EA040003B1 - FARNESOID X-RECEPTOR AGONISTS AND THEIR USE - Google Patents

Description

Link to related applications

This application claims priority under a patent application

US No. 62/219430, filed September 16, 2015, which is incorporated herein by reference in its entirety.

The field of technology to which the present invention relates

This document describes compounds that are farnesoid X receptor agonists, methods for preparing such compounds, pharmaceutical compositions and medicinal preparations containing such compounds, as well as methods for using such compounds in the treatment of 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 glands, 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 treatment for many metabolic and hepatic conditions.

Brief description of the present invention

In one aspect, the present invention describes farnesoid X receptor agonists and their use.

According to one aspect of the invention, there is provided a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof:

Where

R ¹ and R ² are each independently selected from H and D;

R ³ is selected from substituted or unsubstituted cyclohexyl, where if R ³ is substituted then R ³ is substituted with one R ¹² group;

R ¹² is -OR ¹⁰ ;

ring A is phenyl or cyclohexyl;

L ¹ is absent;

ring C is phenyl or pyridinyl;

each R ^c is independently selected from H, D, halogen, -CN, -OR ¹⁰ , -SR ¹⁰ , -N(R ¹⁰ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl;

ring B is phenyl or pyridinyl;

L ³ is absent or is -O-, -CH ₂ -, -CH ₂ CH ₂ -, -CH=CH-, -C=C-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(= O)- or -NR ¹⁰ -;

ring D is phenyl, monocyclic N-containing C ₂ -C ₈ heterocycloalkyl or 5-membered or 6-membered heteroaryl with 1-4 N atoms, 0-1 O atom and 0-1 S atom in the ring;

RD is independently selected from H, D, halogen, -OR ¹⁰ , -CO2R ¹⁰ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, and unsubstituted or substituted C ₃ -C ₆ cycloalkyl;

each R ¹⁰ is independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

p is 0, 1 or 2;

q is 0, 1, 2, 3 or 4;

moreover, the groups are in the 1,3-position relative to each other on the ring B and where the term heteroalkyl refers to an alkyl group in which one skeletal carbon atom of the alkyl is oxygen, -NH-, -N (C ₁ -C ₆ alkyl) - or sulfur;

where heterocycloalkyl contains 1-2 N atoms;

where any substituted group is substituted with one or two substituents independently selected from D, halo, -CN, -NH ₂ , -OH, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , -OCH ₃ and -OCF ₃ .

In one embodiment, ring D is phenyl or ring D is 5-membered or 6-membered heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl,

- 1 040003 imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or ring D is a monocyclic N-containing C2- _C8 heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanil.

According to one embodiment

In one embodiment, the compound is characterized by the following structure:

represents

According to one embodiment, is

In one embodiment, ring A is

In one embodiment, ring A is

In one embodiment, Ring C is phenyl. According to one embodiment, ring C is pyridyl.

According to one embodiment

represents

- 2 040003

In one embodiment, ring A is

or

ring B is phenyl; and ring C is phenyl.

In one embodiment, the connection is

LC(4ADimethylamino)-[u'-biphenyl]-4-yl)methyl)-L ^g- (3-(5-methoxypyridin-3yl)phenyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[ 1, G-biphenyl]-4-yl)methyl)-A-(3'-methoxy-[1,1'-biphenyl]-3yl)cyclohexanecarboxamide;

L ^g -((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-L ^g -(3-(2-methoxypyridin-4yl)phenyl)cyclohexanecarboxamide;

- 3 040003

L-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-A-(4'-methoxy-[1,1'-biphenyl]-3yl)cyclohexanecarboxamide;

(E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-A-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide;

JV-([ 1,1'-Biphenyl]-3-yl)-A-((4'-fluoro-[ 1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide;

7V-([ 1,1'-Biphenyl]-3-yl DASCHDCd imethylamino)-[ 1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-A-(3phenoxyphenyl)cyclohexanecarboxamide;

7V-((4 '-(Dimethylamino)-[ 1, G-biphenyl]-4-yl) methyl)-A-(3-(2-(oxazol-2yl)ethyl)phenyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-AD3-(pyridin-3 yl)phenyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-AD 3 -(5-methylpyridin-3 yl)phenyl)cyclohexanecarboxamide;

7\D(4DDimethylamino)-[1,G-biphenyl]-4-yl)methyl)-MD3-(6-methoxypyridin-2yl)phenyl)cyclohexanecarboxamide;

Methyl 5-(3-(LD(4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)nicotinate;

(E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-LDZ-(2-(pyridin-2yl)vinyl)phenyl)cyclohexanecarboxamide;

(E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-LDZ-(2-(pyridin-4yl)vinyl)phenyl)cyclohexanecarboxamide;

7U-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-LDZ-(2-methoxythiazol-5yl)phenyl)cyclohexanecarboxamide;

7\A(4DDimethylamino)-[1,G-biphenyl]-4-yl)methyl)-LDZ-(2-methoxythiazol-4yl)phenyl)cyclohexanecarboxamide

A-((4'-(Dimethylamino)-[1, T-biphenyl]-4-yl)methyl)-7U-(3-(5-methoxythiophen-2yl)phenyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-A-(3-(4-methoxypyridin-2yl)phenyl)cyclohexanecarboxamide;

A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-7U-(3-(5-ethylpyridin-3yl)phenyl)cyclohexanecarboxamide;

7U-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-7U-(3-(2-methoxypyrimidin-4-4-4040003 yl)phenyl)cyclohexanecarboxamide;

L-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-A-(3-(6-methoxypyrimidin-4yl)phenyl)cyclohexanecarboxamide;

L-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-A-(3-(6-methoxypyrazin-2yl)phenyl)cyclohexanecarboxamide;

-(N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-A(5-methoxypyridin-3-yl)benzamide;

3-(A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-Aphenylbenzamide;

Methyl 3-(3-(7U-((4'-(dimethylamino)-[1,T-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)benzamido)benzoate;

3-(A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-A(pyridin-4-yl)benzamide;

3-(A-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-A(pyridin-2-yl)benzamide;

A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-A-(3-(3-methoxyisothiazol-5yl)phenyl)cyclohexanecarboxamide;

t/?ans-4-Hydroxy-L ^g -((t/?ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-L ^g (3-(3-methoxyazetidin-1-yl)phenyl )cyclohexanecarboxamide;

trsh/s-4-Hydroxy-7U-((from/?sh/s-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-A(3-(3-(methoxymethyl)azetidin-1-yl )phenyl)cyclohexanecarboxamide;

t/?ans-4-Hydroxy-7U-((t/?ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-A(3-(3-methoxypyrrolidin-1-yl)phenyl)cyclohexanecarboxamide ;

t/?ans-4-Hydroxy-7U-((t/?ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-A(3-(3-(methoxymethyl)pyrrolidin-1-yl) phenyl)cyclohexanecarboxamide;

t/?ans-4-Hydroxy-7U-((t/?ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-A(3-(4-methoxypiperidin-1-yl)phenyl) cyclohexanecarboxamide;

t/?ans-4-Hydroxy-7U-((t/?ans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-A(3-(3-methoxypiperidin-1-yl)phenyl)cyclohexanecarboxamide ;

or a pharmaceutically acceptable salt thereof.

According to another aspect of the invention, there is provided a pharmaceutical composition for the treatment of a liver disease or condition, metabolic disorder or inflammation in the intestinal region in a subject, comprising a compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

According to another aspect of the invention, the use of a compound described herein, or a pharmaceutically acceptable salt thereof, is provided for the treatment of a liver disease or condition, metabolic disorder, or inflammation in the intestinal region in a subject.

According to another aspect of the invention, the use of a compound described herein or a pharmaceutically acceptable salt thereof for the treatment of primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), 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-ulcerative dyspepsia (NUD), celiac disease,

- 5 040003 postoperative inflammation, gastric oncogenesis, or any combination thereof in a subject.

Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be appreciated, however, that the detailed description and specific examples, while describing specific embodiments, are for illustrative purposes only, as various changes and modifications to the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description.

Detailed disclosure of the present invention

The nuclear hormone receptor, the farnesoid X receptor (also known as FXR or a member of subfamily 4 of nuclear receptor H group 1 (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, small intestine, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissue. . Bile acids function as endogenous ligands for FXR such that intestinal and systemic release of bile acids induces FXR-targeted changes in gene expression networks. Bile acids are the primary product of cholesterol oxidation, and in some cases, when secreted into the intestinal tract, they are regulators of cholesterol absorption. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by cytochrome p450-dependent cholesterol-7-a-hydroxylase (CYP7A1) and occurs in the liver. Activation of FXR suppresses CYP7A1 transcription by upregulating hepatic expression of the short heterodimer partner (SHP) (also known as group B nuclear receptor subfamily 2 or NR0B2) and intestinal expression of fibroblast growth factor 15 (FGF15) in mice and fibroblast growth factor 19 (FGF19) in humans. SFLP suppresses the liver receptor (LRH-1) homolog, a nuclear receptor required for CYP7A1 gene expression, through its interaction with LRH-1 to form a non-functional heterodimer. In some cases, FGF15/19 released from the intestinal tract then activates the fibroblast growth factor 4 receptor in the liver, leading to activation of the mitogen-activated protein kinase (Mark) signaling pathway that downregulates Cyp7A1.

In some embodiments, elevated bile acid levels have been associated with insulin resistance. For example, insulin resistance sometimes results in reduced uptake of glucose from the blood and increased production of de novo 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 the transcriptional product of the proglucagon gene. It is released in response to food intake, 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)NH ₂ , which result from selective cleavage of the proglucagon molecule. In such cases, FXR activation leading to reduced bile acid production correlates with reduced insulin resistance.

In some embodiments, FXR activation also correlates with secretion of a family of pancreatic polypeptides such as the YY peptide (PYY or PYY3-36). In some cases, the YY peptide is a gut hormone peptide that modulates neuronal activity in the hypothalamic and brainstem regions involved in reward processing. In some cases, reduced PYY levels correlate with increased appetite and weight gain.

In some cases, FXR activation indirectly leads to a decrease in plasma triglycerides. The clearance of triglycerides from the circulation is mediated by lipoprotein lipase (LPL). LPL activity is enhanced by the induction of its activator, apolipoprotein CI, and suppression of its inhibitor, apolipoprotein CC, in the liver occurs upon activation of FXR.

In some cases, FXR activation also modulates energy expenditure, for example, for 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 generate heat in the body, while WAT functions as a fat-storing tissue.

In some cases, FXR is highly expressed in the intestinal tract. In some cases, FXR activation has been shown to induce the expression and secretion of FGF19 (or FGF15 in mice) in the intestinal tract. FGF19 is a hormone that regulates bile acid synthesis as well as influences glucose metabolism, lipid metabolism and energy expenditure. It has also been observed that in some cases FGF19 modulates the function and differentiation of adipocytes. 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)).

It has also been observed that, in some cases, intestinal FXR activity is associated with a reduction in microbiome overgrowth, such as during feeding (Li et al., Nat Sottyp 4:2384, 2013). For example, a study showed that FXR activation correlated with increased expression of several genes in the ileum, such as Ang2, iNos, and Il18, suggesting antimicrobial actions (Inagaki et al., Proc NatlAcadSci USA 103:3920-3925, 2006).

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. When activated by bile acid, TGR5 induces the production of intracellular cAMP, which then triggers an increase in triiodothyronine due to the activation of deiodinase (DIO2) in BAT, resulting in increased 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 proliferation disorders.

In certain embodiments, disclosed herein are compounds that have FXR agonist activity. 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, also disclosed herein are methods of treating or preventing a metabolic disorder such as diabetes mellitus, obesity, impaired glucose tolerance, 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 diseases 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 the FXR agonist to the subject as needed (eg, via the gastrointestinal tract). In additional embodiments, disclosed herein are methods 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 subject as needed. this. In some embodiments, disclosed herein are methods for treating or preventing cholestasis by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, disclosed herein are methods for 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, disclosed herein are methods for treating or preventing NASH by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, disclosed herein are methods for treating or preventing NAFLD by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof.

In further embodiments, disclosed 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 as needed (e.g., via the gastrointestinal tract).

In further embodiments, disclosed 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, e.g., increase FGF19 activity (in mice, FGF15 ), increase secretion

- 7 040003

GLP-1 or increase PYY secretion.

Metabolic disorders

In certain 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 when needed. In some instances, these methods include administering to a subject, in need, that 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 the subject's metabolic disorder.

In some embodiments, the disclosed compounds exhibit systemic effects. In some instances, the disclosed compounds have local effects in the intestine but limited effects in the liver or systemic effects. In some embodiments, local effects of the disclosed compounds in the gut can be demonstrated by regulation of the target FXR gene in the gut. In some embodiments, targeted genes may include SHP, FGF19 (FGF15), IBABP, C3, OST α/β. In some embodiments, the intestinal exposure of the disclosed compounds is approximately 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5 % or more. In some cases, the exposure of the disclosed compounds in the circulation system is approximately 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% or less. In some embodiments, exposure to FXR agonists in the intestinal lumen reduces the likelihood of side effects that result 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 hepatic CYP7A1 gene expression. 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 the FXR-mediated pathway. In some cases, the increase in gene expression is approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 500%, 1000%, 5000%, 10000%, 50000%, 100000%, 500000% or more in the intestine, liver, kidney or other tissues compared to gene expression in the absence of the disclosed compound. In some cases, the reduction in gene expression is approximately 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, 5%, 1%, or less in the intestine, liver, kidney, or other tissues compared to 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 substantially upregulates expression of the target FXR gene in the gut while not substantially increasing expression of the target FXR gene in the liver or kidney, while minimizing 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 disorder that includes an alteration 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 in the metabolic pathway, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids and/or carbohydrates. Factors affecting metabolism include, but are not limited to, an endocrine (hormonal) control system (e.g., the insulin pathway, enteroendocrine hormones, including GLP-1, oxynotomodulin, PYY, or the like) or a neutral control system (e.g., GLP-1 in brain). Typical metabolic disorders include, without limitation, diabetes mellitus, insulin resistance, dyslipidemia, liver disease, inflammation-related intestinal conditions, cell proliferation disorders, or the like.

Diabetes mellitus and diabetes-related conditions or disorders

In some embodiments, disclosed herein are methods of treating a subject having diabetes mellitus or a diabetes-related condition or disorder by administering an FXR agonist described herein. In some cases, diabetes mellitus is type II diabetes mellitus or non-insulin-dependent diabetes mellitus.

- 8 040003 (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 also include secondary complications such as atherosclerosis, stroke, fatty liver disease, blindness, gallbladder disease, or polycystic ovary disease. 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 disease, blindness, gallbladder disease, or polycystic ovary disease.

In some embodiments, a subject with diabetes mellitus (e.g., a subject with type II diabetes mellitus) is further characterized by a body mass index (BMI) of 25 or more, 30 or more, 35 or more, 40 or more, for example, a BMI of 25 to 29, 30 to 34 or 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 hereditary/genetic obesity or obesity due to medication. 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 40%, at least 50% or more. In some cases, the reduction or prevention of weight gain 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 or prevention of weight gain has been compared to the reduction or prevention of weight gain seen in a subject not receiving FXR agonist treatment.

Similarly, in some instances, an FXR agonist reduces the subject's BMI. In some examples, such methods reduce a subject's BMI by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or greater compared to a subject not receiving FXR agonist treatment. 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 cases, the decrease in serum lipids is compared to the serum lipids observed in a subject not receiving FXR agonist treatment.

In some examples, administration of an FXR agonist results in a decrease in triglyceride (eg, hepatic triglyceride). In some cases, the reduction in triglyceride (for example, hepatic triglyceride) 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 triglyceride (eg, hepatic triglyceride) 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 triglyceride (eg, hepatic triglyceride) is compared to the triglyceride (eg, hepatic triglyceride) observed in a subject not receiving FXR agonist treatment.

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 compared with the sensitivity observed in a subject not receiving treatment 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 decrease 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%

- 9 040003 at least 75% or more. In some instances, the reduction in serum insulin levels 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 decrease in serum insulin levels is compared to levels observed in a subject not receiving treatment with an FXR agonist.

In some embodiments, administration of an FXR agonist results in a decrease in the amount of glucose in the blood serum of the subject. In some examples, the decrease 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 instances, the decrease in serum glucose 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 glucose is compared to levels observed in a subject not receiving FXR agonist treatment.

In some examples, the FXR agonist described herein enhances the transformation of white adipose tissue into brown in a subject. In some examples, the degree of enhancement in the subject of the transformation of white adipose tissue to brown is at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more compared to a subject not receiving FXR agonist treatment.

In some embodiments, administration of an FXR agonist does not result in significant changes 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 as a result. In other embodiments, the subject reports that the decrease in appetite is minimal.

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 instances, the metabolic rate is increased 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 compared to the rate observed in a subject not receiving treatment with an FXR agonist.

In some embodiments, the increase in metabolism results from increased oxidative phosphorylation in the subject, which in turn results in increased tissue energy expenditure (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, the increase in BAT activity 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 increase in BAT activity is compared to the BAT activity observed in a subject not receiving FXR agonist treatment.

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, but are not limited to, 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 in the prevention or treatment of alcoholic or non-alcoholic liver disease. In some embodiments, an FXR agonist is used in the prevention or treatment of 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 in the treatment of cholestasis in a subject. Cholestasis is the deterioration or cessation

- 10 040003 decrease in 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 cholelithiasis, cholestasis of pregnancy, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). In some cases, the obstruction is due to a gallstone, injury to the bile ducts, drugs, one or more additional liver diseases, or malignancy. In some cases, the enterohepatic circulation of bile acids is able to absorb fats and fat-soluble vitamins from the intestinal tract and ensure the elimination of cholesterol, toxins, and metabolic by-products such as bilirubin from the liver. In some cases, FXR activation induces the expression of canalicular bile acid transporters BSEP (ABCB11) and multidrug resistance-associated protein 2 (MRP2; ABCC2, cMOAT) and also downregulates genes involved in bile acid biosynthesis, such as, for example, the sterol gene. -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 30%, at least 40% , at least 50% or more. In some cases, the reduction in cholestasis 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 compared with the level of cholestasis in a subject not receiving treatment with an FXR agonist.

Primary biliary cirrhosis and 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 mainly 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. 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 instances, the RBC reduction 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 compared with the level of PBC in a subject not receiving treatment 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, the reduction in cirrhosis 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 compared with the level of cirrhosis in a subject not receiving treatment 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, which is defined by histological signatures 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 advanced fibrosis, hepatocellular carcinoma, or end-stage 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, leading to insulin resistance and impaired lipolysis suppression in adipocytes. In some cases, this disruption of lipolysis inhibition results in the release of free fatty acids (FFA) into the bloodstream 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 activation of pro-inflammatory molecules.

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

In some embodiments, an FXR agonist disclosed herein is used in the treatment of non-alcoholic steatohepatitis (NASH). In some examples, an FXR agonist

- 11 040003 reduces NASH 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 reduction in NASH 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 compared with the level of NASH in a subject not receiving treatment 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 cases, the reduction in NAFLD 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 level of NAFLD is compared to the level of NAFLD in a subject not receiving FXR agonist treatment.

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, the reduction in steatosis 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 compared with the level of steatosis in a subject not receiving treatment 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 more. In some cases, the reduction in alcoholic hepatitis is about 5 to about 50%, about 5 to about 25%, about 10 to about 20%, or about 10 to about 30%. In some cases, the level of alcoholic hepatitis is compared with the level of alcoholic hepatitis in a subject not receiving treatment with an FXR agonist.

Primary sclerosing cholangitis

In some embodiments, an FXR agonist disclosed herein is used in the treatment of primary sclerosing cholangitis (PSC). PSC is a chronic and progressive cholestatic liver disease. PSC is characterized by progressive inflammation, fibrosis, and stenosis in the hepatic ducts. Common symptoms include itching and jaundice. The disease is highly associated with inflammatory bowel disease (IBD) - approximately 5% of patients with ulcerative colitis will develop 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 levels) 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, the reduction in liver enzymes 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 enzyme levels are compared with liver enzyme levels in a subject not receiving FXR agonist treatment.

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 20%, at least 30%, at least 40%, at least 50% or more. In some instances, the reduction in hepatic triglycerides 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, hepatic triglycerides are compared with hepatic triglycerides in a subject not receiving FXR agonist treatment.

Inflammatory intestinal condition

Disclosed herein are methods of treating or preventing inflammatory bowel disease.

- 12 040003 cervical condition. Typical 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 oncogenesis, or gastric oncogenesis 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 having an inflammatory bowel condition. 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 oncogenesis or gastric oncogenesis 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 instances, the reduction in intestinal inflammation 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 compared with the level of intestinal inflammation in a subject not receiving treatment with an FXR agonist.

Disease associated with cell proliferation

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 in the prevention or treatment of adenocarcinomas or carcinomas derived from glandular tissue or in which tumor cells form recognizable glandular structures. In some embodiments, adenocarcinomas are classified by their predominant cell pattern as papillary, alveolar, or by a specific cell product as mucus-forming 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 in the prevention or treatment of a cancer of the intestinal tract, such as a cancer of the colon, for example, a cancer that forms in the tissues of the colon (the longest part of the colon), or a cancer another part of the intestinal tract, such as the small intestine and/or ileum. In some cases, a malignant tumor of the colon is also called a malignant tumor of the colon and rectum. In some cases, the most common type of colon cancer is colon adenocarcinoma.

In some cases, the progression of a malignant tumor is characterized by the stages or extent of the malignant tumor in the body. Staging is usually based on the size of the tumor, the presence of cancer in the lymph nodes, and the presence of cancer at a site other than the site of the primary cancer. The stages of colon cancer include stage I, stage II, stage III, and stage IV. In some embodiments, the colon adenocarcinoma is of 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 as described herein is administered to a subject having stage I, stage II, stage III, or stage IV cancer. In some cases, the FXR agonist described herein is administered to a subject having 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 tumor burden in the colon) in a subject at least

- 13 040003 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 reduction in tumor burden 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 compared with the level of tumor burden in a subject not receiving treatment with an FXR agonist.

In some instances, 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 (such as 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 instances, the reduction in tumor size 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, tumor size is compared to tumor size in a subject not receiving FXR agonist treatment.

In additional embodiments, the FXR agonist disclosed herein reduces the effects of tumor associated cachexia in a subject. In some examples, an FXR agonist reduces the effect of cachexia (such as associated with a colon tumor) 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 cachexia reduction 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 compared to the effect of cachexia in a subject not receiving treatment with an FXR agonist.

In other embodiments, an FXR agonist disclosed herein improves the survival of a subject with a tumor. In some instances, an FXR agonist improves 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 at least 30%, at least 40%, at least 50% or more. In some cases, the improvement in survival 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, survival is compared with survival in a subject not receiving FXR agonist treatment.

In one aspect, this document describes a pharmaceutical composition containing 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.

In another aspect, this document describes a method of treating a disease or condition in a mammal that would benefit from FXR agonism, comprising administering a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to the mammal, if necessary. In some embodiments, the disease or condition is a metabolic condition. In some embodiments, the disease or condition is a hepatic 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 for 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, this document describes a method for treating or preventing a metabolic or hepatic condition in a mammal, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically thereof.

- 14 040003 acceptable salt or solvate to a mammal if necessary. In other embodiments, the metabolic or hepatic condition is treatable with an FXR agonist. In some embodiments, the method further comprises administering a second therapeutic agent to a mammal in addition to a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

According to any of the above aspects, further embodiments are provided, 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) administered orally to the 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 the 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 that provide for single administrations 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 a continuous dosing regimen. In some embodiments, the compound is administered on a continuous daily dosing schedule.

According to any of the above aspects involving the treatment of a disease or condition, additional embodiments are provided, including the administration of at least one additional agent in addition to the administration of a compound of formula (I) 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, this document describes a method for 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 a pharmaceutically acceptable salt or solvate thereof, thereby activating farnesoid X receptors (FXR) in the intestine and treating or preventing a metabolic disorder in a subject. In some embodiments, absorption of the compound is predominantly limited to the intestine. In some embodiments, the method substantially upregulates expression of the target FXR gene in the gut, while there is essentially no increase in expression of the target FXR gene in the liver or kidney. 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 substantially upregulates expression of the target FXR gene in the gut while not substantially increasing expression of the target FXR gene in the liver or kidney, while minimizing 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, the increase in metabolic rate includes an increase in oxidative phosphorylation in a subject. In some embodiments, the method further comprises improving glucose and/or lipid homeostasis in a 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, enhances hepatic insulin sensitivity, reduces hepatic steatosis, promotes BAT activation, reduces blood glucose, enhances weight loss, or any combination thereof. According to

- 15 040003 In some embodiments, the method enhances insulin sensitivity in the liver and activates brown adipose tissue (BAT). 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 nicotinamidribonucleoside analog, or combinations thereof.

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 a pharmaceutically acceptable salt or solvate thereof, to activate the thereby FXR receptors in the intestine and thereby treating or preventing inflammation in the intestinal region of the subject. In some embodiments, absorption of the compound is predominantly limited to the intestine. In some embodiments, the method substantially upregulates expression of the target FXR gene in the gut, while there is essentially no increase in expression of the target FXR gene in the liver or kidney. In some embodiments, the 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) , peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric oncogenesis, or any combination thereof. In some embodiments, the one or more target FXR genes include IABP, OSTa, Per1, FGF15, FGF19, SHP, or combinations thereof. In some embodiments, the method further comprises administering a therapeutically effective amount of an antibiotic therapeutic agent 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 therapeutic agent, nicotinamide ribonucleoside, nicotinamide ribonucleoside analog, or combinations thereof.

In some embodiments, the method enhances 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, a method for treating or preventing a cell proliferation-related disease in a subject is described herein, comprising administering to the subject's gastrointestinal tract a therapeutically effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease associated with cell proliferation is adenocarcinoma. In some embodiments, the adenocarcinoma is a malignant tumor of the colon. In some embodiments, treating the adenocarcinoma reduces the size of the adenocarcinoma, the volume of the adenocarcinoma, the number of adenocarcinomas, cachexia caused by the adenocarcinoma, delays the progression of the adenocarcinoma, improves the survival of the subject, or provides combinations 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 agent, or combinations thereof.

In some embodiments, this document describes 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 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 (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.

Articles are provided that include a packaging material, a compound described herein, or a pharmaceutically acceptable salt thereof in a packaging material, and a label indicating that the compound, or composition, or pharmaceutically acceptable salt, pharmaceutically active metabolite , a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable solvate thereof is used to treat, prevent, or alleviate one or more symptoms of a disease or condition for which FXR agonism is useful.

Connections

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

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

Formula (I) where

R ¹ and R ² are each independently selected from H, D, F, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

or R ¹ and R ² are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;

or R ¹ and R ² are taken together with the carbon atom to which they are attached to form a carbonyl (C=O);

R ³ is selected from substituted or unsubstituted C ₁ -C ₁₀ αalkyl, substituted or unsubstituted C ₂ -C ₁₀ alkenyl, substituted or unsubstituted C ₂ -C ₁₀ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ - C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if R ³ is substituted then R ³ is substituted with one or more R ¹² groups;

each R ¹² is independently selected from D, halo, -CN, -NO2, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -S(=O)2N( R ¹⁰ )2, -NR ¹⁰ S(=O)2R ¹¹ , -C(=O)R ⁿ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -N(R ¹⁰ )2, -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NHC(=O)R ¹¹ , -NHC(=O)OR ¹¹ unsubstituted or substituted C1-C ₁₀ alkylα, unsubstituted or substituted C ₁ -C ₁₀ fluoroalkyl, unsubstituted or substituted C ₂ -C ₁₀ alkenyl, unsubstituted or substituted C ₂ -C ₁₀ alkynyl, unsubstituted or substituted C ₁ -C ₁₀ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and -L ⁵ -L ⁶ -R ¹³ ;

L ⁵ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -NR ¹⁰ -, -C(=O)-, -C(=O) NH-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NH-, -NHC(=O)NH-, -NHC(= O)O-, -(CH2) _r - or -(OCH ₂ CH ₂ )r-, r is 1, 2, 3 or 4;

L ⁶ is absent or is unsubstituted or substituted C ₁ -C ₁₀ alkylene, unsubstituted or substituted C ₁ -C ₁₀ heteroalkylene, unsubstituted or substituted C ₂ -C ₁₀ alkenylene, unsubstituted or substituted C ₂ -C ₁₀ alkynylene, unsubstituted or substituted C ₃ -C ₁₀ cycloalkylene, unsubstituted or substituted C ₂ -C ₁₀ heterocycloalkylene, unsubstituted or substituted arylene or unsubstituted or substituted heteroarylene;

R ¹³ is H, halo, unsubstituted or substituted C ₁ -C ₁₀ alkyl, unsubstituted or substituted C ₂ -C ₁₀ alkenyl, unsubstituted or substituted C ₂ -C ₁₀ alkynyl, unsubstituted or substituted C ₁ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₁ -C ₁₀ heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl;

ring A is a monocyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^{a is} independently selected from H, D, halogen, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ⁿ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O )OR ¹¹ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkylα;

L ¹ is -X1-L ² - or -L2-X ¹ -;

X ¹ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁰ -, -CH2-, -CH=CH- , -OC-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR ¹⁰ -, - NR ¹⁰ C(=O)-, -OC(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)O-, -NR ¹⁰ C(=O)NR ¹⁰ -, -NR ¹⁰ S(=O) 2- or -NR ¹⁰ -;

L ² is absent or represents a substituted or unsubstituted C ₁ -C ₄ alkylene;

ring C is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^c is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -NO2, -N(R ¹⁰ )2,

- 17 040003

-S(=O)2R ¹¹ , -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2 , -C(=O)R ¹¹ , -OC(=O)R ¹¹ , - CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C ₁ -C6 alkyl, substituted or unsubstituted C ₂ -C6 alkenyl, substituted or unsubstituted C ₂ C6 alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C1C6 heteroalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;

ring B is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^B is independently selected from H, D, halogen, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N(R ¹⁰ ) 2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl and substituted or unsubstituted CiC6 heteroalkyl;

L ³ is -X2-L ⁴ - or -L ⁴ -X ² -;

X ² is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁰ -, -CH2-, -CH=CH- , -OC-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR ¹⁰ -, - NR ¹⁰ C(=O)-, -OC(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)O-, -NR ¹⁰ C(=O)NR ¹⁰ -, -NR ¹⁰ S(=O) 2- or -NR ¹⁰ -;

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

ring D is phenyl, a bicyclic carbocycle, a monocyclic N-containing heterocycloalkyl, a monocyclic heteroaryl, or a bicyclic heterocycle;

each RD is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N(R ¹⁰ )2 , -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2 , -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , - C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl , substituted or unsubstituted C ₁ -C ₆ heteroalkyl;

each R ¹⁰ is independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl;

or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹¹ is independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl , substituted or unsubstituted monocyclic heteroaryl and substituted or unsubstituted benzyl;

m is 0, 1 or 2;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3, or 4.

For any and all embodiments, the substituents are selected from a subset of the alternatives set forth. For example, in some embodiments, R ¹ and R ² are each independently selected from H, D, F, C1-C4 alkyl, and C1-C4 fluoroalkyl. In other embodiments, R ¹ and R ² are each independently selected from H, D, F, CH3 and CF ₃ . In some other embodiments, R ¹ and R ² are each independently selected from H or D. In some other embodiments, R ¹ and R ² are each H.

In some embodiments, ring B is a monocyclic carbocycle or a monocyclic heterocycle, where the groups

are in a 1,3 position relative to each other on ring B.

In some embodiments, ring B is a monocyclic carbocycle or a monocyclic heterocycle, where the groups

- 18 040003 are in the 1,4 position on ring B.

In some embodiments, ring B is phenyl.

In some embodiments, ring B is a monocyclic gene

teroaryl.

In some embodiments, ring B is a monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

In some embodiments, is

B ¹ is CR ^B or N;

B ² is CR ^B or N;

B ³ is CR ^B or N;

B ⁴ is CR ^B or N.

According to some embodiments B ¹

B ² is CR ^B ;

B ³ is CR ^B ;

B ⁴ is CR ^B .

According to some embodiments B ¹

B ² is CR ^B or N;

is CR ^B ;

is N;

B ³ is CR ^B ;

B ⁴ is CR ^B .

According to some embodiments B

B ² is CR ^B ;

B ³ is CR ^B or N;

B ⁴ is CR ^B .

In some embodiments, B B ² is CR ^B ;

B ³ is CR ^B ;

B ⁴ is CR ^B or N.

According to some embodiments B ¹

B ² is N;

B ³ is CR ^B ;

B ⁴ is CR ^B or N.

In some embodiments, is is CR ^B or N;

is CR ^B or N;

is CR ^B or N;

- 19 040003

In some embodiments, ring D is phenyl, a bicyclic carbocycle, a monocyclic N-containing heterocycle, or a bicyclic heterocycle.

In some embodiments, Ring D is phenyl, a bicyclic carbocycle, a monocyclic heteroaryl, or a bicyclic heterocycle.

In some embodiments, ring D is phenyl or monocyclic heteroaryl.

In some embodiments, Ring D is a monocyclic heteroaryl.

In some embodiments, ring D is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

In some embodiments, Ring D is phenyl, a bicyclic carbocycle, a monocyclic N-containing heterocycloalkyl, a monocyclic heteroaryl, or a bicyclic heterocycle.

In some embodiments, ring D is phenyl, indanyl, indenyl, or naphthyl.

In some embodiments, ring D is phenyl.

In some embodiments, Ring D is a monocyclic N-containing heterocycle.

In some embodiments, Ring D is a monocyclic N-containing heteroaryl.

In some embodiments, ring D is a monocyclic N-containing heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyri-

midinil, pyrazinyl and pyridazinyl. In some embodiments, is )θ-(κ°) ₄ ^Ά ^<Ρϋ> ' ΐ In some embodiments, is r ^d R ^D _R D , _R D , _R D _R D r ^d _r D _R D Mj' ^rD / ^{^} nR ^d LnV ^rD R ^d R ^{d ,} R ^D , r ^d _R ^D AA R ^d , NN ^{, NN d} %V ^d 6 NS , NN , NN , D ¥(R ^D ) _q ^r( ^RD ) _q T^ ^(rD ^ ^{(R )q} n. a ^(rD) ^ I jt ^(rD) < , N or N . DV( ^RD ) _q R ^D _{rD R} D ^n^ ^rD ^^ ^rD , r ^d , r ^d r ^d , r ^d r ^d , r ^d R ^d , r ^d , r ^d r ^d , r ^d , ' 4% Ar ^RD /N NN _x OA , N =N , R ^D , R ^D , A p ^d A .zN.dD AA , R ^d , R ^D , SN , >N ₄ ___ _r d /___,N._ _r d A / * V / NS OR N- ABOUT .

- 20 040003

D j-(R ^D ) _q

In some embodiments, is •°V^R ^d r ^d r ^d r ^d r ^d r ^d r ^d r ^d r ^d r ^d r ^d

In some embodiments, each ^RD is independently selected from H, D, halogen,

-CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N(R ¹⁰ )2, -NHS(=O)2R ¹¹ , - S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2 , -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , 10 11

-NRC(=O)OR, substituted or unsubstituted C ₁ -C ₆ αalkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl and substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl.

In some embodiments, each ^RD is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N (R ¹⁰ )2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C( =O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C ₁ -C ₆ αalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl and substituted or unsubstituted C ₁ -C ₆ heteroalkyl.

In some embodiments, each ^RD is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N (R ¹⁰ )2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ - C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkylα, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, and substituted or unsubstituted C ₂ -C ₆ heterocycloalkyl.

In some embodiments, each ^RD is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N (R ¹⁰ )2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cr C6 fluoroalkyl, substituted or unsubstituted C1-C6 heteroalkyl and unsubstituted or substituted C3 -C6cycloalkyl. In some embodiments, each ^RD is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -N (R ¹⁰ )2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , C1-C6 alkyl, C2-C6 alkenyl, C2C6 alkynyl, C ₁ -C ₆ fluoroalkylα and substituted or unsubstituted C ₁ -C ₆ heteroalkyl .

In some embodiments, L ³ is -X ² -L ⁴ - or -L4-X ² -; X ² is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O>2NR ¹⁰ -, -CH2-, -CH=CH- , -C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O) -, -NR ¹⁰ S(=O)2- or -NR ¹⁰ - L ⁴ is absent or is -CH2-.

In some embodiments, L ³ is -X ² -.

In some embodiments, L ³ is absent or is -O-, -S-, -SCH2-, -CH2-S-, -CH2-, -CH=CH-, -C=C-, -C(=O) -, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)-, -NR ¹⁰ S(=O)2-, -NR ¹⁰ -, -NR ¹⁰ -CH2- or -CH2-NR ¹⁰ -.

In some embodiments, L ³ is absent or is -O-, -S-, -CH=CH-, -C=C- or -NR ¹⁰ -.

In some embodiments, Ring A is a monocyclic carbocycle.

In some embodiments, Ring A is a monocyclic

- 21 040003 carbocycle, which is phenyl or C ₃ -C ₈ cycloalkyl.

In some embodiments, Ring A is phenyl.

represents

According to some embodiments

In some embodiments, the compound is characterized by the following structure:

In some embodiments, Ring A is a monocyclic C ₃ C ₈ cycloalkyl which is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In some embodiments, Ring A is a monocyclic heterocycle.

In some embodiments, ring A is a monocyclic heterocycle, which is a monocyclic C ₁ -C ₃ heteroarylene containing 1-4 N atoms and 0 or 1 O or S atom.

In some embodiments, ring A is a monocyclic heterocycle, which is a monocyclic C ₁ -C ₃ heteroarylene containing 0-4 N atoms and 1 O or S atom.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 6-membered heteroarylene selected from pyridinylene, pyrimidinylene, pyrazinylene, and pyridazinylene.

represents

According to some embodiments

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 5-membered heteroarylene selected from furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene.

According to some embodiments

represents

- 22 040003

In some embodiments, L ¹ is -X ¹ -L ² - or -L ² -X ¹ -;

X ¹ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁰ -, -CH2-, -CH=CH - , -C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O) -, -NR ¹⁰ S(=O)2- or -NR ¹⁰ -;

L ² is absent or is -CH2-.

In some embodiments, L ¹ is absent or is -O-, -S-, -SCH2-, -CH2-S-, -CH2-, -CH=CH-, -C=C-, -C(=O) -, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)-, -NR ¹⁰ S(=O)2-, -NR ¹⁰ -, -NR ¹⁰ -CH2- or -CH2-NR ¹⁰ -.

In some embodiments, L ¹ is absent.

In some embodiments, a compound of formula (I) has the following structure:

In some embodiments, a compound of formula (I) has the following structure:

In some embodiments, Ring A is a monocyclic carbocycle, a monocyclic heteroaryl; ring C is a monocyclic carbocycle or a monocyclic heterocycle; ring B is a monocyclic carbocycle or a monocyclic heterocycle; ring D is phenyl, monocyclic N-containing heterocycloalkyl or monocyclic heteroaryl.

In some embodiments, Ring A is phenyl, C ₃ -C 6 cycloalkyl, or monocyclic heteroaryl; ring C is phenyl, C ₃ C ₆ cycloalkyl or monocyclic heteroaryl; ring B is phenyl or monocyclic heteroaryl; ring D is phenyl, monocyclic N-containing heterocycloalkyl or monocyclic heteroaryl. In some embodiments, Ring A is phenyl, C ₃ -C ₆ cycloalkyl, or monocyclic heteroaryl; ring C is phenyl or monocyclic heteroaryl; ring B is phenyl or monocyclic heteroaryl; ring D is phenyl, monocyclic N-containing heterocycloalkyl or monocyclic heteroaryl.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic C ₂ -C ₈ heterocycloalkyl containing at least 1 ring N atom.

In some embodiments, ring A is a monocyclic heterocycle, which is a monocyclic C2- _C8 heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.

In some embodiments, is

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

where ring A is a monocyclic heterocycle containing 1-4 N atoms, or a bicyclic heterocycle containing 1-4 N atoms.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 5-membered C1- _C4 heteroarylene containing 1-4 N atoms.

(R'

VI

is a monocyclic 5-membered C ₁ -C ₄ heteroarylene containing 1-4 N atoms, characterized by the structure

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic C ₂ -C ₈ heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.

represents represents

In some embodiments, where t is 1, 2, or 3; u is 1, 2, or 3.

According to some embodiments

- 24 040003

In some embodiments, (R ^A )n is

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 N atoms, or a bicyclic heterocycle containing 1-4 N atoms, which is selected from β-lactam, γ-lactam, δ-lactam, or ε-lactam.

In some embodiments, Ring A is a bicyclic _C5C8 heterocycloalkyl, which is a fused _{bicyclic C5C8} heterocycloalkyl, bridged bicyclic _C5 - _C8 heterocycloalkyl, or spirobicyclic C5- _C8 heterocycloalkyl.

(R^), ¹ AJ

In some embodiments, r is a bicyclic C ₅ C ₈ bridged heterocycloalkyl, which is

: ^A )n

OR m(R ^a )i (R'

In some embodiments, C ₅ -C ₈ heterocycloalkyl, which is spirobicyclic (R ^A ) _r

(R ^a )i (R ^a ) ( ^RA )n OR

In some embodiments, L ¹ is -X ¹ -!?- or -ΐΛχ ¹ -;

X ¹ is absent or is -S(=O)-, -S(=O)2-, -CH2-, -C(=O)-, -OC(=O)-, -NR ¹⁰ C(=O )- or -NR ¹⁰ S(=O)2-;

L ² is absent or is a substituted or unsubstituted C1- _C4 alkylene.

In some embodiments, L ¹ is -X^b ² - or -lAx ¹ -;

X ¹ is absent or represents -S(=O) ₂ -, -CH ₂ - or -C(=O)-;

L ² is absent or is -CH ₂ -.

In some embodiments, Ring C is a monocyclic carbocycle or a bicyclic carbocycle.

In some embodiments, ring C is a monocyclic carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

In some embodiments, ring C is phenyl.

In some embodiments, ring C is a bicyclic carbocycle selected from indanyl, indenyl, and naphthyl.

In some embodiments, Ring C is a monocyclic heterocycle or a bicyclic heterocycle.

In some embodiments, Ring C is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolylene, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.

-25 040003

In some embodiments, is

In some embodiments, ring C is a bicyclic heteroaryl selected from quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzoylazolylazolylazolylox, benzimidazolyl, , azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl and purinyl.

represents

According to some embodiments

In some embodiments, is

- 26 040003

In some embodiments, ring C is a monocyclic heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, homopiperidinyl, , thiepanil, oxazepinil, diazepinil, thiazepinil and 1,2,3,6 tetrahydropyridinyl.

In some embodiments, ring C is a monocyclic C2C8 heterocycloalkyl containing at least 1 ring N atom.

In some embodiments, ring C is a monocyclic C2C8 heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and azepanyl.

In some embodiments, is

represents

In some embodiments, wherein ring C is a 5-membered N-containing heteroaryl or N-containing C ₂ C ₈ heterocycloalkyl.

In some embodiments, ring C is a 5-membered N-containing heteroaryl containing 1-4 N atoms.

According to some embodiments

is a monocyclic 5-membered C ₁ -C ₄ heteroarylene containing 1-4 N atoms, characterized by the structure

In some embodiments, ring C is a monocyclic C ₂ C8 heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and azepanyl.

- 27 040003

According to some embodiments

is where t is 1, 2 or 3;

u is 1, 2, or 3.

According to some embodiments

represents

In some embodiments, ring C is a monocyclic C ₂ C ₈ heterocycloalkyl containing 1 N atom in the ring, which is selected from β-lactam, γ-lactam, δ-lactam, or ε-lactam.

In some embodiments, ring C is a bicyclic C ₅ C ₈ heterocycloalkyl, which is a fused bicyclic C ₅ C ₈ heterocycloalkyl, bridged bicyclic C ₅ -C ₈ heterocycloalkyl, or spirobicyclic C ₅ -C ₈ heterocycloalkyl.

According to some embodiments

is a bicyclic

C ₅ -C ₈ bridged heterocycloalkyl, which is a spirobicyclic

In some embodiments, a C ₅ -C ₈ heterocycloalkyl, which is

In some embodiments, R ³ is selected from substituted or unsubstituted C1C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted aryl, where if R ³ is substituted then R ³ is substituted with one or more R ¹² groups.

In some embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, '''''' , h h h ⁴ and adamantyl. In some embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl. In some embodiments, R ³ is selected from isopropyl, isobutyl, t-butyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopentyl , substituted or unsubstituted cyclohexyl and

- 28 040003 substituted or unsubstituted phenyl. In some embodiments, R ³ is substituted or unsubstituted cyclohexyl.

According to another aspect, the present invention describes a compound having the structure of formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

Formula (IV) where

R ¹ and R ² are each independently selected from H, D, F, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl;

or R ¹ and R ² are taken together with the carbon atom to which they are attached to form a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl or a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;

or R ¹ and R ² are taken together with the carbon atom to which they are attached to form a carbonyl (C=O);

R ³ is selected from substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₂ C ₁₀ alkenyl, substituted or unsubstituted C ₂ -C ₁₀ alkynyl, substituted or unsubstituted C ₃ C ₁₀ cycloalkyl, substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if R ³ is substituted then R ³ is substituted with one or more R ¹² groups;

each R ¹² is independently selected from D, halo, -CN, -NO2, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -S(=O)2N( R ¹⁰ )2, -NR ¹⁰ S(=O)2R ¹¹ , -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -N(R ¹⁰ )2, -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NHC(=O)R ¹¹ , -NHC(=O)OR ¹¹ unsubstituted or substituted C1-C ₁₀ alkyl, unsubstituted or substituted C ₁ -C ₁₀ fluoroalkyl, unsubstituted or substituted C ₂ -C ₁₀ alkenyl, unsubstituted or substituted C ₂ -C ₁₀ alkynyl, unsubstituted or substituted C ₁ -C ₁₀ heteroαalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and -L ⁵ -L ⁶ -R ¹³ ;

L ⁵ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -NR ¹⁰ -, -C(=O)-, -C(=O) NH-, -NHC(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)NH-, -NHC(=O)NH-, -NHC(= O)O-, -(CH2)r- or -(OCH^H^-, r is 1, 2, 3 or 4;

L ⁶ is absent or is unsubstituted or substituted C1- _C10 alkylene, unsubstituted or substituted C1- _C10 heteroalkylene, unsubstituted or substituted _C2 - _C10 alkenylene, unsubstituted or substituted _C2 - _C10 alkynylene, unsubstituted or substituted _C3- C ₁₀ cycloalkylene, unsubstituted or substituted C ₂ -C ₁₀ heterocycloalkyl, unsubstituted or substituted arylene, or unsubstituted or substituted heteroarylene;

R ¹³ is H, halo, unsubstituted or substituted C1- _C10 alkyl, unsubstituted or substituted _C2 - _C10 alkenyl, unsubstituted or substituted _C2 - _C10 alkynyl, unsubstituted or substituted C1- _C10 cycloalkyl, unsubstituted or substituted C1 -C ₁₀ heterocycloalkyl, unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl;

ring A is a monocyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^{a is} independently selected from H, D, halogen, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O )OR ¹¹ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₂ -C 6 alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C 1 -C ₆ fluoroalkyl, substituted or unsubstituted C 1 -C ₆ heteroalkyl;

L ¹ is -X1-L ² - or -L2-X ¹ -;

X ¹ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁰ -, -CH2-, -CH=CH- , -OC-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, -C(=O)NR ¹⁰ -, - NR ¹⁰ C(=O)-, -OC(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)O-, -NR ¹⁰ C(=O)NR ¹⁰ -, -NR ¹⁰ S(=O) ₂ - or -NR ¹⁰ -;

L ² is absent or is a substituted or unsubstituted C1- _C4 alkylene;

ring C is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle, or a bicyclic heterocycle;

each R ^c is independently selected from H, D, halogen, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -NO2, -N(R ¹⁰ )2, -S(= O)2R11, -NHS(=O)2R11, -S(=O)2N(R ¹⁰ )2, -C(=O)R ⁿ , -OC(=O)R ⁿ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O) R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C1-C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ C ₆ alkynyl, substituted or unsubstituted C1-C ₆ fluoroalkyl , substituted or unsubstituted C1C ₆ heteroalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;

- 29 040003 Ring B is a monocyclic carbocycle, a bicyclic carbocycle, a monocyclic heterocycle or a bicyclic heterocycle;

each R ^B is independently selected from H, D, halo, -CN, -OH, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O) ₂ R ¹¹ , -N(R ¹⁰ )2, -NHS(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O) R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ C ₆ alkynyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl and substituted or unsubstituted C1C ₆ heteroalkyl;

R ⁴ is C ₂ -C ₁₀ alkenyl; or

R ⁴ is -N(R ⁹ )2, -(substituted or unsubstituted C1-C6 alkylene)-N(R ⁹ )2, -NR ⁹ C(R ⁷ )(R ⁸ )-CO2R ¹⁰ , -NR ⁹ -( substituted or unsubstituted C1-C ₆ alkylene)-N(R ⁹ ) ₂ - or -L ³ -Y;

L ³ is -C(R ⁵ )(R ⁶ )- or -C(R ⁵ )(R ⁶ )-C(R ⁷ )(R ⁸ )-;

R ⁵ and R ⁷ are each independently selected from H, D, C1-C ₄ alkyl and C ₃ -C ₆ cycloalkyl;

or R ⁵ and R ⁷ are taken together with intermediate atoms to form a double bond;

or R ⁵ and R ⁷ are taken together with intermediate atoms to form an epoxide or or unsubstituted C ₃ -C ₆ cycloalkyl;

R ⁶ and R ⁸ are each independently selected from H, D, C1-C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

substituted

Y is -CH ₂ N(R ⁹ )2, -C(=O)N(R ⁹ )2, each R ⁹ is independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted heterocycle, -S(=O)2R ¹¹ , -S(=O)2N(R ¹⁰ )2, -C (=O)R ¹¹ , -CO2R ¹⁰ or -C(=O)N(R ¹⁰ )2;

or two R ⁹ on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹⁰ is independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl, and substituted or unsubstituted benzyl;

or two R ¹⁰ on the same N atom are taken together with the N atom to which they are attached to form an N-containing heterocycle;

each R ¹¹ is independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted phenyl , substituted or unsubstituted monocyclic heteroaryl and substituted or unsubstituted benzyl;

m is 0, 1 or 2;

n is 0, 1 or 2;

p is 0, 1, 2, 3, or 4.

In some embodiments, ring B is a monocyclic carbocycle or a monocyclic heterocycle, where the groups

R ³ (R ^c ) _f and R ⁴ are in the 1,3 position relative to each other on ring B.

In some embodiments, ring B is a monocyclic carbocycle or a monocyclic heterocycle, where the groups

and R ⁴ are in the 1,4 position on ring B.

In some embodiments, ring B is phenyl.

In some embodiments, ring B is a monocyclic heteroaryl.

In some embodiments, ring B is a monocyclic 6-membered heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

- 30 040003

According to some embodiments

B ¹ is CR ^B or N;

B ² is CR ^B or N;

B ³ is CR ^B or N;

B ⁴ is CR ^B or N.

According to some embodiments B ¹

B ² is CR ^B ;

B ³ is CR ^B ;

B ⁴ is CR ^B .

According to some embodiments B ¹

B ² is CR ^B or N;

B ³ is CR ^B ;

B ⁴ is CR ^B .

According to some embodiments B ¹

B ² is CR ^B ;

B ³ is CR ^B or N;

B ⁴ is CR ^B .

According to some embodiments B ¹

B ² is CR ^B ;

B ³ is CR ^B ;

B ⁴ is CR ^B or N.

According to some embodiments B ¹

B ² is N;

B ³ is CR ^B ;

B ⁴ is CR ^B or N.

represents ;

is CR ^B ;

is N;

According to Carbocycle.

According to

is CR ^B or N;

is CR ^B or N;

is CR ^B or N;

In some embodiments, is

Ring A is monocyclic in some embodiments, in some embodiments, a carbocycle that is phenyl or C ₃ -C ₈ cycloalkyl.

ring A is monocyclic

In some embodiments, Ring A is phenyl.

According to some embodiments

represents

In some embodiments, the compound is characterized by the following structure:

In some embodiments, Ring A is a C ₃ -C ₈ cycloalkyl which is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In some embodiments, Ring A is

In some embodiments, Ring A is a monocyclic heterocycle.

In some embodiments, ring A is a monocyclic heterocycle, which is a monocyclic C ₁ -C ₅ heteroarylene containing 1-4 N atoms and 0 or 1 O or S atom.

In some embodiments, ring A is a monocyclic heterocycle, which is a monocyclic C ₁ -C ₅ heteroarylene containing 0-4 N atoms and 1 O or S atom.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 6-membered heteroarylene selected from pyridinylene, pyrimidinylene, pyrazinylene, or pyridazinylene.

In some embodiments, is

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 5-membered heteroarylene selected from furanylene, thienylene, pyrrolylene, oxazolylene, thiazolylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, isoxazolylene, isothiazolylene, oxadiazolylene, and thiadiazolylene.

In some embodiments, is

In some embodiments, L ¹ is -X ¹ -L ² - or -L ^2- X ¹ -;

X ¹ is absent or is -O-, -S-, -S(=O)-, -S(=O)2-, -S(=O)2NR ¹⁰ -, -CH2-, -CH=CH - , C=C-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)- , -NR ¹⁰ S(=O)2- or -NR ¹⁰ -;

L ² is absent or is -CH ₂ -.

In some embodiments, L ¹ is absent or is -O-, -S-, -SCH2-, -CH2-S-, -CH2-, -CH=CH-, -C=C-, -C(=O) -, -C(=O)O-, -OC(=O)-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)-,

- 32 040003

-NR ¹⁰ S(=O)2-, -NR ¹⁰ -, -NR ¹⁰ -CH2- or -CH2-NR ¹⁰ -.

In some embodiments, L ¹ is absent.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic C2-C8 heterocycloalkyl containing at least 1 ring N atom.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic C2-C8 heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.

represents

According to some embodiments

In some embodiments, a compound of formula (IV) has the structure of formula (II) or a pharmaceutically acceptable salt or solvate thereof

where ring A is a monocyclic heterocycle containing 1-4 N atoms, or a bicyclic heterocycle containing 1-4 N atoms.

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic 5-membered C1- _C4 heteroarylene containing 1-4 N atoms.

In some embodiments, ^Ύ is a monocyclic 5-membered C1- _C4 heteroarylene containing 1-4 N atoms, characterized by the structure

In some embodiments, Ring A is a monocyclic heterocycle, which is a monocyclic C ₂ -C ₈ heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and azepanyl.

represents

In some embodiments, where t is 1, 2, or 3; u is 1, 2 OR 3.

In some embodiments, is

- 33 040003

According to some embodiments

represents

In some embodiments, Ring A is a monocyclic heterocycle containing 1-4 N atoms, or a bicyclic heterocycle containing 1-4 N atoms, which is selected from β-lactam, γ-lactam, δ-lactam, or ε-lactam.

In some embodiments, Ring A is a bicyclic C ₅ C ₈ heterocycloalkyl, which is a fused bicyclic C5C ₈ heterocycloalkyl, bridged bicyclic C5-C ₈ heterocycloalkyl, or spirobicyclic C5-C ₈ heterocycloalkyl.

is a bicyclic C5 According to some embodiments

C ₈ bridged heterocycloalkyl, which is

X ¹ is absent or is -S(=O)-, -S(=O) ₂ -, -CH2-, -C(=O)-, -OC(=O)-, -NR ¹⁰ C(=O )- or -NR ¹⁰ S(=O)2-;

L ² is absent or is a substituted or unsubstituted C1- _C4 alkylene.

In some embodiments, L ¹ is -X ¹ -L ² - or -L2-X ¹ -;

X ¹ is absent or represents -S(=O) ₂ -, -CH ₂ - or -C(=O)-;

L ² is absent or is -CH2-.

In some embodiments, Ring C is a monocyclic carbocycle or a bicyclic carbocycle.

In some embodiments, ring C is a monocyclic carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.

In some embodiments, ring C is phenyl.

In some embodiments, ring C is a bicyclic carbocycle selected from indanyl, indenyl, and naphthyl.

In some embodiments, Ring C is a monocyclic heterocycle or a bicyclic heterocycle.

In some embodiments, Ring C is a monocyclic heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolylene, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.

In some embodiments, is

In some embodiments, ring C is a bicyclic heteroaryl selected from quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzoylazolylazolylazolylox, benzimidazolyl, , azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, azabenzothiazolyl and purinyl.

In some embodiments, is

In some embodiments, ring C is a monocyclic heteroaryl selected from furanyl, thienyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, pyrimidinyl, pyrazinyl, and triazinyl.

In some embodiments, ring C is a monocyclic 6-membered heteroaryl containing 1-3 N atoms.

According to some embodiments

represents

- 35 040003 or

In some embodiments, ring C is a monocyclic 5-membered C1- _C4 heteroaryl.

In some embodiments, ring C is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

represents

According to some embodiments

In some embodiments, ring C is a monocyclic heterocycle selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, , thiepanil, oxazepinil, diazepinil, thiazepinil and 1,2,3,6 tetrahydropyridinyl.

In some embodiments, ring C is a monocyclic C ₂ C ₈ heterocycloalkyl containing at least 1 ring N atom.

In some embodiments, ring C is a monocyclic C ₂ C ₈ heterocycloalkyl containing at least 1 N atom in the ring, which is selected from aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, and azepanyl.

represents represents

In some embodiments, where t is 1, 2, or 3; u is 1, 2, or 3.

According to some embodiments

- 36 040003

In some embodiments, ring C is a C ₂ C ₈ heterocycloalkyl containing 1 N atom in the ring, which is selected from β-lactam, γ-lactam, δ-lactam, or ε-lactam.

In some embodiments, ring C is a bicyclic C ₅ C8 heterocycloalkyl, which is a fused bicyclic C5C ₈ heterocycloalkyl, bridged bicyclic C ₅ -C ₈ heterocycloalkyl, or spirobicyclic C ₅ -C ₈ heterocycloalkyl.

According to some embodiments

C ₈ bridged heterocycloalkyl, which is a bicyclic C ₅ -

In some embodiments, C ₅ -C ₈ heterocycloalkyl, which is spirobicyclic(R ^C ) _P ^P

R ^c (R ^c ) _P - (R ^c ) _f

R ^c ~4 (R ^c )

(R ^c ) _f

P or

^Rc

R ^c (R ^C )|

In some embodiments, R ³ is selected from substituted or unsubstituted C ₁ C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, or substituted or unsubstituted aryl, where if R ³ is substituted then R ³ is substituted with one or more R ¹² groups.

In some embodiments, R ³ is selected from substituted or unsubstituted C ₃ C ₁₀ cycloalkyl or substituted or unsubstituted phenyl, wherein if R ³ is substituted then R ³ is substituted with one or more R ¹² groups.

In some embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl,

and adamantyl.

In some embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl, neohexyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl.

In some embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,3-dimethylbutyl or neohexyl. In certain embodiments, R ³ is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

In some embodiments, R ³ is selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl. In some embodiments, R ³ is substituted or unsubstituted cyclopropyl. In some embodiments, R ³ is substituted or unsubstituted cyclobutyl. In some embodiments, R ³ is substituted or unsubstituted cyclopentyl. In some embodiments, R ³ is substituted or unsubstituted cyclohexyl. In some embodiments, R ³ is substituted or unsubstituted phenyl.

In some embodiments, each R ¹² is independently selected from D, halo, -CN, -NO2, -OR ¹⁰ , -SR ¹⁰ , -S(O)R , -S(=O)2R ¹¹ , -S(=O) 2N(R ¹⁰ )2, -NR ¹⁰ S(=O)2R ¹¹ , -C(=O)R ¹¹ , -OC( O)R , -CO2R ¹⁰ , -OCO2R ¹¹ , -N(R ¹⁰ )2, -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , unsubstituted or substituted C ₁ -C ₁₀ alkyl, unsubstituted or substituted C ₁ -C ₁₀ fluoroalkyl, unsubstituted or substituted C ₂ -C ₁₀ alkenyl, unsubstituted or substituted C ₂ -C ₁₀ alkynyl, unsubstituted or substituted C ₁ -C ₁₀ heteroalkyl, unsubstituted or substituted C ₃ -C ₁₀ cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and -L ⁵ -L ⁶ -R ¹³ .

In some embodiments, each R ¹² is independently selected from D, halo, -CN, -OR ¹⁰ , -SR ¹⁰ , -S(=O)R ¹¹ , -S(=O)2R ¹¹ , -S(=O)2N (R ¹⁰ )2, -NR ¹⁰ S(=O)2R ¹¹ , -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -OCO2R ¹¹ , -N(R ¹⁰ )2 , -C(=O)N(R ¹⁰ )2, -OC(=O)N(R ¹⁰ )2, -NR ¹⁰ C(=O)R ¹¹ , -NR ¹⁰ C(=O)OR ¹¹ , C1 -C6 alkyl, C1C ₆ fluoroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C 3 -C 6 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl and - L ⁵ -L ⁶ -R ¹³ .

In some embodiments, each R ¹² is independently selected from D, halo, -CN, -OR ¹⁰ , -C(=O)R ¹¹ , -OC(=O)R ¹¹ , -CO2R ¹⁰ , -N(R ¹⁰ )2 , -C (= O) N (R ¹⁰ ) 2, -NR ¹⁰ C (= O) R ¹¹ , C 1 -C ₆ alkyl, C ₁ C ₆ fluoroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted C ₃ -C ₆ cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic heteroaryl, and -L ⁵ -L ⁶ -R ¹³ .

In some embodiments, R ¹³ is H, -N(R ¹⁰ ) ₂ , halogen, unsubstituted or substituted C ₁ -C ₁₀ alkyl, unsubstituted or substituted C ₂ -C ₁₀ alkenyl, unsubstituted or substituted C ₂ -C ₁₀ alkynyl, unsubstituted or substituted C ₁ -C ₁₀ cycloalkyl, unsubstituted or substituted C ₁ -C ₁₀ heterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl.

In some embodiments, R ⁴ is

In some embodiments, R ⁴ is

In some embodiments, R ⁴ is

In some embodiments, R ⁴ is

In some embodiments, R ⁴ is -L ³ -Y;

L ³ is -CH ₂ -;

Y represents

The present invention contemplates any combination of the groups described above for various

- 38 040003 variables. Throughout the description, the groups and their substituents are chosen by the person skilled in the art to obtain stable fragments and compounds.

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

Table 1

No. connections Structure chemical name 1 ABOUT N A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-0-(3-(5-methoxypyridin-3 yl)phenyl)cyclohexanecarboxamide 2 About ΖΤλΟ - at ¹ and 0-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-LChZ'-methoxy-[1,1'-biphenyl]-3yl)cyclohexanecarboxamide 3 ao / 0-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-7U-(3-(2-methoxypyridin-4yl)phenyl)cyclohexanecarboxamide 3.1 \ o o Z— / 0-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-7U-(4'-methoxy-[1,1'-biphenyl]-3yl)cyclohexanecarboxamide 4 ABOUT y/ xyOX 1 n 0-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl )-A ^f -(3-((2-methoxyethyl)amino)phenyl)cyclohexanecarboxamide 5 o o o o 1 n 0-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-0-(3-((2-(dimethylamino)ethyl)amino)phenyl)cyclohexanecarboxamide

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6 0 N ^{1 H} 1 ^-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f -(3-(isobutylamino)phenyl)cyclohexanecarboxamide 7 0 ^σγο 1 (E) ^_ A((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-M-(3-(pent-1-en-1yl)phenyl)cyclohexanecarboxamide 8 Cr° A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-((2-oxopyrrolide in-1 yl)methyl)phenyl)cyclohexanecarboxamide 9 0 ^σχο - _N XX^ 1 ^H J Methyl 2-((3 -(Y-((4'-(dimethylamino)-[ 1, Hbiphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)amino)acetate 10 ρΧαχ - _N XX^ ΧΧ^γθ^ । । O Methyl 2-((3 -(Y-((4'-(dimethylamino)-[ 1, Hbiphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)(methyl)amino)acetate AND O / Methyl-3 - (U- ((4'- (dimethylamino) - [ 1, Gbiphenyl] -4yl) methyl) cyclohexanecarboxamido) benzyl carbamate 12 / xz /—\ ABOUT ( z— / (E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f- (3-(3-(methylamino)-3-oxoprop1-en-1- yl)phenyl)cyclohexanecarboxamide 13 0 fVU ⁰ MX ¹ 0 (E)-N-(3-(3-(Dimethylamino)-3-oxoprop-1 en-1-yl)phenyl)-AA((4'-(dimethylamino)-[ 1, Gbiphenyl]-4-yl) methyl) cyclohexanecarboxamide

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14 z— / (E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide 15 0 JV-([ 1,1'-Biphenyl] -3 -yl)-A-((4'-fluoro-[ 1, Hbiphenyl]-4yl)methyl)cyclohexanecarboxamide 16 — z— / (E)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(prop-1-de-1 yl)phenyl)cyclohexanecarboxamide 17 0 (7)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(prop-1-en-1 yl)phenyl)cyclohexanecarboxamide 18 0 #-([ 1,1'-Biphenyl] -3 -yl)-#-((4'(d imethylamino)- [1,1'-biphenyl] -4yl)methyl)cyclohexanecarboxamide 19 Ο ό A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-phenoxyphenyl)cyclohexanecarboxamide 20 0 ^οΥο ίΎ ( 1 ¹ Xf ⁰ 0 _χ Methyl 3 - (3 - (A- ((4'- (dimethylamino) - [ 1, G- biphenyl]-4-yl)methyl) cyclohexanecarboxamido)phenyl) cyclobutanecarboxylate

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21 “Y z— / ^-((4'-(Dimethylamino)-[ 1,1'-biphenyl]-4yl )methyl)-A ^f -(3-vinylphenyl) cyclohexanecarboxamide 22 ,-y Az Z— / #-((4 '-(Dimethylamino)- [ 1, G-biphenyl] -4yl )methyl)-A'-(3 -(2-(oxazol-2yl)ethyl)phenyl)cyclohexanecarboxamide 23 z— / A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f -(3-(pyridin-3 yl)phenyl)cyclohexanecarboxamide 24 oh oh 7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-DA(3-(5-methylpyride in-3yl)phenyl)cyclohexanecarboxamide 25 o ^^000° ^((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-X-(3-(6-methoxypyridin-2yl)phenyl)cyclohexanecarboxamide 26 0 O°M A' ⁴ '!' । 1JN Methyl 5-(3-(7U-((4'-(dimethylamino)-[ 1, Hbiphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)nicotinate 27 О о с ^: > ζ— / (/;)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(2-(pyridin-2yl)vinyl)phenyl)cyclohexanecarboxamide 28 O o s Z— / (/;)-A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(2-(pyridin-4yl)vinyl)phenyl)cyclohexanecarboxamide

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29 O X4(4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f -(3-(2-methoxythiazol-5yl)phenyl)cyclohexanecarboxamide thirty .· O X4(4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-LDZ-(2-methoxythiazol-4yl)phenyl)cyclohexanecarboxamide 31 / -2 O O \ / O X ^- ((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f- (3-(5-methoxythiophen-2yl)phenyl)cyclohexanecarboxamide 32 / o O ^3 /— / ^ζ Ζ— / X ^- ((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(4-methoxypyridin-2yl)phenyl)cyclohexanecarboxamide 33 O X J ί JL । I N X ^- ((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A ^f- (3-(5-ethylpyridin-3yl)phenyl)cyclohexanecarboxamide 34 0 ,^οχο 4 rr _f y.. X((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(2-methoxypyrimidin-4yl)phenyl)cyclohexanecarboxamide 35 0 rvOXO - XJ ¹ N^N X((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(6-methoxypyrimidin-4yl)phenyl)cyclohexanecarboxamide 36 0 rvCC00 N 7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(6-methoxypyrazin-2yl)phenyl)cyclohexanecarboxamide

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37 I i ^o= \ /—\ ZX<> Y o / 3 -(A-((4C(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-A-(5methoxypyridin-3-yl)benzamide 38 _O P \ / ^IZ /—' )^° - Z— / 3 -(A-((4C(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-Aphenylbenzamide 39 \ o _o ъ /— )=o z— / Methyl-3 - (3 - (7U- ((4'- (dimethylamino) - [ 1, Gbiphenyl] -4yl) methyl) cyclohexanecarboxamido) benzamido) benzoate 40 0 ^rVA0 3 -(7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-7U(pyridin-4-yl)benzamide 41 V^ ^z >° ° X /--\ Zl( ) i 3 -(7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-7U(pyridin-2-yl)benzamide 42 0 rWT ⁰ Λ J (J, / i 1 (/D-HP(4DDimethylamino)-[1,1'-biphenyl]-4yl)methyl)-L ^g- (3-(3-methylbut-1-eu-1-yl)phenyl)cyclohexanecarboxamide 43 0 vxbo π i A ¹ Ir 7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(3-methoxyisothiazol-5yl)phenyl)cyclohexanecarboxamide 44 I~I yo O A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(2-methyl-3-oxo-2,3 dihydroisothiazol-5yl)phenyl)cyclohexanecarboxamide

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45 0 οσ° άΡ- ot/?sh/s-4-Hydroxy-A-((from/?sh/s-4-(4-methoxy3-methylphenyl)cyclohexyl)methyl)-A-(3 -(3 methoxyazetidine-1 - yl)phenyl)cyclohexanecarboxamide 46 l / trans AU hydroxy-A-((neg/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3 -(3 (methoxymethyl)azetidin-1 yl)phenyl)cyclohexanecarboxamide 47 0 5σ° trans AU hydroxy-7U-((neg/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3-(3methoxypyrrolidin-1 yl)phenyl)cyclohexanecarboxamide 48 ο ,χ° ά? %U ⁴ 0 trans AU idroxy-7U-((neg/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3 -(3(methoxymethyl)pyrrolidin-1 yl)phenyl)cyclohexanecarboxamide 49 0 ό ^ ^0H trans AU hydroxy-A-((neg/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3-(4methoxypiperidine-1 - yl)phenyl)cyclohexanecarboxamide 50 rr-Yi χ< ώ,^- trans AU hydroxy-A-((neg/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)-A-(3-(3methoxypiperidin-1 yl)phenyl)cyclohexanecarboxamide

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table 2

Structure Name / -Z with? (L)-7U-(4-(6-(Dimethylamino)pyridin-3yl)benzyl)-#-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide / -Z O vJ A-°° (L)-7U-(4-(6-(Dimethylamino)pyridin-3yl)benzyl)-4-hydroxy-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide 0 πγϊΛο A A O^o I nA (L)-7U-(4-(6-(Dimethylamino)pyridin-3yl)benzyl)^-(3-(2-(oxazol-2yl)vinyl)phenyl)tetrahydro-2H-pyran-4carboxamide 0 gua) . jCA 0l _s । N^Z ⁴ ^-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-7U-(3-(5-methoxythiazol-2yl)phenyl)cyclohexanecarboxamide / —Z XX H—Z \=/ n° ^Z A /—\ ^0 \ / ^-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-7U-(3-(oxazol-2yl)phenyl)cyclohexanecarboxamide o ha ^ P ¹ o (L)-7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-7U-(3-(2-(pyridin-3yl)vinyl)phenyl)cyclohexanecarboxamide / —z XX ΛΑ / ^- 4 — z 2=/ Lo ° \ /—\ zz/ \ /^o 3 -(7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-H ^g (oxazol-2-yl)benzamide / z XX o RJ - z ) ⁼ / 3 -(7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)-M(pyridin-3-yl)benzamide 0 ^XrYo ΧΎ^ CX ¹ °T N-(3 -(^-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)oxazole-2-carboxamide

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χγ 1 0 °Ο „0___Ν ⁰ 1Q A-(3-(A-((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)picolinamide ο 00 Y Ν-(3 -(A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- χΥ 1 Ο _ΝΗ ^0< Aj^n yl)methyl)cyclohexanecarboxamido)phenyl) nicotinamide 0 οοΟό Ν-(3 -(A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- Xj A'J'' 1 dI Ο ^< yl)methyl)cyclohexanecarboxamido)phenyl) isonicotinamide 0 A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- H 0 yl)methyl)-A-(3-((oxazol-2- χγ ^M'Zh^ 1 ΟΑ^ο ^Η Ο ylmethyl)amino)phenyl)cyclohexanecarboxamide 0 A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- H 0 yl)methyl)-A-(3 -((pyridine-2- χΥ ^MF^ Ν1 _^ ylmethyl)amino)phenyl) 1 ^Η U cyclohexanecarboxamide 0 A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- H 0 yl)methyl)-A-(3 -((pyridine-3 - χγ ylmethyl)amino)phenyl) 1 Η cyclohexanecarboxamide ο A-((4'-(Dimethylamino)-[ 1,1 '-biphenyl]-4- Ρ Η ό yl)methyl)-A-(3 -((pyridine-4- χγ N ylmethyl)amino)phenyl) 1 ^Η ΙΑ cyclohexanecarboxamide

- 47 040003

Qz— / 0 pr/ 0l Hl) U4(4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-((oxazol-2ylamino)methyl)phenyl)cyclohexanecarboxamide GT 1 Pdb ^HXN > O Y ^- ((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-yY-(3-((pyridin-3ylamino)methyl)phenyl) cyclohexanecarboxamide pt 1 b ^°o^ Methyl-3 - (3 - (U- ((4'- (dimethylamino) - [ 1, Gbiphenyl] -4- yl)methyl)cyclohexanecarboxamido)phenyl)-3hydroxycyclobutanecarboxylate Λ J 1 Άb ^0 _H n2/ (E)-7U-(4-(6-(Dimethylamino)pyridin-3yl)benzyl)-4-hydroxy-A-(4-(2-(oxazol-2yl)vinyl)pyridin-2yl)cyclohexanecarboxamide N^jO Xb (£)-74-((3'-Cyano-4'-methoxy-[1,1'-biphenyl]-4yl)methyl)-74-(3-(2-(4-methyloxazol-2yl)vinyl)phenyl )cyclohexanecarboxamide N^ Ί1 [ij^ N 0 ϊ^'Ν'η^^ι Oh A 74-([2,3'-Bipyridine] -5 -ylmethyl)-4-hydroxy-74(3 -(2-methoxypyridine-4- yl)phenyl)cyclohexanecarboxamide \ /=4°th ^T O νΆ [I.1 ^πη s-G 74-([2,4'-Bipyridine]-2'-yl)-74-((2'-fluoro-5'methoxy-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide Qz— / )— ^ZI ° dr w o N 74-(4-(6-(Dimethylamino)pyridin-3-yl)benzyl)74-(6-methyl-4-((pyridin-3 ylmethyl)amino)pyridin-2yl)cyclohexanecarboxamide

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0 U4(4'-(Dimethylamino)-[1,1'-biphenyl]-4- 1 A yl)methyl)-4-hydroxy-A-(4-((2-methylpyridine- II \ ld 0 3-yl)oxy)pyride in-2- 1 II yl)cyclohexanecarboxamide >/ ^N F D 0 'A^n^ ⁴ Y-(Deutero(2-fluoro-4-(6-methoxypyridine-3- II II N^ II yl)phenyl)methyl)-A-(2'-methoxy-[4,4'- Η Ί bipyridine]-2-yl)tetrahydro-2//-pyran-4- ^Αν χ carboxamide F D D 0 X-((4-(6-(Dimethylamino)pyridin-3-yl)-2- „ ί Αγ^Ν^ fluorophenyl )dideuteromethyl)-X-(2'-methoxy- X N^4 A/^S0 ₂ Me l l |l J [4,4'-bipyridine]-2-yl)-4- 1 Τιί Α- ^ν (methylsulfonyl)cyclohexanecarboxamide D0 A-(Deutero(4-(6-methoxypyridine-3- Ji N N^^i yl)phenyl)methyl)-4-hydroxy-L-(4- A J n Ί methylpyridin-2-yl)cyclohexanecarboxamide 0 _{N_U} A-((5-(4-(Dimethylamino)phenyl)pyridine-2- Ji Τ Ί yl)methyl)-4-hydroxy-A-(4-(isothiazole-5- Xj η Ί he Ό'^ ³ ' ylmethoxy)pyridine-2- 1 L? yl)cyclohexanecarboxamide 0 /==\A JV-((6-( 1 //- And ndazol-1 -yl) pyridin-3 -yl) methyl) - md 7U-(4-(3-methoxyphenyl)-6-methylpyridine-2- \=N d yl)cyclohexanecarboxamide 0 N^ ⁵ 4-Hydro roxy-L-((6-(4-methyl-1 R- p irazol-1 - II\ ^z 'νΆ [I Ί '^ΟΗ yl)pyridin-3 -yl)methyl)-I-(4-(5-methylpyrazin- AN ^ιΓ Ν. Η 2-yl)pyridin-2-yl)cyclohexanecarboxamide 0 (E)-N-(( 1 - (b-(Dimethylamino) pyride in-3 - N yl)piperidin-4-yl)methyl)-4-hydroxy-A-(3-(2- N^< χ/ < '^ Λ J Η Ί (oxazole-2- 1 Ν-Χ yl)vinyl)phenyl)cyclohexanecarboxamide

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about otd A LA Z— / (L)-L((6-(4-(Dimethylamino)phenyl)pyridin-3yl)methyl)-4-hydroxy-A-(3-(2-(thiazol-2yl)vinyl)phenyl)cyclohexanecarboxamide / -Z / o o lch LA • ζ— / 4-(2-(Dimethylamino)ethoxy)-A-(4-(6(dimethylamino)pyridin-3-yl)benzyl)-L(4-(3methoxyphenyl)pyridin-2yl)cyclohexanecarboxamide A I A-(4-(6-(Dimethylamino)pyridin-3-yl)benzyl)4-hydroxy-A-(3-(4-methyl-1H-pyrazol-1-yl)phenyl)cyclohexanecarboxamide Z ^ζ' ζ=\ \ 4 ^A/ ^ζ / ° 7 O O I (£)-3-Hydroxy-R-(4-(1-methyl- 1R-indazol-5 yl)benzyl)-R-(6-(2-(pyridin-3 yl)vinyl)pyrazin-2yl) cyclohexanecarboxamide o Li Li ϊ ί L L ^χ ^Ν ^ΧΧ Ν'^< ^ _Ν /° R-(2-(4-Methoxy-\H-imidazol-1-yl)-6methylpyridin-4-yl)-R-((6'-(pyrrolidin-1-yl)[2,3'-bipyridine] - 5-yl)methyl)tetrahydro-2Yapiran-4-carboxamide O ΓΥαΛ^Ί ¹ ___2 XL A ,ν. N Ν *N - O 11 U II L / \u003d. । ⁿ £ya Ν N ^-(4-(((1H-Indazol-3 yl)methyl)amino)pyrimidin-2-yl)-4-(2(dimethylamino)ethoxy)-H-(4-(6(dimethylamino)pyridine- 3 yl)benzyl)cyclohexanecarboxamide D0 ιπΛΐΛ^ jl ) nJ 1 R-(Deutero(4-(6-(dimethylamino)pyridin-3yl)phenyl)methyl)-R-(4-methylpyridin-2yl)tetrahydro-2R-pyran-4-carboxamide 0 o fnV ^0 ^ν R-(2'-Methoxy-[4,4'-bipyridin]-2-yl)-R-((5-(3(pyrrolidin-1-yl)phenyl)pyridin-2yl)methyl)tetrahydro-2R-pyran -4-carboxamide

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0 ^jcato Hl Hi ''X'X ^{1 H} M ^-((6-((4- (Dimethylamino)phenoxy)methyl)pyridin-3yl)methyl)-A-(2-(((2-methoxypyridin-4yl)methyl)amino)-6-methylpyrimidin-4yl)cyclohexanecarboxamide O Η 7^? τΊ la j uu^ \ nh η ^N N% T,F F^F 5-((4-Hydroxy-A-(4'-methyl-6'-(trifluoromethyl)[2,2'-bipyridine]-6- yl)cyclohexanecarboxamido)methyl)-7U-(1/7indazol-7-yl)picolinamide / Oh w VA Ρχ z=( oX 4^0 (E)-A-((4'-Methoxy-[1,1'-biphenyl]-4-yl)methyl)7U-(4-(2-(oxazol-2-yl)vinyl)pyridin-2yl)tetrahydro -277-pyran-4-carboxamide 0 UX00 A i /^. ^xi^x?^ N Oh ^'iL? (E)-N-(3 -(2-(1-Methyl-177-pyrazole-5- yl)vinyl)phenyl)-7U-(4-(6-(pyrrolidin-1- yl)pyr idine-3 - yl)benzyl)cyclohexanecarboxamide About I xox fj o, Ί GC N A-((4'-(Dimethylamino)-2-methyl-[1,1'-biphenyl]4-yl)methyl)-3-methyl-A-(3-(5-methylpyridin-3yl)phenyl )butanamide O όγγθψ^ ¹ U t 7U-((6'-(Dimethylamino)-[2,3'-bipyridine]-5yl)methyl)-A-(3'-(trifluoromethoxy)-[1, Hbiphenyl]-3-yl)cyclopentanecarboxamide 0 xY^aUoh - _n AA iD^d i O 7U-((6-(4-(Dimethylamino)phenyl)pyridin-3yl)methyl)-4-hydroxy-A-(6-(oxazol-2ylmethoxy)pyridazin-4yl)cyclohexanecarboxamide

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O n-n 0-(4-(5-Methyl-1,3,4-oxad iazol-2-yl)pyridine- 2-yl)-0-((6-(3 -(pyrrolidin-1 - yl)phenyl)pyridin-3-yl)methyl)tetrahydro-2Yapiran-4-carboxamide o .-/00 -.OO^ -/0 0-(4-(6-(Dimethylamino)pyridin-3-yl)benzyl)0-(2-(isoquinolin-5-yl)pyrimidin-4yl)cyclohexanecarboxamide °Gi- 0 I 0-((3'-Cyano-4'-methoxy-[1,1'-biphenyl]-4yl)methyl)-4-hydroxy-0-(4-methylpyridin-2yl)cyclohexanecarboxamide 1 τι Tl 0-(Deutero(5-(4-methoxyphenyl)pyridin-2yl)methyl)-3-methyl-0-(4-((6- (trifluoromethyl)pyridin-3-yl)methyl)pyridin2-yl)butanamide 0 _H n^V/* Ά o N^d^s _x N^ 3-Hydroxy-0-((5-(0-(5-methylpyridin-3 yl)sulfamoyl)pyrazin-2-yl)methyl)-0-(6-(2-(4- methylthiazol-2-yl)ethyl)pyrazin-2yl)cyclohexanecarboxamide /—° - / \ /— (£)-0-(2-Methyl-6-(1-methyl-III-pyrazol-Zyl)pyridin-4-yl)-0-((6-(2-(pyridin-3yl)vinyl)pyridine-3 -yl)methyl)tetrahydro-2R- pyran-4-carboxamide .--> Yz O 4 ⁰ la g z— / (£)-0-(( 1 - (b-(Dimethylamino) pyride in-3 - yl)piperidin-4-yl)methyl)-0-(6-methyl-4-(2- (oxazol-2-yl)vinyl)pyridine-2- yl)cyclohexanecarboxamide / —z O Q at) °4a) ( ^z= / ъ z— / 4-(2-(Dimethylamino)ethoxy)-0-(( 1 -(4(dimethylamino)phenyl)-3-methylpiperidin-4yl)methyl)-0-(2'-methoxy-[4,4'-bipyridine] -2yl)cyclohexanecarboxamide

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about γΧΦ Q H-((1-Benzoylpiperidin-4-yl)methyl)-A-(6methyl-4-((pyridin-3-ylmethyl)amino)pyridin2-yl)cyclohexanecarboxamide I / o o A o Ο /= ^z 4-H hydroxy-Ch-(4-(3-methoxy-5- (trifluoromethyl )phenyl )p iride and n-2-yl )-LD(1-((5methylpyridin-3-yl)sulfonyl)piperidin-4yl)methyl)cyclohexanecarboxamide DuADh 4-((4-(2-(Dimethylamino)ethoxy)-H-(2'-methoxy[3,4'-bipyridine]-5- yl)cyclohexanecarboxamido)methyl)-3-methylN-(1-methyl-1H-indazol-7-yl)piperidine-1 carboxamide ( ^{n x} o z— / 7U-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-4-hydroxy-A-(5-(5-methoxypyridin3-yl)-1-methyl- 1// -pyrazol-3 yl)cyclohexanecarboxamide O . _ν σ0 L J A y ' ia N-((1 -(b-(Dimethylamino)pyridin-3 yl)piperidin-4-yl)methyl)-H-(4-(metatolyl)quinolin-2-yl)isobutyramide 0 ^N ^1 ί ϊ ¹ nC# (E)-3-Hydroxy-7V-((1-(1-methyl-17/-indazol-5yl)piperidin-4-yl)methyl)-7V-(6-(2-(oxazol-2yl)vinyl) pyrazin-2yl)cyclohexanecarboxamide 0 N H-(5'-Methoxy-[3,3'-bipyridine]-5-yl)-U-((1-(6methoxypyride in-3-yl)piperidin-4yl)methyl)cyclohexanecarboxamide

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0 ν V ^J e N-(( 1 - (b- (Dimethylamino) pyridin-3 yl) azetidin-3 -yl) methyl ) -A - (6-methyl-4- (3 methyl- 177-pyrazol-1 -yl) pyridin-2yl )cyclohexanecarboxamide 0 JJ J ^N Y ^k —ΌΗ Q 1 ΓΪ0 X/^N \ N-((1-(4-(Dimethylamino)phenyl)pyrrolidin-3 yl)methyl)-4-hydroxy-A-(4-((1-methyl-1Nindazol-4-yl)oxy)pyridin-2yl)cyclohexanecarboxamide ^ocdo-- । IJ N 4-(2-(Dimethylamino)ethoxy)-A-((3-(4- (dimethylamino)phenyl)-3 - azabicyclo[3.1.1]heptan-6-yl)methyl)-A-(5methoxy-[3,4'-bipyridin]-2'yl)cyclohexanecarboxamide : 1 7-2 c/^ ⁷ >0 J c °>O A-(5-((3- (Methylsulfonyl)benzyl)oxy)isothiazol-3yl)-A-((6'-(pyrrolidin-1-yl)-[2,3'-bipyridin]5-yl)methyl)tetrahydro-2//-pyran-4carboxamide 0 ^<YyAy i x Xd A ^N - O \=N 4-(2-(Dimethylamino)ethoxy)-7U-(( 1 -(4(dimethylamino)phenyl)pyrrolidin-3yl)methyl)-7U-(3-(pyrimidin-4-yl)isoxazol-5yl)cyclohexanecarboxamide 0 cY^N^yY (Ργ ^N '^ if^N ^OH 1 nP (E)-7U-((1-(4-(Dimethylamino)phenyl)piperidin4-yl)methyl)-4-hydroxy-7U-(6-(2-(oxazol-2yl)vinyl)pyridin-2yl)cyclohexanecarboxamide D 0 I /γ^N^^ ⁴ rr ^N ^ A ld D A-(Deutero(1-(4-methoxyphenyl)piperidin-4yl)methyl)-7U-(4-(3-methoxyphenyl)pyridin-2yl)-3-methylbutanamide

- 54 040003

- Hydroxy-L -((2-(methoxymethyl)-1-(1-methyl1H-indazol-5-yl)pyrrolidin-3-yl)methyl)-A-(6(oxazol-2-ylmethoxy)pyrazine -2yl)cyclohexanecarboxamide (E)-N-(l -Methyl-5-(2-(oxazol-2-yl)vinyl)-N1,2,4-triazol-3 -yl)-A-((6-( 3-(pyrrolidin-1 yl)phenyl)pyridin-3-yl)methyl)tetrahydro-2Yapiran-4-carboxamide

N-((1-(4-(Dimethylamino)phenyl)piperidin-4yl)methyl)-4-hydroxy-A-(5-((5-methylpyridin3-yl)oxy)oxazol-2yl)cyclohexanecarboxamide

A-((4'-(Dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-A-(3-(3-methylbut-2-en-1 yl)phenyl)cyclohexanecarboxamide

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

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

The term pharmaceutically acceptable salt refers to the form of the therapeutically effective 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 typically more soluble and more rapidly soluble in the stomach and gastric juice than non-ionic species, and thus usable as a solid dosage form. Moreover, since their solubility is often a function of pH, selective dissolution in one or the other part of the gastrointestinal tract is possible and this ability can be controlled as one aspect of extended and sustained release regimens. Also, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with an acid to form a pharmaceutically acceptable acid addition salt. In some embodiments, the compound described herein (i.e., the 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; 2hydroxyethanesulfonic 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); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid;

- 55 040003 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 (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2sulfonic acid; nicotinic acid; butyric 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 (para) and undecenoic 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 of the present invention 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 cases, the acidic proton of the compound described herein is replaced by a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described in the present invention interact 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, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds of the present invention are provided 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 solvent addition products. In some embodiments, the solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed if the solvent is water, or alcoholates are formed if the solvent is alcohol. Solvates of the compounds described in the present invention for the sake of convenience were obtained or formed during the methods described in the present invention. In addition, the compounds of the present invention optionally exist in unsolvated as well as solvated forms.

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

In some embodiments, sites on organic radicals (eg, alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Inclusion of appropriate substituents on organic radicals will shorten, minimize or eliminate such a metabolic pathway. In particular embodiments, an appropriate substituent for reducing or desensitizing 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, without limitation, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein include isotopically labeled compounds which are identical to the compounds set forth in the various formulas and structures provided herein, but with one or more atoms replaced by an atom with an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be included in the compounds of the present invention 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, compounds in which radioactive

- 56 040003 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 benefits resulting from greater resistance to metabolic inactivation, such as, for example, increased in vivo half-life or reduced dosage. In some embodiments, one or more hydrogen atoms of the compounds described herein have been replaced with deuterium.

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

Individual stereoisomers were obtained, if necessary, by methods such as stereoselective synthesis and/or separation of stereoisomers using 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, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. According to another embodiment, diastereomers are separated by separation/cleavage methods based on differences in solubility. In other embodiments, separation of stereoisomers was performed 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. The term prodrug refers to an agent that is converted to the parent drug in vivo. Prodrugs are often used because they are easier to administer than the parent drug in some situations. They are, for example, bioavailable by oral administration, while the parent drugs are not. The prodrug may be a substrate for the transporter. Alternatively or alternatively, the prodrug also has improved solubility in the pharmaceutical composition compared to the parent drug. In some embodiments, the prodrug design enhances effective water solubility. A non-limiting example of a prodrug is a compound described herein that is administered as an ester (prodrug) but is then metabolically hydrolyzed to provide an active entity. Another example of a prodrug is a short peptide (polyamino acid) linked to an acidic group, the peptide being metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized in one or more steps or one or more processes to the biologically, pharmaceutically or therapeutically active form of the compound.

Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, Nacyloxyalkyl derivatives, tertiary amine quaternary derivatives, Mannich N-bases, Schiff bases, amino acid conjugates, phosphoric acid esters. acids and esters of sulfuric acid. See, for example, Design of Prodrugs, Bundgaard, A. Ed., Elsevier, 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 ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, ether, etc. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (ie, a prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

Prodrugs of the compounds described herein, where the prodrug is metabolized in vivo to provide 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 a prodrug for another derivative or active compound.

In additional or further 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 effect the desired effect, including the desired therapeutic effect.

The term metabolite of a compound disclosed herein means a derivative of the compound that 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 metabolizable refers to the sum of processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) in which a particular substance is altered by the body. Thus, enzymes can provide certain structural changes in compounds. For example, cytochrome P450 catalyses a number of oxidative and reductive 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 the recipient and analyzing tissue samples from the recipient, 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 have substantially reduced FXR agonist activity.

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

In additional or further embodiments, the compounds are rapidly metabolized by the intestinal tract.

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

Synthesis of compounds

The compounds described in the present invention were synthesized using standard synthetic procedures or using methods known in the art in combination with the methods described in the present invention.

Unless otherwise noted, traditional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology were used.

Compounds were 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 synthesis transformations described herein can be used, such as solvent variations, reaction temperature, reaction time, as well as various chemicals and other reaction conditions. The starting materials are available from commercial sources or are readily available.

Suitable reference publications and treatises that describe in more detail the synthesis of the reagents used to prepare the compounds described in the present invention, or which 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., WileyInterscience, New York, 1992 which provide links to articles that describe 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: 0-471-60180-2; Otera, J. (editor) Modern Carbonyl Chemistry (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Func- tional 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 in the present invention were prepared by the general synthetic routes described below in Schemes 1-12.

In some embodiments, the compounds described herein are prepared as described in Scheme 1.

Scheme 1.

1-1 I-2 I-3 G5

Z ¹ \u003d Br, Ph, OPh, CH ₂ NHBoc,

I, CO ₂ Me.-η

CO ₂ Me

In Scheme 1, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, ^RC is -N(R ¹⁰ )2 and p is 1. In some embodiments, R ¹⁰ is methyl. In some embodiments, Z ¹ is a substituent as shown in Scheme 1. In some embodiments, Z ¹ is halo, aryl, -O-aryl, -CH2(NH)(R), CO2R, alkenyl, or cycloalkyl; and R is alkyl such as Me or Boc.

As shown in Scheme 1, compound 1-3 was prepared by subjecting aldehyde I-1 and amine I-2 to reductive amination conditions. In some embodiments, the aldehyde I-1 and amine I-2 are first treated under acidic conditions, e.g., AcOH in DCE at rt. for from about 5 minutes to about 1 hour, followed by the addition of an appropriate reducing agent, such as NaBH(OAc) ₃ , for an appropriate time at a suitable temperature, for example, at room temperature. for about 15 minutes to about 1 hour. In some embodiments, acylation of the amino compound I-3 with acid chloride I-4 gives compound I-5. Suitable acylation conditions include, but are not limited to, TEA or pyridine in a suitable solvent such as DCM for an appropriate time and temperature, such as at about 0°C for about 15 minutes to about 2 hours. In some embodiments, the appropriate time and the temperature is from about 0° C. to rt. for about 2 to about 10 hours.

In some embodiments, the compounds described herein are prepared as described in Scheme 2.

Scheme 2.

11-1 N-2 N-4 N-6

Z ² \u003d NO ₂ , alkenyl, alkenyl heterocycle

In Scheme 2, rings A, B, and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ^c is -N(R ¹⁰ ) ₂ and p is 1. In some embodiments, R ¹⁰ is methyl.

As shown in Scheme 2, compound II-2 can be obtained from the amino compound II-1 according to some embodiments. In some embodiments, acylation of the amino compound II-1 with acid chloride I-4 provides compound II-2. Suitable acylation conditions include, without limitation, TEA or pyridine in a suitable solvent such as DCM or ACN for an appropriate time at a suitable temperature. In some embodiments, the appropriate time and temperature is about 1 hour at about 0°C and then about 11 hours at RT. In some embodiments, the appropriate temperature is from about 0°C to rt. In some embodiments, Compound II-4 is prepared from N-alkylation of Compound II-2 with benzyl bromide II-3 with a suitable base and a suitable solvent such as ACN, THF, or DMF at the appropriate

- 59 040003 temperature for the appropriate time. Suitable bases include, without limitation, CS2CO3 and NaH. In some embodiments, Compound II-2 is pre-treated with a suitable base for an appropriate time at a suitable temperature, eg, about 0.5 hour at about 0° C., prior to addition of II-3 benzyl bromide. In some embodiments, the appropriate time and temperature is from about 3 to about 12 hours and about 90°C. In some embodiments, the appropriate time and temperature is about 2.5 hours and from about 0°C to rt. In some embodiments, the appropriate time and temperature is about 24 hours and about 80°C. In some embodiments, Compound II-6 was prepared from a palladium-catalyzed cross-linking reaction of bromide II-4 with boronic acid II-5. In some embodiments, if R ^c is -N(R ¹⁰ )2, p is 1, and R ¹⁰ is methyl, compound II-5 is in free amine or corresponding salt form. Suitable palladium catalysts for the cross-linking reaction include, without limitation, Pd(PPh3) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd(dppf)Cl ₂ in a suitable solvent such as DMF, dioxane/H ₂ O, THF and EtOH/ H ₂ O, with the appropriate base at the appropriate temperature for the appropriate time. In some embodiments, the appropriate base is Na ₂ CO ₃ , CS ₂ CO ₃ , CsF or NaHCO ₃ . In some embodiments, a suitable temperature is about 75°C, about 80°C, about 90°C, or about 100°C. In some embodiments, the appropriate amount of time is about 5 hours, about 12 hours, or about 24 hours.

In some embodiments, the compounds described herein are prepared as described in Scheme 3.

Scheme 3.

In Scheme 3, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ^c is -F and p is 1.

As shown in Scheme 3, compound III-3 was prepared by subjecting aldehyde III-2 and amine III-1 to reductive amination conditions. In some embodiments, the aldehyde III-2 and amine III-1 are first subjected to acidic conditions, such as AcOH in DCE, then an appropriate reducing agent, such as NaBH(OAc) ₃ , is added for the appropriate time at a suitable temperature, e.g., at r. i.e. for about 1 hour. In some embodiments, acylation of the amino compound III-3 with acid chloride I-4 gave compound III4. Suitable acylation conditions include, but are not limited to, TEA or pyridine in a suitable solvent such as DCM for an appropriate time at a suitable temperature, such as at about 0°C for about 1 hour. In some embodiments, Compound III-6 is prepared from palladium -catalyzed cross-linking reaction of bromide III-4 with boronic acid III-5. Suitable palladium catalysts for the cross-linking reaction include, without limitation, Pd(dppf)Cl ₂ in a suitable solvent such as DMF with an appropriate base at an appropriate temperature for an appropriate time. In some embodiments, the appropriate base is CS2CO3. In some embodiments, a suitable temperature is about 80°C. In some embodiments, the appropriate amount of time is approximately 1 hour.

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

- 60 040003

Scheme 4.

In Scheme 4, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ^c is -N(R ¹⁰ )2 and p is 1. In some embodiments, R ¹⁰ is methyl. In some embodiments, ^RD is -OMe and q is 1. In some embodiments, Z ⁶ is n-propyl. In some embodiments, X is bromine. In some embodiments, X is iodine. In some embodiments, X is chlorine.

In some embodiments, the halide IV-1 is further functionalized by a palladium-catalyzed cross-linking reaction with the appropriate cross-linker. In some embodiments, halide IV-I is reacted with amine IV-2 to give compound IV-3 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, the hydrochloride salt of amine IV-2 was used in place of amine IV-2. In some embodiments, a suitable palladium catalyst is Pd(OAc) ₂ or Pd ₂ (dba) ₃ . Examples of suitable ligands for the cross-linking reaction include, but are not limited to, SPhos, TrixiePhos, and XantPhos. In some embodiments, a suitable solvent is PhMe. In some embodiments, a suitable solvent is dioxane. In some embodiments, the appropriate base is K3PO4. In some embodiments, the appropriate base is CS2CO3. In some embodiments, the corresponding temperature is approximately 100°C. In some embodiments, the appropriate amount of time is about 3 hours. In some embodiments, the appropriate amount of time is from about 18 to about 26 hours.

In some embodiments, halide IV-I is reacted with boronic acid IV-4 to give compound IV-7 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(dppf)Cl ₂ . In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable base is CS ₂ CO ₃ . In some embodiments, a suitable temperature is about 80°C. In some embodiments, the appropriate amount of time is from about 2 to about 22 hours.

In some embodiments, halide IV-I is reacted with boronic acid IV-5 to give compound IV-6 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(dppf)Cl2. In some embodiments, a suitable solvent is dioxane. In some embodiments, a suitable base is K ₂ CO ₃ . In some embodiments, a suitable temperature is about 80°C. In some embodiments, the appropriate amount of time is approximately 5 hours.

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

- 61 040003

Scheme 5.

In Scheme 5, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, ^RC is -N(R ¹⁰ )2 and p is 1. In some embodiments, R ¹⁰ is methyl.

In some embodiments, Compound V-1 is subjected to appropriate acidic conditions to form Compound V-2. In some embodiments, the appropriate acidic conditions are TFA in a suitable solvent, such as DCM, at a suitable temperature for an appropriate time, eg, RT. for about 0.5 hours. In some embodiments, compound V-2 is reacted with methyl chloroformate V-3 to give compound V-4 in the presence of a suitable base and solvent at a suitable temperature for an appropriate time. In some embodiments, a suitable base is TEA. In some embodiments, a suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate time is from about 0°C for about 0.25 hours.

Alternatively, compound V-2 was reacted with acid chloride V-5 to give compound V-6 in the presence of a suitable base and solvent at a suitable temperature for an appropriate time. In some embodiments, a suitable base is TEA. In some embodiments, a suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate time is about 0° C. for about 0.25 hours. In some embodiments, compound V-6 is further processed under basic conditions to give cyclized compound V-7. In some embodiments, a suitable base is NaH. In some embodiments, a suitable solvent is DMF. In some embodiments, the corresponding temperature for the corresponding time is about 0°C for about 0.25 hours.

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

Scheme 6.

In Scheme 6, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, R ^c is -N(R ¹⁰ )2 and p is 1. In some embodiments, R ¹⁰ is methyl.

In some embodiments, as shown in Scheme 6, Compound VI-2 was prepared from a reduction of Compound VI-1. Suitable reaction conditions for reduction include H2 (50 psi) with 10% Pd/C in a suitable solvent at a suitable temperature for an appropriate time. In some embodiments, a suitable solvent is MeOH. In some embodiments, the corresponding temperature is RT and the corresponding time is approximately 24 hours.

In some embodiments, Compound VI-2 is further reacted with Compound VI-3 under basic conditions to provide Compound VI-4. Suitable basic conditions include NaHCO ₃ in a suitable solvent at a suitable temperature in

- 62 040003 for the relevant time. In some embodiments, a suitable solvent is DMF. In some embodiments, the appropriate temperature is about 75°C and the corresponding time is about 6 hours. In some embodiments, compound VI-4 is further N-alkylated to give compound VI-5 by two-step treatment using CH2O with AcOH in a suitable solvent, such as MeOH for an appropriate time at a suitable temperature, for example for about 2 hours at rt. in the first step and a reducing agent such as NaBH ₃ CN for an appropriate time at a suitable temperature, eg for about 16 hours at room temperature. at the second stage.

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

Scheme 7.

^Z8 = Me; VII-1 -----► z ⁸ = H; VII-2

Z ⁹ \u003d H or Me

In Scheme 7, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, ^RC is -N(R ¹⁰ ) ₂ and p is 1. In some embodiments, R ¹⁰ is methyl.

Alternatively, compound VII-1 may be subjected to basic conditions to give compound VII-2. Suitable basic conditions include the use of NaOH (1M) in a suitable solvent for an appropriate time at a suitable temperature, for example, for about 2 hours at rt. In some embodiments, a suitable solvent is THF/MeOH. In some embodiments, compound VII-4 is prepared by treating compound VII-2 with amine VII-3 and a binder in the presence of the appropriate amine in the appropriate solvent for the appropriate time at the appropriate temperature. In some embodiments, Compound VII-2 is pre-treated with a binder for an appropriate time at a suitable temperature, eg, 1 hour at RT, prior to addition of Compound VII-3. In some embodiments, the binder is HATU. In some embodiments, the amine base is iPr ₂ NEt. In some embodiments, a suitable solvent is DMF. In some embodiments, the reaction was allowed to run for about 0.5 hour at rt. after addition of amine VII-3.

In some embodiments, intermediates used in the preparation of the compounds described herein were prepared as described in Scheme 8.

Scheme 8.

In scheme 8, ring B is described in the present invention. In some embodiments, compound VIII-3 was prepared from a palladium-catalyzed Heck cross-linking of VIII-1 iodide with VIII-2 acrylate. Suitable conditions for the palladium-catalyzed cross-linking reaction include an appropriate source of palladium such as Pd ₂ dba ₃ with the appropriate ligand and base and solvent at the appropriate temperature for the appropriate time. In some cases, P(ortho-tolyl) ₃ is a suitable ligand. In some cases, TEA is a suitable base. In some cases, a suitable solvent is DMF. In some cases, the corresponding temperature is about 80°C or about 90°C. In some cases, the appropriate reaction time is from about 5 hours to about 12 hours. In some embodiments, compound VIII-3 is subjected to basic conditions to form acid VIII-4. Examples of suitable basic conditions include, without limitation, the use of LiOH in a suitable solvent, such as THF, at a suitable temperature for an appropriate time, such as at RT for about 12 hours.

- 63 040003 but in some embodiments, the VS-5 compound is prepared by treating the VS-4 compound with PhI(OAc)2 and Et4NBr in a suitable solvent such as DCM for an appropriate time at a suitable temperature, e.g., approximately 16 hours at r.t. In some embodiments, Compound VIII-6 is prepared by reacting Compound VIII-5 with oxazole in the presence of Pd(OAc)2, CuI, and phenanthroline with a suitable base and solvent at a suitable temperature for an appropriate time, e.g., at about 120° C. for about 12 hours. In some embodiments, LiOtBu is a suitable base. In some embodiments, a suitable solvent is dioxane. In some embodiments, more oxazole was added to the reaction mixture after about 12 hours, and the reaction was allowed to run for about another 12 hours at about 120°C. In some cases, the USh-6 compound was subjected to transition metal reduction conditions to give the USh-7 amine. Suitable reaction conditions for mediated transition metal reduction include, but are not limited to, Fe, NH4C1 in suitable solvent mixtures at a suitable temperature for an appropriate time. In some embodiments, a suitable solvent is EtOH and H ₂ O. In other cases, the appropriate temperature is about 90°C and the corresponding time is about 12 hours.

In some embodiments, intermediates used in the preparation of the compounds described herein were prepared as described in Scheme 9.

Scheme 9.

In scheme 9, ring B is described in the present invention. In some embodiments, amide IX-3 is prepared by treating amine IX-1 with acid IX-2 and a binder in the presence of a suitable base in a suitable solvent for an appropriate time at a suitable temperature. In some embodiments, the binder is HATU. In some embodiments, the base is TEA. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable time at a suitable temperature is about 14 hours at RT. In some embodiments, compound IX-4 is prepared by oxidizing compound IX-3 with MnO ₂ in the presence of a suitable solvent for an appropriate time at a suitable temperature. In some embodiments, a suitable solvent is DCM. In some embodiments, a suitable time at a suitable temperature is about 12 hours at about 80°C. In some embodiments, compound IX-5 is prepared from a one-carbon homologation reaction of compound IX-4, such as a Wittig reaction. In some embodiments, the Wittig reaction is carried out with EtPPh3 ⁺ Br with an appropriate base in a suitable solvent. In some embodiments, a suitable base is tBuOK. In some embodiments, a suitable solvent is THF. In some embodiments, the EtPPh ₃ ⁺ Br- is pre-mixed with the base for the appropriate time at the appropriate temperature, eg, 0.5 h at rt, before adding the aldehyde IX-4. In some embodiments, after the addition of aldehyde IX-4, the reaction was carried out at rt. within approximately 12 hours.

In some embodiments, the compounds described herein are prepared as described in Scheme 10.

Scheme 10.

- 64 040003

In Scheme 10, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, ^RC is -N(R ¹⁰ )2 and p is 1. In some embodiments, X is bromine. In some embodiments, X is iodine. In some embodiments, X is chlorine. In some embodiments, IV-2a is a substituted or unsubstituted azetidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted piperidine. In some embodiments, ring D of compound IV-4a is a 6-membered heterocycle or a 5-membered heterocycle. In some embodiments, Z ¹⁰ is a 6-membered heterocycle or a 5-membered heterocycle. In some embodiments, Z ¹⁰ is 2-pyridyl or 4-pyridyl.

In some embodiments, halide IV-1 is further functionalized by a palladium-catalyzed cross-linking reaction with the appropriate cross-linker. In some embodiments, halide IV-I is reacted with amine IV-2a to give compound IV-3a under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, the hydrochloride salt of amine IV-2a was used instead of amine IV-2a. In some embodiments, a suitable palladium catalyst is Pd(OAc) ₂ or Pd ₂ (dba) ₃ . Examples of suitable ligands for the cross-linking reaction include, but are not limited to, SPhos, TrixiePhos, and XantPhos. In some embodiments, a suitable solvent is PhMe. In some embodiments, a suitable solvent is dioxane. In some embodiments, a suitable base is K ₃ PO ₄ . In some embodiments, a suitable base is CS ₂ CO ₃ . In some embodiments, a suitable temperature is about 100°C. In some embodiments, the appropriate amount of time is about 3 hours. In some embodiments, the appropriate amount of time is from about 18 to about 26 hours.

In some embodiments, halide IV-I is reacted with boronic acid IV-4a to give compound IV-7a under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(dppf)Cl ₂ . In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable base is CS ₂ CO ₃ . In some embodiments, a suitable temperature is about 80°C.

In some embodiments, halide IV-I is reacted with compound X-1 to give compound X-2 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(OAc) ₂ . In some embodiments, a suitable ligand is P(ortho-tolyl) ₂ . In some embodiments, a suitable solvent is DMF. In some embodiments, a suitable base is Et ₃ N. In some embodiments, a suitable temperature is approximately 80°C. In some embodiments, the appropriate amount of time is approximately 1 hour.

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

Scheme 11.

In Scheme 11, rings A, B and C are described in the present invention. In some embodiments, R ³ is cyclohexyl. In some embodiments, ^RC is -N(R ¹⁰ ) ₂ and p is 1. In some embodiments, X is bromine. In some embodiments, X is iodine. In some embodiments, X is chlorine. In some embodiments, ring D of compound X1-2 is a 6-membered heterocycle or a 5-membered heterocycle. In some embodiments, X ¹ is bromine or iodine.

In some embodiments, halide IV-1 is further functionalized by a palladium-catalyzed cross-linking reaction with the appropriate cross-linker. In some embodiments, halide IV-I is reacted with (Bpin)2 to give compound X1-1 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(dppf)Cl ₂ . In some embodiments, a suitable solvent is dioxane.

In some embodiments, a suitable base is KOAc. In some embodiments, a suitable temperature is about 80°C. In some embodiments, the appropriate amount of time is all night.

In some embodiments, compound XI-1 is reacted with halide X1-2 to give compound X1-3 under appropriate palladium-catalyzed cross-link reaction conditions. In some embodiments, a suitable palladium catalyst is Pd(dppf)Cl ₂ . In some embodiments, a suitable solvent is dioxane or DMF. In some embodiments, a suitable base is CS ₂ CO ₃ . In some embodiments, a suitable temperature is about 80°C.

In some embodiments, intermediates used in the preparation of the compounds described herein were prepared as described in Scheme 12.

Scheme 12.

In Scheme 12, rings A, B and C are described in the present invention. In some embodiments, p is 2 and each R ^c is independently selected from -OR ¹⁰ and substituted or unsubstituted C ₁ -C ₆ alkyl such as methyl. In some embodiments, R ¹⁰ is methyl. In some embodiments, X is bromine. In some embodiments, X is iodine. In some embodiments, X is chlorine. In some embodiments, X ² is bromine. In some embodiments, X ² is iodine.

In some embodiments, the boronic ester XII-1 is reacted with the halide XII-2 under appropriate palladium-catalyzed cross-link reaction conditions to give compound XII-3. In some embodiments, appropriate conditions for the palladium-catalyzed cross-link reaction include Pd(dppf)Cl ₂ with an appropriate base, such as 1 M Na ₂ CO ₃ , with an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, the appropriate solvent is dioxane. In some embodiments, the corresponding time and the corresponding temperature is about 2.5 hours at about 50°C. In some embodiments, Compound XII-3 has been subjected to suitable palladium-catalyzed hydrogenation conditions followed by treatment under appropriate acidic conditions to give cyclohexanone XII-4. In some embodiments, suitable palladium-catalyzed hydrogenation conditions include 10% Pd/C with hydrogen (1 atm) in a suitable solvent such as EtOAc for an appropriate time at a suitable temperature. In some embodiments, the appropriate amount of time is approximately 4.5 hours at room temperature. In some embodiments, appropriate acidic conditions include formic acid in water and toluene for an appropriate time at a suitable temperature. In some embodiments, a suitable amount of time at a suitable temperature is about 4 hours at about 120°C. In some embodiments, compound XII-4 is reacted under suitable homologation reaction conditions to increase the carbon chain by one atom to give compound XII-5. In some embodiments, suitable conditions for the one atom homologation reaction include pretreatment of (methoxymethyl)triphenylphosphonium chloride [Ph ₃ P ⁺ CH=OCH ₃ Cl ^- ] with an appropriate base, such as NaHMDS, in an appropriate solvent for an appropriate time at a suitable temperature before adding cyclohexanone XII-4. In some embodiments, the appropriate solvent is THF. In some embodiments, the appropriate amount of time at a suitable temperature is about 30 minutes at about 0°C. In some embodiments, after compound XII-4 is added, the reaction is continued for an additional approximately 30 minutes at approximately 0°C. In some embodiments, compound XII-5 is then subjected to suitable acidic conditions to give a mixture of cis- and transaldehydes XII-6. In some embodiments, suitable acidic conditions include formic acid in water/toluene at about 120° C. for about 2 hours. In some embodiments, additional exposure of the aldehyde XII-6 to the appropriate basic conditions yielded most of the trans aldehyde XII-6. In some embodiments, appropriate basic conditions include NaOH in a mixture of suitable solvents such as EtOH and PhMe for an appropriate time at a suitable temperature. In some embodiments, the appropriate amount of time at a suitable temperature is about 5.5 hours at room temperature. In some embodiments, further purification by crystallization or chromatography provides pure trans-aldehyde XII-6. In some embodiments, the trans aldehyde XII-6 is further reacted with the corresponding aniline compound to give compound XII-7. In some embodiments, the trans aldehyde XII-6 is reacted with the corresponding aniline compound under suitable reaction conditions. In some embodiments, suitable reaction conditions include acetic acid in an appropriate solvent, such as DCM, at a suitable temperature for an appropriate time. In some embodiments, the appropriate temperature is approximately room temperature. In some embodiments, a suitable amount of time is from about 5 minutes to about 1 hour. In some embodiments, the reaction is then further subjected to suitable conditions to obtain compound XII-7. In some embodiments, suitable conditions include NaBH(OAc) ₃ for an appropriate time at a suitable temperature. In some embodiments, the appropriate amount of time is from about 1 to about 16 hours. In some embodiments, the appropriate temperature is room temperature.

In some embodiments, compound XII-7 is then subjected to appropriate conditions to give a compound where X ² is R ^B as described in the present invention. In some embodiments, Compound XII-7 is then subjected to appropriate conditions to provide a compound where Ring B is substituted as shown in any of Schemes 1-11, such as Schemes 1, 2, 4, 10, and 11. In some embodiments, compound XII-7 is then subjected to the appropriate conditions to give a compound where X ² is Z ¹ as described in Scheme 1. In some embodiments, compound XII-7 is then subjected to the appropriate conditions to give a compound where X ² is Z ² , as described in diagram 2.

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

Certain terminology

Unless otherwise noted, 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 include, includes, and included is not limited. The section headings used herein are for organizational purposes only and are not intended to limit the subject matter discussed.

As used herein, C ₁ -C _x includes C ₁ -C ₂ , € ₁ - € ₃ . . . C ₁ -C _x . By way of example only, a group denoted as C ₁ -C ₄ means that there are from one to four carbon atoms in the moiety, i. e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, C ₁ -C ₄ alkyl means that the alkyl group has from one to four carbon atoms, i.e., 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. The alkyl group is a branched or straight chain. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms, i.e. C ₁ -C ₁₀ alkyl. In all cases where it occurs, a range of numeric values, such as 1-10, refers to each integer in the represented range; e.g. 1-10 carbons means that the alkyl group consists of 1 carbon, 2 carbons, 3 carbons, 4 carbons, 5 carbons, 6 carbons, etc., up to and including 10 carbons, although the present definition also covers the occurrence of the term alkyl, where the range of numerical values is not indicated. In some embodiments, alkyl is C ₁ -C ₆ αkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,

- 67 040003 sec-butyl, tertiary butyl, pentyl, neopentyl or hexyl.

An alkylene group refers to a divalent alkyl radical. Any of the aforementioned monovalent alkyl groups can be alkylene by removing a 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 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). Exemplary alkylene groups include, without limitation -CH2-, -CH( _CH3 )-, -C( _CH3 ) _2- , -CH2CH2-, -CH2CHCH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2- etc.

Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of the alkyl are 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)=CR ₂ 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(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, 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=CR, where R refers to the remaining moieties 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 -C^CH, -C^CCH ₃ -C^CCH ₂ CH ₃ , -CH ₂ C^CH.

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

The term alkylamine refers to a -K(alkyl) _x H _y group 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 with a delocalized π 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 fused ring polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.

The term carbocyclic or carbocycle refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings or heterocycles in which the ring backbone contains at least one atom that is different from the carbon atom. 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, where 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 -C ₁₀ aryl. Depending on the structure, the aryl group is monoradical or biradical (ie, arylene group).

The term cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, where 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 atom 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 C1-C ₆ fluoroalkyl.

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 C1-C6fluoroalkyl. 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 skeletal alkyl atoms are selected from atoms other than carbon, eg, oxygen, nitrogen (eg, -NH-, -N(alkyl)-), 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 C1- _C6 heteroalkyl.

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, with each heterocyclic group containing from 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 connection links. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Примерами неароматических гетероциклических групп являются пирролидинил, тетрагидрофуранил, дигидрофуранил, тетрагидротиенил, оксазолидинонил, тетрагидропиранил, дигидропиранил, тетрагидротиопиранил, пиперидинил, морфолинил, тиоморфолинил, тиоксанил, пиперазинил, азиридинил, азетидинил, оксетанил, тиетанил, гомопиперидинил, оксепанил, тиепанил, оксазепинил, диазепинил, тиазепинил , 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl , dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3 -dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4dihydroquinoline-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl and quinolisinyl. 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, phthalazinyl , pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. 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) or pyrrol-3-yl (C-attached). In addition, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-linked) . 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, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8naphthyridine, and pteridine. In some embodiments, heteroaryl contains 0-4 ring N atoms. In some embodiments, heteroaryl contains 1-4 ring N atoms. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, heteroaryl is C1-C9heteroaryl. In some embodiments, the monocyclic heteroaryl is C1- _C5 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, without limitation, 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 simple bond refers to a chemical bond between two atoms or two fragments if the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, if the group described herein is a bond, there is no control group, thus allowing bond formation between the remaining established groups.

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

The term optionally substituted or substituted means that the control group is optionally substituted with one or more additional group(s) individually and independently selected from D, halo, -CN, -NH2, -NH(alkyl), -M(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 , alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone and arylsulfone. In certain other embodiments, the optional substituents are independently selected from D, halo, -CN, -NH2, -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -CO ₂ (C ₁ - C4alkyl), -C(=O)NH ₂ , -C(=O)NH(C ₁ C ₄ alkyl), -C(=O)N(C ₁ -C ₄ αkyl) 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, C 1 -C ₄ heteroalkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ fluoroalkoxy, -SC ₁ -C ₄ alkyl, -S (= O)C ₁ -C ₄ alkyl and -S(=O) ₂ C ₁ -C ₄ alkyl. In some embodiments, the optional substituents are independently selected from D, halo, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH ₃ , -CH ₂ CH ₃ , -CF ₃ , - OCH ₃ and -OCF ₃ . In some embodiments, substituted groups are substituted with one or two preceding groups. In some embodiments, the optional substituent on the aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

Used in the present invention, the term acceptable in relation to the composition, composition or ingredient means not having a permanent adverse effect on the general health of the subject who was treated.

As used herein, the term modulate means interacting with a target either directly or indirectly to change the activity of the target, including, by way of example only, increasing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

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

As used herein, the terms administer, administer, administer, etc. refer to methods that can be used to effect delivery of compounds or compositions to a desired site of biological action. Such 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 aware of 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 terms co-administration or the like encompass the administration of selected therapeutic agents to a single patient and 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 the agent or compound to be administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and/or amelioration of the signs, symptoms, or causes of a disease, or some other desired change in the biological system. For example, an effective amount for therapeutic applications is the amount of a composition containing a compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. The appropriate effective amount in any particular case is optionally determined using techniques such as a dose escalation study.

As used herein, the terms enhance or amplify means to increase or prolong either the efficacy or the duration of the desired effect. Thus, in relation to the enhancing effect of therapeutic agents, the term enhancement refers to the ability to increase or prolong either the efficacy or the duration of the effect of other therapeutic agents in the system. As used herein, the term enhancing effective amount refers to an amount suitable to enhance the effect of another therapeutic agent in the desired system.

As used herein, the term pharmaceutical combination means a product that is the result of mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term fixed combination means that the active ingredients, for example both the compound described herein or a pharmaceutically acceptable salt thereof, and the co-agent are administered to the patient simultaneously in the form of a single substance or dosage. The term non-fixed combination means that the active ingredients, for example, both the compound described herein, or a pharmaceutically acceptable salt thereof, and a joint agent, are administered to the patient as separate substances, either simultaneously, in parallel, or sequentially without any specific time intervals. , while such an introduction provides an effective 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 includes mammals. Examples of mammals include, without limitation, any member of the class Mammals: humans, non-human primates such as chimpanzees and other narrow-nosed monkeys, and other types of monkeys; 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, guinea pigs, etc. In one aspect, the mammal is a human.

As used herein, the terms treat, process of treatment, or treatment include reducing, alleviating, or alleviating at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as delaying the development of a disease or condition, ameliorating a disease or condition, providing regression of the disease or condition, amelioration of the condition caused by the disease or condition, or suspension of the 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 conventionally formulated using one or more pharmaceutically acceptable inactive ingredients which facilitate the processing of the active compounds into pharmaceutically useful formulations. The appropriate composition depends on the chosen route of administration. Brief descriptions of the pharmaceutical compositions described herein are, for example, 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

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Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), 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 may be by any method that delivers the compounds to the site of action. These methods include, without limitation, delivery by enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including cutaneous, skin, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and impairment of the recipient. By way of example only, the compounds described herein may be administered locally to the site in need of treatment, such as 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 at the site of the diseased tissue or organ.

In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous medium. , or a non-aqueous medium, 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, and soft, stoppered capsules made from gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be obtained by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine 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 prepared by shaping in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient from them. 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. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain acacia, 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 to identify or characterize different dose combinations of the active compound.

In some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, eg, 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-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, such as saline or sterile, pyrogen-free water. , immediately before use. Extemporaneous injection solutions and suspensions 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, bacteriostatics, and dissolved components that render the formulation isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or carrier vehicles 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 carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to ensure that highly concentrated solutions are 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, compounds can be formulated with 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 by conventional means. Such compositions may contain the active ingredient in a flavor base such as sucrose and gum acacia or gum tragacanth.

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

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

Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetrating the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or patches and drops suitable for administration to the eye, ear or nose. . For topical administration, the active ingredient may comprise from 0.001 to 10% w/w, for example 1 to 2% by weight of the composition.

Pharmaceutical compositions for administration by inhalation are conveniently delivered by insufflator, pressurized aerosol cans, or other suitable aerosol spray delivery means. The pressurized cylinders 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 may 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.

It should be appreciated that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein may include other agents conventional in the art relevant to the type of formulation in question, for example, agents suitable for oral administration, may include flavoring agents.

Dosing routes and treatment regimens

In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the manufacture 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 include administering to said mammal pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt thereof. , active metabolite, prodrug, or pharmaceutically acceptable solvate, in therapeutically effective amounts.

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 a diabetes mellitus-related disorder or conditions, alcoholic or non-alcoholic liver disease, intestinal inflammation-related conditions, or cell proliferation disorders.

In certain embodiments, the compositions containing the compound(s), opi

- 73 040003 referred to herein are administered for prophylactic and/or therapeutic treatments. In some 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 relieve at least one of the symptoms of the disease or condition. Amounts effective for such use will depend upon the severity and course of the disease or condition, prior therapy, the health of the patient, weight and response to drugs, and the judgment of the attending physician. Therapeutically effective amounts are optionally determined by methods including but not limited to dose escalation and/or dose variation clinical trials.

In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for 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 status, weight, etc. When used in patients, effective amounts for such use will depend upon the severity and course of the disease or condition, prior therapy, the health of the patient, weight and response to drugs, and the judgment of the attending physician. In one aspect, prophylactic treatments comprise 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 as described herein, or a pharmaceutically acceptable salt thereof, for prevent the return of symptoms of a disease or condition.

In certain embodiments, if the patient's condition does not improve, then at the physician's discretion, the compounds are administered chronically, that is, for an extended period of time, including throughout the life of the patient, to alleviate or otherwise control or limit the symptoms of the disease or condition of the patient.

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

After the patient's condition improves, if necessary, a maintenance dose is administered. Then, in specific embodiments, the dosage, or frequency of administration, or both, is reduced as a function of symptoms to a level at which improvement in the disease, disorder, or condition is maintained. In certain embodiments, however, intermittent treatment is required on a long-term basis for any recurrence of symptoms.

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

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

In one embodiment, suitable daily dosages for a compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg body weight. In some embodiments, the daily dosage or amount of the active ingredient in dosage form is below or above the ranges set forth herein, depending on a number of variables in an individual treatment regimen. In various embodiments, daily and unit dosages will vary depending on a number of variables, including, without limitation, 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 practitioner.

The toxicity and therapeutic efficacy of such therapeutic regimens is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, without limitation, determination of LD ₅₀ and ED ₅₀ . The ratio of dose to toxic and therapeutic effects is the therapeutic index and is expressed as the ratio of LD ₅₀ to ED ₅₀ .

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In certain embodiments, data obtained from cell culture assays and animal studies is used in formulating a range of therapeutically effective daily dosages and/or a therapeutically effective number of unit dosages for use in mammals, including humans. In some embodiments, the daily dosage 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 the number of unit dosages varies within this range depending on the dosage form used and the route of administration used.

According to any of the above aspects, further embodiments are provided, 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) administered orally to a mammal; and/or (c) administered intravenously to a mammal; and/or (d) administered to the mammal by injection; and/or (e) administered topically to the mammal; and/or (f) administered to the mammal non-systemically or locally.

According to any of the above aspects, additional embodiments are provided, providing for single administrations of an effective amount of the compound, including additional embodiments, in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal several times within one day.

According to any of the above aspects, further embodiments are provided that provide for multiple administrations of an effective amount of a compound, including further embodiments wherein (i) the compound is administered continuously or intermittently as a single dose; (ii) time intervals between multiple injections are 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 further or alternative embodiments, the method comprises a drug holiday in which administration of the compound is temporarily suspended or the dose of the compound to be administered is temporarily reduced; at the end of drug holidays, dosing of the compound is resumed. According to one embodiment, the length of the drug holiday varies from 2 days to 1 year.

In some 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 excipient (i.e., the excipient alone has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by the patient is enhanced by administering one of the compounds described herein with another agent (which also provides for a therapeutic 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 various aspects of the disease, disorder, or condition. to be treated, thereby providing a greater overall benefit than the administration of either therapeutic agent alone.

In any case, with respect to the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be additive from the two therapeutic agents, or the patient may experience a synergistic effect.

In certain embodiments, various therapeutically effective dosages of the compounds disclosed herein will be used in pharmaceutical formulation and/or treatment regimens in which the compounds disclosed herein are administered in combination with one or more additional agents, such as additional a therapeutically effective drug, excipient, or the like. Therapeutically effective dosages of drugs and other agents for use in combination regimens are optionally determined by means such as those set forth above for the active ingredients themselves. In addition, the methods of prevention/treatment described herein involve the use of regular dosing, i.e. provide more frequent, lower doses to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continued up to a point in time. during treatment with a second agent or after the end of treatment

- 75 040003 second means. It also includes treatment in which the compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent to be used in combination are administered simultaneously or at different time points and/or at decreasing or increasing intervals throughout the treatment period. Combination treatment further includes intermittent treatment that is started and stopped at different points in time to ensure the clinical safety of the patient.

It should be appreciated that the dosage regimen for treating, preventing, or alleviating the condition(s) requiring mitigation is modified according to a number of factors (e.g., the disease, disorder, or condition the subject suffers from; age, weight, sex, diet, and medical condition). 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 therapeutics described herein, the dosages of the co-administered compounds will vary depending on the type of drug being co-administered, the particular drug being used, the disease or condition being treated, and so forth. In additional embodiments, when administered in conjunction 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 the case of combination therapeutics, multiple therapeutics (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If the administration is simultaneous, then several therapeutic agents, by way of example only, are provided in a single unitary form or in several forms (for example, as a single pill or as two separate pills).

The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapeutic agents, are administered before, during, or after the onset of a disease or condition, and the timing of administration of a composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used prophylactically and administered chronically 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 possible after the onset of a disease or condition, identified or suspected, and for the length of time necessary to treat the disease. In some embodiments, the length of time required for treatment varies and the duration of treatment is set to meet the specific needs of each subject. For example, in specific embodiments, a compound as 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 a diabetes-related disorder or condition.

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, gemigliptin, or dutogliptin) , catecholamine (such as epinephrine, norepinephrine, or dopamine), peroxisome proliferator-activated receptor (PPAR) gamma agonist (such as thiazolidinedione (TZD) (such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone), aleglitazar, farglitazar, muraglitazar, or tezaglitazar ) or a combination of them. 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 thereof, or combinations thereof. In some cases, nicotinamide ribonucleoside or analogs thereof promote the production of NAD+, a substrate for many enzymatic reactions, including p450, which is a target for FXR (see, for example, 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, gemigliptin, 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, farg

- 76 040003 litazar, muraglitazar or tezaglitazar) 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 thereof, or combinations thereof, to treatment of diabetes mellitus or diabetes-related disorders or conditions.

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 or a diabetes-related disorder or condition such as weight loss and/or postprandial elevated blood glucose.

In some embodiments, the farnesoid X receptor agonist is administered with at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is a glucose lowering agent. In some embodiments, the at least one additional therapeutic agent is an anti-obesity agent. In some embodiments, the at least one additional therapeutic agent is selected from a peroxisome proliferator-activated receptor (PPAR) agonist (gamma, dual, or common), a dipeptidyl peptidase (IV) inhibitor, a glucagon-like peptide-1 (GLP-I) analog, insulin, or a insulin, insulin secretagogue, sodium-dependent glucose transporter 2 (SGLT2) inhibitor, glucophage, human amulin analog, biguanide, alpha-glucosidase inhibitor, meglitinide, thiazolidinedione, and sulfonylurea. In some embodiments, at least one additional therapeutic agent 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, the at least one additional therapeutic agent is a lipid-lowering agent. In certain embodiments, at least one additional therapeutic agent is administered at the same time as the farnesoid X agonist. In certain embodiments, the at least one additional therapeutic agent is administered less frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapeutic agent is administered more frequently than the farnesoid X receptor agonist. In certain embodiments, at least one additional therapeutic agent is administered prior to administration of the farnesoid X receptor agonist. In certain embodiments, at least one additional therapeutic agent 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, a tumor necrosis factor (TNF) inhibitory agent, or a combination thereof.

In some embodiments, the FXR agonist is administered in combination with an additional therapeutic agent, such as an antioxidant, corticosteroid, tumor necrosis factor (TNF) inhibitory agent, or a combination thereof, for the treatment of alcoholic or non-alcoholic liver disease. In some embodiments, an FXR agonist is administered in combination with an antioxidant, a vitamin precursor, a corticosteroid, a tumor necrosis factor (TNF) inhibitor, 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 an additional anti-inflammatory or immunomodulatory therapeutic agent.

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 therapeutic agent, to treat inflammation-related intestinal conditions. In some instances, an FXR agonist is administered in combination with metronidazole, vancomycin, fidaxomicin, a corticosteroid, or combinations thereof to treat inflammation-related intestinal conditions.

As discussed above, inflammation is sometimes associated with pseudomembranous colitis. In some cases, pseudomembranous colitis is associated with bacterial overgrowth (such as 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 proliferation disorders. In some embodiments, the additional therapeutic agent includes a chemotherapeutic agent, a biologic agent (e.g., an antibody, e.g., bevacizumab, cituximab, 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 agent, a biological agent, a radiotherapy agent, or combinations thereof, to treat a cell proliferation disorder. In some cases, an FXR agonist is administered in combination with an antibody (eg, bevacizumab, cituximab, or panitumumab), a chemotherapy agent, FOLFOX, FOLFIRI, CapeOX, 5-FU, leucovorin, regorafenib, irinotecan, or oxaliplatin, or combinations thereof, to treat a disorder of cell proliferation .

Examples

The following examples are presented for illustrative purposes only and do not limit the scope of the claims presented in the present invention.

Used above and throughout the description of the present invention, the following abbreviations, unless otherwise noted, should be understood as characterized by the following meaning:

ACN or MeCN acetonitrile ace acetyl ASON acetic acid BINAP 2,2'-bis(diphenylphosphino)-1,G-dinaphthyl Vp benzyl VOS or Vos mpem-buti l carbamate t-Bu mpem-butyl Su cyclohexyl DBA or dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane (C1CH ₂ CH ₂ C1) DCM dichloromethane (CH ₂ C1 ₂ )

- 78 040003

DIPEA or DIEA diisopropylethylamine DMAP 4-(A,A-dimethylamino)pyridine DMF dimethylformamide DMA ΛζΑ-dimethylacetamide DMSO dimethyl sulfoxide dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Eq. equivalent(s) Et ethyl Et20 diethyl ether EtOH ethanol EtOAc ethyl acetate HATU 1 -[bis(d imethylamino)methylene] -1 Η-1,2,3 -triazolo[4,5 - b]pyridinium 3-oxide hexafluorophosphate HPLC high performance liquid chromatography LAH lithium aluminum hydride LCMS liquid chromatography-mass spectrometry Me methyl MeOH methanol MS mass spectrometry NMM A-methylmorpholine NMP A-methyl-pyrrolidin-2-one NMR nuclear magnetic resonance PCC pyridinium chlorochromate Ph phenyl pin pinacolato z-Pr isopropyl RP-HPLC high performance liquid chromatography reversed phase TBS /reot-butyldimethylsilyl TFA trifluoroacetic acid TEA triethylamine TrixiePhos rac-2-(di-tert-butylphosphino)-1,1'-binaphthyl THF tetrahydrofuran TLC thin layer chromatography Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Intermediate 1. 4'-(Dimethylamino)-[1,1'-biphenyl]-4-carbaldehyde

I

A mixture of 4-bromo-N,N-dimethylaniline (21.28 g, 106.4 mmol), (4-formylphenyl)boronic acid (19.09 g, 127.4 mmol), tribasic potassium phosphate (67.77 g, 319.4 mmol), 2-dicyclohexylphosphino2',6'-dimethoxybiphenyl (4.38 g, 10.7 mmol), toluene (100 mL), isopropanol (100 mL) and water (100 mL) were degassed with vacuum/ nitrogen (3x). Palladium acetate (1.22 g, 5.42 mmol) was added and a mixture of alternating

- 79 040003 was washed at room temperature for 3 hours. The reaction mixture was diluted with DCM (800 ml) and water (500 ml), filtered through Celite and the Celite was washed with DCM (200 ml). The layers were separated and the organic layer was washed (500 ml water). The combined aqueous layer was extracted with DCM (200 ml). The organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting solid was stirred in 1:1 hexane/ethyl acetate (400 mL) for 15 min and filtered to give 4'-(dimethylamino)-[1,1'-biphenyl]-4-carbaldehyde (21.17 g, 88% ) as a yellow solid. The filtrate was concentrated, stirred in 1:1 hexane/ethyl acetate (200 mL) for 15 min and filtered to give additional material (2.30 g, ~90% pure, 8%).

L NMR (400 MHz, DMSO-d ₆ ): δ 9.98 (s, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.66 (d, J= 8.9 Hz, 2H), 6.82 (d, J=8.9 Hz, 2H), 2.96 (s, 6H).

Intermediate 2 N-(3-Bromophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide o

Step 1: 4'-(((3-Bromophenyl)amino)methyl)-N,N-dimethyl-[1,1'-biphenyl]-4-amine

A solution of intermediate 1 (3.30 g, 14.7 mmol), 3-bromoaniline (2.4 ml, 22 mmol) and acetic acid (1.7 ml, 29.3 mmol) in DCM (50 ml) was stirred at 25° C. for 1 hour and then sodium triacetoxyborohydride (15.5 g, 73.3 mmol) was added. The reaction mixture was stirred at 25°C for 11 h, washed with saturated NaHCO ₃ (2x30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 50:1) to give 4'-(((3-bromophenyl)amino)methyl)-N,N-dimethyl-[1,1'-biphenyl]-4-amine (4.0 g, 64%) as a yellow oil.

1Н NMR (CDCl ₃ ): δ 7.51-7.60 (m, 4H), 7.40 (d, 2H), 7.01-7.09 (m, 1H), 6.80-6.90 (m, 4H), 6.56-6.62 (m, 1H) , 4.34 (br s, 2H), 4.12 (br s, 1H), 3.00–3.08 (m, 6H); MS: 381.0 [M+H]+.

Step 2: N-(3-bromophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexane carboxamide

Cyclohexanecarbonyl chloride (2.10 ml, 15.8 mmol) was added to a solution of 4'-(((3bromophenyl)amino)methyl)-N,N-dimethyl-[1,1'-biphenyl]-4-amine (4 g , 10.5 mmol) and TEA (4.36 ml, 31.5 mmol) in DCM (100 ml) for 2 hours at 0°C. The mixture was stirred at 25° C. for 10 h and then washed (50 ml water followed by 50 ml brine). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 50/1) to give N-(3-bromophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide (4.5 g, 84%) as a yellow solid.

'H NMR (CDCl ₃ ): δ 7.38-7.52 (m, 5H), 7.10-7.22 (m, 4H), 6.88 (d, 1H), 6.73 6.81 (m, 2H), 4.70-4.86 (m, 2H) , 2.97 (s, 6H), 2.12 (br s, 1H), 1.55–1.76 (m, 7H), 1.13–1.23 (m, 1H), 0.90–1.06 (m, 2H); MS: 491.0 [M+H] ⁺ .

The intermediates described below were synthesized from the appropriate starting materials based on the procedures described for Intermediate 2.

Intermediate conn. Structure Name [M+H] + 2.1 GT G n ⁿ । L-(3-(Aminomethyl)phenyl)-L-((4'(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide 542.3 2.2* . ¹ νη ₂ X-((4'-(Dimethylamino)-[ 1, Gbiphenyl] -4-yl)methyl)-A-(3 -((2(dimethylamino)ethyl)amino)phenyl) cyclohexanecarboxamide 442.3 2.3 7V-([ 1,1'-Biphenyl]-3 -yl)-#-(4bromobenzyl)cyclohexanecarboxamide

- 80 040003

2.4 1 A-((4'-(Dimethylamino)-[1,1 biphenyl]-4-yl)methyl)-A-(3 iodine phenyl)cycle hexanecarboxamide 539.6 2.5 ί o 3 -(^((4' -(Dimethylamino)- [ 1, G biphenyl]-4-yl)methyl) cyclohexanecarboxamido)benzyl cyclohexanecarboxylate 553.3 2.6 - pH / _o sh o mpanc-N-(3-Bromophenyl ^-((tert-butyldimethylsilyl)oxy)-/U((trsh/s-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide 628.5 2.7 ;° / trans-A-trat- Butyldimethylsilyl)oxy)-7U-(3 iodophenyl)-A-((t/?ans-4-(4-methoxy3-methylphenyl)cycle ohexyl)methyl)cyclohexanecarboxamide 676.7 2.8 O P su. Methyl 3-(A-((4'-(dimethylamino)[1,1'-biphenyl]-4-yl)methyl) cyclohexanecarboxamido)benzoate 471.3

Various reductive amination conditions: 1.0-1.5 eq. aniline; 1.5-5 eq. sodium triacetoxyborohydride; DCM or DCE; 0.5-2 hours. Various acylation conditions: 1.3-2 eq. acid chloride; 2-4 eq. TEA or pyridine; the acid chloride was added at 0° C. or RT; 0.5-10 h. *Synthesized from intermediate 2.1 by removing Boc (TFA/DCM).

Intermediate 3 N-(3-Aminophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide

Step 1: N-(3-nitrophenyl)cyclohexanecarboxamide

Triethylamine (22 g, 217 mmol) was slowly added to a solution of 3-nitroaniline (15 g, 109 mmol) in acetonitrile (200 ml) at 0°C. After stirring the mixture for 30 minutes, cyclohexanecarbonyl chloride (23.9 g, 163 mmol) was added slowly. The resulting mixture was left to warm to 16°C. Water (300 ml) was added and the mixture was extracted with ethyl acetate (2x300 ml). The combined organic layers were washed with brine (600 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate; 50/1-5/1) to give N-(3-nitrophenyl)cyclohexanecarboxamide (15 g, 43%) as a white solid. MS: 249.2 [M+H]+.

Step 2: N-(4-Bromobenzyl)-N-(3-nitrophenyl)cyclohexanecarboxamide

Mixture of N-(3-nitrophenyl)cyclohexanecarboxamide (10 g, 40.3 mmol) and 1-bromo-4(bromomethyl)benzene (10.1 g, 40.3 mmol) and CS2CO3 (39.4 g, 121 mmol) in acetonitrile (100 ml) was heated under reflux (oil bath 90°C) for 3 h. Water (300 ml) was added at 25°C and the mixture was extracted with ethyl acetate (2x400 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by recrystallization from petroleum ether (20 ml) to give N-(4-bromobenzyl)-N-(3-nitrophenyl)cyclohexanecarboxamide (8.0 g, 24%) as a yellow solid. MS: 417.1 [M+H] ⁺ .

Step 3: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-nitrophenyl)cyclohexanecarboxamide

Mixture of (4-(dimethylamino)phenyl)boronic acid (3.56g, 21.6mmol), N-(4-bromobenzyl)-N-(3nitrophenyl)cyclohexanecarboxamide (6.0g, 14.4mmol), Pd (PPh ₃ ) ₄ (2.5 g, 2.16 mmol) and CS2CO3 (14.1 g, 43.1 mmol) in DMF (50 mL) were degassed with vacuum/nitrogen (3x) cycles, stirred at 75°C for for 24 h, and then cooled to 15°C. Water (200 ml) and DCM (200 ml) were added and the mixture was extracted with DCM

- 81 040003 (3x100 ml). The combined organic layers were washed with brine (2x500 ml), dried over

Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ ,

DCM/methanol; 10/1) to give N-((4'-(dimethylamino)-[1,1'-buphenyl]-4-yl)methyl)-N-(3-nitrophenyl)cyclohexanecarboxamide (2.8 g, 40%) as a red solid. MS: 458.3 [M+H]+

Step 4: N-(3-Aminophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexane carboxamide

A carbon-supported palladium catalyst (700 mg, 10%) was added to a solution of N-((4'(dimethylamino)-[1,1'-buphenyl]-4-yl)methyl)-N-(3-nitrophenyl)cyclohexanecarboxamide ( 2.8 g, 6.12 mmol) in methanol (160 ml). The suspension was degassed and purged with H ₂ (3x) and then stirred under H ₂ (50 psi) at 15° C. for 24 h. -aminophenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide (2.5 g, 86%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.50 (dd, 4H), 7.19-7.28 (m, 2H), 7.11 (t, J= 7.8 Hz, 1H), 6.75-6.86 (m, 2H), 6.57 -6.66 (m, 1H), 6.42 (d, 1H), 6.33 (br s, 1H), 4.81-4.90 (m, 2H), 3.71 (br s, 2H), 3.01 (s, 6H), 2.21-2.38 (m, 1H), 1.54-1.76 (m, 7H), 1.14-1.30 (m, 1H), 0.94-1.11 (m, 2H); MS: 428.3 [M+H] ⁺ .

Intermediate 4. (E)-Methyl-3-(3-nitrophenyl)acrylate

NO, ϊ° ^!

Du.

A mixture of 1-iodo-3-nitrobenzene (30 g, 120 mmol), methylprop-2-enoate (43 ml, 482 mmol), Pd ₂ (dba) ₃ (5.52 g, 6.02 mmol), P (ortho -tolyl)3 (9.17 g, 30.1 mmol) and TEA (83 ml, 602 mmol) in DMF (300 ml) were degassed with vacuum/nitrogen cycles (3x) and stirred at 90° C. for 12 h. the mixture was filtered, diluted with water (800 ml) and extracted with ethyl acetate (3x400 ml). The combined organic layers were washed with water (3x800 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Methyl tert-butyl ether (50 ml) was added to the residue and the mixture was stirred for 2 hours. The resulting solid was filtered and dried in vacuo to give (E)-methyl-3-(3nitrophenyl)acrylate (20 g, 74%) as a light yellow solid. 1Н NMR (CDCl ₃ ): δ 8.39 (s, 1H), 8.25 (dd, 1H), 7.84 (d, 1H), 7.74 (d, 1H), 7.61 (t, 1H), 6.58 (d, 1H), 3.85 (s, 3H); MS: 208.0 [M+H] ⁺ .

Intermediate 5 (E)-1-(2-Bromovinyl)-3-nitrobenzene

Step 1: (E)-3-(3-Nutrophenyl)acrylic acid

Lithium hydroxide monohydrate (2.73 g, 910 mmol) was added to a solution of intermediate 4 (13.5 g, 65.2 mmol) in THF (200 ml) and water (200 ml). The mixture was stirred at 25° C. for 12 h, acidified with 1 N HCl to pH 1, and then extracted with ethyl acetate (3x100 ml). The combined organic layers were washed with water (100 ml), dried over Na2SO4, filtered and concentrated to give (E)-3-(3-nitrophenyl)acrylic acid (12 g, crude) as a white solid. MS: 192.1 [M-H] ^- .

Step 2: (E)-1-(2-Bromovinyl)-3-nitrobenzene (E)-3-(3-Nitrophenyl)acrylic acid (12.0 g, 62.1 mmol) was added to a solution of diacetoxyiodobenzene (29 ml, 93.2 mmol) and tetraethylammonium bromide (17.5 ml, 93.2 mmol) in DCM (240 ml). The reaction mixture was stirred at 25°C for 16 h. Water (100 ml) was added and the mixture was extracted with DCM (2x200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by MPLC (petroleum ether/ethyl acetate; 50/1-10/1) to give (E)-1-(2bromovinyl)-3-nitrobenzene (2.6 g, 17%) as a yellow oil.

1H NMR (CDCl ₃ ): δ 8.15-8.19 (m, 2H), 7.62-7.64 (m, 1H), 7.52-7.56 (m, 1H), 7.17-7.21 (d, 1H), 7.02-6.98 (d, 1H).

Intermediate 6. (E)-3-(2-(Oxazol-2-yl)vinyl)aniline

Step 1: (E)-2-(3-Nitrostyryl)oxazole

Lithium tert-butoxide (2.29 g, 28.5 mmol), Cul (434 mg, 2.28 mmol), phenanthroline (616 mg, 3.42 mmol) and Pd(OAc) ₂ (512 mg, 2.28 mmol) was added to a solution of intermediate 5 (2.6 g, 11.4 mmol) and

- 82 040003 oxazole (3.54 g, 51.3 mmol) in dioxane (50 ml). The mixture was stirred at 120° C. for 12 hours, additional oxazole (3.54 g, 51.3 mmol) was added again and stirred at 120° C. for another 12 hours. Water (50 ml) and ethyl acetate (100 ml) were added and the reaction mixture was filtered. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 10/1) to give (E)-2-(3-nitrostyryl)oxazole (1.3 g, 24%) as a yellow oil.

1H NMR (CDCl3): δ 8.30 (s, 1H), 8.10-8.12 (d, 1H), 7.75-7.78 (m, 1H), 7.61 (s, 1H), 7.46-7.54 (m, 2H), 7.17- 7.19 (m, 1H), 7.00-7.04 (d, 1H); MS: 217.1 [M+H] ⁺ .

Step 2: (E)-3-(2-(Oxazol-2-yl)vinyl)aniline

Ammonium chloride (1.48 g, 27.8 mmol) and Fe (1.55 g, 27.8 mmol) were added to a solution of (E)-2-(3nitrostyryl)oxazole (1.20 g, 5.55 mmol) in ethanol (200 ml) and water (50 ml). The mixture was heated at 90° C. for 12 h, filtered and concentrated to give (E)-3-(2-(oxazol-2-yl)vinyl)aniline (1.0 g, crude) as a yellow oil.

Intermediate 7 (E)-N-(4-Bromobenzyl)-N-(3-(prop-1-en-1-yl)phenyl)cyclohexanecarboxamide

Step 1: N-(3-(Hydroxymethyl)phenyl)cyclohexanecarboxamide

HATU (3.09 g, 8.12 mmol) was added to a mixture of (3-aminophenyl)methanol (1.0 g, 8.12 mmol), cyclohexanecarboxylic acid (1.14 g, 8.93 mmol) and TEA (1 .64 g, 16.2 mmol) in DMF (10 ml) at 25°C. The reaction mixture was stirred for 10 h, diluted with water (30 ml) and then extracted with ethyl acetate (3x20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate; 5/1-1/1) to give N-(3-(hydroxymethyl)phenyl)cyclohexanecarboxamide (1.5 g, 71%) as a white solid.

Step 2: N-(3-Formylphenyl)cyclohexanecarboxamide

Manganese(IV) oxide (9.32 g, 107.15 mmol) was added to a solution of N-(3(hydroxymethyl)phenyl)cyclohexanecarboxamide (2.5 g, 10.7 mmol) in THF (15 ml) and DCM (15 ml). The mixture was stirred at 80°C for 12 h, filtered and concentrated to give N-(3formylphenyl)cyclohexanecarboxamide (1.5 g, crude) as a yellow solid. MS: 232.1 [M+H] ⁺ .

Step 3: (E)-N-(4-Bromobenzyl)-N-(3-(prop-1-en-1-yl)phenyl)cyclohexanecarboxamide Potassium tert-Butoxide (1.82 g, 16.2 mmol) parts was added to a solution of (methyltriphenylphosphoranyl)methyl bromide (6.02 g, 16.2 mmol) in THF (20 ml) at 25°C. After stirring the mixture for 30 minutes, N-(3-formylphenyl)cyclohexanecarboxamide (1.5 g, crude) was added in portions. The resulting mixture was stirred for 12 hours, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate; 15/1) to give (E)-N-(3-(prop-1-en-1yl)phenyl)cyclohexanecarboxamide (1.5 g, 92%) as a colorless oil. MS: 244.2 [M+H] ⁺ .

Intermediate 8 (E)-3-(3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)acrylic acid o o

Aqueous sodium hydroxide (1 N, 23 ml, 23 mmol) was added to a mixture of (E)-methyl-3-(3-(N-((4'(dimethylamino)-[1,1'-biphenyl]-4-yl )methyl)cyclohexanecarboxamido)phenyl) acrylate (2.31 g, 4.64 mmol), THF (46 ml) and methanol (23 ml) at room temperature. The reaction mixture was stirred for 2 h, concentrated and diluted with water (100 ml). The mixture was acidified (1 N HCl, pH = 4), stirred for 15 min and filtered. The filter cake was washed (50 ml water) and dried to give (E)-3-(3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido) phenyl) acrylic acid (2.22 g, 99%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6): δ 12.46 (br, 1H), 7.65 (d, 1H), 7.61-7.59 (m, 1H), 7.56 (d, 1H), 7.52-7.45 (m, 4H) , 7.40 (t, 1H), 7.19-7.00 (m, 3H), 6.78 (d, 2H), 6.54 (d, 1H), 4.85 (s, 2H), 2.92 (s, 6H), 2.22-2.10 (m , 1H), 1.75-1.55 (m, 4H), 1.54-1.47 (m, 1H), 1.46-1.30 (m, 2H), 1.26-1.11 (m, 1H), 0.95-0.80 (m, 2H); LCMS: 483.7 [M+H] ⁺ .

The intermediate described below was synthesized from intermediate 2.8 based on the procedure described for intermediate 8.

- 83 040003

Intermediate conn. Structure Name [M+N] ⁺ 8.1 \ / ° / — ° \ GU 7 Z— / 3 - (A- ((4' - (Dimethyl amino) - [ 1, G biphenyl] -4-yl) methyl) cyclohexanecarboxamido) benzoic acid 457.5

Intermediate 9 -dioxaborolan-2-yl)phenyl)cyclohexanecarboxamide o

To a solution of intermediate 2 (7.00 g, 14.24 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi(1,3,2 -dioxaborolane) (7.23 g, 28.48 mmol) in dioxane (200 ml) under N ₂ was added AcOK (3.48 g, 35.46 mmol) and Pd(dppf)Cl ₂ (1.04 g, 1.42 mmol). The reaction mixture was heated to 80°C overnight, filtered and concentrated. The residue was dissolved in EtOAc (300 ml) and washed with water (100 ml x 2). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give N-((4'-(dimethylamino)-[1,1'biphenyl] -4-yl)methyl)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclohexanecarboxamide (5.21 g, 8.44 mmol, 59.30% yield, 87.28% purity) as a yellow solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.66 (d, 1H), 7.51-7.29 (m, 5 H), 7.25-7.19 (m, 1 H), 7.11 (d, 2 H), 6.90 (d, 1 H), 6.71 (d, 2 H), 4.80 (br s, 2 H), 2.91 (s, 6 H), 2.12–2.00 (m, 1 H), 1.69–1.42 (m, 7 H), 1.27 (s, 12 H), 1.171.03 (m, 1 H), 0.97–0.85 (m, 2 H); MS: 539.5 [M+H]+.

Intermediate 10 Methyl 3-(3-aminophenyl)cyclobutanecarboxylate

Step 1: Methyl 3-(3-bromophenyl)-3-hydroxycyclobutanecarboxylate

To a solution of 1,3-dibromobenzene (30.06 g, 127.17 mmol) in THF (300 ml) at -78° C. was slowly added n-BuLi (2.5 M, 50 ml, 127.17 mmol). The reaction mixture was stirred at -78°C for 1 h and then added dropwise to a solution of methyl 3-oxocyclobutanecarboxylate (15.82 g, 123.47 mmol) in THF (300 ml) at -78°C. The mixture was stirred at -78°C for 2 h, added to us. aq. NH ₄ Cl (500 ml) and then concentrated. The aqueous residue was extracted with EtOAc (1000 ml x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate; 10:1) to give methyl 3-(3-bromophenyl)-3hydroxycyclobutanecarboxylate (15.20 g, 47.98 mmol, 38.86% yield, 90% purity ) as a yellow oil.

1Н NMR (400 MHz, CDCl ₃ ): δ 7.68 (s, 1Н), 7.52-7.39 (m, 2Н), 7.30-7.24 (m, 1Н), 3.78 (s, 3Н), 3.26 (br s, 1Н) , 2.98-2.81 (m, 3H), 2.72-2.56 (m, 2H); MS: 267.1 [M-OH] ⁺ .

Step 2: Methyl 3-(3-bromophenyl)cyclobutanecarboxylate

Et ₃ SiH (20.44 g, 175.78 mmol ).

The reaction mixture was stirred at 0°C for 0.5 h, heated to rt. and stirred for another 2.5 h. The mixture was concentrated, dissolved in EtOAc (1000 ml) and then washed with us. aq. NaHCO ₃ (200 ml x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate; 100:1) to give methyl 3-(3-bromophenyl)cyclobutanecarboxylate (5.08 g, 18.87 mmol, 71.5% yield) as a yellow oil .

1H NMR (400 MHz, CDCl ₃ ; cis/trans mixture): δ 7.40-7.30 (m, 2H), 7.23-7.09 (m, 2H), 3.75 (s, 1H), 3.70 (s, 2H), 3.44- 3.35 (m, 1H), 3.20-3.04 (m, 1H), 2.74-2.54 (m, 2H), 2.46-2.34 (m, 2H); MS: 269.1 [M+H] ⁺ .

Step 3: Methyl 3-(3-((diphenylmethylene)amino)phenyl)cyclobutanecarboxylate

To a solution of methyl 3-(3-bromophenyl)cyclobutanecarboxylate (2.66 g, 9.88 mmol) and diphenylmethanimine (2.15 g, 11.86 mmol) in toluene (120 ml) at r.t. BINAP (1.19 g, 1.91 mmol), Cs ₂ CO ₃ (8.07 g, 24.77 mmol) and Pd ₂ (dba) ₃ (905.7 mg, 989.06 µmol) were added. The reaction mixture was stirred at 100° C. overnight under N ₂ , filtered and concentrated to give methyl 3-(3-84040003((diphenylmethylene)amino)phenyl)cyclobutanecarboxylate (5.22g, crude) as a yellow oil.

MS: 370.1 [M+H]+.

Step 4: Methyl 3-(3-aminophenyl)cyclobutanecarboxylate

TFA (110.88 g, 972, 46 mmol). The reaction mixture was stirred at rt. overnight, concentrated, dissolved in EtOAc (1000 ml) and then washed with us. aq. NaHCO ₃ (300 ml x 2). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate; 5:1) to give methyl 3-(3-aminophenyl)cyclobutanecarboxylate (2.26 g, 10.22 mmol, 52.95% yield, 92.84% purity) as a yellow oil.

¹ H NMR (400 MHz, CDCl3, cis/trans mixture): δ 7.16-7.05 (m, 1H), 6.69-6.47 (m, 3H), 3.74 (s, 1H), 3.69 (s, 2H), 3.64 (br s, 2Н), 3.43-3.28 (m, 1Н), 3.17-3.01 (m, 1Н), 2.66-2.52 (m, 2Н), 2.45-2.36 (m, 2Н);

MS: 206.1 [M+H]+.

Intermediate 11 (Isobutylsulfonyl)benzene

CL.1%

A stirred mixture of benzenesulfonyl chloride (1.62 g, 9.17 mmol), NaHCO ₃ (1.53 g, 18.16 mmol) and Na ₂ SO ₃ (2.34 g, 18.53 mmol) in water (7 ml) heated to 95-100°C for 1 h in a nitrogen atmosphere. The reaction mixture was cooled to 50° C. and n-Bu ₄ NBr (105.2 mg, 326.33 µmol) and 1-bromo-2-methylpropane (1.41 g, 10.29 mmol) were added. The reaction mixture was heated at 70° C. overnight, cooled, treated with water (10 ml) and then extracted with DCM (15 ml x 3). The combined organic layers were dried with MgSO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate; 3:1) to give (isobutylsulfonyl)benzene (389.6 mg, 1.96 mmol, 21.43 % yield) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 7.91 (d, 2H), 7.67-7.61 (m, 1H), 7.59-7.52 (m, 2H), 2.98 (d, 2H), 2.292.14 (m, 1Н), 1.05 (d, 6Н);

MS: 199.2 [M+H]+.

Intermediate 12 5-Chloro-3-(methoxymethoxy)isothiazole ^Cl \0\ >^0/

Chlorine(methoxy )methane (5.74 g, 71.3 mmol) in THF (40 mL). The mixture was heated to rt. and stirred for 16 hours. EtOAc (300 ml) was added and the solution was washed with water (100 ml). The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 100/1) to give 5-chloro-3(methoxymethoxy)isothiazole (701.5 mg, 3.91 mmol, 52.92 % yield) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ): δ 6.59 (s, 1H), 5.43 (s, 2H), 3.52 (s, 3H); MS: 180.1 [M+H]+.

Intermediate 13: 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), 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) (1.38 g, 1.89 mmol), dioxane (470 ml) and 1 M Na ₂ CO ₃ (282 ml, 282 mmol) degassed 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 ethyl acetate (500 ml) and washed with saturated NaHCO ₃ (500 ml x 2). The aqueous layers were re-extracted with ethyl acetate (200 ml). The combined ethyl acetate extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexane) to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec- 7-ene (19.9 g, 81%).

1H 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, 3Н), 1.77 (t, 2Н);

MS: 261.1 [M+H]+.

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

A carbon-supported palladium catalyst (10 wt.%, 8.08 g, 7.59 mmol) was added to a solution of 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene ( 19.8 g, 76.1 mmol) in ethyl acetate (300 ml) at rt. in N ₂ atmosphere. The N ₂ inlet was replaced with an H ₂ balloon. The reaction mixture was stirred for 4.5 h, filtered through celite with ethyl acetate, and then concentrated to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (18.2 g; contains 13% ketone) in

- 85 040003 as a white solid.

1H NMR (400 MHz, DMSO-06): 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);

MS: 263.1 [M+H]+.

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

Formic acid (96%, 14 mL, 356 mmol) followed by water (2.20 mL, 122 mmol) was added to a solution of 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane ( 18.2 g) in toluene (60 ml) at rt. in an N2 atmosphere. The reaction mixture was heated at 120°C for 4 h, allowed to cool to rt, and then poured into 200 ml H2O and 200 ml toluene. The toluene layer was washed with 200 ml of H2O and then with 200 ml of saturated NaHCO ₃ . The aqueous layers were re-extracted with 100 ml of toluene. The combined toluene extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-(4-methoxy-3methylphenyl)cyclohexanone (15.5 g, 88% over 2 steps) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): 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);

MS: 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 (exotherm to 7.3°C). Residual cyclohexanone was washed into the reaction mixture with THF (20 ml). The reaction mixture was stirred at 0°C for 25 min and then poured into 400 ml of 1000 ml and 400 ml of toluene. The toluene layer was washed with 400 ml H2O, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexane) to give 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)- 2-methylbenzene (15.6 g, 95%) as a pale gold 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);

MS: 247.1 [M+H] ⁺ .

Stage 5: trans-4-(4-Methoxy-3-methylphenyl)cyclohexanecarbaldehyde

Formic acid (96%, 12.5 ml, 331 mmol) followed by water (2.5 ml, 139 mmol) was added to a solution of 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene (16 05 g, 65.15 mmol) in toluene (130 ml) under N ₂ atmosphere. The reaction mixture was heated at 120°C for 2 h, left to cool to rt, and then poured into 350 ml of ethyl acetate and 350 ml of H ₂ O. The organic layer was washed with 350 ml of H ₂ O, dried (Na ₂ SO ₄ ) , filtered and concentrated to give 4-(4-methoxy-3methylphenyl)cyclohexanecarbaldehyde (15.05 g) as a 1:1 mixture of stereoisomers. Aqueous sodium hydroxide (3.2 M, 31 ml, 99 mmol) was added to a solution of this mixture (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 observed by NMR) and then poured into 350 ml of H ₂ O and 350 ml of ethyl acetate. The organic layer was washed with 350 ml H ₂ O and the aqueous layers were back-extracted with 150 ml ethyl acetate. The combined extracts were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (0-5% ethyl acetate in hexane) to give trans-4-(4-methoxy-3-methylphenyl)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);

MS: 233.0 [M+H] ⁺ .

Intermediate 14. 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-4-hydroxycyclohexanecarboxylic acid (10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol) and DMF (140 ml) at rt. in an atmosphere of N ₂ (exothermic effect of the reaction up to 32°C). The reaction mixture was stirred at rt. for 2 hours and then diluted with 300 ml of diethyl ether. The organic layer was washed with 1 N HCl (2 x 300 ml), washed with 300 ml brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl) hydroxy)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 water (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 room temperature under N ₂ . The reaction mixture was stirred at rt. over 3 h, concentrated to the remaining 300 ml, diluted with 600 ml of saline, and then acidified to pH 2-3 with 20% NaHSO ₄ (550 ml). The aqueous layer was extracted with 800 ml diethyl ether. The organic layer was washed with 800 ml brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (17.3 g, 96% over 2 steps) as white solid.

1H NMR (400 MHz, DMSO-d6): 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).

Step 3: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride

Potassium carbonate (17.69 g, 128 mmol) in a round bottom flask under high vacuum was heated with a hot air dryer for 5 minutes and then allowed to cool to rt. (Chloromethylene)dimethylimine chloride (6.47 g, 50.5 mmol) was added, the reaction mixture was placed under N ₂ atmosphere, and then toluene (100 ml) was added. After stirring for 10 minutes, trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (6.51 g, 25.2 mmol) was added. The reaction mixture was stirred for 30 minutes, celite was added to the reaction mixture, and then the reaction mixture was filtered through celite, washing with toluene (3 x 25 ml). The filtrate was partially concentrated to give a solution of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride in toluene (18.55 g, 32.8 wt%). This solution was used immediately.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.66-3.58 (m, 1H), 2.76-2.67 (m, 1H), 2.23-2.14 (m, 2H), 1.98-1.89 (m, 2H), 1.67-1.56 (m, 2H), 1.44-1.32 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H).

Compound 1. N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(5-methoxypyridin-3yl)phenyl)cyclohexanecarboxamide

Mixture of intermediate 2 (100 mg, 0.20 mmol), (5-methoxypyridin-3-yl)boronic acid (50 mg, 0.33 mmol), cesium carbonate (199 mg, 0.61 mmol), [1, 1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (16 mg, 0.022 mmol) and DMF (2 ml) were degassed by nitrogen bubbling for 10 minutes. The reaction mixture was heated at 80°C overnight, cooled to room temperature and diluted with ethyl acetate (50 ml). The organic phase was washed (50 ml saturated NaHCO ₃ ), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography to give N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(5-methoxypyridin3-yl)phenyl)cyclohexanecarboxamide (45 mg, 43%) as a white solid.

1H NMR (400 MHz, DMSO-d): δ 8.41 (d, 1H), 8.27 (d, 1H), 7.72 (d, 1H), 7.57 (t, 1H), 7.54-7.49 (m, 5H), 7.48 (d, 1H), 7.23-7.16 (m, 3H), 6.77 (d, 2H), 4.91 (s, 2H), 3.85 (s, 3H), 2.92 (s, 6H), 2.30-2.18 (m, 1H ), 1.781.57 (m, 4H), 1.55-1.50 (m, 1H), 1.50-1.38 (m, 2H), 1.18-1.05 (m, 1H), 0.95-0.80 (m, 2H);

LCMS: 520.8 [M+H]+.

The following compounds were synthesized from the appropriate starting materials based on the procedure described for compound 1.

Comm. Structure Name [M+N] ⁺ 2 About Λ ¹ and A-((4'-(Dimethylamino)-[ 1, Gbiphenyl]-4-yl)methyl)-?/-(3'-methoxy[1,1'-biphenyl]-3yl)cyclohexanecarboxamide 519.3

- 87 040003

3 o ⁷ O 1 Z— / L-((4'-(Dimethylamino)-[ 1, Gbiphenyl]-4-yl)methyl)-A-(3-(2methoxypyridin-4yl)phenyl)cyclohexanecarboxamide 520.2 3.1 / -Z Ooo O \ A-((4'-(Dimethylamino)-[1,1 biphenyl]-4-yl)methyl)-A-(4'-methoxy[1,G-biphenyl]-3yl)cyclohexanecarboxamide 519.4

Various reaction conditions: 1.5-2 eq. boronic acid; 3-4 eq. CS ₂ CO ₃ ; 0.03-.01M DMF;70-80°C.

Compound 4

A mixture of intermediate 2 (101 mg, 0.21 mmol), K ₃ PO ₄ (87 mg, 0.41 mmol), Pd(OAc) ₂ (10 mg, 0.045 mmol), Trixiephos (34 mg, 0.085 mmol) and toluene (2 ml) was degassed with three vacuum/N cycles. Added 2-methoxyethylamine (35 μl, 0.40 mmol) and the reaction mixture was stirred at 100°C for 18 hours, the Reaction mixture was left to cool to room temperature, diluted with ethyl acetate (20 ml) and water (20 ml). The aqueous layer was re-extracted with more ethyl acetate (20 ml). The combined organics were washed with water (30 ml), washed with brine (30 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (10-40% ethyl acetate in hexane). The compound was repurified by reverse phase HPLC (30-51% acetonitrile/water with 0.1% TFA). Fractions were concentrated to dryness, diluted with ethyl acetate (20 ml) and then washed with saturated NaHCO ₃ (2x20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered and concentrated to give N-((4'- (dimethylamino)[1,1'-biphenyl]-4-yl)methyl)-N-(3-((2-methoxyethyl)amino)phenyl)cyclohexanecarboxamide (38 mg, 37%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 7.53-7.46 (m, 4H), 7.17 (d, 2H), 7.05 (t, 1H), 6.78 (d, 2H), 6.53 (d, 1H), 6.31 (s, 1H), 6.27 (d, 1H), 5.82 (t, 1H), 4.76 (s, 2H), 3.38 (t, 2H), 3.21 (s, 3H), 3.12-3.06 (m, 2H), 2.96 (s, 6H), 2.34-2.26 (m, 1H), 1.70-1.59 (m, 4H), 1.58-1.50 (m, 1H), 1.49-1.37 (m, 2H), 1.16-1.06 (m, 1H ), 1.01-0.87 (m, 2H);

LCMS: 486.8 [M+H]+.

The compounds described below were synthesized based on the procedure described for compound 4.

Comm. Structure Name [M+N] ⁺ 5 IZ y--/ Z— / A-((4'-(Dimethylamino)-[ 1, Gbiphenyl]-4-yl)methyl)-A-(3-((2(dimethylamino)ethyl)amino)phenyl)cyclohexanecarboxamide 499.8 6* ABOUT A-((4'-(Dimethylamino)-[ 1, Gbiphenyl]-4-yl)methyl)-A-(3(isobutylamino)phenyl) cyclohexanecarboxamide 484.8

*XantPhos and Pd ₂ (dba) ₃ were used instead of Trixiephos and Pd(OAc) ₂ .

Compound 7 (E)-N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(nent-1-en-1-yl) phenyl)cyclohexanecarboxamide

Mixture of intermediate 2 (500 mg, 1.02 mmol), (E)-pent-1-en-1-ylboronic acid (128 mg, 1.12 mmol) K ₂ CO ₃ (281 mg, 2.03 mmol) and Pd(dppf)Cl ₂ (74 mg, 0.10 mmol) in dioxane (20 ml) de

- 88 040003 was gassed with vacuum/nitrogen cycles (3x) and stirred at 80°C for 5 hours. The reaction mixture was quenched with water (30 ml) and then extracted with ethyl acetate (3x30 ml). The combined organic phases were washed with brine (2x30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC to give (E)-N-((4'-(dimethylamino)-[1,1'biphenyl]-4-yl)methyl)-N-(3-(pent-1-ene -1-yl)phenyl)cyclohexanecarboxamide (45 mg, 9%) as a light yellow solid.

'H-NMR (DMSO-di): δ 7.47-7.54 (m, 4H), 7.27-7.38 (m, 2H), 7.18 (d, 3H), 6.96 (d, 1H), 6.79 (d, 2H), 6.34-6.41 (m, 1H), 6.21-6.30 (m, 1H), 4.83 (br s, 2H), 2.94 (s, 6H), 2.14 (q, 3H), 1.65 (t, 4H), 1.38-1.55 (m, 5H), 1.06–1.25 (m, 1H), 0.90 (t, 5H);

MS: 481.4 [M+H]+.

Compound 8

Step 1: N-(3-((4-Chlorobutanamido)methyl)phenyl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamide

4-Chlorobutanoyl chloride (40 µl, 0.36 mmol) was added to a mixture of intermediate 2.2 (105 mg, 0.24 mmol), trimethylamine (50 µl, 0.36 mmol) and DCM (2.4 ml) at 0°C . The reaction mixture was stirred for 15 min, diluted with DCM (20 ml), washed (2x20 ml saturated NaHCO ₃ ), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(3-((4-chlorobutanamido)methyl)phenyl)-N-((4'-(dimethylamino)-[1,1'biphenyl]-4-yl)methyl)cyclohexanecarboxamide (84 mg, 65%) as a white solid.

'H NMR (400 MHz, DMSO-d ₆ ): δ 8.41 (t, 1H), 7.53-7.43 (m, 4H), 7.33 (t, 1H), 7.18 (m, 1H), 7.14 (d, 2H) , 7.05 (s, 1H), 7.00 (d, 1H), 6.77 (d, 2H), 4.80 (s, 2H), 4.23 (d, 2H), 3.57 (t, 2H), 2.92 (s, 6H), 2.24 (t, 2H), 2.202.10 (m, 1H), 1.95-1.85 (m, 2H), 1.70-1.55 (m, 4h), 1.54-1.47 (m, 1H), 1.46-1.35 (m, 2H ), 1.18–1.05 (m, 1H), 0.95–0.80 (m, 2H);

LCMS: 546.8 [M+H] ⁺ .

Step 2: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-((2-oxopyrrolidin-1-yl)methyl)phenyl)cyclohexanecarboxamide

Sodium hydride (60% in mineral oil dispersion, 4 mg, 0.10 mmol) was added to a solution of N(3-((4-chlorobutanamido)methyl)phenyl)-X-((4'-(dimethylamino)-[ 1 ,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamide (38 mg, 0.070 mmol) and DMF (1 ml) at 0°C. The reaction mixture was stirred for 15 min at room temperature, diluted with water (10 ml) and extracted with ethyl acetate (20 ml). The organic phase was dried (Na ₂ SO ₄ ), concentrated and then purified by silica gel chromatography to give N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N- (3-((2-oxopyrrolidin-1yl)methyl)phenyl)cyclohexanecarboxamide (20 mg, 57%) as a white solid.

'H NMR (DMSO-d6): δ 7.53-7.45 (m, 4H), 7.38 (t, 1H), 7.19 (d, 1H), 7.16-7.10 (m, 3H), 6.83 (s, 1H), 6.77 (d, 2H), 4.80 (s, 2H), 4.30 (s, 2H), 2.99 (t, 2H), 2.92 (s, 6H), 2.19-2.05 (m, 3H), 1.80-1.68 (m, 2H ), 1.68-1.55 (m, 4H), 1.54-1.47 (m, 1H), 1.46-1.35 (m, 2H), 1.18-1.05 (m, 1H), 0.95-0.80 (m, 2H);

LCMS: 510.8 [M+H] ⁺ .

Compound 9. Methyl 2-((3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)amino)acetate

A mixture of intermediate 3 (1.0 g, 2.1 mmol), methyl 2-bromoacetate (220 μl, 2.31 mmol), NaHCO ₃ (388 mg, 4.62 mmol) and DMF (10 ml) was degassed by cycles vacuum/nitrogen (3x), stirred at 75°C for 6 h, diluted with water (100 ml) and then extracted with ethyl acetate (3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by reverse phase HPLC to give methyl 2-((3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]4-yl)methyl)cyclohexanecarboxamido)phenyl)amino)acetate (230 mg, 21%) as a white solid.

'HNMR (400 MHz, DMSO-d ₆ ): δ 7.51 (d, 4H), 7.17 (d, 2H), 7.08 (t, 1H), 6.80 (d, 2H), 6.53 (d, 1H), 6.276. 36 (m, 2H), 6.22 (t, 1H), 4.76 (s, 2H), 3.85 (d, 2H), 3.61 (s, 3H), 2.94 (s, 6H), 2.20-2.37 (m, 1H) , 1.65 (d, 4H), 1.55 (d, 1H), 1.34–1.49 (m, 2H), 1.14 (q, 1H), 0.95 (d, 2H);

MS: 500.3 [M+H] ⁺

- 89 040003

Compound 10. Methyl 2-((3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)(methyl)amino)acetate

A solution of compound 9 (340 mg, 0.68 mmol), formaldehyde (250 μl, 3.40 mmol) and acetic acid (19 μl, 0.34 mmol) in methanol (3 ml) was stirred for 2 h. Sodium cyanoborohydride was added (128 mg, 2.04 mmol) and the solution was stirred for 16 h at 25°C. The reaction was quenched with water (50 ml) and then extracted with DCM (3x50 ml). The combined organic layers were washed with brine (200 ml), concentrated and purified by reverse phase HPLC to give methyl 2-((3-(N-((4'-(dimethylαmino)-[1,1'-biphenyl]-4- yl)methyl)cyclohexanecarboxamido)phenyl)(methyl)amino)acetate (75 mg, 21%) as a white solid.

¹ H NMR (400 MHz, CDCl3): δ 7.47 (dd, 4H), 7.15-7.27 (m, 3H), 6.80 (d, 2H), 6.62 (dd, 1H), 6.41 (d, 1H), 6.18 ( s, 1H), 4.84 (s, 2H), 3.95 (s, 2H), 3.66 (s, 3H), 2.92-3.03 (m, 9H), 2.26 (t, 1H), 1.58-1.75 (m, 7H) , 1.131.28 (m, 1H), 0.93–1.09 (m, 2H);

MS: 514.4 [M+H]+.

Compound 11. Methyl 3-(N-((4'-(dimethylαmino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)benzylcarbamate

Methyl chloroformate (16 μl, 0.21 mmol) was added to a mixture of intermediate 2.2 (58 mg, 0.13 mmol), trimethylamine (35 μl, 0.25 mmol) and DCM (1.3 ml) at 0°C. The reaction mixture was stirred for 15 min, diluted with DCM (20 ml), washed (2x20 ml saturated NaHCO ₃ ), dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by silica gel chromatography to give methyl 3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)benzylcarbamate (45 mg, 68%) in form of a white solid.

¹ H NMR (DMSO-d ₆ ): δ 7.69 (t, 1H), 7.51-7.47 (m, 4H), 7.33 (t, 1H), 7.19 (d, 1H), 7.15 (d, 2H), 7.08 ( s, 1H), 7.01 (d, 1H), 6.77 (d, 2H), 4.80 (s, 2H), 4.15 (d, 2H), 3.50 (s, 3H), 2.92 (s, 6H), 2.20-2.10 (m, 1H), 1.691.57 (m, 4H), 1.55-1.47 (m, 1H), 1.46-1.36 (m, 2H), 1.14-1.08 (m, 1H), 0.97-0.82 (m, 2H) ;

LCMS: 500.8 [M+H] ⁺ .

Compound 12 en-1 -yl)phenyl)cyclohexanecarboxamide

HATU (83 mg, 0.22 mmol) was added to a mixture of intermediate 8 (95 mg, 0.20 mmol), DIEA (0.07 ml, 0.41 mmol) and DMF (4 ml) at room temperature. After stirring the mixture for 1 h, DIEA (0.17 ml, 0.98 mmol) and methylamine hydrochloride (67 mg, 0.99 mmol) were added. The mixture was stirred for 30 min, diluted with water (10 ml) and extracted with ethyl acetate (2x20 ml). The combined organic extracts were washed (10 ml water followed by 10 ml brine), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography to give (E)-N-((4'-(dimethylαmino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-(methylamino) -3-oxoprop-1-en-1-yl)phenyl)cyclohexanecarboxamide (48 mg, 49%).

1H NMR (DMSO-d6): δ 8.06-8.00 (m, 1H), 7.55-7.46 (m, 5H), 7.43-7.34 (m, 3H), 7.16 (d, 2H), 7.12 (d, 1H), 6.77 (d, 2H), 6.58 (d, 1H), 4.84 (s, 2H), 2.92 (s, 6H), 2.68 (d, 3H), 2.23-2.08 (m, 1H), 1.72-1.67 (m, 4H), 1.66-1.47 (m, 1H), 1.47-1.34 (m, 2H), 1.15-1.04 (m, 1H), 0.97-0.82 (m, 2H);

LCMS: 496.3 [M+H] ⁺ .

The compound described below was synthesized based on the procedure described for compound 12.

Comm. Structure Name [M+N] ⁺ 13 ABOUT 1 O (£) -7 / - (3 - (3 - (Dimethylamino) -3 oxoprop-1 -en-1 -yl) phenyl) - A - ((4' (dimethylamino) - [ 1,1 '-biphenyl] - 4yl)methyl)cyclohexanecarboxamide 510.2

- 90 040003

Compound 14 ) phenyl) cyclohexane carboxamide

Step 1: (E)-N-(3-(2-(Oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide

Cyclohexanecarbonyl chloride (790 μl, 5.91 mmol) was added over 1 h to a solution of intermediate 6 (1.0 g, 5.37 mmol) and TEA (2.2 ml, 16.1 mmol) in DCM (30 ml ) at 0°C. The mixture was stirred at 25°C for 11 h and then washed with water (2x20 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 1/1) to give (E)-N-(3-(2-(oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide (1.3 g, 74%) as a yellow oil.

1H NMR (CDCl ₃ ): δ 7.78 (s, 1H), 7.65 (m, 1H), 7.48-7.52 (m, 2H), 7.28-7.36 (m, 2H), 7.21 (s, 1H), 6.967.00 (d, 1H), 2.01-2.27 (m, 1H), 1.97 (m, 2H), 1.88-1.89 (m, 2H), 1.85 (m, 1H), 1.56-1.59 (m, 2H), 1.29-1.32 (m, 3H); MS: 297.2 [M+H]+.

Step 2: (E)-N-(4-Bromobenzyl)-N-(3-(2-(oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide

Cesium carbonate (5.72 g, 17.6 mmol) was added to a solution of (E)-N-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide (1.3 g, 4.4 mmol) and 1-bromo-4-(bromomethyl)benzene (2.74 g, 10.97 mmol) in acetonitrile (50 ml). The mixture was heated at reflux for 12 hours and then concentrated. Water (50 ml) was added and the mixture was extracted with DCM (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 1/1) to give (E)-N-(4-bromobenzyl)-N-(3-(2-(oxazol-2yl)vinyl)phenyl)cyclohexanecarboxamide (1, 8 g, 79%) as a yellow oil.

1H NMR (CDCl ₃ ): δ 7.65 (s, 1H), 7.40-7.51 (m, 1H), 7.33-7.37 (m, 4H), 7.20-7.26 (d, 1H), 7.05-7.07 (m, 3H) , 6.88-6.92 (m, 2H), 4.80 (s, 2H), 2.14-2.17 (m, 1H), 1.52-1.68 (m, 6H), 1.25-1.27 (m, 1H), 0.91-0.96 (m, 3H);

MS: 465.0 [M+H] ⁺ .

Step 3: (E)-N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-(oxazol-2-yl)vinyl) )phenyl)cyclohexanecarboxamide

Sodium carbonate (454 mg, 4.28 mmol) and Pd(dppf)Cl ₂ (157 mg, 0.21 mmol) were added to a solution of (E)N-(4-bromobenzyl)-N-(3-(2-( oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide (500mg, 1.07mmol) and [4-(dimethylamino)phenyl]boronic acid hydrochloride (431mg, 2.14mmol) in dioxane (40ml) and H2O ( 5 ml). The mixture was heated at 100°C for 12 h, filtered and extracted with ethyl acetate (100 ml). The organic layer was washed with water (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate; 3/1) to give (E)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N- (3-(2-(oxazol-2-yl)vinyl)phenyl)cyclohexanecarboxamide (150mg, 27%).

1H NMR (DMSO-d ₆ ): δ 8.13 (s, 1H), 7.60-7.74 (m, 2H), 7.45-7.54 (m, 5H), 7.40 (t, 1H), 7.34 (s, 1H), 7.147 .28 (m, 3H), 7.10 (d, 1H), 6.76-6.79 (d, 2H), 4.88 (br s, 2H), 2.93 (s, 6H), 2.23 (m, 1H), 1.58-1.73 ( m, 4H), 1.41-1.55 (m, 3H), 1.11-1.19 (m, 1H), 0.93 (d, 2H);

MS: 506.3 [M+H] ⁺ .

The compound described below was synthesized from intermediate 2.3 and (4fluorophenyl)boronic acid based on the procedure described for compound 14 (step 3).

Comm. Structure Name [M+N] ⁺ 15 o goo ^o.f o A-([ 1,1-Biphenyl]-3-yl)-7U-((4'fluoro-[1, G-biphenyl]-4-yl)methyl) cyclohexanecarboxamide 464.7

The compounds described below were synthesized from intermediate 7 based on the procedure described for compound 14 (steps 2 and 3).

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Comm. Structure Name [M+N] ⁺ 16* O GU OL 1 (£)-U-((4'-(Dimethylamino)-[ 1, Gbiphenyl] -4-yl )methyl)-A-(3 (prop-1-eu-1-yl)phenyl) cyclohexanecarboxamide 453.3 17** o GuuA Αχ (2)-U-((4'-(Dimethylamino)-[ 1, Gbiphenyl] -4-yl )methyl )-A-(3 (prop-1-eu-1-yl)phenyl) cyclohexanecarboxamide 453.3

*Pd(PPh ₃ ) ₄ was used instead of Pd(dppf)Cl2.

**Isolated during the purification of compound 16.

The compounds described below were synthesized from the corresponding amines based on the procedures described for Intermediate 2.

Comm. Structure Name [M+N] ⁺ 18 / —Ζ xx XX ja O O Y-([1,1'-Biphenyl]-3 -yl)-Y-((4'(dimethylamino)- [1,1'-biphenyl]-4yl)methyl)cyclohexanecarboxamide 489.7 19 / —Ζ XX XX Yar A-((4'-(Dimethylamino)-[ 1, Gbiphenyl] -4-yl) methyl )-A-(3 phenoxyphenyl) cyclohexanecarboxamide 505.7 20 O Ji Τ A ¹ \A/° °\ Methyl-3 - (3 - (7U- ((4'- (dimethylamino) [1, G-biphenyl] -4yl) methyl) cyclohexanecarboxamido) phenyl) cyclobutane carboxylate 525.6 21 about assUo aa 1 A-((4'-(Dimethylamino)-[ 1, Gbiphenyl] -4-yl) methyl )-A-(3 vinylphenyl) cyclohexanecarboxamide 439.6

Various reductive amination conditions: 1-2 eq. acetic acid; NaBH ₃ CN, MeOH or NaBH(OAc) ₃ , DCM. Various acylation conditions: 1.2-1.5 eq. acid chloride; 2-3 eq. TEA; 0.03-0.1 M DCM; addition of acid chloride at 0°C or RT

The compound described below was synthesized from compound 14 using standard hydrogenation conditions (1 atm H2, 10% Pd/C, EtOAc, rt).

Comm. Structure Name [M+N] ⁺ 22 O Al η 1nA U-((4 '-(Dimethylamino)- [ 1, G biphenyl]-4-yl)methyl)-U-(3-(2(oxazol-2-yl)ethyl)phenyl) cyclohexanecarboxamide 508.4

The compounds described below were synthesized from intermediate 2.4 and the corresponding boronic acid using standard Suzuki conditions [Pd(dppf)Cl ₂ , Cs ₂ CO ₃ , DMF, 80°C].

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Comm. Structure Name [M+N] ⁺ 23 O I/ N A-((4'-(D-imethylamino)-[1,1-biphenyl]-4-yl)methyl)-A ^g- (3-(pyridin-3-yl)phenyl)cyclohexanecarboxamide 490.8 24 Oh Oh YES ΛΑ Z— / A-((4'-(D imethylamino)-[1,1 biphenyl]-4-yl)methyl)-/U-(3-(5methylpyridin-3 yl)phenyl)cyclohexanecarboxamide 504.8 25 / ABOUT About AE wah oh Z / A((4'-(dimethylamino)-[1, Hbiphenyl]-4-yl)methyl)-X-(3-(6methoxypyridin-2yl)phenyl)cyclohexanecarboxamide 520.8 26 ΑΧλ°Ό ₀ N Methyl 5-(3-(7C-((4'-(dimethylamino)[1,G-biphenyl]-4yl)methyl)cyclohexanecarboxamido)phenyl)nicotinate 548.8

Compound 27 )phenyl)cyclohexanecarboxamide

Mixture of intermediate 2.4 (150 mg, 0.279 mmol), 2-vinylpyridine (0.06 ml, 0.556 mmol), palladium acetate (6 mg, 0.027 mmol), tri(orthotolyl)phosphine (34 mg, 0.112 mmol), triethylamine ( 1.5 ml) and DMF (1.5 ml) were degassed by bubbling N ₂ for 10 min, heated at 80°C for 1 h, and then left to cool to rt. Ethyl acetate was added to the mixture and the solution was washed with water ( 2x20 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel chromatography followed by reverse phase HPLC. The resulting material was worked up to isolate the free base with ethyl acetate and saturated NaHCO3 to give compound 27 as a yellow solid (97 mg, 68%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.56 (d, 1H), 7.77 (td, 1H), 7.66-7.63 (m, 1H), 7.61 (s, 1H), 7.53-7.47 (m, 6Н), 7.40 (t, 1H), 7.32-7.24 (m, 2H), 7.19 (d, 2H), 7.09 (d, 1H), 6.77 (d, 2H), 4.87 (s, 2H), 2.92 (s , 6Н), 2.27-2.16 (m, 1H), 1.74-1.58 (m, 4H), 1.54-1.37 (m, 3Н), 1.15-1.05 (m, 1H), 0.97-0.82 (m, 2Н);

LCMS: 516.8 [M+H]+.

The compound described below was synthesized from intermediate 2.4 and 4-vinylpyridine based on the procedure described for compound 27.

Comm. Structure Name [M+N] ⁺ 28 / —Ζ Oh oh 7 O 0 (£)-A-((4'-(Dimethylamino)-[1,1 biphenyl]-4-yl)methyl)-A-(3-(2(pyridin-4-yl)vinyl)phenyl) cyclohexanecarboxamide 516.8

Compound 29. N-((4'-(Dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-H-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide

A mixture of intermediate 9 (155 mg, 0.288 mmol), 5-bromo-2-methoxythiazole (89 mg, 0.489

- 93 040003 mmol), Pd(dppf)Cl ₂ (20 mg, 0.027 mmol), cesium carbonate (280 mg, 0.862 mmol) and DMF (1.5 ml) were degassed by bubbling N2 for 10 min, heated at 80°C for 2 h, and then left to cool to rt. Ethyl acetate was added to the mixture and the solution was washed with water (2x20 ml), dried (Na ₂ SO ₄ ) and concentrated. The crude material was purified by silica gel chromatography to give compound 29 (63 mg, 42%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.69 (s, 1H), 7.52-7.45 (m, 5H), 7.38 (t, 1H), 7.34 (t, 1H), 7.17 (d, 2H) , 7.04 (d, 1H), 6.77 (d, 2H), 4.56 (s, 2H), 4.02 (s, 3H), 2.92 (s, 6H), 2.25-2.14 (m, 1H), 1.72-1.58 (m , 4H), 1.551.36 (m, 3H), 1.15–1.08 (m, 1H), 0.98–0.82 (m, 2H);

LCMS: 526.5 [M+H]+.

The compounds described below were synthesized from intermediate 9 and the corresponding aryl bromide or aryl iodide based on the procedure described for compound 29.

Comm. Structure Name [M+N] ⁺ thirty ABOUT' LA LA Z— / 0-((4'-(Dimethyl ^a mino)-[ 1, Hbiphenyl]-4-yl)methyl)-0-(3-(2methoxythiazol-4-yl)phenyl) cyclohexanecarboxamide 526.3 31 / —Z al AL Ργ° Λ ω < 2 _χ ο 0-((4'-(Dimethylamino)-[ 1, Hbiphenyl]-4-yl) methyl)-A-(3-(5methoxythiophen-2-yl)phenyl) cyclohexanecarboxamide 525.3 32 / -z O al Q o o / 0-((4'-(Dimethylamino)-[ 1, Hbiphenyl]-4-yl)methyl)-0-(3-(4methoxypyridin-2-yl)phenyl) cyclohexanecarboxamide 520.8 33 ABOUT N 0-((4'-(Dimethyl ^a mino)-[ 1, Hbiphenyl] -4-yl) methyl)-A-(3-(5ethylpyridin-3-yl)phenyl) cyclohexdncdrboxdmid 518.8 34 0 aOC0O ¹ 0-((4'-(Dimethyl ^a mino)-[ 1, Hbiphenyl]-4-yl)methyl)-0-(3-(2methoxypyrimidin-4-yl)phenyl) cyclohexdnkdrboxdmid 521.8 35 0 aOO0O । aOT 0-((4'-(Dimethyl ^a mino)-[ 1, Hbiphenyl]-4-yl)methyl)-0-(3-(6methoxypyrimidin-4-yl)phenyl) cyclohexdnkdrboxdmid 521.6 36 2 about / 0-((4'-(Dimethyl ^a mino)-[ 1, Hbiphenyl]-4-yl)methyl)-0-(3-(6methoxypyrdzine^-wOphenyl) cyclohexdncdrboxdmid 521.6

Various reaction conditions: 0.1-0.2 eq. Pd(dppf)Cl ₂ ; 3-4 eq. CS2CO3; DMF or dioxane.

The compounds described below were synthesized from intermediate 8.1 and the corresponding amine using standard HATU acylation conditions (HATU, iPr ₂ NEt, DMF, rt).

- 94 040003

Comm. Structure Name [M+N] ⁺ 37 / -z O ° \ /—\ 0 about / 3 -(/V-((4'-(D imethylamino)- [ 1, G biphenyl]-4-yl)methyl) cyclohexanecarboxamido)-A-(5methoxypyr idin-3-yl)benzamide 563.8 38 gY \ / ^IZ / - 0 ° Z - / 3 -(A-((4'-(D-imethylamino)- [ 1, G biphenyl]-4-yl)methyl) cyclohexanecarboxamido)-Aphenylbenzamide 532.7 39 o , ', ₌ Λ Methyl-3 - (3 - (A- ((4'- (dimethylamino) [1, G-biphenyl] -4- yl)methyl)cyclohexanecarboxamido)benzamido)benzoate 590.7 40 41 gY gG \ / ¹² \ / ^ΙΖ /—)=° ) b to QQ z— z— / / 3 -(^((4'-(Dimethylamino)-[1,1'biphenyl]-4-yl)methyl) cyclohexanecarboxamido)-A(pyridin-4-yl)benzamide 3 -(A-((4'-(Dimethylamino)-[ 1, Gbiphenyl]-4-yl)methyl) cyclohexanecarboxamido)-A(pyridin-2-yl)benzamide 533.6 533.6

Compound 42 )phenyl)cyclohexanecarboxamide

Step 1: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(hydroxymethyl)phenyl)cyclohexanecarboxamide

To a mixture of intermediate 2.5 (1.33 g, 2.41 mmol) in H2O (20 mL) and THF (40 mL) at rt. NaOH (492.2 mg, 12.31 mmol) was added. The mixture was stirred at rt. overnight and then concentrated to remove THF. The suspension was extracted with DCM (100 ml). The organic layer was dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate; 2:1) to give N-((4'-(dimethylamino)-[1,1'-biphenyl] -4-yl)methyl)-N(3-(hydroxymethyl)phenyl)cyclohexanecarboxamide (948.30 mg, 1.82 mmol, 75.57% yield) as a light yellow solid.

1Н NMR (400 MHz, CDCl ₃ ): δ 7.49 (m, 4Н), 7.34 (d, 2Н), 7.21 (d, 2Н), 7.04 (s, 1Н), 6.93 (br s, 1Н), 6.82 (d , 2Н), 4.89 (s, 2Н), 4.69 (d, 2Н), 3.01 (s, 6Н), 2.19 (t, 1Н), 1.82-1.63 (m, 7Н), 1.34-1.16 (m, 1Н), 1.10-0.89 (m, 2 H); MS: 443.2 [M+H]+.

Step 2: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-formylphenyl)cyclohexanecarboxamide

N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(hydroxymethyl)phenyl)cyclohexanecarboxamide mixture (823.7 mg, 1.86 mmol) in DCM (20 ml) was vigorously stirred. Dess-Martin reagent (928.9 mg, 2.19 mmol) was added and the system was degassed with 3 vacuum/N ₂ cycles. The mixture was stirred at rt. for 2 h in an N2 atmosphere. Saturated aqueous NaHCO ₃ (10 ml) and saturated aqueous Na ₂ S ₂ O ₃ (10 ml) were added and the mixture was stirred for 30 min before extraction with DCM (20 ml x 3). The combined organic layers were dried with MgSO ₄ , filtered and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate; 2:1) to give N-((4'-(dimethylamino)-[1,1' -biphenyl]-4-yl)methyl)-N-(3formylphenyl)cyclohexanecarboxamide (453.20 mg, 1.03 mmol, 55.34% yield) as a light yellow solid.

1H NMR (400 MHz, CDCU): δ 9.89 (s, 1H), 7.82-7.68 (m, 1H), 7.45-7.28 (m, 6H), 7.18-7.05 (m, 3H), 6.71 (d, 2H) , 4.83 (s, 2H), 2.91 (s, 6H), 2.09-1.95 (m, 1H), 1.67-1.45 (m, 7H), 1.12-1.05 (m, 1H), 0.96-0.84 (m, 2H );

MS: 441.2 [M+H] ⁺ .

- 95 040003

Step 3: 1-(3-(N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)-3-methyl-2-(phenylsulfonyl)butyl acetate

To a solution of intermediate 11 (134.2 mg, 676.82 μmol) in THF (1 ml) at -78°C was added n-BuLi (2.5 M, 200 μl). The mixture was stirred at -78°C for 30 min, and then N-((4'(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N[-(3-formylphenyl)cyclohexanecarboxamide was added (177.6 mg, 403.10 µmol) in THF (0.5 ml). The mixture was vigorously stirred and maintained at -78°C for 3 h. Ac ₂ O (109.0 mg, 1.07 mmol) was added dropwise at -78°C. The mixture was maintained at -78°C for 1 h, the bath was removed, and the reaction mixture was left to warm to RT overnight. The reaction was quenched with saturated aqueous NH ₄ Cl (5 ml) and was extracted with EtOAc (15 ml x 3). The combined organic layers were dried with MgSO ₄ , filtered, concentrated and then purified by prep-TLC (EtOAc:PE=1:2) to give 1-(3-(N-((4'-(dimethylamino)-[1 ,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)-3-methyl-2-(phenylsulfonyl)butyl acetate (61.6 mg, 90.47 µmol, 22.89% yield) as a white solid .

¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.77-7.70 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.34 (m, 6H), 7.18-7.14 (m, 1H), 7.05 ( t, 2H), 6.98-6.87 (m, 1H), 6.79 (d, 1H), 6.75-6.69 (m, 2H), 6.19 (s, 1H), 6.02 (d, 1H), 4.95-4.82 (m, 1H), 4.61-4.58 (m, 1H), 3.10-3.05 (m, 1H), 2.92 (s, 6H), 2.38-2.23 (m, 1H), 2.19-2.09 (m, 1H), 1.96 (s, 3Н), 1.581.49 (m, 6Н), 1.11 (d, 6Н), 0.90-0.77 (m, 4Н);

MS: 681.4 [M+H]+.

Step 4: (Z)-N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-methyl-2-(phenylsulfonyl)but) -1-en-1-yl)phenyl)cyclohexanecarboxamide

To a solution of 1 -(3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)-3-methyl-2-(phenylsulfonyl)butyl acetate ( 93.2 mg, 136.88 µmol) in THF (2 ml), DBU (128.4 mg, 843.41 µmol) was added dropwise. The solution was stirred at rt. overnight, concentrated and then purified by prep-TLC (EtOAc:PE=1:2) to give (2)-N[-((4'-(dimethylamino)-[1,1'biphenyl]-4-yl )methyl)-N-(3-(3-methyl-2-(phenylsulfonyl)but-1-en-1-yl)phenyl)cyclohexanecarboxyamide (67.8 mg, 109.21 µmol, 79.78% yield) in form of a yellow solid.

1Н NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, 1H), 7.73 (s, 1H), 7.54-7.29 (m, 8Н), 7.18-7.14 (m, 1Н), 7.09 (d, 2Н), 7.02 -6.91 (m, 2H), 6.83 (br s, 1H), 6.71 (d, 2H), 4.80 (br s, 2H), 2.92 (s, 6H), 2.84-2.74 (m, 1H), 2.13- 1.98 (m, 1H), 1.70-1.53 (m, 8H), 1.23-1.09 (m, 2H), 0.85 (d, 6H);

MS: 621.4 [M+H] ⁺ .

Step 5: (E)-N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-methylbut-1-ene-1- yl)phenyl)cyclohexanecarboxamide

A mixture of (Z)-N[-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-methyl-2-(phenylsulfonyl)but- 1-en-1-yl)phenyl)cyclohexanecarboxamide (65.6mg, 105.66µmol), 1,3-dimethyltetrahydropyrimidin-2(1H)-one (137.8mg, 1.08mmol) in THF (4 ml) was degassed with 3 vacuum/N ₂ cycles. Methanol (34.8 mg, 1.09 mmol) was added followed by diiodosamarium (0.1 M, 9.00 mL, 0.9 mmol, THF solution). The mixture was stirred at rt. for 2.5 hours under N ₂ , concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate; 2:1) to give (E)-N-((4'(dimethylamino)-[1,1' -biphenyl]-4-yl)methyl)-N-(3-(3-methylbut-1-en-1-yl)phenyl)cyclohexanecarboxamide (29.3 mg, 60.96 µmol, 57.69% yield) in as a light yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ: 7.46 (dd, 4H), 7.35-7.22 (m, 2H), 7.17-7.08 (m, 3H), 6.90 (d, 1H), 6.74 (d, 2Н), 6.28 (d, 1Н), 6.21 (dd, 1Н), 4.79 (br s, 2Н), 2.89 (s, 6Н), 2.42-2.32 (m, 1Н), 2.21-2.08 (m, 1Н), 1.61 (t, 4H), 1.52-1.31 (m, 3H), 1.17-1.03 (m, 1H), 0.98 (d, 6H), 0.91-0.79 (m, 2H);

MS: 481.4 [M+H] ⁺ .

Compound 43

Step 1: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-(methoxymethoxy)isothiazol-5yl)phenyl)cyclohexanecarboxamide

Pd(dba) ₂ (644.9 mg, 1 .12 mmol), S-Phos (920.9 mg, 2.24 mmol) and K3PO4 (3.57 g, 16.82 mmol). The mixture was heated under reflux for 6 h, added EtOAc (300 ml) and water (150 ml) and then the mixture was filtered. The organic layer was separated, washed with water (150 ml), dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc = 5/1) to give N-((4'-(dimethylamino) [1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-(methoxymethoxy)isothiazol-5-yl)phenyl)cyclohexanecarboxamide (2.03 g, 2.04 mmol, 36.36 % yield, 55.79% pure) as a yellow oil.

- 96 040003

MS: 556.4 [M+H]+.

Step 2: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-hydroxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide

To a solution of N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-(methoxymethoxy)isothiazol5-yl)phenyl)cyclohexanecarboxamide (2, 71 g, 4.88 mmol) in MeOH (100 ml) at rt. added conc. HC1 (13.4 ml, 12 M, 161.43 mmol). The reaction mixture was stirred for 16 h, concentrated and then dissolved in EtOAc (200 ml). This mixture was washed with aqueous NaHCO ₃ (50 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel column chromatography (petroleum ether/EtOAc = 2/1) to give N-((4'- (dimethylamino)-[1,1'-biphenyl]-4yl)methyl)-N-(3-(3-hydroxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide (924 mg, 1.77 mmol, 36.19% yield, 97.79% pure) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d6): δ 11.63 (br s, 1H), 7.70-7.45 (m, 7H), 7.29-7.13 (m, 3H), 7.04 (s, 1H), 6.79 (d, 2Н), 4.89 (s, 2Н), 2.93 (s, 6Н), 2.15-2.05 (m, 1Н), 1.78-1.59 (m, 4Н), 1.58-1.39 (m, 3Н), 1.22-1.08 (m, 1Н), 0.99-0.82 (m, 2Н);

MS: 512.2 [M+H]+.

Step 3: N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-methoxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide

To a solution of N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-hydroxyisothiazol-5yl)phenyl)cyclohexanecarboxamide (462 mg, 902, 91 µmol) in THF (35 ml) and MeOH (5 ml) at 0°C was added diazomethyl(trimethyl)silane (2 M, 1.20 ml). The mixture was heated to rt. for 15 h and then EtOAc (50 ml) was added. The solution was washed with 1 N HCl (30 ml), washed with NaHCO ₃ solution (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude material which was purified by prep-HPLC (reverse phase; water (10 mM NH ₄ HCO ₃ )-CH ₃ CN) to give N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(3-methoxyisothiazol-5- yl)phenyl)cyclohexanecarboxamide (109.4 mg, 207.29 µmol, 22.96% yield, 99.61% pure) as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.78-7.70 (m, 1H), 7.66-7.56 (m, 6H), 7.40-7.23 (m, 4H), 6.87 (d, 2H), 4.97 (s , 2Н), 4.03 (s, 3Н), 3.02 (s, 6Н), 2.35-2.20 (m, 1Н), 1.86-1.66 (m, 4Н), 1.65-1.45 (m, 3Н), 1.28-1.16 (m , 1H), 1.06–0.91 (m, 2H);

MS: 526.3 [M+H]+.

Compound 44 yl)phenyl)cyclohexanecarboxamide o

During the purification of compound 43, compound 44 (108.8 mg, 205.64 µmol, 22.78% yield, 99.36% purity) was isolated as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1H), 7.55-7.41 (m, 6H), 7.28 (d, 1H), 7.17 (d, 2H), 6.85-6.74 (m, 3H) , 4.88 (s, 2Н), 3.23 (s, 3Н), 2.92 (s, 6Н), 2.24-2.10 (m, 1Н), 1.74-1.57 (m, 4Н), 1.54-1.35 (m, 3Н), 1.181 .05 (m, 1Н), 0.95-0.82 (m, 2Н);

MS: 526.3 [M+H]+.

Compound 45

Step 1: trans-4-((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxyazetidine-1- yl)phenyl)cyclohexanecarboxamide

Mixture of intermediate 2,6 (138 mg, 0.22 mmol), 3-methoxyazetidine hydrochloride (32 mg, 0.26 mmol), CS ₂ CO ₃ (215 mg, 0.66 mmol), Xantphos (17 mg, 0.029 mmol), Pd ₂ (dba) ₃ (8 mg, 0.014 mmol) and dioxane (1.5 ml) were degassed with 3 vacuum/N ₂ cycles, stirred at 100°C for 3 h, and then left to cool to rt . The reaction mixture was poured into 20 ml of saturated NaHCO ₃ and was extracted with 20 ml of ethyl acetate. The organic layer was washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-20% ethyl acetate in hexanes) to give trans-4-((tert-butyldimethylsilyl)oxy)-N -((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide (119 mg, 86%) as pale yellow foam.

1H NMR (400 MHz, DMSO-d6): δ 7.25 (t, 1H), 6.98-6.93 (m, 2H), 6.78 (d, 1H), 6.55 (d, 1H), 6.44 (d, 1H),

- 97 040003

6.27 (br s, 1H), 4.35-4.28 (m, 1H), 4.05 (t, 2H), 3.72 (s, 3H), 3.64-3.58 (m, 2H), 3.54-3.45 (m, 3H), 3.24 (s, 3H),

2.37-2.28 (m, 1H), 2.09 (s, 3H), 2.13-2.03 (m, 1H), 1.78-1.68 (m, 6H), 1.65-1.57 (m, 2H), 1.50-1.38 (m, 3H ),

1.35-1.22 (m, 2H), 1.09-0.96 (m, 2H), 0.80 (s, 9H), 0.92-0.77 (m, 2H), -0.013 (s, 6H);

LCMS: 635.7 [M+H]+.

Step 2: trans-4-Hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide

Aqueous hydrochloric acid (6 N, 0.24 ml, 1.4 mmol) was added to a solution of trans-4((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl )methyl)-N-(3-(3methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide (113 mg, 0.178 mmol), THF (1 ml) and MeOH (1 ml) at r.t. The reaction mixture was stirred for 45 min and then poured into a mixture of 20 ml of saturated NaHCO ₃ and 20 ml of ethyl acetate. The separated organic layer was 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 (40-80% ethyl acetate in hexanes) to give trans-4-hydroxyN- ((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-N-(3-(3-methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide (61 mg, 66%) as a white foam.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.25 (t, 1H), 6.98-6.93 (m, 2H), 6.78 (d, 1H), 6.56 (d, 1H), 6.44 (d, 1H) , 6.28 (br s, 1H), 4.43 (d, 1H), 4.36-4.29 (m, 1H), 4.09-4.03 (m, 2H), 3.72 (s, 3Н), 3.64-3.58 (m, 2H), 3.52-3.45 (m, 2H), 3.24 (s, 3H), 3.30-3.22 (m, 1H), 2.38-2.28 (m, 1H), 2.09 (s, 3H), 2.10-2.00 (m, 1H), 1.78-1.67 (m, 6H), 1.63-1.55 (m, 2H), 1.47-1.34 (m, 3H), 1.34-1.22 (m, 2H), 1.09-0.97 (m, 2H), 0.84-0.72 (m , 2H); LCMS: 521.5 [M+H] ⁺ .

The following compounds were synthesized from intermediate 2.6 or 2.7 and the corresponding amine based on the procedures described for compound 45.

Comm. Structure Name [M+N] ⁺ 46 o Yj^ Αγ ^>he trans-4-Hydroxy-^((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-A(3-(3-(methoxymethyl)azetidin-1 yl)phenyl)cyclohexanecarboxamide 535.9 47 o TO ⁰ Υ trans-4-Hydroxy-^((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-A(3-(3-methoxypyrrolidin-1 yl)phenyl)cyclohexanecarboxamide 535.9 48 O yj^di ^όη Su ⁴ o trans-4-Hydroxy-^((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-A(3-(3-(methoxymethyl)pyrrolide in-1 yl)phenyl)cyclohexanecarboxamide 549.9 49 o A'' ⁴ N Αγ ^he trans-4-Hydroxy-^((trans-4-(4methoxy-3- methylphenyl) cyclohexyl) methyl) -A (3 - (4-methoxypiper idin-1 yl) phenyl) cyclohexanecarboxamide 549.5 50 o γγ^ A ' ^he trans-4-Hydroxy-^((trans-4-(4methoxy-3- methylphenyl)cyclohexyl)methyl)-A(3-(3-methoxypiperidin-1 yl)phenyl)cyclohexanecarboxamide 549.6 Example A-1. Parenteral pharmaceutical composition

To obtain a parenteral pharmaceutical composition suitable for injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, was dissolved in sterile water, and then mixed with 10 ml of 0 .9% sterile saline. An appropriate buffer was optionally added, as well as an optional acid or base to adjust the pH. The mixture was formulated into a unit dosage form suitable for injection.

Example A-2. oral solution

To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, was added to water (with optional solubilizer(s), optional buffer(s), and taste masking excipients) to provide a solution of 20 mg/ml .

Example A-3. oral tablet

A tablet is prepared by mixing 20-50% by weight of a 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 were obtained by direct compression. The total weight of the compressed tablets was maintained at 100-500 mg.

Example A-4. oral capsule

To obtain a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, was mixed with starch or other suitable powder mixture. The mixture is included in an oral dosage unit 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 capped.

Example A-5. Topical gel formulation

To prepare a pharmaceutical topical gel composition, the compound described herein, or a pharmaceutically acceptable salt thereof, was mixed with hydroxypropyl cellulose, propylene glycol, isopropyl myristate, and USP purified alcohol. The resulting gel mixture is then enclosed in containers, such as tubes, which are suitable for topical administration.

Example B-1. In vitro FXR assay (PGL3)

sowing

CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask with DMEM + 10% double-purified activated charcoal FBS and incubated at 37° C. in 5% CO 2 for 18 hours (O/N).

Transfection

After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% highly purified activated charcoal serum.

To prepare the transfection reaction mixture, the transfection reagent (X-tremeGENE HP from Roche, catalog # 06366236001) was added to a 1.5 ml microcentrifuge tube labeled A at a ratio of 1:3 (DNA in µg: transfection reagent in µl). OptiMEM medium (Life Technologies, cat # 31985-062) was added to provide a total volume of 1 ml. The transfection reaction mixture was then briefly vortexed and incubated at room temperature for 5 min.

In a separate 1.5 ml microcentrifuge tube labeled B, 100 μl of OptiMEM and plasmids XPD90Gal pCMXhFXRfl, pCMXhRXRfl + PGL3-ECRE*6-luc + CMX-YFP were added at a ratio of 2 mg:2 μg: 18 μg:3 μg. This microcentrifuge tube B was then briefly vortexed and incubated at room temperature for 5 minutes.

The total volume from tube labeled A was then transferred to tube labeled B. The mixture was then briefly vortexed and the transfection reagent/DNA complex was then incubated for approximately 15-20 min at room temperature.

After incubation, the transfection reagent/DNA complex mixture was then added to the cells in a T175 flask and the cells were incubated for 8 h (O/N) at 37° C. in 5% CO ₂ .

Compounds tested

A semi-log serial dilution was prepared in a 96-well plate. OptiMEM was used as a diluent. Using any of the compounds described herein, a 10 mM stock solution of the compound was prepared. An initial dilution of 1:100 was made in the first well for a final concentration of 100 μM. Final concentrations in a 96-well plate were prepared using a multichannel pipette to transfer 5 μl of the diluted compound into a 384-well plate in quadruplicate.

The cells in the T175 flask were trypsinized and the cells were resuspended in 40 ml DMEM without phenol red + 10% highly charcoal purified FBS. Typically, one T175 flask was enough to seed two 384-well plates. CV-1 cells were seeded at 45 μl of cell suspension/well using a multichannel pipette or a 384-well Multidrop dispenser. Cells were then incubated for 18 hours overnight.

Reading

After removing the plates from the incubator, the medium was removed from the plate and the 384-well plate was turned upside down on a paper towel. The rest of the medium was carefully tapped out. Then, 15 μl of lysis buffer was added to each well using a multichannel pipette or a 384-well Multidrop dispenser. After incubation for 10 minutes at room temperature in a shaker, 30 μl of luciferase buffer was added to each well. The number of luminescence pulses was obtained directly using Perkin Elmer Envision.

The ability of the compounds disclosed herein to inhibit FXR activity was quantified and the corresponding EC ₅₀ value was determined. Table 3 presents the activity of various compounds disclosed in this document. Fex = fexaramine.

Table 3

where comp./Fex means the ratio of the EC ₅₀ for the test compound relative to the EC ₅₀ fexaramine control.

+++ means conn./Fex <10;

++ means conn./Fex >10 and <100;

+ means conn./Fex >100.

Example B-2. In vitro FXR (TK) assay

sowing

CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask with DMEM + 10% double-purified activated charcoal FBS 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% highly purified activated charcoal serum. In a polypropylene tube, 2500 µl of OptiMEM (Life Technologies, catalog # 31985-062) were combined with expression plasmids for hFXR, hRXR, TK-ECRE-luc and pCMX-YFP. Then the tube was briefly unscrewed on a vortex and incubated at room temperature for 5 min. The transfection reagent (X-tremeGENE FTP from Roche, cat # 06366236001) was added to the OptiMEM/plasmid mixture, vortexed and incubated at room temperature for 20 min. After incubation, the transfection reagent/DNA complex mixture was then 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).

- 100 040003

Compounds tested

Compounds were serially diluted with DMSO and added to transfected CV1 cells. The cells were then incubated for 18 days. The next day, the cells were lysed and checked for luminescence.

The following table provides typical data for typical compounds disclosed in this document.

Table 4

- 101 040003

++ means EC ₅₀ >3 and <10;

+ means EC ₅₀ >10.

Compounds with maximum potency <25% of the fexaramine control were classified as +.

Example B-3. NASH activity study (STZ model)

NASH can be induced in male C57BL/6 mice by a single subcutaneous injection of 200 μg STZ 2 days postnatally followed by ad libitum high fat diet (HFD) feeding after 4 weeks of age. With continued 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 using a clinical chemistry analyzer. TG contents in liver tissue can be measured using the Triglyceride E-test kit (Wako, Tokyo, Japan). Histological analysis of liver sections can be performed on tissue embedded with Tissue-TEK OCT, flash frozen in liquid nitrogen and stored at -80°C. Sections can be cut (5 µm), air dried and fixed in acetone. For hematoxylin and eosin staining, liver sections can be pre-fixed with Bouin's solution and then stained with hematoxylin and eosin solution. The degree (zone-3) of liver fibrosis can be assessed by staining with Sirius red.

Example B-4. NASH activity study (AMLN model)

NASH can be induced in male C57BL/6 mice by nutritional induction with the AMLN diet (DIO-NASH) (D09100301, Research Diet, USA) (40% fat (18% trans fat), 40% carbohydrate (20% fructose) and 2% cholesterol). Animals were kept on this diet for 29 weeks. After 26 weeks of nutritional induction, liver biopsies were performed for initial histological evaluation of disease progression (hepatosteatosis and fibrosis), stratified and randomized into treatment groups according to liver fibrosis stage, steatosis score, and body weight. Three weeks after biopsy, mice were stratified into treatment groups and FXR agonists were administered daily by oral gavage for 8 weeks. At the end of the study, liver biopsies were performed to evaluate liver steatosis and fibrosis by examining tissue sections stained with H&E and Sirius red, respectively. The total content of collagen in the liver was measured by colorimetric determination of hydroxyproline residues during acid hydrolysis of collagen. Triglycerides and total cholesterol in liver homogenates were measured in single determinations using a Cobas C-111 autoanalyzer with a commercial kit (Roche Diagnostics, Germany) according to the manufacturer's instructions.

Example B-5. Model of intrahepatic cholestasis

Experimental intrahepatic cholestasis induced by 17-ethynylestradiol (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 10 mg/kg 17a-ethinylestradiol (E2) daily for 5 days. Testing for FXR ligands can be performed by administering compounds upon E2 induction of cholestasis. Cholestatic effects can be quantified by assessing the liver/body mass ratio and measuring total serum bile acids, and alkaline phosphatase levels can be measured using reagents and

- 102 040003 controls from Diagnostic Chemicals Ltd. and analyzer Cobas Mira plus CC (Roche Diagnostics). For histology and mitosis measurements, liver samples from each mouse can be fixed in 10% neutral buffered formalin. Slides were stained with hematoxylin and eosin using standard protocols and examined under a microscope for structural changes. Hepatocyte proliferation was assessed by immunohistochemical staining for Ki67.

Example B-6. Direct regulation of target genes

Direct regulation of target genes by FXR ligands can be assessed by administering either acute or chronic doses of compounds to mice and harvesting tissues at different time points post-dose. RNA can be isolated from tissues such as ileum and liver and reverse transcribed into cDNA for quantitative PCR analysis of genes known from the literature to be directly and indirectly regulated by FXRs such as SHP, BSEP, IBABP, FGF15, Cyp7a1, Cyp8Y and C3.

Example B-7. Pharmacokinetic study in mice

Plasma pharmacokinetic parameters of any of the compounds disclosed herein, as a test drug, were measured after a single bolus intravenous and oral administration to mice (CD-1, C57BL and mice with induced obesity). The test preparation was formulated for intravenous administration in a carrier medium solution of DMSO, PEG400, hydroxypropyl-β-cyclodextrin (HPeCD) and administered in a dose volume of 3 ml/kg at selected dose levels. The oral dosing formulation was formulated in appropriate oral dosing 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) were collected by the cheek pouch method at predetermined time intervals after intravenous or oral doses in tubes containing EDTA. Plasma was isolated by centrifugation of blood at 10,000 g for 5 min, aliquots were transferred to a 96-well plate and stored at -60°C or below until analysis.

Calibration standards of the test preparation were obtained by dilution with DMSO of the stock solution in DMSO over a range of concentrations. Aliquots of the DMSO calibration standards were pooled with untreated mouse plasma such that final plasma concentrations of the calibration standards were 10-fold lower than the DMSO calibration standards. PK plasma samples were combined with pure DMSO to match the matrix. Calibration standards and RA samples were combined with ice-cold acetonitrile containing an analytical internal standard and centrifuged at 1850 g for 30 min at 4°C. Supernatant fractions were analyzed by LC/MS/MS and quantified from 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 (V _dss ) and mean retention time (MRT)) were calculated by non-compartmental analysis using Microsoft Excel (version 2013).

Example B-8. Rat model ANIT

The compound described herein was evaluated in a chronic cholestasis treatment model over a dose range of 0.01 to 10 mg/kg. This model was used to assess the acceptability of the use of FXR agonists, for example, the compound described herein, for the treatment of cholestatic disorders of the liver, such as malabsorption of bile acids (for example, primary or secondary hologenic diarrhea), biliary reflux gastritis, collagenous colitis, lymphocytic colitis, inflammation in the disconnected gut, unspecified colitis, Alagille syndrome, biliary atresia, ductopenic liver transplant rejection, bone marrow or stem cell transplantation-associated graft-versus-host disease, cystic fibrosis-induced liver disease, and parenteral nutrition-associated liver disease.

Rats were treated with alpha-naphthyl isothiocyanate (ANIT) (0.1% w/w) in feed for 3 days prior to treatment with a compound described herein at doses of 0.01 to 10 mg/kg (carrier medium). The non-cholestatic control group was kept on a standard balanced diet without ANIT and used as non-cholestatic controls (control). 14 days after oral dosing, the serum of rats was analyzed for the content of analytes. LLQ - lower limit of quantitation. Mean ± SEM; n = 5.

Serum levels of indicators of hepatobiliary damage in rats, such as elevated levels of circulating aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and bile acids, were measured. Exposure to ANIT induced deep cholestasis and hepatocellular injury. A compound that improves many of these indicators is useful in the treatment of the aforementioned 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 are consistent with the pharmacological action of an FXR agonist. Improvement in serum conjugated bilirubin (a direct indicator of liver function) implies recovery from cholestasis with improved bile secretion.

In addition, an assay was performed to elucidate the effects of the compound described herein on the expression of serum fibroblast growth factor 15 FGF15 (FGF15 in rodents; FGF19 in humans), a hormone that is secreted into the portal blood and signals the liver to downregulate 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 for detecting the interaction of FXR agonists with a target.

Serum FGF15 levels were quantified using the FGF15 Meso Scale Discovery (MSD) assay. For example, an anti-mouse FGF15 antibody from R&D Systems (AF6755) was used as both a capture and a detection antibody in the assay. The MSD SULFO-TAG NHS ester was used to label an anti-FGF15 antibody. Standard 96-well MSD plates were coated with immobilized anti-FGF15 antibody and the plates were blocked with MSD Blocker A (R93AA-2). After washing the plate with PBS + 0.05% Tween 20, 4 MSD diluent was dispensed into each well and incubated for 30 minutes. 25 pi calibration dilutions or samples (serum or plasma EDTA) were dispensed into each well and incubated with shaking at room temperature.

After washing, detection antibody was added and incubated with shaking for 1 hour at room temperature. After washing and adding MSD Read (R92TC-2) buffer, the plate was read on an MSD SECTOR Imager 6000. Standard curve and unknown sample plots were generated using the MSD data analysis software.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested by those skilled in the art are within the spirit of this application and the scope of the appended claims.

Claims (15)

CLAIM 1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof Formula (I) where R ¹ and R ² are each independently selected from H and D; R ³ is selected from substituted or unsubstituted cyclohexyl, where if R ³ is substituted then R ³ is substituted with one R ¹² group; R ¹² is -OR ¹⁰ ; ring A is phenyl or cyclohexyl; L ¹ is missing; ring C is phenyl or pyridinyl; each R ^c is independently selected from H, D, halogen, -CN, -OR ¹⁰ , -SR ¹⁰ , -N(R ¹⁰ ) ₂ , substituted or unsubstituted C ₁ -C ₆ alkyl; ring B is phenyl or pyridinyl; L ³ is absent or is -O-, -CH ₂ -, -CH2CH2-, -CH=CH-, -C=C-, -C(=O)NR ¹⁰ -, -NR ¹⁰ C(=O)- or -NR ¹⁰ -; ring D is phenyl, monocyclic N-containing C ₂ -C ₈ heterocycloalkyl or 5-membered or 6-membered heteroaryl with 1-4 N atoms, 0-1 O atom and 0-1 S atom in the ring; RD is independently selected from H, D, halogen, -OR ¹⁰ , --CO2R ¹⁰ , substituted or unsubstituted C _r C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ heteroalkyl, and unsubstituted or substituted C ₃ C ₆ cycloalkyl; each R ¹⁰ is independently selected from H, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl; p is 0, 1 or 2; q is 0, 1, 2, 3 or 4; and the groups - 104 040003 are in the 1,3 position relative to each other on ring B and where the term heteroalkyl refers to an alkyl group in which one skeletal carbon atom of the alkyl is oxygen, -NH-, -N(C ₁ -C ₆ alkyl) - or sulfur ; where heterocycloalkyl contains 1-2 N atoms; where any substituted group is substituted with one or two substituents independently selected from D, halo, -CN, -NH2, -OH, -NH(CH3), -HCH3b, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring D is phenyl or ring D is 5-membered or 6-membered heteroaryl selected from pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl , isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or ring D is a monocyclic N-containing C ₂ -C ₈ heterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azepanil. 3. The compound according to claim 1 or its pharmaceutically acceptable salt, where its pharmaceutically acceptable salt, where is is 4. Connection according to claim 1 or fight 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: 6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is - 105 040003 7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl. 9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein ring C is pyridyl. (R ^c )pH С j 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, where ^v is 11. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is ring B is phenyl; and ring C is phenyl. 12. The compound according to claim 1, where the compound is N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(5-methoxypyridin-3-yl)phenyl)cyclohexanecarboxamide; N-((4'-(Dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3'-methoxy-[1,1'-biphenyl]-3-yl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-methoxypyridin-4-yl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(4'-methoxy-[1,1'-biphenyl]-3-yl)cyclohexanecarboxamide; (E)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-(oxazol-2-yl)vinyl)phenyl) cyclohexanecarboxamide; N-([1,1'-biphenyl]-3-yl)-N-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamide; N-([1,1'-biphenyl]-3-yl)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-phenoxyphenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-(oxazol-2-yl)ethyl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(pyridin-3-yl)phenyl)cyclohexanecarboxyamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(5-methylpyridin-3-yl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(6-methoxypyridin-2-yl)phenyl)cyclohexanecarboxamide; methyl 5-(3-(N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)phenyl)nicotinate; (E)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-(pyridin-2-yl)vinyl)phenyl) cyclohexanecarboxamide; (E)-N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-(pyridin-4-yl)vinyl)phenyl) cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(2-methoxythiazol-5-yl)phenyl)cyclohexanecarboxamide; - 106 040003 N((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)-M-(3-(2-methoxythiazol-4-yl)phenyl)cyclohexanecarboxamide N-((4'-(dimethylamino)-[1, T-biphenyl]-4-yl)methyl)-N-(3-(5-methoxythiophen-2-yl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1, T-biphenyl]-4-yl)methyl)-I-(3-(4-methoxypyridin-2-yl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-I-(3-(5-ethylpyridin-3-yl)phenyl)cyclohexanecarboxamide; N-((4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-I-(3-(2-methoxypyrimidin-4-yl)phenyl)cyclohexanecarboxamide; K-((4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-K-(3-(6-methoxypyrimidin-4-yl)phenyl)cyclohexanecarboxamide; K-((4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-K-(3-(6-methoxypyrazin-2-yl)phenyl)cyclohexanecarboxamide; 3-(14-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-I-(5-methoxypyridin-3-yl)benzamide; 3-(14-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)-N-phenylbenzamide; methyl-3-(3-(T4-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)benzamido)benzoate; 3-(14-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)^-(pyridin-4yl)benzamide; 3-(14-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methyl)cyclohexanecarboxamido)^-(pyridin-2yl)benzamide; K-((4'-(dimethylamino)-[1,G-biphenyl]-4-yl)methyl)-K-(3-(3-methoxyisothiazol-5-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(3-methoxyazetidin-1-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(3-(methoxymethyl)azetidin-1-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(3-methoxypyrrolidin-1-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(3-(methoxymethyl)pyrrolidin-1-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(4-methoxypiperidin-1-yl)phenyl)cyclohexanecarboxamide; trans-4-hydroxy-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)-M-(3-(3-methoxypiperidin-1-yl)phenyl)cyclohexanecarboxamide; or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition for the treatment of a liver disease or condition, metabolic disorder or inflammation in the intestinal region in a subject, comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 14. The use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the treatment of a liver disease or condition, metabolic disorder, or intestinal inflammation in a subject. 15. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the treatment of primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), 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-ulcerative dyspepsia (NUD), celiac disease, postoperative inflammation, gastric oncogenesis, or any their combinations in the subject.