trans-4-((3-(1isopropyl-1H-pyrazol-4-yl)phenyl)((trans -4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)acetic acid (70 mg, 73%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (s, 1H), 7.95 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7, 45 (t, 1H), 7.147.05 (m, 1H), 7.02-6.87 (m, 2H), 6.83-6.70 (m, 1H), 4.59-4.42 ( m, 1H), 3.85-3.55 (m, 5H), 3.15-3.01 (m, 2H), 2.88-2.72 (m, 1H), 2.40-2, 27 (m, 1H), 2.21-2.03 (m, 4H), 2.01-1.85 (m, 2H), 1.85-1.65 (m, 6H), 1.53- 1.24 (m, 11H), 1.15-0.86 (m, 4H); LCMS: 601.4 [M+H]+.

Compound 3 0 trans-N-(3 -(1-Cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-4- (3-methoxycyclobutanecarboxamido)cyclohexanecarboxamide

Mixture of compound 26, Step 2 (80 mg, 0.15 mmol), 3-methoxycyclobutanecarboxylic acid (30 mg, 0.23 mmol), EDCI (47 mg, 0.24 mmol), iPr ₂ NEt (89 μl, 0. 51 mmol) and dichloromethane (0.8 ml) were stirred at rt. for 4 h and then diluted with EtOAc (10 ml). The organic phases were washed with water (10 ml), washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-10% methanol in dichloromethane) to give trans-N -(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamido)cyclohexanecarboxamide as a pale yellow foam (77 mg, 79% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.93 (s, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 7.44 (t, 1H), 7.40 (d, 1H), 7.10 (d, 1H), 6.97-6.92 (m, 2H), 6.78 (d, 1H), 3.77- 3.69 (m, 4H), 3.69-3.60 (m, 1H), 3.60-3.49 (m, 2H), 3.46-3.35 (m, 1H), 3. 07 (s, 3H), 2.38-2.25 (m, 2H), 2.23-2.14 (m, 2H), 2.11-2.01 (m, 4H), 1.89- 1.80 (m, 2H), 1.80-1.61 (m, 8H), 1.48-1.36 (m, 3H), 1.36-1.22 (m, 2H), 1, 11-0.95 (m, 6H), 0.84-0.70 (m, 2H); LCMS: 653.6 [M+H]+.

The following compound was synthesized from the appropriate amine and the appropriate acid according to the procedure described for compound 30.

Comm. Structure Name [M+N] ⁺ 30.01 o O Ύτ -pl ^k -NHud II J H J n o ⁴ ° trans-4-(Cyclobutanecarboxamido)-U-(3(1-cyclopropyl-17/-pyrazol-4-yl)phenyl)U-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide 623.5 30.02 0 0 yM A CAM trans-4-(cyclobutanecarboxamido)-trans(4-(2-cyclopropyloxazol-4-yl)pyridin2-yl)-U-((trans-4-(5-methoxy-6methylpyridin-2- yl)cyclohexyl)methyl)cyclohexanecarboxyamide 626.5 30.03 ry Ίο a Ai Ah ° ^z trans-L ^g -(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-U-((trans-4-(5-methoxy6-methylpyridin-2yl)cyclohexyl)methyl)-4-(3-methoxycyclobutanecarboxamido )cyclohe xancarboxamide 656.7 30.04 0 ΓΎΧ ιΊ ⁿ η and A trans-4-(Cyclobutanecarboxamidomethyl)U-(4-(2-cyclopropyloxazole-4- yl)pyridin-2-yl)-U-((trans-4-(5-methoxy6-methylpyridin-2- yl)cyclohexyl)methyl)cyclohexanecarboxyamide 640.6 May 30 OS* Hm° trans-Ty-(4-(2-Cyclopropyloxazol-4yl)pyridin-2-yl)-4-((3 - (dimethylamino)cyclobutanecarboxamido)methyl)-U-((trans-4-(5-methoxy-6methylpyridine-2- yl)cyclohexyl)methyl)cyclohexanecarboxyamide 683.4 30.06 ¹ 0 NPA! II Η o Am ^th trans-tU-(3-(2-Cyclopropylthiazol-5yl)phenyl)-tU-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonamido)acetamido)cyclohexancarboxamide 693.3

1EDCI, HOBt, iPr ₂ NEt, DMF, 0°C-rt, overnight.

Compound 31: Methyl-(2-((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl)carbamate o o

Triethylamine (449.1 mg, 4.44 mmol) was added to a solution of compound 26, Step 2 (200 mg, 0.37 mmol) and 2-((methoxycarbonyl)amino)acetic acid (147.7 mg, 1.11 mmol ) in DMF (3 ml) in atmosphere

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N2 at 0°C. Then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifosfinan-2,4,6 trioxide (942 mg, 1.48 mmol, 50% purity) was added dropwise at 0°C. The mixture was allowed to warm to rt. and stirred overnight. The mixture was poured into H2O (40 ml) and then extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by reverse phase prep. HPLC (water(10 mM NH ₄ HCO ₃ )/MeCN) to give methyl-(2-((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans4-( 4-Methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2-oxoethyl)carbamate (35.1 mg, 14%) as a white solid.

Ή NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7.55 (s, 1H), 7, 51-7.41 (m, 2H), 7.18-7.08 (m, 2H), 6.97-6.92 (m, 2H), 6.81-6.74 (m, 1H), 3.78-3.69 (m, 4H), 3.65-3.52 (m, 2H), 3.49 (s, 3H), 3.46-3.38 (m, 3H), 2, 38-2.28 (m, 1H), 2.12-2.03 (m, 4H), 1.81-1.62 (m, 8H), 1.50-1.37 (m, 3H), 1.35-1.22 (m, 2H), 1.12-0.95 (m, 6H), 0.91-0.77 (m, 2H); LCMS: 656.3 [M+H] ⁺ .

The following compounds were synthesized from compound 26, Step 2 or compound 25, Step 2 and the appropriate acids according to the procedure described for compound 31.

Comm. Structure Name [M+N] ⁺ 31.01 At ZZ °h trans-4-(2-Acetamide oacetamido)-A-(3- (1-Cyclopropyl- 1H-pyrazol-4yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 640.6 31.02 trans-A-(3 -(1-Cyclopropyl-\Hpyrazol-4-yl)phenyl)-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonyl)acetamido)cyclohex ancarboxamide 661.3 31.03 γΑυτ - UUx % th trans-A-(3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfonamido)acetamido)cyclohexanecarboxamide 676.6 31.04 ¹ trans-A-(3 -(1-Cyclopropyl- 1Hpyrazol-4-yl)phenyl)-A-((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-4-(2(methylsulfinyl)acetamido)cyclohex ancarboxamide 645.3 May 31 Δ A s / Methyl-(2-((trans-4-((3 -(2-cycle opropylthiaz ol-5 yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)- 2oxoethyl)carbamate 673.3 31.06 ABOUT '-Ν trans-L-(3 -(2-Cyclopropylthiazol-5 yl)phenyl)-4-(2- (dimethylamino)acetamido)-A-((trans- 4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 643.4

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31.07 ³ A trans-4-(2-Aminoacetamido)-A-(3-(2cyclopropylthiazol-5-yl)phenyl)A((trans-4-(4-methoxy-3- methyl l phenyl) cycle ohexyl) methyl) cyclo og exancarboxamide 615.4 31.08 ³ V Ru _o ΖΖ / trans-R-(3-(2-Cyclopropylthiazol-5yl)phenyl)-A ^g -((trans-4-(4-methoxy-3methyl phenyl)cyclohexyl)methyl)-4-(2(methylamino)acetamido )cyclohexane rboxamide 629.5 31.09 O A HA trans-4-(2-Acetamidoacetamido)-A ^g -(3(2-cyclopropylthiazol-5-yl)phenyl)-mU((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 657.4 31.10 .33 Ru _o ω / trans-A ^g -(3-(2-Cyclopropylthiazol-5yl)phenyl)-A ^g -((trans-4-(4-methoxy-3methyl phenyl) cyclohexyl) methyl) -4-(2(methylthio) acetamido)cyclohexanecarb oxamide 646.6 31.P ² 0 Oh Oh A* Ra A trans-R-(3-(2-Cyclopropylthiazol-5yl)phenyl)-A ^g -((trans-4-(4-methoxy-3methyl phenyl)cyclohexyl)methyl)-4-(2(methylsulfinyl)acetamido )cyclohex ancarboxamide 662.5 31.12 / o=ot=o Chu A 4 / trans-A ^g -(3-(2-Cyclopropylthiazol-5yl)phenyl)-A ^g -((trans-4-(4-methoxy-3methyl phenyl) cyclohexyl) methyl) -4-(2(methylsulfonyl) acetamido)cyclohex ancarboxamide 678.5 31.13 ¹ RF about trans-A-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3(methylsulfinyl)propanamido)cyclog exancarboxamide 676.2 31.14 \ O-P-O 4xV ΐ trans-R-(3-(2-Cyclopropylthiazol-5 yl)phenyl)-A ^g -((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(3(methylsulfonyl)propanamido)cyclog exancarboxamide 692.5 31.15 o 0 N=\ A A'y trans-4-(2-(1H-Imid azol-4yl)acetamido)-R-(3-(2cyclopropylthiazol-5-yl)phenyl)-A((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 666.5

1As a result of sulfide oxidation (NaOI4, THF/H2O, 0°C-rt, overnight).

2From compound 31.10 (m-CPBA, CH2Cl2, 0°С-rt, 2 h).

³ After removal of Boc (HCl/EtOAc).

Compound 32: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)acetamido)-X-((trans-4-(4- methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

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Step 1: trans-4-(2-Chloroacetamido)-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-M-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexanecarboxamide

A solution of compound 26, Step 2 (500 mg, 0.924 mmol) and pyridine (789.9 mg, 9.99 mmol) in CH ₂ Cl ₂ (5 mL) was degassed and purged with N2 3 times at 0°C. 2-Chloroacetyl chloride (313.3 mg, 2.77 mmol) was added. The mixture was allowed to warm to rt. and stirred for 2 h under N2. The mixture was poured into water (60 ml) and extracted with EtOAc (3x40 ml). The organic layer was combined, dried over Na ₂ SO ₄ , filtered, concentrated and then purified by prep. TLC (SiO ₂ , CH ₂ Cl ₂ /CH ₃ OH = 10/1) to give trans-4-(2-chloroacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl )-N-((trans4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (400 mg, 70%) as a black brown solid.

¹ H NMR (400 MHz, CDCl ,): δ 7.75 (d, 2H), 7.51-7.40 (m, 2H), 7.29-7.24 (m, 1H), 7, 04 (d, 1H), 6.99-6.93 (m, 2H), 6.74 (d, 1H), 6.23 (d, 1H), 3.98 (s, 2H), 3.80 (s, 3H), 3.78-3.71 (m, 1H), 3.70-3.57 (m, 3H), 2.46-2.34 (m, 1H), 2.25-2 .11 (m, 4H), 2.07-1.92 (m, 2H), 1.92-1.68 (m, 8H), 1.43-1.28 (m, 2H), 1.27 -1.05 (m, 7H), 1.030.87 (m, 2H); LCMS: 617.2 [M+H]+.

Step 2: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)acetamido)-M-((trans-4-(4- methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Sodium hydride (12.2 mg, 0.303 mmol, 60% purity) was added to a solution of propane-1,3-diol (31.4 mg, 0.413 mmol) in DMF (5 mL) at 0°C under N2 atmosphere. After 30 min at 0°C, trans-4-(2-chloroacetamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy -3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (170 mg, 0.275 mmol) and the reaction mixture was allowed to stir at rt. during the night. The mixture was poured into water (30 ml) and extracted with EtOAc (3x50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by reverse phase HPLC (water (10 mM NH ₄ HCO ₃ )/MeCN) to give trans-M-(3-(1-cyclopropyl-1 H -pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)acetamido)-M-((trans-4(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (18.1 mg, 10%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.93 (s, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 7, 44 (t, 1H), 7.37 (d, 1H), 7.10 (d, 1H), 7.01-6.88 (m, 2H), 6.84-6.68 (m, 1H) , 4.45-4.41(m, 1H), 3.81-3.71(m, 5H), 3.64-3.45(m, 3H), 3.45-3.39(m, 5H), 2.39-2.26 (m, 1H), 2.12-2.01 (m, 4H), 1.84-1.54 (m, 10H), 1.52-1.35 ( m, 3H), 1.33-1.21 (m, 2H), 1.14-0.85 (m, 8H); LCMS: 657.4 [M+H] ⁺ .

The following compounds were synthesized from the appropriate starting materials according to the procedures described for compound 32.

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32.01 O o °4γ C4 o / trans-U-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-(2-(2hydroxyethoxy)acetamido)-U-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 643.8 32.02 O 40^4^0^% θ trans-Y-(3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2-(2- hydroxyethoxy)acetamido)-U-((trans4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 660.6 32.03 ABOUT trans-U-(3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2-(3 hydroxypropoxy)acetamido)-U((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 674.5 32.04 \ Z - $ A A 4 / trans-A-(3-(2-Cyclopropylthiazol-5yl)phenyl)-4-(2-(2- (dimethylamino)ethoxy)acetamido)-U((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 687.6 32.05 ¹ 4 about ζ trans-4-(2-(2- Aminoethoxy)acetamido)-U-(3-(2cyclopropylthiazol-5-yl)phenyl)-U((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclog exancarboxamide 659.5 32.06 trans-U-(3-(2-Cyclopropylthiazol-5yl)phenyl)-U-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)-4-(2(2- (methylamino)ethoxy)acetamido)cyclog exancarboxamide 673.5

1From Boc-protected amino alcohol (NaOH, TBAI, toluene, 80°C; then TFA/CH2C12, rt, 3

Compound 33: trans-N-(3-(2-Cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2H-tetrazole -5-yl)cyclohexanecarboxamide o o

A solution of intermediate 21.21 (345 mg, 0.607 mmol), TMSN3 (700 mg, 6.08 mmol), dibutylstannanone (75.63 mg, 0.303 mmol) and toluene (25 mL) was heated at 120°C overnight under N2 , allowed to cool to rt. and then concentrated to dryness. The crude product was purified by reverse phase prep. HPLC (water(0.05% HCl))/CH ₃ CN) to give trans-N-(3-(2cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5-yl)cyclohexanecarboxamide (108.2 mg, 29%) as a white solid.

'H NMR (400 MHz, CD3OD): δ 7.99 (s, 1H), 7.69 (d, 1H), 7.63-7.56 (m, 2H), 7.34 (d, 1H) , 7.01-6.91 (m, 2H), 6.77 (d, 1H), 3.78 (s, 3H), 3.76-3.60 (m, 2H), 3.09-2 .96 (m, 1H), 2.47-2.32 (m, 3H), 2.15 (s, 3H), 2.07 (d, 2H), 1.98-1.82 (m, 6H ), 1.81-1.68 (m, 2H), 1.64-1.51 (m, 1H), 1.49-1.30 (m, 4H), 1.30-1.17 (m , 4H), 1.14-1.08 (m, 2H); LCMS: 611.3 [M+H]+.

The following compound was synthesized from intermediate 21.23 according to the procedure described for compound 33.

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Comm. Structure

Name [M+N] ⁺

trans-L-(3-(1-Cyclopropyl-1Hpyrazol-4-yl)phenyl)-U-((trans-4(4-methoxy-3methylphenyl)cyclohexyl)methyl)4-(2R-tetrazol-5yl)cyclohexanecarboxamide

594.3

Compound 34:

mpaHC-N-(3 -(1-Cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(5 -oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexanecarboxamide

Step 1: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-((Z)-N'-hydroxycarbamimidoyl)N-((trans-4-(4-methoxy -3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide

Hydroxylamine hydrochloride (1.21 g, 17.43 mmol) in water (5 ml) was added dropwise to a solution of sodium carbonate (1.54 g, 18.30 mmol) in water (25 ml). This mixture was added to a solution of intermediate 21.23 (240 mg, 0.435 mmol) in EtOH (10 ml). The mixture was heated at 80° C., stirred overnight and then allowed to cool to rt. The organic solvent was removed from the mixture. The aqueous layer was extracted with i-PrOH/CHCl ₂ (1:3; 3x20 ml). The combined layers were washed with water (5 ml), washed with brine (5 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by prep. TLC (SiO ₂ , 100% EtOAc) to give trans-N-(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)-4-((Z)-N-hydroxycarbamimidoyl)-N-((trans- 4-(4-Methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (200 mg, 79%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.60 (d, 1H), 7, 54 (s, 1H), 7.44 (t, 1H), 7.10 (d, 1H), 7.00-6.90 (m, 2H), 6.81-6.74 (m, 1H) , 5.19 (s, 2H), 3.82-3.69 (m, 4H), 3.66-3.45 (m, 2H), 3.31-3.28 (m, 1H), 2 .38-2.29 (m, 1H), 2.18-2.12 (m, 1H), 2.09 (s, 3H), 1.92-1.85 (m, 1H), 1.78 -1.60 (m, 7H), 1.50-1.37 (m, 3H), 1.35-1.20 (m, 3H), 1.10-1.05 (m, 4H), 1 .04-0.95 (m, 3H); LCMS: 584.3 [M+H] ⁺ .

Step 2: trans-N-(3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexanecarboxamide

A mixture of trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-((Z)-N-hydroxycarbamimidoyl)-N((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (200 mg, 0.342 mmol), CDI (83.3 mg, 0.513 mmol) and dioxane (2 ml) were stirred at 100°C for 0.5 h and then allowed to cool to rt . The mixture was poured into water (40 ml) and extracted with EtOAc (3x5 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by prep. TLC (SiO ₂ , 100% EtOAc) to give trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexanecarboxamide (42.5 mg, 20%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.477.43 (m, 1H), 7.12 (d, 1H), 6.99-6.90 (m, 2H), 6.81-6.74 (m, 1H), 3.78-3.68 (m, 4H), 3.67-3.46 (m, 2H), 2.572.51 (m, 1H), 2.36-2.31 (m, 1H) , 2.2-2.15 (m, 1H), 2.09 (s, 3H), 1.86-1.69 (m, 8H), 1.58-1.37 (m, 3H), 1 .36-1.21 (m, 3H), 1.12-1.04 (m, 5H), 1.02-0.96 (m, 2H); LCMS: 610.4 [M+H] ⁺ .

Example A-1 Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of the compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 ml of sterile saline at a concentration of 0, 9%. If desired, a suitable buffer is added, and optionally an acid or base to adjust the pH. The mixture is formulated into a unit dosage form suitable for administration by injection.

Example A-2 Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of the compound described herein or a pharmaceutically acceptable salt thereof (with optional solubilizer(s), optional buffer(s), and taste-masking excipients) is added to water to obtain a solution at a concentration of 20 mg/ml .

Example A-3 Oral Tablet

A tablet is prepared by mixing 20-50% by weight of the compound described herein or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose and 1-10% by weight of magnesium stearate or other suitable excipients. Tablets are prepared by direct compression. The total mass of pressed

- 288 040704 tablets maintained at 100-500 mg.

Example A-4 Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder mixture. The mixture is placed in a dosage unit for oral administration, such as a hard gelatin capsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is placed in a size 4 capsule or a size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.

Example A-5: Gel composition for topical application

To prepare a pharmaceutical gel composition for topical use, the compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate, and USP purified alcohol. The resulting gel mixture is then injected into containers, such as test tubes, which are suitable for topical use.

Example B-1: In Vitro FXR Assay (TK) Seeding

CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask with DMEM + 10% double desorption FBS on charcoal and incubated at 37° C. in 5% CO ₂ for 18 h (O/N).

Transfection

After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% charcoal superdesorbed serum. In a polypropylene tube, 2500 µl of OptiMEM (Life Technologies, cat. no. 31985-062) were combined with expression plasmids for hFXR, hRXR, TK-ECRE-luc and pCMX-YFP. The tube was then briefly shaken and incubated at room temperature for 5 min. The transfection reagent (X-tremeGENE HP from Roche, cat. no. 06366236001) was added to the OptiMEM/plasmid mixture, shaken and incubated at room temperature for 20 minutes. After incubation, the transfection reagent/DNA complex was added to the cells in a T175 flask and the cells were incubated at 37° C. in 5% CO ₂ for 18 h (O/N).

Test compounds

Compounds were serially diluted in DMSO and added to transfected CV-1 cells. The cells were then incubated for 18 hours. The next day, the cells were lysed and examined for luminescence.

Representative data for exemplary compounds disclosed herein are presented in the following table.

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Table 3

connection no. TK hFXR: ECso (μM) 1 +++ 1.01 +++ 1.02 +++ 1.03 +++ 1.04 +++ 1.05 +++ 1.06 +++ 1.07 +++ 1.08 +++ 1.09 +++ 1.10 +++ 2 +++ 2.01 +++ 2.02 +++ 2.03 +++ 2.04 +++ 2.05 +++ 2.06 +++ 2.07 +++ 2.08 +++ 3 +++ 3.01 +++ 3.02 +++ 3.03 +++ 3.04 +++ 3.05 +++ 4 +++ 4.01 +++ 4.02 +++ 4.03 +++ 4.04 +++ 4.05 +++ 4.06 +++ 4.07 +++ 4.08 +++ 4.09 +++ 4.10 +++ 4.11 +++ 4.12 +++ 4.13 +++ 4.14 +++ 4.15 +++ 4.16 +++ 4.17 +++ 4.18 +++ 4.19 +++

connection no. TK hFXR: ECso (μM) 4.20 +++ 4.21 +++ 4.22 +++ 4.23 +++ 4.24 +++ 4.25 +++ 4.26 +++ 4.27 +++ 4.28 +++ 5 +++ 5.01 +++ 5.02 +++ 5.03 +++ 5.04 +++ 5.05 +++ 5.06 +++ 5.07 +++ 5.08 +++ 5.09 +++ 5.10 +++ 5.11 +++ 5.12 +++ 5.13 +++ 5.14 +++ 5.15 +++ 5.16 +++ 5.17 +++ 5.18 +++ 5.19 +++ 5.20 +++ 5.21 +++ 5.22 +++ 5.23 +++ 5.24 +++ 5.25 +++ 5.26 +++ 5.27 +++ 5.28 +++ 5.29 +++ 5.30 +++ 5.31 +++ 5.32 +++ 5.33 +++ 5.34 +++ 5.35 +++ 5.36 +++

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7.24 +++ 7.25 +++ 7.26 +++ 7.27 +++ 7.28 +++ 7.29 +++ 7.30 +++ 7.31 +++ 7.32 +++ 7.33 +++ 7.34 +++ 7.35 +++ 7.36 +++ 7.37 +++ 7.38 +++ 7.39 +++ 7.40 +++ 7.41 +++ 7.42 +++ 7.43 +++ 7.44 +++ 7.45 +++ 7.46 +++ 7.47 +++ 7.48 +++ 7.49 +++ 7.50 +++ 7.51 +++ 7.52 +++ 7.53 +++ 7.54 +++ 7.55 +++ 7.56 +++ 7.57 +++ 7.58 +++ 7.59 +++ 7.60 +++ 7.61 +++ 7.62 +++ 7.63 +++ 7.64 +++ 7.65 +++ 7.66 +++ 7.67 +++ 7.68 +++ 7.69 +++

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7.70 +++ 7.71 +++ 7.72 +++ 7.73 +++ 7.74 +++ 7.75 +++ 7.76 +++ 7.77 +++ 7.78 +++ 7.79 +++ 7.80 +++ 7.81 +++ 7.82 +++ 7.83 +++ 7.84 +++ 7.85 +++ 7.86 ++ 7.87 +++ 7.88 +++ 7.89 +++ 7.90 +++ 7.91 +++ 7.92 +++ 7.93 +++ 7.94 +++ 7.95 +++ 7.96 ++ 7.97 +++ 7.98 +++ 7.99 +++ 7.100 +++ 7.101 +++ 7.102 +++ 7.103 +++ 7.104 +++ 7.105 +++ 7.106 +++ 7.107 +++ 7.108 +++ 7.109 +++ 8 +++ 8.01 +++ 9 +++ 10 +++ eleven ++ 12 +++

13 +++ 13.01 +++ 13.02 +++ 13.03 +++ 13.04 +++ 13.05 ++ 14 +++ 15 +++ 15.01 +++ 15.02 +++ 15.03 +++ 15.04 +++ 16 +++ 17 +++ 17.01 +++ 17.02 +++ 17.03 +++ 17.04 +++ 17.05 +++ 17.06 +++ 17.07 +++ 17.08 +++ 17.09 +++ 17.10 ++ 17.11 +++ 17.12 +++ 17.13 +++ 17.14 +++ 17.15 +++ 17.16 +++ 17.17 +++ 17.18 ++ 17.19 +++ 17.20 +++ 17.21 + 17.22 +++ 17.23 ++ 17.24 +++ 17.25 +++ 17.26 +++ 17.27 + 18 +++ 18.01 +++ 18.02 +++ 18.03 +++ 18.04 +++

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18.05 +++ 18.06 +++ 18.07 +++ 18.08 +++ 18.09 +++ 18.10 +++ 18.11 + 18.12 + 18.13 +++ 18.14 +++ 18.15 +++ 18.16 +++ 18.17 ++ 18.18 +++ 18.19 +++ 18.20 +++ 18.21 +++ 18.22 +++ 18.23 +++ 18.24 +++ 19 +++ 20 +++ 20.01 +++ 20.02 +++ 20.03 +++ 20.04 +++ May 20 +++ 20.06 +++ 20.07 +++ 20.08 +++ 20.09 +++ 20.10 +++ 20.11 +++ 20.12 +++ 20.13 +++ 20.14 +++ 20.15 +++ 20.16 +++ 21 +++ 21.01 +++ 21.02 +++ 21.03 +++ 21.04 + May 21 +++ 21.06 +++ 21.07 +++

21.08 +++ 21.09 +++ 21.10 +++ 21.11 +++ 21.12 +++ 21.13 +++ 22 +++ 22.01 +++ 22.02 +++ 22.03 + 22.04 +++ May 22 ++ 22.06 ++ 23 ++ 24 +++ 24.01 +++ 24.02 +++ 24.03 +++ 24.04 +++ May 24 ++ 24.06 +++ 25 +++ 25.01 ++ 25.02 ++ 25.03 + 25.04 +++ May 25 +++ 25.06 +++ 25.07 +++ 25.08 +++ 25.09 +++ 25.10 +++ 25.11 +++ 25.12 +++ 25.13 +++ 25.14 +++ 25.15 +++ 25.16 +++ 25.17 +++ 25.18 +++ 26 +++ 26.01 +++ 26.02 +++ 26.03 +++ 26.04 +++ May 26 +++

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26.06 +++ 26.07 +++ 26.08 +++ 26.09 +++ 26.10 +++ 26.11 +++ 26.12 +++ 26.13 +++ 26.14 +++ 26.15 +++ 26.16 +++ 26.17 +++ 26.18 +++ 26.19 +++ 26.20 +++ 26.21 +++ 26.22 + 26.23 +++ 26.24 +++ 26.25 +++ 26.26 +++ 26.27 +++ 26.28 +++ 26.29 ++ 26.30 +++ 26.31 +++ 26.32 +++ 26.33 +++ 26.34 +++ 26.35 +++ 26.36 +++ 26.37 +++ 27 +++ 27.01 +++ 27.02 +++ 27.03 ++ 27.04 +++ May 27 + 27.06 + 28 +++ 29 + thirty +++ 30.01 +++ 30.02 +++ 30.03 +++ 30.04 +++

May 30 + 30.06 +++ 31 +++ 31.01 + 31.02 ++ 31.03 + 31.04 ++ May 31 +++ 31.06 +++ 31.07 ++ 31.08 +++ 31.09 +++ 31.10 +++ 31.11 +++ 31.12 +++ 31.13 ++ 31.14 +++ 31.15 +++ 32 +++ 32.01 +++ 32.02 +++ 32.03 +++ 32.04 +++ May 32 ++ 32.06 + 33 +++ 33.01 +++ 34 +++

Where +++ means EC50 < 0.25 µM;

++ means EC ₅₀ > 0.25 μM and < 1 μM;

+ means EC ₅₀ > 1 µM.

Compounds with maximum potency <25% of the fexarmine control were classified as +.

Example B-2: In Vitro FXR Assay (hSHP)

sowing

CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask with DMEM + 10% double desorption FBS on charcoal and incubated at 37° C. in 5% CO ₂ b for 18 h (O/N).

Transfection

After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% charcoal superdesorbed serum. In a polypropylene tube, 2500 µl of OptiMEM (Life Technologies, cat. no. 31985-062) were combined with expression plasmids for hFXR, hRXR, hSHP-luc and pCMXYFP. The tube was then briefly shaken and incubated at room temperature for 5 min. The transfection reagent (X-tremeGENE HP from Roche, cat. no. 06366236001) was added to the OptiMEM/plasmid mixture, shaken and incubated at room temperature for 20 minutes. After incubation, the transfection reagent/DNA complex was added to the cells in a T175 flask and the cells were incubated at 37° C. in 5% CO ₂ for 18 h (O/N).

Test compounds

Compounds were serially diluted in DMSO and added to transfected CV-1 cells. The cells were then incubated for 18 hours. The next day, the cells were lysed and examined for luminescence.

Example B-3. NASH Activity Assay (STZ Model) NASH can be induced in a C57BL/6 male by a single subcutaneous injection of 200 µg STZ 2 days after birth followed by an unrestricted high fat diet (HFD) after 4 weeks of age. Continuing

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HFD compounds can be dosed over 4-8 weeks to determine effects on NASH. Fasting glucose can be measured throughout the study using a hand-held glucometer. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride (TG) can be measured with a clinical chemistry analyzer. TG content in liver tissue can be measured using a triglyceride assay kit (Wako, Tokyo, Japan). Histological analysis of liver sections can be performed on tissue immersed in Tissue-TEK OCT compound, quickly frozen in liquid nitrogen and stored at -80°C. Sections (5 µm) can be made, air dried and fixed in acetone. For staining with hematoxylin and eosin, liver sections can be pre-fixed with Buin's solution and then stained with a solution of hematoxylin and eosin. The degree (zone-3) of liver fibrosis can be assessed by staining with Sirius red.

Example B-4. NASH activity study (AMLN model)

NASH was induced in male C57BL/6 mice by induction with the AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18% trans fat), 40% carbohydrates (20% fructose) and 2% cholesterol). Animals are kept on a diet for 29 weeks. After 26 weeks of dietary induction, liver biopsies are performed for baseline histological assessment of disease progression (hepatosteatosis and fibrosis), divided and randomized into treatment groups depending on the stage of liver fibrosis, steatosis scores, and body weight. Three weeks after biopsy, mice are divided into treatment groups and FXR agonists are administered orally via gavage daily for 8 weeks. At the end of the study, liver biopsies are performed to evaluate liver steatosis and fibrosis by examining tissue sections stained with H&E and Sirius red, respectively. The content of total collagen in the liver is measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. The content of triglycerides and total cholesterol in liver homogenates was measured in single determinations using a Cobas C-111 autoanalyzer with a commercial kit (Roche Diagnostics, Germany) in accordance with the manufacturer's instructions.

Example B-5. CCl4 fibrosis model

Fibrosis can be induced in male BALB/c mice by two weeks of CCl4 administered by intraperitoneal injection. CCl ₄ make up 1:1 in oil and injected with IP at a dose of 1 ml/kg. After 2-4 weeks of induction of fibrosis, the compounds can be administered daily orally via gavage for 2-6 weeks of treatment while continuing to administer CCl ₄ . At the end of the study, the liver can be fixed with formalin and stained with Sirius red for histopathological assessment of fibrosis. Total collagen content can be measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) can be measured using a clinical chemistry analyzer.

Example B-6 Intrahepatic cholestasis model

Experimental intrahepatic cholestasis induced by 17a-ethinylestradiol (EE2) treatment in rodents is a widely used in vivo model to study the mechanisms involved in estrogen-induced cholestasis. Intrahepatic cholestasis can be induced in adult male mice by subcutaneous injection of 17a-ethinylestradiol (E2) at a dose of 10 mg/kg daily for 5 days. The study of FXR ligands can be carried out by the introduction of compounds during the induction of E2 cholestasis. Cholestatic effects can be quantified by assessing the ratio of liver weight to body weight, and measurement of serum total bile acids and alkaline phosphatase can be measured using reagents and controls from Diagnostic Chemicals Ltd. and analyzer Cobas Mira plus CC (Roche Diagnostics). To measure histology and mitosis, liver samples from each mouse can be fixed in 10% neutral buffered formalin. Slides are stained with hematoxylin and eosin using standard protocols and examined microscopically for structural changes. Hepatocyte proliferation is assessed by immunohistochemical staining for Ki67.

Example B-7. Direct regulation of target genes

Direct regulation of target genes by FXR ligands can be assessed by acutely or chronically administering compounds to mice and harvesting tissues at various time points post-dose. RNA can be isolated from tissues such as the ileum and liver and subjected to cDNA reverse transcription to quantify PCR genes known in the literature that are directly and indirectly regulated by FXRs such as SHP, BSEP, IBABP, FGF15, CYP7A1, CYP8B1 and C3.

Example B-8. PK study in mice

The plasma pharmacokinetics of any of the compounds described herein as an investigational device is measured after a single bolus intravenous and oral administration in mice (CD-1, C57BL and diet-induced obesity mice). The study product is formulated for intravenous administration in a vehicle solution of DMSO, PEG400, hydroxypropyl-β-cyclodextrin (HPeCD) and administered (eg, at a dose of 3 ml/kg) at selected dose levels. Composites

- 296 040704 Oral dosage is prepared in appropriate oral vehicles (vegetable oils, PEG400, Solutol, citrate buffer or carboxymethyl cellulose) and administered in a dose volume of 5-10 ml/kg at selected dose levels. Blood samples (approximately 0.15 ml) are collected by the cheek pouch method at predetermined time intervals after intravenous or oral administration in tubes containing EDTA. Plasma is isolated by centrifugation of blood at 10,000 g for 5 min and aliquots are transferred to a 96-well plate and stored at or below 60° C. until analysis.

Test product calibration standards are prepared by diluting a stock solution of DMSO over a range of concentrations. Aliquots of the DMSO calibration standards are pooled with naïve mouse plasma so that the final plasma concentrations of the calibration standards are 10-fold lower than the DMSO calibration standards. Plasma PK samples are combined with pure DMSO to match the matrix. Calibration standards and PK samples are combined with ice-cold acetonitrile containing an analytical internal standard and centrifuged at 1850 g for 30 min at 4°C. The supernatant fractions are analyzed by LC/MS/MS and compared quantitatively with a standard curve. Pharmacokinetic parameters (area under the curve (AUC), C _max , T _max , half-life (T _1/2 ), clearance (CL), volume of distribution at steady state (Vdss) and mean residence time (MRT)) are calculated through non-compartmental analysis using Microsoft Excel (version 2013).

Example B-9. ANIT model in rats

The compound described herein is evaluated in a chronic treatment model for cholestasis over a range of doses (eg, doses ranging from 0.01 to 100 mg/kg). This model is used to assess the suitability of using FXR agonists, for example, the compound described herein for the treatment of cholestatic liver diseases such as bile acid malabsorption (eg, primary or secondary chologogenic diarrhea), biliary reflux gastritis, collagenous colitis, lymphocytic colitis, diversionary colitis, indefinite colitis, Alagille syndrome, biliary atresia, duodenal transplant rejection, bone marrow or stem cell transplant associated with graft versus host disease, cystic fibrosis of the liver, and parenteral nutrition-associated liver disease.

Rats receive alpha-naphthyl isothiocyanate (ANIT) (0.1% w/w) in food for 3 days prior to exposure to a compound described herein over a range of doses (e.g. doses ranging from 0.01 to 100 mg/kg ). The non-cholestatic control group receives a standard diet without ANIT and serves as non-cholestatic control animals (control). After 14 days of oral administration, the serum of rats is analyzed for the content of analytes. LLQ, lower limit of quantitation. Mean ± SEM; n = 5.

Levels of indicators of hepatobiliary damage are measured in rat serum, for example, elevated levels of circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and bile acids. Exposure to ANIT causes deep cholestasis and hepatocellular damage. A compound that improves many of these parameters is useful in the treatment of the above diseases or conditions.

Decreased accumulation of bile acids in the liver, increased excretion of bile acids in the biliary tract, and inhibition of bile acid synthesis is consistent with the pharmacological action of an FXR agonist. Improvement in serum-conjugated bilirubin (a direct indicator of hepatic function) suggests recovery from cholestasis with improved bile excretion.

In addition, an assay was performed to determine the effect of a compound described herein on serum fibroblast growth factor FGF15 expression (FGF15 in rodents; FGF19 in humans), a hormone that is secreted in portal blood and signals to the liver to suppress CYP7A1 expression synergistically with SHP. The direct FXR-dependent induction of FGF15/19 along with the anticholestatic properties of FGF15/19 makes it a convenient serum biomarker to detect the targeting of FXR agonists.

Serum FGF15 levels are quantified using the FGF15 Meso Scale Discovery (MSD) assay. For example, the mouse FGF15 antibody from R&D Systems (AF6755) is used in the assay as both a capture and detection antibody. MSD SULFO-TAG NHS-Ester is used to label the FGF15 antibody. Standard 96-well MSD plates are coated with FGF15 capture antibody and the plates are blocked with MSD Blocker (R93AA-2). After washing the plate with PBS + 0.05% Tween 20, MSD 4 diluent was dosed into each well and incubated for 30 minutes. 25 µl of dilutions or calibrator samples (serum or plasma with EDTA) are placed in each well and incubated with shaking at room temperature.

After washing, detecting antibody is added and incubated with shaking for 1 hour at room temperature. After washing and adding MSD Reading Buffer (R92TC2), the plate is read on an MSD SECTOR Imager 6000. Standard curve and unknown sample plots are calculated using the MSD data analysis software.

- 297 040704

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are to be included within the spirit and scope of this application and the scope of the appended claims.

Example B-10. DSS mouse model of chronic colitis

A mouse with chronic dextran sodium sulfate (DSS) induced colitis can be used to test the therapeutic potential of compounds against inflammatory bowel disease (IBD). Chronic colitis can be caused by mice getting DSS in their drinking water. For example, 2% DSS in drinking water for 5 days and normal drinking water for 5 days, then this production cycle can be repeated two more times with higher concentrations of DSS, 2.5 and 3%, respectively, for a total of three cycles. Colitis develops approximately after the first DSS cycle, which can be monitored by weight loss, stool consistency, and rectal bleeding. The FXR agonist can be investigated by co-administration in mice starting water with 2% DSS. Alternatively, the FXR agonist assay can be performed after the first cycle of 2% DSS water and plain water. During the period of administration of an FXR agonist to mice, therapeutic effects can be monitored by observing body weight, stool consistency, and rectal bleeding. Following euthanasia, disease progression and FXR agonist effects can be further quantified by measuring colon mass and length, colon histology by H&E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of genes associated with the disease.

Example B-11. Model of adoptive T-cell transfer in mice with colitis

The adoptive T cell transfer colitis model is accepted as a relevant mouse model for human inflammatory bowel disease (IBD). To induce colitis in this model, a population of CD4 T lymphocytes is isolated from the spleens of donor mice, then a subset of CD4+CD45RB high T cells is purified by cell sorting using flow cytometry. Purified CD4+CD45RB high T cells are injected into the abdominal cavity of recipient SCID mice. Colitis develops approximately three to six weeks after T cell transfer, which can be monitored by weight loss (although weight loss may be variable), inconsistent stools, or bloody diarrhea. An FXR agonist study can be initiated simultaneously with injection of purified CD4+CD45RB high T cells into recipient SCID mice. Alternatively, the FXR agonist can be administered two or three weeks after T cell transfer when the model has already developed colitis. During the period of administration of an FXR agonist to mice, therapeutic effects can be monitored by observing body weight, stool consistency, and rectal bleeding. Following euthanasia, disease progression and FXR agonist effects can be further quantified by measuring colonic mass and length, colonic and ileal histology by H&E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of genes associated with disease.

Example B-12. Mdr1a-/mouse model The Mdr1a-/- mouse model is a model of spontaneous colitis that is used in the study of novel treatments for human IBD. Loss of the Mdr1a gene in this model results in impaired gut barrier function, leading to increased intestinal bacterial infiltration and subsequent colitis. Under proper housing conditions, Mdr1a -/- mice can develop colitis between 8 and 13 weeks of age. During disease progression, disease activity index (DAI), which summarizes clinical observation scores for rectal prolapse, stool consistency, and rectal bleeding, can be used to monitor disease. An FXR agonist study can be started early in the course of the disease, typically with a DAI score of less than 1.0. Alternatively, administration of an FXR agonist may be initiated when colitis has developed, typically with a DAI score greater than 2.0. The therapeutic effects of an FXR agonist can be monitored by measuring DAI and the study can be terminated when the desired disease severity is reached, typically with a DAI score of approximately 5.0. Following euthanasia, disease progression and the effects of an FXR agonist can be further quantified by measuring colonic mass and length, colonic histology by H&E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of disease-associated genes.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are to be included within the spirit and scope of this application and the scope of the appended claims.

Claims (26)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof Formula (I) wherein ring A is a 5-membered heteroaryl which is oxazolyl, thiazolyl, pyrazolyl or isothiazolyl; or ring A is a 6-membered heteroaryl which is pyridinyl or pyrimidinyl; X ¹ represents CH or N; R ¹ is H, D, halogen, -CN, -OH, -N(R ¹⁵ )2, C1-C ₄ alkyl, C1-C ₄ alkoxy, C1-C ₄ deuteroalkyl, C1-C ₄ deuteroalkoxy, C1- C ₄ fluoroalkyl or C 1 -C ₄ fluoroalkoxy; X ² is CR ² or N; R ² is H, D, halogen, -CN, -OH, -N(R ¹⁵ ) ₂ , C ₁ -C ₄ alkyl, C 1 -C ₄ alkoxy, C _g C ₄ deuteroalkyl, C 1 -C ₄ deuteroalkoxy, C 1 -C ₄ fluoroalkyl or C ₁ -C ₄ fluoroalkoxy; or R ¹ and R ² are taken together with intermediate atoms to form a fused 5-membered ring with 2 N atoms, where said ring is optionally substituted with 2 substituents selected from fluorine and methyl; X ³ is CR ³ or N; R ³ is H, D, halogen, -CN, -OH, -N(R ¹⁵ ) ₂ , C _g C ₄ alkyl, C1-C ₄ alkoxy, C1-C ₄ deuteroalkyl, C1-C ₄ deuteroalkoxy, C1- C ₄ fluoroalkyl or C 1 -C ₄ fluoroalkoxy; each X ⁴ is independently CH or N; R ⁴ is H; R ⁵ is H; or R ⁴ and R ⁵ are taken together to form a bridge which is -CH2CH2-; each R ⁶ is independently H, D, F, -OH or -CH ₃ ; m is 0; R ⁷ is H; L is absent or is -Y2-L ¹ -; Y ² represents -C=C-; L ¹ is absent; R ⁸ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ deuteroalkyl, C ₁ -C ₆ fluoroalkyl, or unsubstituted C3-C6 cycloalkyl; R ⁹ is H; R ¹⁰ is -CO2H, -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ¹⁵ S(=O)2R ¹⁴ , -NR ¹⁵ C( =O)R ¹⁴ , -C(=O)N(R ¹² )2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² )2 or -NR ¹⁵ C(=O )N(R ¹² )2; or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ; L ² is absent or represents an unsubstituted C1-C ₆ alkylene; L ³ is absent or is -O-, -S-, -S(=O)-, -S(=O) ₂ -, -NR ¹⁵ -, -C(=O)-, -C(=O) NR ¹⁵ -, -NR ¹⁵ C(=O)-, -C(=O)O-, -OC(=O)- or -OC(=O)NR ¹⁵ -; L ⁴ is an unsubstituted C1-C ₆ alkylene; R ¹³ is H, -CN, -OH, -N(R ¹² )2, -NR ¹⁵ S(=O)2R ¹⁴ , -SR ¹² , -S(=O)R ¹⁴ , -S(=O) 2R ¹⁴ , -OC(=O)R ¹⁴ , -CO2H, -CO2R ¹⁴ , -OC(=O)OR ¹⁴ , -NR ^I5 C(=O)R ¹⁴ , -C(=O)N(R ¹² ) 2, -NR ¹⁵ C(=O)OR ¹⁴ , -OC(=O)N(R ¹² ) ₂ , unsubstituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, which optionally substituted with methoxy or dimethylamino; phenyl which is optionally substituted with methoxy; tetrazolyl or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl; R ¹¹ is H or -CH ₃ ; or R ⁹ and R ¹¹ are taken together to form a bridge which is -CH2CH2-; each R ¹² is independently H, C ₁ -C ₄ alkyl, hydroxycarbonylmethyl, methoxycarbonyl, methoxycarbonylmethyl, 2-hydroxyethyl, 2-aminoethyl, 2-methoxyethyl, 2-(dimethylamino)ethyl, 3hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropane- 2-yl, 1,3-dihydroxypropan-2-yl, 2,3dihydroxypropyl, 2-hydroxy-2-methylpropyl, 3-(dimethylamino)propyl, 4-(dimethylamino)butyl, 2hydroxy-2-methylbutyl, 2-hydroxy- 3-methylbutyl, 3-hydroxybutan-2-yl, 2-hydroxy-2,3-dimethylbutyl, 5-(dimethylamino)pentyl, methylsulfonyl, methylcarbonyl, cyclopropyl, oxetanyl, azetidinyl which is optionally substituted with methyl or t-butoxycarbonyl; piperidinyl which is optionally substituted with methyl; 1H-imidazol-2-ylmethyl, 1H-pyrazol-4-ylmethyl or 2-((N-methyl-N-t-butoxycarbonyl)amino)ethyl; R ¹⁴ is C ₁ -C ₄ alkyl; cyclohexyl, which is optionally substituted with hydroxy, 2 - 299 040704 (methylamino)ethyl or hydroxycarbonylmethoxy; cyclobutyl which is optionally substituted with methoxy or dimethylamino; azetinidyl which is optionally substituted with -CN, methyl, ethyl, isopropyl, t-butyl, ethynyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, methylthio, methylthiomethyl, methylsulfonyl, hydroxycarbonyl, methoxycarbonyl, hydroxymethyl, methoxymethyl, hydroxycarbonylmethyl, methoxycarbonylmethyl, 2- hydroxyethoxy, 2-methoxyethoxy, 2hydroxypropan-2-yl, amino, methylamino, dimethylamino, dimethylamino-methyl, methylsulfinyl, methylsulfinylmethyl, methylsulfonylmethyl, t-butoxycarbonylamino, t-butoxycarbonyl-(N-methyl)amino, oxetanyl, 4-hydroxyazetidin-1-yl; oxetanil; morpholinyl which is optionally substituted with 1-2 methyls; thiomorpholinyl; thiomorpholinyl-1-oxide; thiomorpholinyl-1,1-dioxide or piperazinyl which is optionally substituted with methyl, ethyl or isopropyl; R ¹⁵ represents H or unsubstituted C1-C ₆ alkyl; R ¹⁶ is -N(R ¹⁵ ) ₂ or C1-C ₄ alkoxy; and n is 0, 1 or 2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl which is thiazolyl, oxazolyl, or pyrazolyl. 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, where is is 4. The compound according to claim 1 or its pharmaceutically acceptable salt, where represents 5. The compound according to claim 1 or its pharmaceutically acceptable salt, where 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein L is absent. 7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable compound thereof, wherein L is -C^C-. - 300 040704 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is H, or R ⁹ and R ¹¹ are taken together to form a bridge which is -CH2CH2-. 9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (II) Formula (II). 10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (III) Formula (III). 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (IV) Formula (IV). 12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (V) (R ⁶ )m (R ¹⁶ ) _n Formula (V). 13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is -CO2H, -C(=O)OR ¹⁴ , -OC(=O)R ¹⁴ , -NR ¹⁵ C(=O)R ¹⁴ , -C(=O)N(R ¹² )2, - NR ¹⁵ C(=O)OR ¹⁴ or -OC(=O)N(R ¹² )2 or R ¹⁰ is -L ² -L ³ -L ⁴ -R ¹³ ; L ² is absent or is -CH ₂ -; L ³ is absent or is -O-, -NH-, -C(=O)NH-, -NHC(=O)- or -NHC(=O)O-; L ⁴ is -CH2-, -CH2CH2- or -CH2CH2CH2-. 14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is H, -CN, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CO2H, -C (=O)NHCH3, -OC(=O)NHCH3, cyclobutyl which is optionally substituted with methoxy or dimethylamino, phenyl which is optionally substituted with methoxy or tetrazolyl. 15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein X ² is CR ² ; X ³ is CR ³ or N; each X ⁴ is CH or each X ⁴ is N; or one X ⁴ is N and the other X ⁴ is CH. 16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, D, F, Cl, -CN, -OH, -NH2, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -OCH3, - 301 040704 -OCH2CH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; R ² is H, D, F, Cl, -CH ₃ , -CH2CH3, -OCH ₃ , -OCH2CH3, -CD3, -OCD ₃ , -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; R ³ is H, D, F, Cl, -CH3, -OCH3, -CD3, -OCD3, -CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2 or -OCF3. 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -OH, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -OCH ₃ , -CD ₃ , -OCD ₃ , -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCF3 or -OCH2CF3; R ² is H, D, F, Cl, -CH ₃ , -CD ₃ , -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is H. 18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, where is 19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein represents 20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CD3, - CH2F, -CHF2, -CF3, -CH2CF3, -CHFCH3, -CH2CH2F, unsubstituted cyclopropyl or unsubstituted cyclobutyl. 21. A compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁶ is independently -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OCH ₃ , -OCH2CH3 , or -OCH(CH3)2. 22. A compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, where n is 0. 23. A compound which is trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl) cyclohexylmethyl carbamate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; 4-((3 -(2-cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexyl-trans - methyl carbamate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; 4-((3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl) cyclohexyl-trans-methylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate; 4-((3-(1-Cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl) cyclohexyl-trans-carbamate; trans-4-((3 -(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl) methyl)carbamoyl)cyclohexylmethylcarbamate; - 302 040704 trans-4-((3-(1-isopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl )cyclohexylmethylcarbamate; trans-4-((3-(3-cyclopropylisothiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; 4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexyl- trans-methylcarbamate; trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(thiazol-2-ylethynyl)phenyl)carbamoyl)cyclohexylmethylcarbamate; 4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(3-(thiazol-2-ylethynyl)phenyl)carbamoyl)cyclohexyl-trans-methylcarbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; 4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-trans-methylcarbamate; 4-((3-(3-cyclopropylisothiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-trans-methylcarbamate; 4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexyl-trans - methyl carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; 4-((3-(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)carbamoyl)cyclohexyl-trans-methylcarbamate; trans-4-((4-(1-cyclopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate; 4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl )-trans-carbamate; 4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexyl-( 2-hydroxyethyl)-trans-carbamate; 4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl- (2-hydroxyethyl)-trans-carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylisopropylcarbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-methoxyazetidine- 1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-( dimethylamino)ethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl ) carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-( dimethylamino)propyl)carbamate; 4-((3-(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan-1-yl) methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)-trans-carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((1H- imidazol-2-yl)methyl)carbamate; tert-Butyl-(2-((((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)oxy)carbonyl)amino)ethyl)(methyl)carbamate; - 303 040704 trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-( (1H-imidazol-4-yl)methyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-aminoethyl ) carbamate; tert-butyl-3 -((((trans-4-((3-(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)carbamoyl)cyclohexyl)oxy)carbonyl)amino)azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylazetidin-3-ylcarbamate; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (2-hydroxyethyl)carbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(4-( dimethylamino)butyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(5-( dimethylamino)pentyl)carbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl) carbamate; 4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexyl-trans -(2-hydroxyethyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxyethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - hydroxyazetidine-1-carboxylate; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-hydroxyazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(( methylthio)methyl)azetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylethylcarbamate; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropylthiazol-5yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol5-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-cyclopropylthiazol5-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(5-chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(1-isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate ; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)carbamoyl) cyclohexylmethyl carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; - 304 040704 trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl) cyclohexylmethyl carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; cis-4-(((4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-(tert-butyl)-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylmethylcarbamate; trans-4-((3-(1-cyclobutyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyldimethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylmethylcarbamate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylethyl carbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl) carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-cyclopropyl-1Hpyrazol-4-yl)pyridin-2-yl)carbamoyl) cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-isopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)carbamoyl) cyclohexylethyl carbamate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(6-(dimethylamino)pyridin-3-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(6-cyclopropylpyridin-3-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(2-(dimethylamino)pyrimidin-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((6-(dimethylamino)-[3,4'-bipyridin]-2'-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(6-(dimethylamino)pyridin-3-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol4-yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-isopropyloxazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexylmethylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-isopropyloxazol-4yl)phenyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylethylcarbamate; - 305 040704 trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylcarbamate ; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethyl carbonate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((4-(2-ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylcarbamate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)-1-methylcyclohexylmethylcarbamate; cis-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)-1-methylcyclohexylmethylcarbamate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4- carboxylate; 4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)-trans - carbamate; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((4-(2-isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((3-(2-isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((3-(2-isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl ) carbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol5-yl)phenyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate ; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- hydroxyethyl) carbamate; trans-4-((3-(1-isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2- hydroxyethyl) carbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-methoxyethyl ) carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1,3 -dihydroxypropan-2-yl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((S) -2,3-dihydroxypropyl) carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-((R) -2,3-dihydroxypropyl) carbamate; trans-4-((3-(1-isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3- hydroxypropyl) carbamate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (2-hydroxyethyl)carbamate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (3-hydroxypropyl)carbamate; trans-4-((4-(1-isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl -(2-hydroxyethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1-methylazetidine -3-yl)carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2-hydroxyethyl) carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-isopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate ; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-( 2-hydroxyethyl) carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-(2 -hydroxyethyl)carbamate; trans-4-(((trans-4-(5-chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexyl-(2 -hydroxyethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyloxetan-3-ylcarbamate; - 306 040704 trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4 -methylpiperazine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-methoxyethyl )(methyl)carbamate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-Spyrazol-4-yl)phenyl)carbamoyl)cyclohexyl-(2 -hydroxyethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfonyl )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylthio )azetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylcyclopropyl carbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl) carbamoyl)cyclohexylisopropylcarbamate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)carbamoyl) cyclohexylcyclopropyl carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-(2 -methoxyethyl)carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylcyclopropylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- (methylsulfonyl)azetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylmorpholine-4- carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-4- methylpiperazine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-(methylsulfonyl)azetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylmorpholine-4-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-4-methylpiperazine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-(methylsulfonyl)azetidine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine- 4-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 4-methylpiperazine-1-carboxylate; 4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-trans-(2 -hydroxyethyl)carbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl ) carbamate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate ; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3-hydroxypropyl)carbamate ; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-hydroxyethyl ) carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate ; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol4-yl)phenyl)carbamoyl)cyclohexyl-(2-hydroxyethyl)carbamate ; - 307 040704 trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -(2-methoxyethyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylcyclopropylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylisopropylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylmorpholine-4- carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyloxetane-3- ilcarbamate; trans-M-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M-((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-( 2-(3-(methylsulfonyl)azetidin-1-yl)-2-oxoethyl)cyclohexanecarboxamide; trans-M-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-4-(2-((3-hydroxypropyl)amino)-2-oxoethyl)-K-((trans-4- (5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-K-((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-( 2-((2-methoxyethyl)(methyl)amino)-2-oxoethyl)cyclohexanecarboxamide; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-methylpiperazin- 1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4- methylpiperazine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( S)-2,3-dihydroxypropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxypropyl)(methyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-2,3-dimethylbutyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-2-methylbutyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-2-methylpropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1 -hydroxypropan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxypropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3 -hydroxybutan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylethyl(2- hydroxyethyl) carbamate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (methylsulfonyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (2-hydroxyethoxy)azetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4- methylpiperazine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylpiperazin-1- carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1 -methylpiperidin-4-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( R)-1-methylpiperidin-3-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4- ethylpiperazine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4- isopropylpiperazine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-2, 2-dimethylmorpholine-4-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (oxetan-3-yl)azetidine-1-carboxylate; trans-4-((4-(2-ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (2-hydroxyethyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-2-methylpropyl)(methyl)carbamate; - 308 040704 trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -(2-hydroxyethyl)(methyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(3 -hydroxypentan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-3-methylbutyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(1 -hydroxy-2-methylpropan-2-yl)carbamate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-2-methylpropyl)carbamate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-(2-hydroxy-2-methylpropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 -carboxylate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((4-(2-isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((3-(2-isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((4-(2-isopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropylthiazol-5yl)pyridin-2-yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol5-yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-cyclopropylthiazol5-yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; 4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl- trans-3-hydroxyazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine -1 -carboxylate; trans-4-((3-(1-isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine -1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-hydroxyazetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl -3-hydroxyazetidine-1-carboxylate; methyl-2-((((trans-4-((3-(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)oxy)carbonyl)amino)acetate; 2-((((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)oxy)carbonyl)amino)acetic acid; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3 -(1-cyclopropyl-1 H-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 -carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-isopropyl-III-pyrazol-4yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-cyclopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3 -hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(5-chloro-6-methoxypyridin-3-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-hydroxyazetidine-1-carboxylate; - 309 040704 trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -3-hydroxyazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methoxymethyl )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(hydroxymethyl )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate- 1-oxide; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylthiomorpholine-4-carboxylate- 1,1-dioxide; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 -(( dimethylamino)methyl)azetidine-1-carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-cyclopropyl-Spyrazol-4-yl)phenyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; 1 -(trans-4-((3 -(1 -cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) -3-methylazetidine-1,3-dicarboxylate; 1 -(((trans-4-((3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl)oxy)carbonyl)azetidine-3-carboxylic acid; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(( tert-butoxycarbonyl)(methyl)amino)azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylamino )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(( tert-butoxycarbonyl)amino)azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-aminoazetidine- 1-carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2-yl)carbamoyl) cyclohexyl-3-hydroxyazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(2 -methoxy-2-oxoethyl)azetidine-1-carboxylate; 2-(1 -(((trans-4-((3-(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)oxy)carbonyl)azetidin-3-yl)acetic acid; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(1-isopropyl-1Hpyrazol-4-yl)phenyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexylisopropyl carbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyldimethylcarbamate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylazetidine-1- carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- ethylazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- methoxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- isopropoxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- (dimethylamino)azetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- (hydroxymethyl)azetidine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-methoxyazetidine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-(dimethylamino)azetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-ethylazetidine-1-carboxylate; trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-methoxyazetidine-1-carboxylate; - 310 040704 trans-4-((4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl )carbamoyl)cyclohexyl-3-isopropoxyazetidine-1-carboxylate; trans-4-((4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-isopropylazetidine-1-carboxylate; trans-4-((4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-(dimethylamino)azetidine-1-carboxylate; trans-4-((4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3-(hydroxymethyl)azetidine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-ethylazetidine-1-carboxylate; trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-(hydroxymethyl)azetidine-1-carboxylate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 -carboxylate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate; trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol4-yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol4-yl)pyridin-2-yl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-isopropyloxazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl-3-hydroxyazetidine- 1-carboxylate; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-isopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1- carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexylazetidine-1- carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- methoxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (methoxymethyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyldimethylcarbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - (dimethylamino)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (hydroxymethyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(dimethylamino )azetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- methoxyazetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- isopropoxyazetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - (dimethylamino)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (2-methoxy-2-oxoethyl)azetidine-1-carboxylate; 2-(1-(((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexyl)oxy)carbonyl)azetidin-3-yl)acetic - 311 040704 acid; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ethoxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- cyanoazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - methylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ethylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- isopropoxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - (dimethylamino)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- methoxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(6-methoxy-5-methylpyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (2-methoxyethoxy)azetidine-1-carboxylate; 4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-cis-3 - hydroxyazetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (hydroxymethyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ethinylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (2-hydroxypropan-2-yl)azetidine-1-carboxylate; trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ethylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ((methylsulfonyl)methyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- isopropylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- (tert-butyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- propoxyazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- propylazetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- ((dimethylamino)methyl)azetidine-1-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-2- methylmorpholine-4-carboxylate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3- hydroxy-[1,3'-biazetidine]-1'-carboxylate; trans-4-((4-(2-ethyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl- 3-hydroxyazetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(( methylsulfinyl)methyl)azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(methylsulfinyl )azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-(( methylsulfonyl)methyl)azetidine-1-carboxylate; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-trans-4- hydroxycyclohexanecarboxylate; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)ethoxy )cyclohexanecarboxamide hydrochloride; 2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) hydroxy)acetic acid; trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)cyclohexyldimethylcarbamate; trans-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-methoxyethoxy)-M-(3-(2-312 040704 methoxythiazol-5-yl)phenyl) cyclohexanecarboxamide; trans-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-methoxypropoxy)-M-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-4-(2-hydroxyethoxy)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-4-(3-hydroxypropoxy)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-(dimethylamino)ethoxy)-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide ; ethyl 2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)carbamoyl )cyclohexyl)acetate; trans-N-(3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)-4-(hydroxymethyl)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-(hydroxymethyl)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(hydroxymethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-(hydroxymethyl)-K-(4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)-M-((trans-4-(5-methoxy-6-methylpyridine- 2-yl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-4-(hydroxymethyl)-K-((trans-4-(5-methoxy6-methylpyridin-2-yl)cyclohexyl) methyl)cyclohexanecarboxamide; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; 4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1-carboxylic acid ; trans-4-(((trans-4-(3-chloro-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(3-fluoro-1-methyl-1H-indazol-5-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid ; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((4-(6-(dimethylamino)pyridin-3-yl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol5-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-(((trans-4-(3-chloro-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(3-fluoro-1-methyl-1H-indazol-5yl)cyclohexyl)methyl) carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan1-yl)methyl)carbamoyl) cyclohexanecarboxylic acid; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo- 313 040704 lo[2.2.2] octan-1-yl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(1-cyclopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid ; trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylic acid; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; 2-(trans-4-((4-(1-Cyclopropyl-III-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl)methyl )carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl )acetic acid; 2-(trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin2-yl)cyclohexyl)methyl )carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1 H-pyrazol-4yl)pyridin-2-yl)carbamoyl) cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl-1Hpyrazol-4-yl)pyridin-2-yl )carbamoyl)cyclohexyl)acetic acid; trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexanecarboxylic acid; trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylic acid; trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol4-yl)phenyl)carbamoyl)cyclohexanecarboxylic acid; trans-methyl-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-methyl-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexanecarboxylate; trans-methyl-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-methyl-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexanecarboxylate; methyl-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5-yl)phenyl)carbamoyl)bicyclo[2.2.2]octane-1- carboxylate; trans-4-(benzyloxy)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-((4-methoxybenzyl)oxy)-M-(3(2-methoxythiazol-5-yl)phenyl) cyclohexanecarboxamide; trans-methyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-methyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; tert-Butyl-(4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl )methyl)carbamoyl)cyclohexyl)-trans-carbamate; tert-Butyl(trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) carbamate; trans-methyl-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexanecarboxylate; ethyl-2-(trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl )cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate; trans-methyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; ethyl 2-(trans-4-((4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl )cyclohexyl)methyl)carbamoyl)cyclohexyl)acetate; ethyl 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl )carbamoyl)cyclohexyl)acetate; ethyl 2-(trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(4-(1-isopropyl- 314 040704 1H-pyrazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetate; trans-methyl-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl) cyclohexanecarboxylate; trans-methyl-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexanecarboxylate; 2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5yl)phenyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropylthiazol-5-yl)phenyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(2-cyclopropylthiazol-5-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl )acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropylthiazol-5yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid ; 2-(trans-4-((3-(2-isopropylthiazol-5-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; trans-2-(4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1-yl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(1-cyclopropyl-1H-pyrazol4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid ; 2-(trans-4-((3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3yl)cyclohexyl)methyl)carbamoyl) cyclohexyl)acetic acid; 2-(trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl )acetic acid; 2-(trans-4-((3-(1-isopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(1-isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)acetic acid; 3 -(trans-4-((3 -(1 -isopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) propanoic acid; trans-2-(4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl )methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((cis-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4yl)phenyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((3-(2-cyclopropyloxazol-4-yl)phenyl)((trans-4-(6-(dimethylamino)pyridin-3-yl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid ; 2-(trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl )acetic acid; 2-(trans-4-((3-(2-isopropyloxazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-((4-(2-isopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(3-(2-isopropyloxazol-4-315 040704 yl)phenyl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-isopropyloxazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(3-cyano-4-methoxyphenyl)cyclohexyl)methyl)(4-(2-cyclopropyloxazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyl)acetic acid; 2-(trans-4-(((trans-4-(6-cyano-5-methoxypyridin-2-yl)cyclohexyl)methyl)(3-(2-cyclopropyloxazol-4-yl)phenyl)carbamoyl)cyclohexyl)acetic acid; trans-propyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-isopropyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-butyl 4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-pentyl 4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-isobutyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-isopentyl-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexanecarboxylate; trans-propyl-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl) methyl)carbamoyl)cyclohexanecarboxylate; trans-N ¹ -(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N ⁴ -(2-hydroxyethyl)-N ¹ -((trans-4-(4-methoxy3-methylphenyl)cyclohexyl )methyl)cyclohexane-1,4-dicarboxamide; trans-M ¹ -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M ¹ -(3-(2-methoxythiazol-5-yl)phenyl)-K ⁴ -methylcyclohexane-1, 4-dicarboxamide; trans-K ¹ -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-K ¹ -(3-(2-methoxythiazol-5-yl)phenyl)cyclohexane-1,4-dicarboxamide; trans-M ¹ - ((trans-4- (4-methoxy-3-methylphenyl) cyclohexyl) methyl) - M ¹ - (3- (2-methoxythiazol-5-yl) phenyl) - K ⁴ , K ⁴ -dimethylcyclohexane -1,4-dicarboxamide; trans-K ¹ -(2-hydroxyethyl)-K4-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-K4-(3-(2methoxythiazol-5-yl)phenyl)cyclohexane-1 ,4-dicarboxamide; trans-K ¹ -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-K4-(2-methoxyethyl)-K ¹ -(3-(2methoxythiazol-5-yl)phenyl)cyclohexane- 1,4-dicarboxamide; trans-K ¹ -(2-(dimethylamino)ethyl)-K4-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-K4(3-(2-methoxythiazol-5-yl)phenyl )cyclohexane-1,4-dicarboxamide; trans-K ¹ -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-K ¹ -(3-(2-methoxythiazol-5yl)phenyl)-K4-(methylsulfonyl)cyclohexane-1, 4-dicarboxamide; methyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate; tert-butyl (trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)carbamate; tert-butyl-((trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol5-yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate; trans-4-(aminomethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-4-acetamido-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; methyl (trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)carbamate; trans-4-(acetamidomethyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; methyl-((trans-4-(((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)(3-(2-methoxythiazol-5yl)phenyl)carbamoyl)cyclohexyl)methyl)carbamate; trans-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)-4-(methylsulfonamidomethyl)cyclohexanecarboxamide; trans-4-acetamido-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(N-methylacetamido)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(methylsulfonamido)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohex- 316 040704 sil)methyl)-4-(2- methoxyacetamido)cyclohexanecarboxamide; 2-((trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2 -oxoethyl acetate; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxyacetamido)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; 2-((trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino)-2 -oxoethyl methyl carbamate; trans-4-butyramido-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-pentanamidocyclohexanecarboxamide; trans-M-(3-(2-cyclopropylthiazol-5-yl)phenyl)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-methylbutanamido)cyclohexanecarboxamide; methyl (trans-4-((3-(1 -cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate ; trans-4-acetamido-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-K-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-K-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(methylsulfonamido )cyclohexanecarboxamide; trans-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-hydroxyacetamido)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide; 2-((trans-4-((3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl )amino)-2-oxoethylmethylcarbamate; 2-hydroxyethyl (trans-4-((3-(1 -cyclopropyl-1 H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl ) carbamate; trans-M-(3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)-4-(trans-4-hydroxycyclohexanecarboxamido)-N-((trans-4-(4-methoxy-3-methylphenyl) cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-acetamido-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-M-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1-yl)methyl)cyclohexanecarboxamide; 2-((4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)cyclohexyl)amino)-2-oxoethyl-trans-acetate; trans-K-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-4-(2-hydroxyacetamido)-K-((4-(4-methoxy-3 methylphenyl)bicyclo[2.2. 2]octan-1-yl)methyl)cyclohexanecarboxamide; trans-4-acetamido-N-(3-(1-isopropyl-III-pyrazol-4-yl)phenyl)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; 2-((trans-4-((3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)-2-oxoethyl acetate; trans-4-(2-hydroxyacetamido)-K-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)-K-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide; trans-4-(acetamidomethyl)-N-(3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; methyl-((trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) methyl) carbamate; trans-K-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-K-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(methylsulfonamidomethyl )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-4-(2-hydroxyacetamido)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; 2-((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)-2-oxoethyl acetate; trans-N-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-4-(2-hydroxyacetamido)-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide; trans-4-acetamido-N-(3-(2-cyclopropyloxazol-4-yl)phenyl)-M-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-acetamido-N-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; methyl (trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl)carbamoyl) cyclohexyl) carbamate; trans-4-(aminomethyl)-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M-((trans-4-(5-methoxy-6methylpyridin-2-yl)cyclohexyl) methyl)cyclohexanecarboxamide; trans-4-((3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2-acetamidoethyl ) carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl- (2-(methylsulfonamido)ethyl)carbamate; trans-4-((3-(1-cyclopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexylmethylethane-1,2- diyl dicarbamate; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-K-((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-( methylsulfonamidomethyl)cyclohexanecarboxamide; methyl-((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)methyl)carbamate; ethyl-((trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl)methyl) carbamoyl)cyclohexyl)methyl)carbamate; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-4-((2-hydroxyacetamido)methyl)-M-((trans4-(5-methoxy-6-methylpyridin-2 -yl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-acetamido-N-(4-(1-cyclopropyl-III-pyrazol-4-yl)pyridin-2-yl)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide; 2-((trans-4-((4-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) carbamoyl)cyclohexyl)amino)-2-oxoethyl acetate; trans-N-(4-(1-cyclopropyl-III-pyrazol-4-yl)pyridin-2-yl)-4-(2-hydroxyacetamido)-M-((trans-4(4-methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-acetamido-N-(4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)-M-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide; 2-((trans-4-((4-(1-isopropyl-1 H-pyrazol-4-yl)pyridin-2-yl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl )carbamoyl)cyclohexyl)amino)-2-oxoethyl acetate; trans-4-(2-hydroxyacetamido)-N-(4-(1-isopropyl-III-pyrazol-4-yl)pyridin-2-yl)-M-((trans-4-(4methoxy-3-methylphenyl) cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-methylureido)cyclohexanecarboxamide; trans-K-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3 -methylureido)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxy-2-methylpropanamido)-M-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-hydroxypropanamido)-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; N-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)oxetan-3-carboxamide ; trans-4-(2-(III-imidazol-1-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-M-((trans-4-(4methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-(2-(III-imidazol-2-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-M-((trans-4-(4methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; K-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)-1-methylazetidine- 3-carboxamide; N-(trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)azetidine-3-carboxamide ; 2-hydroxyethyl (trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)carbamate; 2-((trans-4-((3-(1-isopropyl-III-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl) amino)acetic acid; trans-K-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3 -methoxycyclobutanecarboxamido)cyclohexanecarboxamide; trans-4-(cyclobutanecarboxamido)-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-(cyclobutanecarboxamido)-trans-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M-((trans4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl) methyl)cyclohexanecarboxamide; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M-((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)-4-( 3-methoxycyclobutanecarboxamido)cyclohexanecarboxamide; trans-4-(cyclobutanecarboxamidomethyl)-N-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-M((trans-4-(5-methoxy-6-methylpyridin-2-yl)cyclohexyl )methyl)cyclohexanecarboxamide; trans-K-(4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)-4-((3-(dimethylamino)cyclobutanecarboxamido)methyl)-K-((trans-4-(5-methoxy- 6-methylpyridin-2-yl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonamido)acetamido )cyclohexanecarboxamide; methyl-(2-((trans-4-((3 -(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl )cyclohexyl)amino)-2-oxoethyl)carbamate; - 318 040704 trans-4-(2-acetamidoacetamido)-M-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-M-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl )methyl)cyclohexanecarboxamide; mpaHC-N-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2 -(methylsulfonyl)acetamido)cyclohexanecarboxamide; trans-N-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2 -(methylsulfonamido)acetamido)cyclohexanecarboxamide; trans-N-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2 -(methylsulfinyl)acetamido)cyclohexanecarboxamide; methyl-(2-((trans-4-((3-(2-cyclopropylthiazol-5-yl)phenyl)((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl)amino )-2-oxoethyl)carbamate; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-(dimethylamino)acetamido)-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide ; trans-4-(2-aminoacetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylamino)acetamido )cyclohexanecarboxamide; trans-4-(2-acetamidoacetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylthio)acetamido )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfinyl)acetamido )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(methylsulfonyl)acetamido )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-(methylsulfinyl)propanamido )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(3-(methylsulfonyl)propanamido )cyclohexanecarboxamide; trans-4-(2-(1H-imidazol-4-yl)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(3-hydroxypropoxy)acetamido)-N((trans-4-(4-methoxy-3- methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(1-cyclopropyl-1H-pyrazol-4-yl)phenyl)-4-(2-(2-hydroxyethoxy)acetamido)-N-((trans4-(4-methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-(2-hydroxyethoxy)acetamido)-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-(3-hydroxypropoxy)acetamido)-N-((trans-4(4-methoxy-3-methylphenyl)cyclohexyl) methyl)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-4-(2-(2-(dimethylamino)ethoxy)acetamido)-N((trans-4-(4-methoxy-3-methylphenyl )cyclohexyl)methyl)cyclohexanecarboxamide; trans-4-(2-(2-aminoethoxy)acetamido)-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4methoxy-3-methylphenyl)cyclohexyl)methyl )cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2-(2-( methylamino)ethoxy)acetamido)cyclohexanecarboxamide; trans-N-(3-(2-cyclopropylthiazol-5-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2H-tetrazol-5- yl) cyclohexanecarboxamide; trans-N-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(2Н -tetrazol-5-yl)cyclohexanecarboxamide; trans-N-(3 -(1-cyclopropyl-1 H-pyrazol-4-yl)phenyl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-4-(5 -oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclohexanecarboxamide; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( S)-1-hydroxypropan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( R)-1-hydroxypropan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( R)-2-hydroxypropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( S)-2-hydroxypropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxybutyl)(methyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(2 -hydroxy-3-methylbutyl)(methyl)carbamate; - 319 040704 trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl -((8)-1-hydroxypropan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( K)-1-hydroxypropan-2-yl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( K)-2-hydroxypropyl)carbamate; trans-4-((4-(2-cyclopropyloxazol-4-yl)pyridin-2-yl)((trans-4-(5-methoxy-6-methylpyridin-2yl)cyclohexyl)methyl)carbamoyl)cyclohexyl-(( 8)-2-hydroxypropyl)carbamate or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition containing a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 25. The use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount, for the treatment of a liver disease or condition or a gastrointestinal disease or condition in a mammal. 26. Use according to claim 25 wherein the liver disease or condition or gastrointestinal disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), fatty liver ( steatosis), cirrhosis, alcoholic hepatitis, intrahepatic cholestasis, extrahepatic cholestasis, hepatitis C virus (HCV), Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and liver cirrhosis, chronic viral hepatitis, alcoholic steatohepatitis (ASH), biliary liver cirrhosis, inflammatory bowel disease, necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GERD), peptic ulcer, non-ulcerative dyspepsia (NUD) ), celiac disease, intestinal celiac disease, postopera cationic inflammation, gastric carcinogenesis, graft versus host disease, or any combination thereof.