EA047314B1 - FARNEZOID X RECEPTOR AGONISTS AND THEIR APPLICATION - Google Patents

Description

The present invention describes compounds that are farnesoid X receptor agonists, methods for preparing such compounds, pharmaceutical compositions and drugs containing such compounds, and methods of using such compounds in the treatment of conditions, diseases or disorders associated with farnesoid X receptor activity. .

Background of the present invention

The farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver, intestine, kidney, adrenal gland, and adipose tissue. FXR regulates a wide variety 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 disorders, liver diseases or conditions, inflammatory conditions, gastrointestinal diseases or diseases associated with cell proliferation.

Summary of the present invention

In accordance with one aspect, the present invention provides a compound of formula (I') or a pharmaceutically acceptable salt thereof:

Where:

ring A represents

X ¹ represents N;

X ⁵ , X ⁶ and X ⁷ each represent CR ⁷ ;

R ¹ represents C _g C ₄ -alkoxy;

X ² represents CR ² ;

R ² represents C ₁ -C ₄ -αlkyl;

X ³ represents CR ³ ;

R ³ represents H, C ₁ -C ₄ -alkyl;

each X ⁴ represents CH;

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

L missing;

each R ⁷ is independently selected from H and halogen;

R ⁸ is C ₄ -C ₈ -alkyl or C ₄ -C ₈ -haloalkyl;

R ⁹ represents H;

R ¹⁰ is -OC(=O)N(R ¹² )(R ¹³ );

R ¹¹ represents H;

R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl ring substituted with 1, 2 or 3 groups selected from -OH, -N(C1-C4-alkyl) 2, C1C6-alkyl, -S(=O)2(C1-C4-alkyl), -C1-C4-alkyl-S(=O)2(C1-C4-alkyl), -C1-C6-alkyl-OR ¹⁷ and -O-C1-C ₆ -alkylOR ¹⁷ ;

R ¹⁷ represents H or C1-C ₆ -alkyl;

m represents 0; and n represents 0.

In a preferred embodiment, the present invention relates to a compound having the structure of formula (1a'), or a pharmaceutically acceptable salt thereof:

- 1 047314

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein X ⁵ , X ⁶ and X ⁷ are CH.

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein wherein R ⁸ is -C(CH ₃ ) ₃ .

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 4-membered or 5-membered heterocycloalkyl ring substituted with 1 or 2 groups , selected from -OH, -N(C ₁ -C ₄ -alkyl) ₂ and C _g C ₆ -alkyl.

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is ^he

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is ¹

In another preferred embodiment, the present invention relates to the above compound or a pharmaceutically acceptable salt thereof, wherein X ³ represents CH.

In another preferred embodiment, the present invention relates to a compound which is a compound of the following structure:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a compound selected from compounds of the following structure:

- 2 047314

- 3 047314

- 4 047314

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention relates to a pharmaceutical composition containing the above compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Detailed Description of the Present Invention

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

In some embodiments, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance sometimes results in decreased absorption of glucose from the blood and increased de novo glucose production in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting glucagon-like peptide-1 (GLP1) secretion from intestinal L cells. GLP-1 is an incretin derived from the transcription product of the proglucagon gene. It is released in response to food intake and controls appetite and gastrointestinal function, and promotes insulin secretion by the pancreas. Biologically active forms of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH ₂ , which arise from selective cleavage of the proglucagon molecule. In such cases, activation of FXR, leading to decreased bile acid production, correlates with decreased insulin resistance.

In accordance with some embodiments, activation of FXR also correlates with the secretion of a pancreatic polypeptide, such as peptide YY (PYY or PYY3-36). In some cases

- 5 047314 peptide YY is a gastrointestinal hormone peptide that modulates neuronal activity in the hypothalamus and brainstem, areas of the brain involved in reward processing. In some cases, decreased PYY levels correlate with increased appetite and weight gain.

In some cases, activation of FXR indirectly leads to a decrease in plasma triglycerides. Clearance of triglycerides from the bloodstream occurs through lipoprotein lipase (LPL). LPL activity is enhanced by induction of its activator apolipoprotein CII, and activation of FXR results in suppression of its inhibitor apolipoprotein CIII.

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

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

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

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

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

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

Therefore, the 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, dysregulation of metabolic processes such as bile acid synthesis, bile acid circulation, glucose metabolism, lipid metabolism or insulin sensitivity leads to metabolic diseases such as diabetes or diabetes-related conditions or disorders, alcoholic or non-alcoholic disease or condition liver, intestinal inflammation or cell proliferation disorders.

The compounds disclosed herein, in certain embodiments, have FXR agonist activity. In accordance with some embodiments, the FXR agonists described herein are structurally different from bile acids, other synthetic FXR ligands, and other natural FXR ligands.

Metabolic disorders.

In accordance with some embodiments, the disclosed compounds exhibit systemic effects. In some cases, the disclosed compounds have local effects in the intestine and limited effects in the liver or systemically. Local effects of the disclosed compounds in the intestine can be demonstrated through the regulation of FXR target genes in the intestine. Target genes may include SHP, FGF19 (FGF15), IBABP, C3, OST α/β. In some embodiments, the exposure of the disclosed compounds is approximately 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, 99.5% or more in the intestine. In some cases, the exposure of the disclosed compounds is approximately 0.5, 1, 5, 10, 15, 20, 25, 30, 40, 50% or less in

- 6 047314 general blood circulation. Exposure of FXR agonists to the intestinal lumen reduces the likelihood of side effects that result from systemic action, thereby improving the safety profile of the treatment. The disclosed compounds enhance the expression of FXR target genes in the intestine. The disclosed compounds further modulate gene expression in the FXR-mediated pathway, such as FGF19 (FGF15), which suppresses the expression of the CYP7A1 and CYP8B1 genes in the liver. In some cases, the disclosed compounds enhance gene expression in the FXR-mediated pathway. In other cases, the disclosed compounds reduce or suppress 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, 100,000, 500,000% or more in the intestine, liver, kidney or other tissues, relative to gene expression in the absence of the disclosed compounds. 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, relative to expression genes in the absence of disclosed compounds.

In the context of the present invention, a metabolic disorder refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. In some cases, metabolic disorder is associated with either a deficiency or excess in a metabolic pathway, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids and/or carbohydrates. Factors influencing metabolism include, but are not limited to, the endocrine (hormonal) control system (eg, the insulin pathway, enteroendocrine hormones including GLP-1, oxyntomodulin, PYY and the like) or the neural control system (eg, GLP-1 in the brain). Examples of metabolic disorders include, but are not limited to, diabetes, insulin resistance, dyslipidemia, liver disease, intestinal conditions associated with inflammation, cell proliferation disorders, and the like.

Diabetes mellitus and diabetes-related conditions or disorders.

Disclosed herein are methods of treating a subject suffering from diabetes mellitus or a diabetes-related condition or disorder comprising administering an FXR agonist described herein. In some cases, diabetes is type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM). In some cases, diabetes-related conditions or disorders include obesity, impaired glucose tolerance, dyslipidemia, and insulin resistance. In some cases, diabetes-related conditions or disorders additionally 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 2 diabetes, obesity, impaired glucose tolerance, dyslipidemia, insulin resistance, or secondary complications such as atherosclerosis, stroke, fatty liver disease, blindness, gallbladder disease, or polycystic ovary disease. .

The diabetic subject (eg, a type 2 diabetic subject) further has a body mass index (BMI) of 25 or more, 30 or more, 35 or more, 40 or more, such as a BMI of 25 to 29, from 30 to 34 or from 35 to 40.

In some examples, an 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 drug-induced obesity. In some examples, such methods reduce or prevent weight gain in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more. In some cases, weight gain is reduced or prevented by 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, reduction or prevention of weight gain is reported in relation to reduction or prevention of weight gain observed in a subject not treated with an FXR agonist.

Likewise, in some cases, an FXR agonist reduces a 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 more, relative to the subject. for which no FXR agonist treatment has been performed. 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 FXR leads to a decrease in serum lipids. In some examples, the reduction in serum lipids occurs by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60 %, at least 70%, at least 75% or more. In some cases, a decrease in the amount of serum lipids occurs by approx.

- 7 047314 specifically 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 reported relative to the amount of serum lipids observed in a subject not treated with an FXR agonist.

In some examples, administration of an FXR agonist results in a decrease in triglyceride levels (eg, liver triglycerides). In some cases, the reduction in triglyceride levels (eg, liver triglycerides) occurs by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75% or more. In some cases, the reduction in triglyceride levels (eg, liver triglycerides) occurs by about 5% to about 50%, from about 5% to about 25%, from about 10% to about 20%, from about 10% to about 70%, or by about 10% to about 30%. In some cases, the reduction in triglyceride levels (eg, liver triglycerides) is given relative to the reduction in triglyceride levels (eg, liver triglycerides) observed in a subject not treated with an FXR agonist.

In some examples, administration of an FXR agonist results in increased insulin sensitivity in relation to insulin in the liver. In some cases, an increase in insulin sensitivity occurs 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 increase in insulin sensitivity occurs by 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 given relative to the sensitivity observed in a subject not treated with an FXR agonist.

In some cases, 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 occurs by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60%, at least 70%, at least 75% or more. In some cases, serum insulin is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, by about 10% to about 70%, or by about 10 % to approximately 30%. In some cases, decreases in serum insulin levels are reported relative to levels observed in a subject not treated with an FXR agonist.

In some cases, administration of an FXR agonist results in a decrease in serum glucose in the subject. In some examples, the reduction in serum glucose occurs by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 50%, at least 60 %, at least 70%, at least 75% or more. In some cases, serum glucose decreases by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, by about 10% to about 70%, or by approximately 10% to approximately 30%. In some cases, reductions in serum glucose levels are reported relative to levels observed in a subject not treated with an FXR agonist.

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

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

In some cases, administration of an FXR agonist results in an increase in the metabolic rate of the subject. In some cases, an FXR agonist increases the metabolic rate of a subject. In some cases, the subject's metabolic rate increases by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% , at least 60%, at least 70%, at least 75% or more. In some cases, the metabolic rate increases by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, by about 10% to about 70%, or by about 10% % to approximately 30%. In some cases, the increase in metabolic rate is given relative to the level observed in

- 8 047314 subject for whom no FXR agonist treatment was performed.

In some embodiments, increased metabolic rate results in increased oxidative phosphorylation in the subject, which in turn results in increased energy expenditure in tissues (such as BAT). In such cases, the FXR agonist promotes increased 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 60%, at least 70%, at least 75% or more. In some cases, BAT activity is increased by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, by about 10% to about 70%, or by about 10% % to approximately 30%. In some cases, the increase in BAT activity is given relative to the BAT activity observed in a subject not treated with an FXR agonist.

Alcoholic and non-alcoholic liver disease or condition.

Disclosed herein are methods of preventing and/or treating alcoholic or non-alcoholic liver diseases or conditions. Exemplary alcoholic or nonalcoholic liver diseases or conditions include, but are not limited to, cholestasis, cirrhosis, steatosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), elevated liver enzyme levels, and elevated triglyceride levels . In some embodiments, an FXR agonist is used to prevent or treat alcoholic or non-alcoholic liver disease. In some embodiments, the agonist is used to prevent or treat cholestasis, cirrhosis, steatosis, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis (PSC).

Cholestasis.

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

In some examples, an FXR agonist reduces cholestasis in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50 % or more. In some cases, cholestasis is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the level of cholestasis is given relative to the level of cholestasis in a subject who was not treated with an FXR agonist.

Biliary primary cirrhosis of the liver and cirrhosis of the liver.

The FXR agonist disclosed herein is used to treat primary biliary cirrhosis (PBC) in a subject. PBC is a liver disease that primarily results from autoimmune destruction of the bile ducts that transport bile acids (BAs) from the liver, leading to cholestasis. As PBC develops, persistent accumulation of BA toxicants causes progressive liver damage. Chronic inflammation and fibrosis can progress to cirrhosis. In some examples, an FXR agonist reduces a subject's PBC 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, PBC is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the PBC level is given relative to the PBC level in a subject who was not treated with an FXR agonist.

In some cases, an FXR agonist disclosed herein reduces liver cirrhosis in a subject. In some examples, an FXR agonist reduces liver 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, liver cirrhosis is reduced by about 5% to about 50%, by about 5% to approx.

- 9 047314 specifically 25%, by approximately 10% to approximately 20%, or by approximately 10% to approximately 30%. In some cases, the level of liver cirrhosis is given relative to the level of liver cirrhosis in a subject who was not treated with an FXR agonist.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is associated with excess fat in the liver (steatosis) and in some cases progresses to NASH, which is defined by histological features 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 medications, 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 proinflammatory molecules such as cytokines and chemokines, leading to insulin resistance and impaired lipolysis suppression in adipocytes. In some cases, this failure to suppress lipolysis results in the release of free fatty acids (FFA) into the bloodstream and uptake by 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 up-regulation of pro-inflammatory molecules.

In some cases, activation of FXR inhibits triglyceride (TG)/fatty acid (FA) synthesis, which is facilitated by downregulation of sterol regulatory element binding protein 1c (SREBP1c) through SHP activation. In some cases, FXR further increases TG clearance through stimulation of lipoprotein lipase (LPL) activity, as well as hepatic uptake of debris and low-density lipoprotein through induction of syndecan 1 (SDC1) and VLDL receptor (VLDLR).

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

In some cases, an FXR agonist disclosed herein is used to treat NAFLD. In some examples, an FXR agonist reduces a subject's NAFLD 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, NAFLD is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the NAFLD level is given relative to the NAFLD level in a subject who was not treated with an FXR agonist.

Steatosis.

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

Ballooning.

Ballooning of hepatocytes, a sign indicating cellular damage, is a hallmark of NASH. Ballooning is a sign that signifies progressive NASH (types 3 and 4). This term refers to enlarged, swollen-appearing hepatocytes, the affected cells often confluent in areas of steatosis and, in classic steatohepatitis, in perivenular areas. Hepatocellular ballooning is most often noted in areas of perisinusoidal fibrosis detected by H and E. Ballooned hepatocytes are most easily seen when they contain MH (either typical or poorly formed). Ballooning of hepatocytes is a structural manifestation of microtubule disruption and severe cell damage.

In some cases, an FXR agonist disclosed herein reduces hepatic ballooning in a subject. In some examples, an FXR agonist reduces liver ballooning in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least at least 50% or more. In some cases, liver ballooning is reduced by approximately 5% to approximately 50%, by approximately

- 10 047314 from 5% to about 25%, from about 10% to about 20%, or from about 10% to about 30%. In some cases, the ballooning level is relative to the ballooning level in a subject not treated with an FXR agonist.

Alcoholic hepatitis.

In some cases, an FXR agonist disclosed herein reduces alcoholic hepatitis in a subject. In some examples, an FXR agonist reduces a subject's alcoholic hepatitis 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 level of alcoholic hepatitis is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the level of alcoholic hepatitis is given relative to the level of alcoholic hepatitis in a subject who was not treated with an FXR agonist.

Primary sclerosing cholangitis.

In some cases, an FXR agonist disclosed herein is used to treat primary sclerosing cholangitis (PSC). PSC is a chronic, progressive cholestatic liver disease. PSC is characterized by progressive inflammation, fibrosis, and stricture formation in the liver ducts. Common symptoms include itching and jaundice. The disease is strongly associated with inflammatory bowel disease (IBD)—approximately 5% of patients with ulcerative colitis 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 cases, the FXR agonist disclosed herein decreases liver enzymes in a subject. In some examples, the 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 cases, liver enzyme levels are reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, liver enzyme levels are given relative to liver enzyme levels in a subject not treated with an FXR agonist.

In some cases, an FXR agonist disclosed herein reduces liver triglycerides in a subject. In some examples, the FXR agonist reduces liver 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 cases, liver triglyceride levels are reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, liver triglyceride levels are given relative to liver triglyceride levels in a subject not treated with an FXR agonist.

Inflammatory bowel condition.

Disclosed herein are methods of treating or preventing an inflammatory bowel condition. Examples of inflammatory bowel 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), gastric and duodenal ulcers , non-ulcer dyspepsia (NUD), celiac disease, celiac disease, gastrointestinal complications after bariatric surgery, gastric carcinogenesis or gastric carcinogenesis after gastric or intestinal resection. In some embodiments, the inflammatory condition is NEC and the subject is a newborn or premature infant. In some embodiments, the subject is an enterally or formula-fed infant.

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

- 11 047314

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

Diseases of the gastrointestinal tract.

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

Irritable bowel syndrome.

Irritable bowel syndrome (IBS) is characterized by a combination of symptoms including abdominal pain and changes in bowel habits that persist for a long period of time, often years. The causes of IBS remain unclear, but problems with intestinal motility, food sensitivities, genetic factors, bacterial overgrowth in the small intestine and problems with the gut-brain connection are thought to play a potential role. In some cases, IBS is accompanied by diarrhea and is subdivided into IBS with diarrhea (IBS-D). In some cases, IBS is accompanied by constipation and is subdivided into IBS with constipation (IBS-C). In some cases, IBS is accompanied by alternating diarrhea and constipation and is classified as mixed IBS (IBS-M). In some cases, IBS is accompanied by neither diarrhea nor constipation and is classified as IBS of undetermined subtype (IBS-U). In some cases, IBS has four different variants: IBS-D, IBS-C, IBS-M and IBS-U.

In some cases, the symptoms of IBS are mimicked by another disease. In some embodiments, sugar malnutrition, celiac disease, non-celiac gluten intolerance, exocrine pancreatic insufficiency, small intestinal bacterial overgrowth, microscopic colitis, or bile acid malabsorption (BAM) mimic IBS-D. In some embodiments, anismus, pelvic floor dyssynergia or puborectal spasm or perineal prolapse mimics IBS-C.

In some cases, an FXR agonist disclosed herein is used to treat IBS or any of its variants in a mammal. In some examples, an FXR agonist therapeutic agent reduces symptoms of IBS in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more.

Malabsorption of bile acids.

Bile acid malabsorption (BAM), also known as hologenic diarrhea (BAD), bile acid-induced diarrhea, cholera or choleretic enteropathy, or bile salt malabsorption, is a condition in which the presence of bile acids in the colon causes diarrhea. VAM is caused by a number of conditions such as Crohn's disease, cholecystectomy, celiac disease, radiation therapy, and pancreatic diseases. In some cases, VAM is caused by medications such as metformin. In some cases, VAM is caused by overproduction of bile acids. Bile acid synthesis is negatively regulated by the ileal hormone fibroblast growth factor 19 (FGF-19), low levels of FGF-19 lead to increased bile acids. Activation of FXR promotes the synthesis of FGF-19, therefore reducing bile acid levels.

In some cases, an FXR agonist disclosed herein is used to treat VAM in mammals. In accordance with some embodiments, an FXR agonist disclosed herein reduces the synthesis of bile acids. In some cases, the FXR agonist disclosed herein reduces bile acid levels. In accordance with some embodiments, an FXR agonist and an additional therapeutic agent disclosed herein result in the prevention of BAD. In some examples, an FXR agonist reduces symptoms of VAM in a mammal by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50% or more.

Graft-versus-host disease (GvHD).

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Graft-versus-host disease (GvHD) is a medical complication that occurs after transplantation of tissue or cells from a histo-incompatible donor (ie, a genetically or immunologically different donor). Immune cells in the donor tissue or cells (graft) recognize the recipient (host) as foreign, initiate and attack. Non-limiting examples of transplanted tissue or cells causing GvHD include blood products, stem cells such as bone marrow cells, and organs. There are different types of GvHD depending on where symptoms appear or develop: skin GvHD, liver GvHD, ocular GvHD, neuromuscular GvHD, genitourinary GvHD, and gastrointestinal GvHD. Gastrointestinal symptoms of GvHD include difficulty swallowing, pain when swallowing, weight loss, nausea, vomiting, diarrhea, and/or abdominal cramps. GvHD of the gastrointestinal tract leads to mucosal detachment and severe intestinal inflammation. Inflammation of the biliary epithelium can be controlled through nuclear receptors such as the glucocorticoid receptor (GR), FXR, or peroxisome proliferator-activated receptors (PPARs).

In some cases, an FXR agonist disclosed herein is used to treat GvHD or a complication of GvHD in a mammal. In accordance with some embodiments, an FXR agonist disclosed herein is used to treat gastrointestinal GvHD or a gastrointestinal GvHD complication in a mammal. In some examples, an FXR agonist reduces gastrointestinal GvHD or a gastrointestinal GvHD complication in a mammal 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, gastrointestinal GvHD or the complication of gastrointestinal GvHD is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10 % to approximately 30%. In some cases, the FXR agonist disclosed herein reduces intestinal inflammation caused by GvHD of the gastrointestinal tract. In some cases, the FXR agonist disclosed herein reduces intestinal inflammation caused by gastrointestinal GvHD by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20% % or by about 10% to about 30%.

Kidney diseases.

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

Diabetic nephropathy.

Diabetic nephropathy is a kidney disease characterized by damage to the glomeruli. Diabetes promotes excessive production of reactive oxygen species, leading to nephrotic syndrome and glomerular scarring. As diabetic nephropathy progresses, the glomerular filtration barrier (GFB) becomes increasingly damaged and, consequently, proteins in the blood leak through the barrier and accumulate in Bowman's space.

In some cases, an FXR agonist disclosed herein is used to treat diabetic nephropathy in a mammal.

Kidney fibrosis.

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

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

Described herein is a method of treating or preventing a kidney disease or condition in a mammal, comprising administering to the mammal an FXR agonist disclosed herein, or a pharmaceutically acceptable salt or solvate thereof. In some cases, the kidney disease or condition is diabetic nephropathy, kidney disease associated with fibrosis, kidney disease not associated with fibrosis, kidney fibrosis, kidney disease associated with metabolic disease, chronic kidney disease, polycystic kidney disease, acute kidney disease, or any their combination.

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A disease associated with cell proliferation.

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

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

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

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

In some cases, the FXR agonist disclosed herein further reduces the tumor burden in a subject. In some examples, the FXR agonist reduces the tumor burden (such as colon cancer tumor burden) 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 tumor burden is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the tumor load level is given relative to the tumor load level in a subject who was not treated with an FXR agonist.

In some cases, an FXR agonist disclosed herein further reduces the size and/or volume of a tumor in a subject. In some cases, 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 cases, tumor size is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, tumor size is given relative to the size of the tumor in a subject who was not treated with an FXR agonist.

In some cases, an FXR agonist disclosed herein reduces the effects of cachexia resulting from a tumor in a subject. In some examples, the FXR agonist reduces the effect of cachexia (such as due to a colon tumor) in a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30% , at least 40%, at least 50% or more. In some cases, the effect of cachexia is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the effect of cachexia is given relative to the effect of cachexia in a subject not treated with an FXR agonist.

In some cases, an FXR agonist disclosed herein increases the survival rate of a subject with a tumor. In some cases, an FXR agonist increases the survival rate in a subject with a tumor (such as colon cancer) in the 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 survival rate is increased by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some cases, the survival rate is given relative to the rate

- 14 047314 survival in a subject not treated with an FXR agonist.

Connections.

The compounds described in the present invention, including their pharmaceutically acceptable salts, are farnesoid X receptor agonists.

Any combination of the groups described above for the various variables is contemplated in the present invention. Throughout the description, the groups and their substituents are selected by one skilled in the art to ensure stable moieties and compounds.

In accordance with some embodiments, the compounds described in the present invention include, without limitation, the compounds described in table. 1.

Table 1

Compound Structure Chemical name 1 A x>-o IZ th from/?ads-4-((4-(2-(t/?eot-butyl)thiazol-5yl)pyridin-2-yl)(((from/?w/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl(tetrahydro-27/-pyran-4yl)carbamate 1.01 o I from/?ads-4-((4-(2-(t/?eot-butyl)thiazol-5yl)pyridin-2-yl)(((from/?w/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate

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1.02 7 I I t/?ans-4-((4-(2-(from/?eot-butyl)thiazol-5yl)pyridin-2-yl)(((from/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxy-2,2dimethylazetidine-1-carboxylate 1.03 O from/?ans-4-((4-(2-(from/?eot-butyl)thiazol-5yl)pyridin-2-yl)(((from/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-hydroxypiperidine-1 carboxylate 1.04 ι O A ' o / t/?ans-4-((4-(2-(t/?eot-butyl)oxazol-4yl)pyridin-2-yl)(((ot/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 1.05 I A b / t/?ans-4-((4-(2-(t/?eot-butyl)oxazol-4yl)pyridin-2-yl)(((ot/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxy-2,2dimethylazetidine-1-carboxylate 1.06 o θ 1 J 1 LJ d Y^l L 1 ° ^N l^L 4- ^Х)н Ά ^ζ ' t/?ans-4-((4-(2-(t/?eot-butyl)oxazol-4yl)pyridin-2-yl)(((ot/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-hydroxypiperidine-1 carboxylate 1.07 • / IZ ъ t/?ans-4-((4-(2-(t/?eot-butyl)oxazol-4yl)pyridin-2-yl)(((ot/?sh/s)-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl(tetrahydro-2R-pyran-4yl)carbamate

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1.08 f O F )=o o I from/?sh/s-4-((4-( 1 -(from/?eot-butyl)-1H-pyrazol-4yl)pyridin-2-yl)((from/?sh/s-4-(4 -methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1 carboxylate 1.09 J'o >=° A I from/?sh/s-4-((4-( 1 -(from/?eot-butyl)-1H-pyrazol-4yl)pyridin-2-yl)((from/?sh/s-4-(4 -methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3-hydroxy-2,2dimethylazetidine-1-carboxylate 1.10 00° from/?sh/s-4-((4-( 1 -(from/?eot-butyl)-1H-pyrazol-4yl)pyridin-2-yl)((from/?sh/s-4-(4 -methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4-hydroxypiperidine-1 carboxylate 1.11 o X aUaD 11 J η J , n ^Χ m/?awc-4-((4-( 1 -(from/?eot-butyl)-1 R-pyrazol-4yl)pyridin-2-yl)((from/?w/s-4-(4- methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl(tetrahydro-2R-pyran-4yl)carbamate 1.12 Xw, QU X / and _he ^F b _N '\ 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol-4-yl)-5fluoropyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2] octane-1- yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 1.13 z O d ° = ( C / F i / 4-((2-(1 -(mpem-butyl)-1R-pyrazol-4yl)pyridin-4-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate

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1.14 o /Fu / ^on °\ ^N \ 4-((5-(1 -(tert-butyl)-III-pyrazol-4yl)pyridin-3-yl)((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 1.15 J o I 4-((6-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1 yl)methyl )carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 2 '--ο ^χ 4-((4-(2-(/77/?с/7?-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/7?/7<7//c-cyclohexyl)(3hydroxypropyl)carbamate 2.01 γυ Ήη- 4-((4-(2-(/7?/7st7?-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/7?/7<7//c-cyclohexyl)-3hydroxy-3-methylazetidine-1-carboxylate 2.02 4-((4-(2-(/77/?с/77-butyl)thiazol-5-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/7?/7<7//c-cyclohexyl)(3hydroxypropyl)carbamate 2.03 4-((4-(2-(/77/?с/7?-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/7?/7<7//c-cyclohexyl)-3- (methylsulfonyl)azetidine-1-carboxylate

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2.04 O a Z/° ссАА C-N' 4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)oxetan-3-ylcarbamate 2.05 YA '“-N ^x 4-((4-(2-(from/?eot-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl)cyclohexyl-4hydroxypiperidine-/7у><7//с-1-carboxylate 2.06 4-((4-(2-(t/?eth-butyl)thiazol-5-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl(2hydroxyethyl)ot/?w/s-carbamate 2.07 γΜοχ - _o ju A: va _o ^oh CN ' 4-((4-(2-(t/?eth-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(da/l7//s-cyclohexyl)3- (2-hydroxyethoxy)azetidine-1-carboxylate 2.08 ΑίΑ g? 4-((4-(2-(/and/?<li-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)(3hydroxy-3-methylbutyl)carbamate 2.09 4-((4-(2-(from/?eot-butyl)thiazol-5-yl)pyridin2-yl)((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-3(d methylamino)pyrrole ide ip-trans-1 carboxylate

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2.10 (5)-4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane- 1yl)methyl)carbamoyl)cyclohexyl-2(hydroxymethyl)azetidine-ot/?sh/s-1 carboxylate 2.11 (5)-4-((4-(2-(ot/?eot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane- 1yl)methyl)carbamoyl)cyclohexyl-2(hydroxymethyl)azetide in-/7?/l7//c-1 carboxylate 2.12 5 / 4-((4-(2-(from/?eot-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/7?/l7//c'-cyclohexyl)-3hydroxy-3-methylazetidine-1-carboxylate 2.13 7 οΧ ,ν> ο' \ 4-((4-(2-(/77/?e/77-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/77/?sh/s-cyclohexyl)-3(methylsulfonyl)azetidine-1-carboxylate 2.14 -jj ^Dgm- L--0' 4-((4-(2-(/77/?e/77-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/77/?sh/s-cyclohexyl)-3(2-hydroxyethoxy)azetidine-1-carboxylate 2.15 4-((4-(2-(/77/?e/77-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(/77/?sh/s-cyclohexyl)-3(hydroxymethyl)azetidine-1-carboxylate

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2.16 ΧίΧ and ⁷ 4-((4-(2-(t/2eth-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-3(d IMeTYLAMINO)pyrrole ID IN-/77/L7//S-1 carboxylate 2.17 4-((4-(2-(from/?eot-butyl)oxazol-4-yl)pyridin- 2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-4hydroxypiperide t-traps-1-carboxylate 2.18 ΙΖ and 4-((4-(2-(from/?eot-butyl)oxazol-4-yl)pyridin2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)oxetan-3-ylcarbamate 2.19 4-((4-(2-(from/?eot-butyl)oxazol-4-yl)pyridin- 2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)dtrs/c-carbamate 2.20 axUU ⁸ ''*” U ⁷ ' 4-((4-(2-(t/?eth-butyl)oxazol-4-yl)pyridin- 2-yl)((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)(3hydroxy-3-methylbutyl)carbamate 2.21 (S)-4-((4-( 1 -(ot/?eot-butyl)- 1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2 ]octan-1yl)methyl)carbamoyl)cyclohexyl-2(hydroxymethyl)azetide wa-trans-1 carboxylate

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2.22 %'\ 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)(from/?ans-cyclohexyl)-3hydroxy-3-methylazetidine-1-carboxylate 2.23 4-((4-(1 -(m/tem-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)(from/?w/s-cyclohexyl)-3(methylsulfonyl)azetidine-1-carboxylate 2.24 4-((4-(1 -(from/?eot-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)(from/?w/s-cyclohexyl)-3((methylsulfonyl)methyl)azetidine-1 carboxylate 2.25 mW / JM ML/\ / ^{oh 0} fN—4- ^X 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)(from/?w/s-cyclohexyl)-3(2-hydroxyethoxy)azetidine-1-carboxylate 2.26 4-((4-(1 -(m/tem-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)cyclohexyl-3(d methylamino)pyrrole ide wa-trans-1 carboxylate 2.27 4-((4-(1 -(mpem-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)cyclohexyl-4hydroxypiperide ναι-trans-1-carboxylate

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2.28 ΣΙ A / 4-((4-(1 -(tert-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)(trbts-cyclohexyl)oxetan-3-ylcarbamate 2.29 o II Ί l II n ^X 4-((4-(1 -(mpem-butyl)-1 R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl )carbamoyl)cyclohexyl/7?rb///s(tetrahydro-2R-thiopyran-4yl)carbamate 2.30 4-((4-(1 -(from/?eot-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)cyclohexyl-(2hydroxyethyl)/7?/l7//s-carbamate 2.31 χΑΑλ?' ⁰ ' ⁸ ' ⁸ '^'™ 4-((4-(1 -(/ttreot-butyl)-1 R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)(t77/?ans-cyclohexyl)(3hydroxypropyl)carbamate 2.32 1= _Ν ' \ 4-((4-(1 -(/ttreot-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl )carbamoyl)(t77/?ans-cyclohexyl)(3hydroxy-3-methylbutyl)carbamate 2.33 (7?)-4-((4-( 1 -(/ttreot-butyl)- Ш-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2] octan-1yl)methyl)carbamoyl)cyclohexyl-777/?sh/s-3hydroxypyrrolidine-1-carboxylate

- 23 047314

2.34 (5)-4-((4-(1 -(ot/?eot-butyl)- 1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2 ]octan-1yl)methyl)carbamoyl)cyclohexyl-ot/?sh/s-3hydroxypyrrolidine-1-carboxylate 2.35 4-((4-(3 -(t/?eth-butyl)-1 R-p-irazol-1 yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2] octan-1yl)methyl)carbamoyl)cyclohexyl-ot/?bss-3hydroxyazetidine-1-carboxylate 2.36 ζ Ο d °=( χ / 4-((6-(1 -(tl-butyl)-1R-pyrazol-4yl)pyrimidin-4-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 2.37 X ο d °=( K'o / 4-((6-(1 -(tl-butyl)-1R-pyrazol-4yl)pyrimidin-4-yl)((4-(4-methoxy-3,5d imethylphenyl)bicyclo[2.2.2]octane- 1 yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 2.38 ,χγΧΧ 4= _Ν ' \ (1 r,4r)-4-((4-( 1 -(ot/?eot-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[ 2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl-(1 oxide otetrahydro-2R-thiopyran-4yl)carbamate 2.39 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)cyclohexyl-ot/?sh/s(1,1-dioxide otetrahydro-2R-thiopyran-4yl)carbamate

- 24 047314

3 0 A 0°u r ^z \ yun 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)carbamoyl)cyclohexyl-3hydroxyazetide and rapeseed-1-carboxylate 3.01 fL φ / ^H \ N—у A ⁴ ^0 4-((4-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)cyclohexyl(tetrahydro-2R-pyran-4-yl)ot/?w/s-carbamate 3.02 .τσ^?λ?' ^οΙ ΰ^^L==n' ^he 4-((4-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)(from/?w/s(4-(4-methoxy-3methylphenyl)bicyclo[2.2.2] octane-1- yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3(hydroxymethyl)azetidine-1-carboxylate 3.03 And he 4-((4-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl) carbamoyl)(from/?w/s-cyclohexyl)-3hydroxypyrrolidine-1-carboxylate 3.04 Yj A SS Ж о >=о Γ ^ζ \ Chn 4-((4-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(4-methoxy-3,5 d imylphenyl)bicyclo[2.2.2]octane- 1 yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 3.05 A 0. So Ж o' % )=о Γ ^ζ \ yun 4-((4-(1 -(tert-butyl)-1R-pyrazol-4yl)pyridin-2-yl)((4-(6-methoxy-5methylpyridin-3 -yl)bicyclo[2.2.2]octane -1 yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate

- 25 047314

3.06 υι / Ν—Υ ^Х Chn 4-((4-(1 -(tert-butyl)-III-pyrazol-4yl)pyridin-2-yl)((4-(6(dimethylamino)pyridin-3 - yl)bicycle o [2.2.2] octane-1 - yl)methyl)carbamoyl)(trbts-cyclohexyl)-3hydroxyazetidine-1-carboxylate II 1 3.07 L o cP Ar a°u Gz yun 4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)cyclohexyl-trbts-3hydroxyazetidine-1-carboxylate 3.08 γ A AA%L _l ^Ν ^ ^he 4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)(trbts-cyclohexyl)-3(hydroxymethyl)azetidine-1-carboxylate 3.09 A U AJ > ϊ^χ^* ⁰ « ^o 4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin- 2-yl)((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl(tetrahydro-2R-pyran-4-yl)trc-carbamate 3.10 L o cP Ar X °)=o d yun 4-((4-(2-(tert-butyl)oxazol-4-yl)pyridin- 2-yl)((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)carbamoyl)cyclohexyl-3- Roxyazetide hydride and n-trsts-1-carboxylate 3.11 Ίί cP Ag N" IZ ^o 4-((4-(2-(tert-butyl)oxazol-4-yl)pyridin- 2-yl)((4-(4-metho xi-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl(tetrahydro-2H-pyran-4-yl)trc-carbamate

- 26 047314

3.12 d° If / 4-((6-(1 -(m/tem-butyl)-1R-pyrazol-4yl)pyrazin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 3.13 z О d °=( ψ w O ' O / 4-((6-(1 -(m/tem-butyl)-1R-pyrazol-4yl)pyrazin-2-yl)((4-(4-methoxy-3,5 d imylphenyl)bicyclo[2.2.2] octan-1 yl)methyl)carbamoyl)(ot/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 3.14 4 w P About ZE 4-((4-(1 -(m/tem-butyl)-1R-pyrazol-4yl)pyrimidin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl) methyl)carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 3.15 o AN^N ° T \ , ^Ν \ ^Ν ^X 4-((4-(1 -(m/tem-butyl)-III-pyrazol-4yl)pyrimide in-2-yl)((4-(4-methoxy-3,5 d immethylphenyl)bicyclo[2.2.2 ] octan-1 yl)methyl)carbamoyl)(/77/l7//s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 4 •A and / 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl )(4-(1 -(tert-pentyl)-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyltrans-3-hydroxyazetidine-1-carboxylate 4.01 O / 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl )methyl )(4-(1 -(tert-pentyl)-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyltrans-3-hydroxy-3-methylazetidine-1 carboxylate

- 27 047314

4.02 -Ζ-χ AYU _ON 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)(4-(1 -(tert-pentyl)-1 R-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexyltrans-4-hydroxyl and perid and u-1-carboxylate 4.03 Α\ 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl )methyl )(4-(1 -(tert-pentyl)-III-pyrazol-4yl)pyridin-2-yl)carbamoyl)cyclohexylot/?w/s-(3-hydroxypropyl)carbamate 4.04 X d° »5φ - / 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)(4-( 1 -(3 -methylpentan-3 -yl)- 1Hpyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl-ot/?sh/s-3hydroxyazetidine-1-carboxylate 4.05 ΧθΧ II\tII.—lA-oh '° 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)(4-( 1 -(3 -methylpentan-3 -yl)-\Npyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl-ot/?sh/s-3hydroxy-3-methylazetidine-1-carboxylate 4.06 -ν\ Α^όη 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octane-1- yl)methyl)(4-( 1 -(3 -methylpentan-3 -yl)- 1Hpyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl-ot/?sh/s-4hydroxypiperidine-1-carboxylate

- 28 047314

4.07 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)(4-( 1 -(3 -methylpentan-3 -yl)- 1Hpyrazol-4-yl)pyridin-2- yl)carbamoyl)cyclohexyl-ot/?sh/s-(3hydroxypropyl)carbamate 4.08 C _N ' 2 ^x 4-((4-(1-(3-ethylpentan-3-yl)-1H- and irazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane -1yl)methyl)carbamoyl)cyclohexyl-/??/g///c-3hydroxyazetidine-1-carboxylate 4.09 t A / 4-(((4-(4-methoxy-3 - methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)(4-(1 -(1,1,1-trifluoro-2methylpropan-2-yl)-1R-pyrazol-4yl)pyridin-2-yl)carbamoyl) cyclohexyltrans-3-hydroxyazetidine-1-carboxylate 4.10 TAZH 4-((4-(1 -(tl-butyl)-1H-pyrazol-3 yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1yl)methyl )carbamoyl)cyclohexyl-ot/?sh/s-3hydroxyazetidine-1-carboxylate 4.11 )=/ ^=о τΖ o ι 4-((4-(4-(ot/?eot-butyl)-1 V-imidazol-1 yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane -1yl)methyl)carbamoyl)cyclohexyl-ot/?sh/s-3hydroxyazetidine-1-carboxylate

In accordance with some embodiments, the present invention provides a pharmaceutically acceptable salt of the compound described in table. 1.

In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.

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 the compound and is relatively non-toxic, i.e. the substance is administered to an individual without causing undesirable biological effects or interacting adversely with any of the components of the composition in which it is contained.

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

In some embodiments, pharmaceutically acceptable salts are prepared by reacting a compound described herein with an acid

- 29 047314 to obtain a pharmaceutically acceptable acid addition salt. In accordance with some embodiments, the compound described herein (ie, in free base form) is basic and reacts with an organic acid or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid; 2,2dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-1,2disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric 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-2-sulfonic acid; nicotinic acid; oleic acid; oxalinic 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 undecylenic acid.

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

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

In accordance with some embodiments, a compound described herein is acidic and reacts with a base. In such situations, 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 herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, 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 contain 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 provided herein are provided as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt, or ammonium salt.

In accordance with some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter exists independently in either an R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropiomeric and epimeric forms, as well as appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, interextended (E) and interextended (Z) isomers, as well as appropriate mixtures thereof.

The individual stereoisomers are obtained, if necessary, by methods such as stereoselective synthesis and/or separation of stereoisomers using chiral chromatography columns. In some 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, resolving the diastereomers, and recovering the optically pure enantiomers. In some embodiments, enantiomer resolution is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated using separation/resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is performed by chromatography or by the formation of diastereomeric salts and separation by recrystallization or chromatography, or any of the above.

- 30 047314 combinations. 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.

Synthesis of compounds.

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

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

The compounds were prepared using standard organic chemistry techniques, such as those described in, for example, March's Advanced Organic Chemistry, ^6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for synthesis transformations described herein may be used, such as variations in solvent, reaction temperature, reaction time, as well as various chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are easily obtained.

Suitable reference works and treatises that describe in more detail the synthesis of the reagents used to prepare the compounds described herein, or that 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. Additional suitable references and treatises that describe in more detail the synthesis of the reagents used to prepare the compounds described herein, or which provide links to articles that describe the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. 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 Functional Groups (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. Organic Chemistry 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., Intermediate Organic Chemistry 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, in over 55 volumes; and Chemistry of Functional Groups John Wiley & Sons, in 73 volumes.

The compounds described in the present invention were prepared by the general synthetic routes described below in Schemes 1-11.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 1.

Scheme 1

In Scheme 1, X ¹ , X ⁵ , X ⁶ and X ⁷ are described in the present invention. In accordance with some embodiments, X is CH or N. In accordance with some embodiments, X is CH. In accordance with some embodiments, X is N. In accordance with some embodiments, R is an alkyl group. In accordance with some embodiments, R is hydrogen. In accordance with some embodiments, R is independently an alkyl group or hydrogen. In accordance with some embodiments, alkyl groups bonded to the same boron atom through corresponding oxygen atoms at the same boron atom are

- 31 047314 are an alkylene group bearing two oxygen atoms with the same boron atom. In some embodiments, a boron atom, two oxygen atoms on the same boron atom, and a carbon atom of an alkylene group that bridges the two oxygen atoms form a five- or six-membered ring. In some embodiments, the bridging alkylene group is -C(CH ₃ ) ₂ C(CH ₃ )2- and is part of a five-membered ring.

In some embodiments, heteroaryl I-1 is reacted under suitable SN1 conditions to produce heteroaryl halide I-2. In some embodiments, suitable SN1 conditions include reacting Compound I-1 with tBuOH and a suitable acid at a suitable temperature for a suitable time. In accordance with some embodiments, the corresponding acid is a strong acid. In some embodiments, the strong acid is sulfuric acid, hydrochloric acid, or hydrobromic acid. In some embodiments, the strong acid is sulfuric acid. In some embodiments, the strong acid is concentrated sulfuric acid. In some embodiments, the appropriate time ranges from about 1 hour to about 12 to 18 hours, wherein the time range from about 12 to 18 hours is interchangeably referred to herein as overnight. In accordance with some embodiments, a suitable temperature is from about 60°C to about 110°C. In some embodiments, a suitable temperature is from about 80°C to about 90°C.

In some embodiments, boron reagent 1-3 is reacted with heteroaryl halide 1-2 under suitable metal-catalyzed cross-coupling reaction conditions to produce compound 1-4. In accordance with some embodiments, the boron reagent is an arylboronic acid. In accordance with some embodiments, the boron reagent is an aryl boronic acid ester. In accordance with some embodiments, the boron reagent is a substituted pyridine boronic acid. In some embodiments, the heteroaryl halide is pyrazolyl bromide. In some embodiments, the heteroaryl halide is 3-bromopyrazole. In some embodiments, the heteroaryl halide is 4-bromopyrazole. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium, an appropriate base, and an appropriate solvent for an appropriate period of time and at an appropriate temperature. In some embodiments, palladium is obtained in the form of Pd(dppf)Cl ₂ . In accordance with some embodiments, the suitable base is an inorganic base. In some embodiments, the inorganic base is a carbonate, phosphate, oxide, or hydroxide. In accordance with some embodiments, the inorganic base is an inorganic alkali metal base. In some embodiments, the alkali metal is sodium, potassium, cesium, or combinations thereof. In accordance with some embodiments, the inorganic base is Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , or combinations thereof. In accordance with some embodiments, the combination is a combination of Na2CO3 and K2CO3. In accordance with some embodiments, the inorganic base is K2CO3. In accordance with some embodiments, the inorganic base is Cs2CO3. In accordance with some embodiments, the suitable solvent is an aqueous solvent. In some embodiments, the suitable solvent is a mixture of water and an organic solvent. In accordance with some embodiments, the organic solvent in the mixture is a C _1-4 alcohol, THF, 2-MeTHF, DMF, dioxane, or a combination thereof. In accordance with some embodiments, the organic solvent in the mixture is dioxane. In some embodiments, the appropriate time is from about 1 hour to about 12-18 hours. In some embodiments, the appropriate temperature is from about 50°C to about 115°C. In some embodiments, the appropriate temperature is approximately 80°C. In accordance with some embodiments, the reaction is carried out under microwave irradiation. In some embodiments, the appropriate time is from about 10 minutes to about 30 minutes. In accordance with some embodiments, a suitable temperature is from about 130°C to about 170°C. In some embodiments, a suitable temperature is from about 150°C to about 160°C.

In some embodiments, an aryl halo is reacted

- 32 047314 genide 1-5 with boron reagent 1-6 under suitable metal-catalyzed cross-coupling reaction conditions to give compound 1-4. In accordance with some embodiments, the aryl halide is an aryl bromide. In accordance with some embodiments, the aryl halide is a substituted pyridyl halide. In accordance with some embodiments, the aryl halide is a substituted pyridyl bromide. In some embodiments, the aryl halide is a substituted 4-bromopyridine. In accordance with some embodiments, the boron reagent is a heteroarylboronic acid. In accordance with some embodiments, the boron reagent is a heteroarylboronic acid ester. In accordance with some embodiments, the boron reagent is a heteroarylpinacolylboronic acid ester. In accordance with some embodiments, the heteroarylboronic reagent is a pyrazolylboronic reagent. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium, an appropriate base, and an appropriate solvent for an appropriate period of time and at an appropriate temperature. In some embodiments, palladium is obtained in the form of Pd(dppf)Cl ₂ . In accordance with some embodiments, the suitable base is an inorganic base. In some embodiments, the inorganic base is a carbonate, phosphate, oxide, or hydroxide. In accordance with some embodiments, the inorganic base is an inorganic alkali metal base. In some embodiments, the alkali metal is sodium, potassium, cesium, or combinations thereof. In some embodiments, the inorganic base is _Na2CO3 , _K2CO3 , _Cs2CO3 , or combinations thereof. In accordance with some embodiments, the combination is a combination of Na ₂ CO ₃ and K ₂ CO ₃ . In accordance with some embodiments, the inorganic base is K ₂ CO ₃ . In accordance with some embodiments, the inorganic base is Cs ₂ CO ₃ . In accordance with some embodiments, the suitable solvent is an aqueous solvent. In some embodiments, the suitable solvent is a mixture of water and an organic solvent. In accordance with some embodiments, the organic solvent in the mixture is C ₁ . ₄ -alcohol, THF, 2-MeTHF, DME, DMF, dioxane or a combination thereof. In accordance with some embodiments, the organic solvent in the mixture is dioxane. In accordance with some embodiments, the organic solvent in the mixture is 2-MeTHF. In accordance with some embodiments, the organic solvent in the mixture is DME. In some embodiments, the appropriate time and temperature are from about 2 hours to overnight and at about 90°C. In accordance with some embodiments, the reaction is carried out under microwave irradiation. In some embodiments, the appropriate time is from about 10 minutes to about 30 minutes. In accordance with some embodiments, a suitable temperature is from about 130°C to about 170°C. In accordance with some embodiments, a suitable temperature is from about 150°C to about 160°C.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 2.

Scheme 2

In Scheme 2, X is C-H or N. In some embodiments, the 5-membered heterocycle of compound II-2 is pyrazolyl, pyrrolyl, imidazolyl, or triazolyl. In some embodiments, R is NHBoc, iodide, bromide, chloride, or trifluoromethanesulfonate (triflate, -OTf, CF3SO3-). In accordance with some embodiments, R is NHBoc. In accordance with some embodiments, R is a bromide or chloride. In accordance with some embodiments, R is a chloride.

In some embodiments, aryl fluoride II-1 is reacted with heteroaryl II-2 under suitable reaction conditions S _N Ar to produce compound II

- 33 047314

3. In some embodiments, heteroaryl II-2 is reacted with aryl fluoride II-1, wherein R is chlorine. In some embodiments, heteroaryl II-2 is reacted with aryl fluoride II-1, wherein R is NHBoc. In accordance with some embodiments, suitable SNAr reaction conditions include an appropriate base and an appropriate solvent, for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the suitable base is an inorganic base. In accordance with some embodiments, the inorganic base is a carbonate base. In accordance with some embodiments, the carbonate base is an alkali metal carbonate. In accordance with some embodiments, the alkali metal carbonate is K ₂ CO ₃ . In some embodiments, the suitable solvent is DMSO, NMP, toluene, or combinations thereof. In some embodiments, the suitable solvent is a mixture of water and DMSO, NMP, toluene, or combinations thereof. In some embodiments, the suitable solvent is NMP. In some embodiments, the corresponding time and the corresponding temperature are overnight and approximately 100°C.

In some embodiments, compound II-3 is subjected to suitable palladium-catalyzed cross-coupling reaction conditions in the presence of a suitable ammonium source to produce compound II-4. In some embodiments, compound II-3, wherein R is a halogen, is subjected to suitable palladium-catalyzed cross-coupling reaction conditions in the presence of a suitable ammonium source to produce compound II-4. In some embodiments, compound II-3, wherein R is bromine or chlorine, is subjected to suitable palladium-catalyzed cross-coupling reaction conditions in the presence of a suitable ammonium source to produce compound II4. In some embodiments, compound II-3, wherein R is chlorine, is subjected to suitable palladium-catalyzed cross-coupling reaction conditions in the presence of a suitable ammonium source to produce compound II-4. In accordance with some embodiments, a suitable ammonium source is LiHMDS. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include tris(dibenzylideneacetone)dipalladium(0), an appropriate ligand, and an appropriate solvent for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the corresponding ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. In some embodiments, the suitable solvent is dioxane or THF. In some embodiments, the appropriate time and appropriate temperature are from about 2 hours to overnight and about 100°C. In some embodiments, the appropriate time and the appropriate temperature are overnight and approximately 60°C.

In some embodiments, suitable hydrolysis reaction conditions are sufficient to deprotect the tert-butyloxycarbonyl-protected aniline II-3 to produce compound II-4. In some embodiments, suitable hydrolysis reaction conditions are sufficient to deprotect tert-butyloxycarbonyl-protected aniline II-3, wherein R is NHBoc, to yield compound II-4. In accordance with some embodiments, suitable hydrolysis reaction conditions include an appropriate acid and an appropriate solvent, for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the corresponding acid is aqueous HCl. In accordance with some embodiments, the suitable solvent is methanol. In accordance with some embodiments, the suitable solvent is EtOAc. In some embodiments, the corresponding acid is HCl in EtOAc. In accordance with some embodiments, the corresponding time and the corresponding temperature are approximately overnight and 50°C.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 3.

- 34 047314

Scheme 3

In the diagram, 3 X ¹ and R ⁸ are described in the present invention. In accordance with some embodiments, R is an alkyl group. In accordance with some embodiments, R is hydrogen. In accordance with some embodiments, R is independently an alkyl group or hydrogen. In some embodiments, alkyl groups bonded to the same boron atom through corresponding oxygen atoms on the same boron atom are an alkylene group bearing two oxygen atoms on the same boron atom. In some embodiments, a boron atom, two oxygen atoms on the same boron atom, and a carbon atom of an alkylene group that bridges the two oxygen atoms form a five- or six-membered ring. In accordance with some embodiments, the bridging alkylene group is -C(CH3) ₂ C(CH3) ₂ - and is part of a five-membered ring.

In some embodiments, thioamide III-1 is reacted with bromoacetaldehyde dimethyl acetal (2-bromo-1,1-dimethoxyethane) under suitable condensation reaction conditions followed by suitable bromination reaction conditions to produce 2-bromothiazole III-2. In some embodiments, suitable condensation reaction conditions are sufficient to produce a 2-substituted thiazole intermediate, which provides 2-bromothiazole III-2 after bromination under suitable bromination reaction conditions. In accordance with some embodiments, suitable condensation reaction conditions include a suitable acid catalyst and a suitable solvent for a suitable period of time at a suitable temperature. In some embodiments, the corresponding acid is p-toluenesulfonic acid. In some embodiments, the suitable solvent is acetic acid. In some embodiments, the appropriate time and the appropriate temperature are overnight and approximately 120°C. In some embodiments, suitable bromination reaction conditions are sufficient to brominate the 2-substituted thiazole intermediate to produce compound III-2. In accordance with some embodiments, suitable bromination reaction conditions include a suitable bromination agent and a suitable solvent for a suitable period of time at a suitable temperature. In accordance with some embodiments, the suitable brominating agent is NBS. In accordance with some embodiments, the suitable solvent is DMF. In some embodiments, the appropriate time and the appropriate temperature are approximately 1 hour and room temperature.

In some embodiments, boron reagent III-3 is reacted with 2-bromothiazole III-2 under suitable metal-catalyzed cross-coupling reaction conditions to produce compound III-4. In some embodiments, the 2-bromothiazole is a 5-bromo-2-substituted thiazole. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium, an appropriate base, and an appropriate solvent for an appropriate period of time and at an appropriate temperature. In some embodiments, palladium is obtained in the form of Pd(dppf)Cl ₂ . In accordance with some embodiments, the suitable base is an inorganic base. In accordance with some embodiments, the inorganic base is a carbonate, phosphate, oxide, or hydroxide. In accordance with some embodiments, the inorganic base is an inorganic alkali metal base. In some embodiments, the alkali metal is sodium, potassium, cesium, or combinations thereof. In accordance with some embodiments, the inorganic base is Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , or combinations thereof. In accordance with some embodiments, the combination is a combination of Na ₂ CO ₃ and K ₂ CO ₃ . In accordance with some embodiments, the inorganic base is K ₂ CO ₃ . According to some

- 35 047314 In other embodiments, the inorganic base is Cs ₂ CO ₃ . In accordance with some embodiments, the suitable solvent is an aqueous solvent. In some embodiments, the suitable solvent is a mixture of water and an organic solvent. In accordance with some embodiments, the organic solvent in the mixture is a C _1-4 alcohol, THF, DMF, dioxane, or a combination thereof. In accordance with some embodiments, the organic solvent in the mixture is dioxane. In some embodiments, the appropriate time and the appropriate temperature are overnight and approximately 80°C.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 4.

Scheme 4

In some embodiments, pyridine carboxylic acid IV-1 is converted to methyl ketone IV-2. In some embodiments, compound IV-1 is converted to compound IV-2 using a reaction sequence referred to alternatively as the Weinreb ketone synthesis. In some embodiments, compound IV-1 is reacted under a series of suitable reaction conditions to produce compound IV-2. In accordance with some embodiments, the series includes suitable carboxylic acid activation reaction conditions, suitable Weinreb amide formation reaction conditions, and suitable alkylation reaction conditions related to such sequence. In accordance with some embodiments, the carboxylic acid activation reaction conditions include an appropriate carboxylic acid activator and a solvent for an appropriate period of time and at an appropriate temperature. In accordance with some embodiments, the carboxylic acid activator is a carbonyldiimidazole. In accordance with some embodiments, the solvent is DCE or DCM. In some embodiments, the time and temperature are 15 minutes to 60 minutes and room temperature. In some embodiments, the Weinreb amide reaction conditions include an N,O-dimethylhydroxylamine acid salt and an appropriate solvent for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the acid salt of N,O-dimethylhydroxylamine is a hydrochloride salt. In accordance with some embodiments, the solvent is the same as that included in the carboxylic acid activation reaction conditions. In accordance with some embodiments, the time and temperature are overnight and room temperature. In some embodiments, the alkylation reaction conditions include an appropriate organometallic alkyl agent and a solvent for an appropriate period of time and at an appropriate temperature. In accordance with some embodiments, the organometallic alkyl agent is CH ₃ MgBr, CH ₃ MgCl, CH ₃ MgI, (CH ₃ ) ₂ Mg, or CH ₃ Li. In accordance with some embodiments, the organometallic alkyl agent is CH ₃ MgBr. In accordance with some embodiments, the solvent is THF, Et ₂ O, or combinations thereof. In accordance with some embodiments, the solvent is THF. In accordance with some embodiments, the time and temperature are overnight and from 0°C to room temperature. In some embodiments, the initial temperature is maintained for the first time, after which the temperature is allowed to warm to the second temperature for the second time. In some embodiments, the initial temperature is approximately 0°C, the first time is from 15 minutes to 60 minutes, the second temperature is room temperature, and the second time is overnight.

- 36 047314

In some embodiments, α-bromoketone IV-3 is prepared by subjecting ketone IV-2 to suitable bromination conditions. In some embodiments, suitable bromination conditions include bromine, HBr and acetic acid for a suitable time at a suitable temperature. In accordance with some embodiments, a suitable time is overnight. In accordance with some embodiments, a suitable temperature is approximately room temperature.

In some embodiments, the α-haloketone IV-3 is treated with amide IV-4 and the corresponding silver salt in an appropriate solvent for an appropriate period of time at an appropriate temperature to obtain compound IV-5. In some embodiments, the silver salt is AgOTf, AgBF4, AgClO4, or

_AgSbF6 . According to some embodiments, the silver salt is

_AgSbF6 . According to some embodiments, the silver salt is

AgOTf. In accordance with some embodiments, the solvent is

EtOAc, dioxane or DCE. In accordance with some embodiments, the time is all night. In accordance with some embodiments, the temperature is from about 50°C to about 100°C. In accordance with some embodiments, the temperature is about 70°C or about 100°C.

In some embodiments, compound IV-5 is subjected to suitable palladium-catalyzed cross-coupling reaction conditions in the presence of a suitable ammonium source to produce compound IV-6. In accordance with some embodiments, a suitable ammonium source is LiHMDS. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include tris(dibenzylideneacetone)dipalladium(0), an appropriate ligand, and an appropriate solvent for an appropriate period of time at an appropriate temperature. In some embodiments, the corresponding ligand is 2dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. In some embodiments, the suitable solvent is dioxane or THF. In some embodiments, the appropriate time and the appropriate temperature are from about 2 hours to overnight and about 100°C. In some embodiments, the appropriate time and the appropriate temperature are overnight and approximately 60°C.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 5.

Scheme 5

OOO no'Xhu ------ but' ^Lch uy ---- ci'^yxy \X-'OH ^X'OR ^'OR

V-1 V-2 V-3

In accordance with some embodiments, R is an alcohol protecting group. In some embodiments, the alcohol protecting group is a methyl, substituted methyl group, substituted ethyl group, substituted benzyl group, or silyl group, as described in, for example, Wuts, P. G. M. Greene's Protective Groups in Organic Synthesis (2014) John Wiley & Sons ISBN: 978-1-118-05748-3. In accordance with some embodiments, the alcohol protecting group is a silyl group. In accordance with some embodiments, the silyl group is t-butyldimethylsilyl.

In some embodiments, compound V-1 is subjected to suitable alcohol protection reaction conditions to form a bis-silyl intermediate, followed by suitable hydrolysis reactions to yield compound V-2 when R is a silyl group. In some embodiments, R is tert-butyldimethylsilyl and the alcohol protection reaction conditions include tert-butyldimethylsilyl halide and the appropriate base in an appropriate solvent for an appropriate period of time at an appropriate temperature. In some embodiments, the tert-butyldimethylsilyl halide is tert-butyldimethylsilyl chloride. In some embodiments, the base is an imidazole. In accordance with some embodiments, the solvent is DMF. In some embodiments, the time is approximately 2 hours and the temperature is approximately room temperature. In some embodiments, the bis-silyl intermediate (silyl ester) is subjected to suitable hydrolysis reaction conditions to form compound V-2. In accordance with some embodiments, suitable reaction conditions

- 37 047314 hydrolysis involves a base in an appropriate solvent for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the base is K2CO3. In some embodiments, the solvent is a mixture of water, ethanol, and THF. In some embodiments, the solvent is aqueous ethanol, aqueous THF, or combinations thereof. In some embodiments, the time is 3 hours and the temperature is approximately room temperature.

In some embodiments, where R is methyl, a substituted methyl group, a substituted ethyl group, or a substituted benzyl group, compound V-1 is subjected to suitable alcohol protection reaction conditions to form a bis-alkyl intermediate (where both the carboxylic acid and the alcohol -OH are alkylated to form an ester and an ether, respectively, and, for the purposes of Scheme 5 and schemes referring to Scheme 5, or schemes referring to intermediates or products disclosed in Scheme 5, alkyl groups on a bis-alkyl intermediate is methyl, a substituted methyl group, a substituted ethyl group or a substituted benzyl group) followed by suitable hydrolysis reaction conditions to obtain compound V-2.

In some embodiments, the protected alcohol V-2 is converted to the acid chloride V-3 under suitable chlorination reaction conditions. In some embodiments, the chlorination reaction conditions include (chloromethylene)dimethyliminium chloride and an appropriate base in an appropriate solvent for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the base is anhydrous K ₂ CO ₃ . In some embodiments, the solvent is toluene. In some embodiments, the time is from about 0.5 hour to about 2 hours. In some embodiments, the temperature is about 0°C. In accordance with some embodiments, the temperature is room temperature.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 6.

Scheme 6

In the diagram 6 X ² and R ¹ are described in the present invention. In accordance with some embodiments, X is a halide. In accordance with some embodiments, the halide is a chloride, bromide, or iodide. In accordance with some embodiments, the halide is a bromide. In accordance with some embodiments, R is -CO2R' or -CN. In accordance with some embodiments, R' is -P^alkyl. In accordance with some embodiments, R' is -CH ₃ , -C(CH ₃ ) ₃ , or -CH ₂ CH ₃ . According to some embodiments, R'

- 38 047314 represents -CH2CH3.

In some embodiments, the VI-1 halide is cooled to an appropriate temperature, reacted under suitable metal-halogen exchange conditions with an appropriate solvent for an appropriate period of time and at an appropriate temperature, and then later reacted with an appropriate VI-2 ketone for an appropriate period of time and at an appropriate temperature to obtain a tertiary alcohol. In accordance with some embodiments, suitable metal halide exchange conditions include an organometallic agent. In accordance with some embodiments, the suitable solvent is THF. In accordance with some embodiments, the organometallic agent is an alkyl lithium. In accordance with some embodiments, the alkyllithium is n-butyllithium. In accordance with some embodiments, compound VI-1 was cooled to about -78°C before adding the organometallic agent. In some embodiments, compound VI-1 is reacted for about one hour at about -78°C before adding ketone VI-2. In some embodiments, compound VI-1 is reacted within approximately 2 hours after addition of ketone VI-2. In accordance with some embodiments, the appropriate temperature for the reaction of compound VI-1 and ketone VI-2 is approximately -78°C. In some embodiments, the tertiary alcohol is reacted under appropriate allylation conditions, which include the use of an allylating agent and a Lewis acid, in an appropriate solvent for an appropriate period of time and at an appropriate temperature to form compound VI-3. In accordance with some embodiments, the suitable allylating agent is allyltrimethylsilane. In accordance with some embodiments, the corresponding Lewis acid is BF ₃ -OEt ₂ . In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate time is about -78°C for about 1 hour. In some embodiments, the reaction is further warmed to about room temperature overnight. In accordance with some embodiments, the corresponding temperature for the corresponding time is approximately 0°C throughout the night.

In some embodiments, the VI-1 halide is cooled to an appropriate temperature, reacted under suitable metal-halogen exchange conditions with an appropriate solvent for an appropriate period of time and at an appropriate temperature, and then later reacted with an appropriate VI-4 ketone for an appropriate period of time and at an appropriate temperature to obtain a tertiary alcohol. In accordance with some embodiments, suitable metal halide exchange conditions include an organometallic agent. In some embodiments, the suitable solvent is THF. In accordance with some embodiments, the organometallic agent is an alkyl lithium. In accordance with some embodiments, the alkyllithium is n-butyllithium. In accordance with some embodiments, compound VI-1 was cooled to about -60°C before adding the organometallic agent. In some embodiments, compound VI-4 was added slowly over about 45 minutes at about -60°C. In some embodiments, compound VI-1 is reacted for about 1 hour at -60°C after complete addition of ketone VI-4. In accordance with some embodiments, the appropriate temperature for the reaction of compound VI-1 and ketone VI-4 is approximately -60°C. In some embodiments, the tertiary alcohol is reacted under suitable allylation conditions, which include the use of an allylating agent and a Lewis acid, in an appropriate solvent for an appropriate period of time and at an appropriate temperature to form compound VI-5. In accordance with some embodiments, the suitable allylating agent is allyl trimethylsilate. In accordance with some embodiments, the corresponding Lewis acid is BF ₃ -OEt ₂ . In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate time is about -65°C for about 1 hour.

In some embodiments, compound VI-5 is reacted under 1,3-dioxalane deprotection conditions for an appropriate period of time in an appropriate solvent and at an appropriate temperature, followed by reductive cyanidation of the resulting ketone intermediate for an appropriate period of time in an appropriate solvent and at the appropriate temperature from to

- 39 047314 irradiation of connection VI-6. In some embodiments, the 1,3-dioxalane deprotection conditions include the use of an appropriate acid. In accordance with some embodiments, the corresponding acid is formic acid. In accordance with some embodiments, the suitable solvent is a mixture of THF/water. In some embodiments, the appropriate temperature for the appropriate time is from about 40°C to about 65°C overnight. In some embodiments, the resulting ketone is reacted under appropriate reductive cyanidation conditions for an appropriate period of time in an appropriate solvent and at an appropriate temperature to form compound VI-6. In accordance with some embodiments, appropriate conditions for reductive cyanidation include the use of an appropriate cyanidation agent and an appropriate base. In accordance with some embodiments, the corresponding cyanidation agent is a corresponding isocyanide. In some embodiments, the corresponding isocyanide is toluenesulfonylmethyl isocyanide (Tos-MIC). In accordance with some embodiments, the corresponding base is a strong, non-nucleophilic base. In some embodiments, the strong, non-nucleophilic base is t-BuOK. In accordance with some embodiments, the suitable solvent is DME. In some embodiments, the ketone intermediate and the corresponding cyanidation agent were cooled to about 0-5°C before adding the appropriate base. In some embodiments, the appropriate base is added slowly over about 1 hour at about 0 to 5°C. In some embodiments, the reductive cyanidation reaction occurs within approximately 1 hour at 25°C after complete addition of the base. In some embodiments, the reductive cyanidation reaction occurs for approximately 2 hours at 25°C after base addition is complete. In accordance with some embodiments, the appropriate temperature for the reductive cyanidation reaction is approximately 25°C.

In some embodiments, compound VI-3 or compound VI-6 is reacted under suitable oxidative cleavage conditions for an appropriate period of time in an appropriate solvent and at an appropriate temperature to produce compound VI-7. In some embodiments, the oxidative cleavage conditions include the use of an osmium agent and N-methylmorpholine-N-oxide to form a diol intermediate. In some embodiments, the osmium agent is OsO ₄ or K ₂ OsO ₄ -2H ₂ O. In some embodiments, the appropriate solvent is an ACN/water mixture. In some embodiments, the suitable solvent is an acetone/water mixture. In some embodiments, the appropriate temperature for the appropriate time is from about 0° C. to about room temperature overnight. In accordance with some embodiments, the corresponding temperature for the corresponding time is from about 0°C to about room temperature for 2 hours. In accordance with some embodiments, the corresponding temperature for the corresponding time is about room temperature for 2 hours. in some embodiments, the diol is cleaved to form compound VI-7 under appropriate oxidative cleavage conditions for an appropriate period of time in an appropriate solvent and at an appropriate temperature. In accordance with some embodiments, suitable oxidative cleavage conditions include the use of NaIO ₄ . In accordance with some embodiments, the suitable solvent is a mixture of THF/water. In some embodiments, NaIO ₄ is added to the diol intermediate over about 0.5 hour at about 0-5°C. In some embodiments, the appropriate temperature for an appropriate time after completion of the addition of NaIO ₄ is from about 0° C. to about room temperature for 3 hours. In accordance with some embodiments, the appropriate temperature for an appropriate time after completion of the addition of NaIO 4 is approximately room temperature for 3 hours.

In some embodiments, compound VI-7 is reduced to a primary alcohol under suitable reduction conditions and then halogenated under suitable halogenation conditions to produce compound VI-8. In accordance with some embodiments, suitable reduction conditions include the use of a borohydride agent. In accordance with some embodiments, the reduction conditions include the use of NaBH ₄ in an appropriate solvent, at an appropriate temperature for an appropriate

- 40 047314 of the current time period. In accordance with some embodiments, the suitable solvent is THF. In some embodiments, the appropriate temperature for the appropriate time is about 0°C for about 1 hour. In some embodiments, the reaction is heated to about room temperature for about 3 hours. In some embodiments, the reaction is carried out primary alcohol under suitable halogenation conditions to produce an alkyl halide. In some embodiments, suitable halogenation conditions are bromination conditions that include the use of CBr ₄ in an appropriate solvent at an appropriate initial temperature followed by PPh ₃ in an appropriate solvent at an appropriate temperature for an appropriate period of time. In accordance with some embodiments, the suitable solvent is a halogenated solvent such as DCM. In accordance with some embodiments, a suitable starting temperature is approximately 0°C. In accordance with some embodiments, the appropriate initial temperature is approximately 0°C, and PPh ₃ is added slowly over about 1 hour. In accordance with some embodiments, the appropriate temperature and time after completion of addition of PPh ₃ is approximately 25°C over approximately 1.5 hours. In some embodiments, a suitable solvent for adding PPh ₃ is THF. In some embodiments, the reaction is further warmed to approximately room temperature overnight.

In some embodiments, compound VI-8 is subjected to intramolecular alkylation conditions to form compound VI-9. In some embodiments, the intramolecular alkylation conditions include a suitable base in an appropriate solvent at an appropriate temperature for an appropriate period of time. In some embodiments, a suitable base is lithium diisopropylamide. In accordance with some embodiments, the suitable solvent is a mixture of HMPA and THF. In some embodiments, a suitable base is added slowly over 1 hour at approximately -65°C. In some embodiments, the appropriate temperature for an appropriate period of time after completion of addition of the appropriate base is about -65°C for about 3 hours.

In some embodiments, when R is -CN, compound VI-9 is reduced to aldehyde VI-10 under suitable reduction conditions. In some embodiments, if R is -CO ₂ Et, compound VI-9 is reduced by suitable reduction conditions and then oxidized to aldehyde VI-10 by suitable oxidation conditions. In accordance with some embodiments, suitable reduction conditions include the use of DIBALH in an appropriate solvent at an appropriate temperature for an appropriate period of time. In some embodiments, the suitable solvent is toluene. In some embodiments, DIBALH is added at the appropriate temperature for the appropriate time. In some embodiments, DIBALH was added slowly over 1 hour at approximately -65°C. In some embodiments, the appropriate temperature for an appropriate time after completion of the addition of DIBALH is about -65°C for about 1 hour. In some embodiments, suitable oxidation conditions are chromium-based oxidations. In accordance with some embodiments, suitable oxidation conditions include the use of PCC in an appropriate solvent at an appropriate temperature for an appropriate period of time. In some embodiments, silica gel is added. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, a suitable temperature is approximately room temperature for about 2 hours. Alternatively, in some embodiments, the oxidation conditions include the use of oxalyl chloride and DMSO with an amine base in an appropriate solvent at an appropriate temperature for an appropriate period of time . In some embodiments, the corresponding amine base is TEA. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate period of time is about -78°C for about 1 hour.

In some embodiments, the aldehyde VI-10 is converted to the bisulfite adduct VI-11 under suitable conditions. According to some embodiments

- 41 047314 suitable conditions include the use of the appropriate reagent in the appropriate solvent at the appropriate temperature for the appropriate period of time. In accordance with some embodiments, the corresponding reagent is an aqueous potassium metabisulfite. In accordance with some embodiments, the suitable solvent is THF. In some embodiments, the appropriate temperature and time is about 45°C for about 3.5 hours. In some embodiments, the reaction is further cooled to about room temperature overnight.

In some embodiments, the bisulfite adduct VI-11 is converted back to the aldehyde VI-10 under suitable conditions. In accordance with some embodiments, suitable conditions include the use of an appropriate base in an appropriate solvent at an appropriate temperature for an appropriate period of time. In accordance with some embodiments, the corresponding base is a carbonate salt. In some embodiments, the suitable base is aqueous sodium carbonate. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature and time is about 25°C for about 1 hour.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 7.

Scheme 7

In diagram 7, X ² , X ³ , X ⁴ , R ¹ and R ² are described in the present invention. According to some embodiments, both X ² and X ³ are N. According to some embodiments, either X ² or X ³ is N and the other is CR ^2. According to some embodiments, both X ² and X ³ represent CR ² .

In some embodiments, halide VII-1 is cooled to an appropriate temperature and reacted under suitable metal-halogen exchange conditions with an appropriate solvent for an appropriate period of time and at an appropriate temperature to produce an aryl or heteroaryl magnesium bromide salt of VII-2. In accordance with some embodiments, suitable metal-halogen exchange conditions include a metal reagent. In some embodiments, the suitable solvent is THF. In accordance with some embodiments, the metal reactant is magnesium. In accordance with some embodiments, suitable metal-halogen exchange conditions include a salt. In accordance with some embodiments, a suitable salt includes lithium chloride. In accordance with some embodiments, suitable metal-halogen exchange conditions include a magnesium activating reagent. In accordance with some embodiments, a suitable magnesium activating reagent includes DIBAL-H. In accordance with some embodiments, a suitable metal, a suitable salt and a suitable solvent are combined at 10°C or at room temperature. In some embodiments, magnesium, lithium chloride, and THF were combined at 10°C. In some embodiments, magnesium, lithium chloride, and THF are combined at room temperature. In some embodiments, DIBAL-H is added to a mixture of a suitable metal, a suitable salt and a suitable solvent at 10° C. or room temperature, and the reaction mixture is stirred for approximately 15 minutes. In accordance with some embodiments, the temperature is lowered or maintained. In some embodiments, the temperature is lowered to 0°C. In accordance with

- 42 047314 In some embodiments, a solution of compound VII-1 in THF was added to the reaction. In some embodiments, Compound VII-1 is reacted for about 1 hour to two hours after addition of Compound VII-1. In some embodiments, Compound VII-1 is reacted for about 1 hour at about 10°C. In accordance with some embodiments, the appropriate temperature for reacting Compound VII-1 is approximately 25°C.

In some embodiments, the aryl or heteroaryl magnesium bromide salt of VII-2 is reacted under suitable zinc replacement conditions with an appropriate solvent for an appropriate period of time and at an appropriate temperature to produce a zinc aryl or heteroaryl dimer VII-3. In accordance with some embodiments, suitable zinc replacement conditions include a zinc halide salt. In accordance with some embodiments, suitable zinc replacement conditions include zinc chloride. In accordance with some embodiments, the suitable solvent is THF. In some embodiments, Compound VII-2 is reacted for about 1 hour after addition of the zinc halide salt. In some embodiments, Compound VII-2 is reacted for about 1 hour at about 25°C after adding the zinc halide salt. In accordance with some embodiments, the appropriate temperature for reaction of compound VII-2 is approximately 25°C.

In some embodiments, 1,4endoethylenecyclohexylcarboxylic acid is reacted with N-hydroxyphthalimide under suitable coupling reaction conditions to produce compound VII-4. In accordance with some embodiments, suitable coupling reaction conditions include a suitable coupling agent, a suitable base and a suitable solvent for a suitable period of time and at a suitable temperature. In accordance with some embodiments, the coupling agent is N.N-diisopropylcarbodiimide. In accordance with some embodiments, the base is DMAP. In accordance with some embodiments, the solvent is DCM or DCE. In accordance with some embodiments, the time and temperature are overnight and room temperature.

In some embodiments, compound VII-2 is reacted with compound VII-4 under suitable aryl-alkyl cross-coupling reaction conditions to produce aryl-alkyl VII-5. In some embodiments, compound VII-3 is reacted with compound VII-4 under suitable aryl-alkyl cross-coupling reaction conditions to produce aryl-alkyl VII-5. In some embodiments, compound VII-4 is reacted under suitable aryl-alkyl cross-coupling reaction conditions to produce aryl-alkyl VII-5. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include nickel. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include nickel, where X ² is -CMe and X ³ is -CMe, or where X ² is -CMe and X ³ is -CH . In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include nickel, where X ² is -CMe and X ³ is -CMe. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include nickel, where X ² is -CMe and X ³ is -CH. In some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include a suitable Ni source, a suitable arylzinc or heteroarylzinc reagent, a suitable auxiliary ligand, and a solvent for a suitable period of time at a suitable temperature. In accordance with some embodiments, the Ni source is nickel(II) acetylacetonate. In accordance with some embodiments, the Ni source is a Ni(II) halide or solvate thereof. In some embodiments, the Ni(II) halide is Ni(II) chloride or Ni(II) bromide. In some embodiments, the arylzinc reactant is a substituted phenylzinc reactant. In accordance with some embodiments, the substituted phenylzinc reagent is a methoxyphenylzinc reagent. In some embodiments, the methoxyphenylzinc reagent is bis(4-methoxy-3-methylphenyl)zinc or bis(4-methoxy-3,5-dimethylphenyl)zinc. In accordance with some embodiments, the heteroarylzinc reagent is a substituted pyridinylzinc reagent. In accordance with some embodiments, the substituted pyridinylzinc reagent is a methoxypyridinylzinc reagent. In accordance with some embodiments, the methoxypyridinylzinc reagent is bis(6-methoxy-5-methylpyridin-3-yl)zinc. In accordance with some embodiments, the auxiliary ligand is

- 43 047314

2,2'-bipyridine. In some embodiments, if X ² is CMe and X ³ is -CMe, the auxiliary ligand is 2,2'-bipyridine. In accordance with some embodiments, the auxiliary ligand is an alkyl-substituted 2,2'-bipyridine. In some embodiments, the alkyl-substituted 2,2'-bipyridine is 6,6'-dimethyl-2,2'-bipyridine or 4,4'-di-tert-butyl-2,2'bipyridine. In some embodiments, the alkyl-substituted 2,2'-bipyridine is 6,6'-dimethyl-2,2'-bipyridine. In some embodiments, when X ² is -CMe and X ³ is -CH, the alkyl-substituted 2,2'-bipyridine is 6,6'-dimethyl-2,2'-bipyridine. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include iron. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include iron, wherein X ² is -CMe and X ³ is N. In accordance with some embodiments, suitable aryl-alkyl cross-coupling reaction conditions include including iron, where compound VII-2 is X ² which is -CMe and X ³ is N, and reacted with compound VII-4. In some embodiments, the solvent is acetonitrile, N,N'dimethylpropylene urea (DMPU), DMF, THF, or combinations thereof. In accordance with some embodiments, the solvent is DMPU. In some embodiments, the time and temperature are overnight and 25°C.

In some embodiments, the aryl-alkyl compound VII-5 is reduced to an alcohol by suitable reduction conditions, followed by oxidation to the aldehyde VII-6 by suitable oxidation conditions. In accordance with some embodiments, suitable reduction conditions include the use of DIBALH in an appropriate solvent at an appropriate temperature for an appropriate period of time. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate time is about -78°C for about 1 hour. In some embodiments, the reaction is further warmed to about room temperature for about two hours to produce an alcohol. In accordance with some embodiments, suitable oxidation conditions are chromium-based oxidations. In accordance with some embodiments, suitable oxidation conditions include the use of PCC in an appropriate solvent at an appropriate temperature for an appropriate period of time. In some embodiments, silica gel is added. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, a suitable temperature is approximately room temperature for about 2 hours. Alternatively, in some embodiments, the oxidation conditions include the use of oxalyl chloride and DMSO with an amine base in an appropriate solvent at an appropriate temperature for an appropriate period of time . In some embodiments, the corresponding amine base is TEA. In accordance with some embodiments, the suitable solvent is DCM. In some embodiments, the appropriate temperature for the appropriate period of time is approximately 78°C for approximately 1 hour.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 8.

Scheme 8

In Scheme 8, the substituents X ² , X ³ , X ⁴ , R ¹ , R ² and R ³ are described in the present invention. In accordance with some embodiments, X ² is CR ² , X ³ is CH, and each X ⁴ is CH. According to some embodiments, X represents

- 44 047314 is a halide. In some embodiments, the halide is a chloride, bromide, or iodide.

In some embodiments, boronic acid ester VIII-2 is reacted with halide VIII-1 under suitable metal-catalyzed cross-coupling reaction conditions to produce compound VIII-3. In accordance with some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In accordance with some embodiments, suitable metal-catalyzed cross-coupling reaction conditions include palladium, an appropriate base, and an appropriate solvent for an appropriate period of time and at an appropriate temperature. In some embodiments, palladium is obtained in the form of Pd(dppf)Cl ₂ or Pd(PPh ₃ ) ₄ . In accordance with some embodiments, the suitable base is an inorganic base. In some embodiments, the inorganic base is a carbonate, phosphate, oxide, or hydroxide. In accordance with some embodiments, the inorganic base is an inorganic alkali metal base. In some embodiments, the alkali metal is sodium, potassium, cesium, or combinations thereof. In accordance with some embodiments, the inorganic base is Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , or combinations thereof. In accordance with some embodiments, the combination is a combination of Na ₂ CO ₃ and K ₂ CO ₃ . In accordance with some embodiments, the inorganic base is K ₂ CO ₃ . In accordance with some embodiments, the inorganic base is Cs2CO3. In accordance with some embodiments, the suitable solvent is an aqueous solvent. In some embodiments, the suitable solvent is a mixture of water and an organic solvent. In some embodiments, the organic solvent in the mixture is a Ci-4 alcohol, THF, DMF, DME, dioxane, acetonitrile, or a combination thereof. In accordance with some embodiments, the organic solvent in the mixture is dioxane. In some embodiments, the appropriate time ranges from about 1 hour to overnight. In accordance with some embodiments, a suitable temperature is from about 50°C to about 115°C. In accordance with some embodiments, a suitable temperature is approximately 50°C. In accordance with some embodiments, the appropriate temperature is approximately 100°C.

In some embodiments, compound VIII-3 is subjected to suitable hydrogenation conditions followed by treatment under appropriate acidic conditions to produce cyclohexanone VIII-4. In accordance with some embodiments, suitable hydrogenation conditions include a palladium catalyst. In some embodiments, the palladium-catalyzed hydrogenation conditions include 10% Pd/C in an atmosphere including hydrogen gas in an appropriate solvent for an appropriate period of time at an appropriate temperature. In some embodiments, hydrogen gas is present in the atmosphere at a partial pressure of approximately 1 atm. In some embodiments, the solvent is EtOAc, ethanol, methanol, or a combination thereof. In some embodiments, the appropriate time is from about 4.5 hours to overnight, and the appropriate temperature is approximately room temperature. In some embodiments, the acidic conditions include formic acid in a mixture of water and toluene for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the corresponding time is approximately 4 hours, and the corresponding temperature is approximately 120°C. In some embodiments, the corresponding time is overnight and the corresponding temperature is the boiling point of the solvent. In some embodiments, the acidic conditions include PPTS in a mixture of acetone and water for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the corresponding time is approximately 10 hours, and the corresponding temperature is approximately 60°C. In some embodiments, the acidic conditions include 3 M HCl and THF for an appropriate period of time at an appropriate temperature. In some embodiments, the appropriate time is from about 3 hours to overnight, and the appropriate temperature is about 60°C.

In some embodiments, compound VIII-4 is reacted under suitable homologation conditions to increase the carbon chain by one atom to produce enol ester VIII-5. In some embodiments, suitable homologation conditions for increasing the carbon chain by one atom include deprotonation

- 45 047314 adding a phosphonium salt with an appropriate base in an appropriate solvent for an appropriate first time at an appropriate first temperature before adding cyclohexanone VIII-4 for a second time at a second temperature. In accordance with some embodiments, the phosphonium salt is an alkyltriphenylphosphonium salt. In accordance with some embodiments, the alkyltriphenylphosphonium salt is alkyltriphenylphosphonium chloride. In some embodiments, the alkyltriphenylphosphonium chloride is (methoxymethyl)triphenylphosphonium chloride [Ph ₃ P ⁺ CH2OCH ₃ Cl ^- ]. In some embodiments, the suitable base is LiHMDS, NaHMDS, or KHMDS. In some embodiments, the suitable base is NaHMDS. In some embodiments, the suitable solvent is THF. In accordance with some embodiments, the corresponding first time is from about 0.5 hour to about 2 hours, and the corresponding first temperature is about 0°C. In accordance with some embodiments, the corresponding second time is from about 0.5 hours to about 3 hours, and the corresponding first temperature is about 0°C. In some embodiments, the corresponding second time is overnight, and the corresponding second temperature starts at 0°C and is allowed to rise to approximately room temperature during the second time.

In some embodiments, the enol ester VIII-5 is hydrolyzed under suitable acidic conditions to produce a mixture of cis and trans aldehydes, wherein the trans aldehyde is compound VIII-6. In accordance with some embodiments, suitable acid conditions include a suitable acid in a suitable solvent for a suitable period of time at a suitable temperature. In some embodiments, the acid is formic acid, the solvent is a mixture of water and toluene, the time is from about 2 hours to overnight, and the temperature is from about 120°C to about 130°C. In some embodiments, the acid is HCl, the solvent is THF, the time is from about 1 hour to about 6 hours, and the temperature is about 60°C. In some embodiments, treating a mixture of cis- and trans-aldehydes under suitable basic conditions produces a mixture of further trans-aldehyde-enriched compound VIII-6. In accordance with some embodiments, suitable base conditions include an appropriate base in an appropriate solvent for an appropriate period of time at an appropriate temperature. In some embodiments, the base is NaOH. In accordance with some embodiments, the solvent is an aqueous solvent mixture that includes EtOH, toluene, THF, or combinations thereof. In accordance with some embodiments, the aqueous solvent mixture includes toluene. In accordance with some embodiments, the aqueous solvent mixture includes THF. In some embodiments, the appropriate time is from about 5 hours to overnight, and the appropriate temperature is approximately room temperature. In accordance with some embodiments, the base is NaOMe. In accordance with some embodiments, the solvent is a C _1-4 alcohol or mixtures thereof. In accordance with some embodiments, the solvent is methanol or ethanol. In accordance with some embodiments, the solvent is methanol. In some embodiments, the appropriate time is from 4 hours to overnight, and the appropriate temperature is approximately room temperature. In some embodiments, further purification of the mixture of cis and trans aldehydes produces transaldehyde VIII-6. In accordance with some embodiments, further purification includes crystallization, chromatography, or combinations thereof. In accordance with some embodiments, further purification includes crystallization.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 9.

- 46 047314

Scheme 9

IX-1 IX-2 IX-3

VIII-4 VIII-5 VIII-6

In Scheme 9, the substituents X ² , X ³ , X ⁴ , R ¹ , R ² , R ³ and m are described in the present invention. In accordance with some embodiments, X ² is CR ² , X ³ is CH, and each X ⁴ is CH. In accordance with some embodiments, X is a halide. In accordance with some embodiments, the halide is a chloride, bromide, or iodide.

In some embodiments, compound IX-1 is cooled to an appropriate temperature, reacted under suitable metal-halogen exchange conditions in an appropriate solvent for an appropriate first time and at an appropriate first temperature, and then later reacted with an appropriate ketone IX-2 at for a suitable second time and at a suitable second temperature to obtain compound IX-3. In accordance with some embodiments, suitable metal-halogen exchange conditions include an organometallic agent. In accordance with some embodiments, the organometallic agent is an alkyl lithium reagent. In accordance with some embodiments, the alkyllithium reagent is nbutyllithium. In some embodiments, the suitable solvent is THF. In accordance with some embodiments, compound IX-1 was cooled to about -78°C before adding the organometallic agent. In accordance with some embodiments, the first time is from about 1 hour to about 2 hours, and the first temperature is -78°C. In accordance with some embodiments, the second time is about 3 hours, and the second temperature is about -78°C. In some embodiments, the second time is overnight, and the second temperature is initially approximately 78°C and is allowed to warm to room temperature for the second time.

In some embodiments, alcohol IX3 is reacted under suitable reduction conditions to form a mixture of saturated and unsaturated substituted cyclohexyl ketals derived from compound IX-3. In some embodiments, suitable reduction conditions include an appropriate reducing agent and an appropriate acid in an appropriate solvent for an appropriate period of time and at an appropriate temperature. In accordance with some embodiments, the reducing agent is a silyl hydride and the acid is trifluoroacetic acid. In accordance with some embodiments, the silyl hydride is triethylsilane. In accordance with some embodiments, the solvent is dichloromethane. In some embodiments, the time ranges from about 1 hour to overnight. In accordance with some embodiments, the temperature is from about 0°C to about room temperature. In accordance with some embodiments, the temperature is approximately 0°C. In some embodiments, a mixture of saturated and unsaturated substituted cyclohexyl ketals derived from compound IX-3 is reacted under suitable hydrolysis reaction conditions to form a mixture of saturated and unsaturated substituted cyclohexyl ketones including saturated ketone VIII-4. In accordance with some embodiments, suitable hydrolysis reaction conditions include an appropriate acid in an appropriate solvent for an appropriate period of time at an appropriate temperature. In some embodiments, the acid is formic acid, the solvent is a toluene/water mixture, the temperature is approximately 130°C, and the time is overnight. In some embodiments, the acid is formic acid, the solvent is a THF/water mixture, the temperature is approximately 80°C, and the time is overnight. According to some embodiments, a mixture of saturated and unsaturated substituted cyclohexyl ketones, including the saturated ketone VIII-4, is reduced

- 47 047314 was poured under suitable reduction reaction conditions to convert the unsaturated components into compound VIII-4. In accordance with some embodiments, suitable reduction reaction conditions include an appropriate reducing agent and an appropriate solvent for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, the reducing agent is hydrogen. In accordance with some embodiments, the hydrogen is delivered at a pressure of from about 15 psig. inch to approximately 30 psi. inch. In accordance with some embodiments, suitable reduction reaction conditions include a catalyst. In accordance with some embodiments, the catalyst includes palladium. In accordance with some embodiments, the catalyst that includes palladium is 10% palladium on a carbon support. In some embodiments, the solvent is ethyl acetate and concentrated HCl. In accordance with some embodiments, the solvent is ethyl acetate. In some embodiments, the time ranges from about 30 minutes to about overnight. In accordance with some embodiments, the temperature is approximately room temperature.

In some embodiments, ketone VIII-4 is converted to trans-aldehyde VIII-6 under reaction conditions also suitable for converting ketone VIII-4 to trans-aldehyde VIII-6, as described in Scheme 8.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 10.

Scheme 10

X-4

In Scheme 10, ring A, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ and substituents R ¹ , R ² and R ⁸ are described in the present invention. In accordance with some embodiments, R is a halide or -OH. In accordance with some embodiments, the halide is iodine, bromine, or chlorine. In accordance with some embodiments, the halide is chlorine. In accordance with some embodiments, R is -OH. In accordance with some embodiments, R is an alcohol protecting group. In some embodiments, the alcohol protecting group is a methyl, substituted methyl group, substituted ethyl group, substituted benzyl group, or silyl group, as described in, for example, Wuts, PGM Greene's Protective Groups in Organic Synthesis (2014) John Wiley & Sons ISBN: 978-1-118-05748-3. In accordance with some embodiments, the alcohol protecting group is a silyl group. In accordance with some embodiments, the silyl group is tert-butyldimethylsilyl.

In some embodiments, aldehyde VIII-6 (as in Scheme 8, where X ³ and each X ⁴ is CH, for example) is reacted with aniline X-1 under suitable reductive amination reaction conditions to produce compound X-2a. In accordance with some embodiments, suitable reductive amination reaction conditions include an appropriate reducing agent and an appropriate solvent, at an appropriate temperature for an appropriate period of time. In some embodiments, the reducing agent is picolinaborane, sodium borohydride, or sodium triacetoxyborohydride. According to some

- 48 047314 In some embodiments, the reducing agent is sodium triacetoxyborohydride. In some embodiments, the solvent is DCM, DCE, THF, acetonitrile, DMF, or N-dimethylacetamide. In accordance with some embodiments, the solvent is DCM, DCE, or combinations thereof. In accordance with some embodiments, the solvent is DCM. In some embodiments, the time is from about 30 minutes to overnight, and the temperature is initially about 0°C and raised to about room temperature over time. In accordance with some embodiments, the temperature is approximately room temperature.

In some embodiments, aldehyde VI-10 (as in Scheme 6, where X ³ and each X ⁴ is CH, for example) is reacted with aniline X-1 under suitable reductive amination reaction conditions to produce compound X-2b. In accordance with some embodiments, suitable reductive amination reaction conditions include, optionally, a suitable condensation catalyst, a suitable reducing agent and a suitable solvent, at a suitable temperature for a suitable period of time. In some embodiments, suitable reductive amination reaction conditions include holding compound VI-10, compound X-1, and a condensation catalyst in an appropriate solvent at a first temperature for a first period of time, and then adding a reducing agent and holding the resulting mixture at a second temperature during the second period of time. In accordance with some embodiments, the solvent is an alcohol. In accordance with some embodiments, the solvent is methanol. In accordance with some embodiments, the condensation catalyst is acetic acid. In accordance with some embodiments, the first temperature is from about room temperature to about 60°C and the first time period is from about 3 hours to about 68 hours. In accordance with some embodiments, the first temperature is about room temperature and the first time period is yourself all night. In accordance with some embodiments, the first temperature is approximately 60°C and the first time period is approximately 4 hours. In accordance with some embodiments, the reducing agent is picoline-BH ₃ . In accordance with some embodiments, the second temperature is room temperature. In accordance with some embodiments, the second temperature is approximately 40°C. In accordance with some embodiments, the second period of time ranges from overnight to about 4 days.

In some embodiments, suitable reductive amination reaction conditions include adding a suitable reducing agent to a mixture of compound VI-10, compound X-1 and an appropriate solvent and maintaining the resulting mixture at an appropriate temperature for an appropriate period of time. In some embodiments, the reducing agent is sodium triacetoxyborohydride. In some embodiments, 1 equivalent of AcOH is added before the reducing agent. In accordance with some embodiments, the solvent is DCM or DCE. In accordance with some embodiments, the time is approximately overnight and the temperature is approximately room temperature. In accordance with some embodiments, the temperature is 45°C.

In some embodiments, amine X2a or amine X-2b (referred to generically and alternatively as X-2 in the present invention with respect to Scheme 10) is reacted with cyclohexane X-3 (as in Scheme 10, for example) under suitable reaction conditions acylation followed by suitable hydrolysis reaction conditions to obtain compound X-4, respectively. In accordance with some embodiments, cyclohexane X-3 is an acid chloride or carboxylic acid. In some embodiments, if compound X-3 is an acid chloride, suitable acylation reaction conditions are sufficient to provide a cyclohexyl alcohol protected intermediate to provide compound X-4 after deprotection under suitable hydrolysis reaction conditions. In some embodiments, X ¹ is N or CH, and the acylation reaction conditions include an appropriate base, an appropriate solvent, and optionally DMAP, at an appropriate temperature for an appropriate period of time. In some embodiments, the base is TEA or pyridine. In some embodiments, the solvent is DCE, DCM, toluene, pyridine, or combinations thereof. In accordance with some embodiments, the solvent is

- 49 047314

DCM. In accordance with some embodiments, the solvent is toluene. In some embodiments, the temperature is 80°C and the time is from about 1 hour to overnight. In some embodiments, the temperature is room temperature and the time is from 1 hour to overnight. In some embodiments, the initial temperature is 0°C and the reaction is warmed to room temperature and the time is from about 15 minutes to about 5 hours. In some embodiments, the reaction conditions include DMAP. In some embodiments, X ¹ is N, the reaction conditions include DMAP, the base is TEA, the solvent is toluene, the temperature is about 80° C., and the time is from about 1 hour to about 2 hours. According to in some embodiments, X ¹ is N, the reaction conditions include DMAP, the base is pyridine, the solvent is toluene, the temperature is about 80°C, and the time is from about 1 hour to overnight. In some embodiments, X ¹ is CH, the base is TEA, the solvent is toluene, the temperature is about room temperature, and the time is from about 1 hour to about 2 hours. In some embodiments, X ¹ is CH, the base is pyridine, the solvent is toluene, the temperature is about room temperature and the time is from about 1 hour to overnight. In some embodiments, if compound X-3 is a carboxylic acid, a coupling reagent is used. In some embodiments, the coupling reagent is HATU, EDC, T3P, HBTU, BCTU, or pyBOP. In some embodiments, compound X-3 is a carboxylic acid, the base is triethylamine, the solvent is DCM, the coupling reagent is T3P, and optionally DMAP, at an appropriate temperature for an appropriate period of time. In some embodiments, the base is TEA or pyridine. In some embodiments, the solvent is DCE, DCM, toluene, pyridine, or combinations thereof. In accordance with some embodiments, the solvent is DCM. In some embodiments, the temperature is 40°C and the time is from about 2 hours to about 63 hours. In some embodiments, the temperature is room temperature and the time is from 1 hour to overnight. In some embodiments, the initial temperature is 25°C and the reaction is heated to 40°C and the time is from about 2 hours to about 63 hours. In some embodiments, the reaction conditions include DMAP.

In some embodiments, suitable hydrolysis reaction conditions are sufficient to deprotect the protected cyclohexyl alcohol intermediate to produce compound X-4. In accordance with some embodiments, the hydrolysis reaction conditions include an appropriate acid, an appropriate solvent, at an appropriate temperature for an appropriate period of time. In accordance with some embodiments, the acid is aqueous HCl. In some embodiments, the concentration of aqueous HCl is approximately 1 M. In some embodiments, the solvent is THF, methanol, or combinations thereof. In some embodiments, the temperature is from about 0° C. to about room temperature and the time is from about 1 hour to about 4 hours. In some embodiments, R is tert-butyldimethylsilyl, the acid is 1 M HCl, the solvent is is a combination of THF and methanol, the temperature is from about 0° C. to about room temperature, and the time is from about 1 hour to about 19 hours. In some embodiments, R is other than tert-butyldimethylsilyl, and the protecting group, R, was removed to obtain compound X-4 according to appropriate methods, as disclosed, for example, in Greene's Protective Groups in Organic Synthesis.

In accordance with some embodiments, the intermediates used in the preparation of the compounds described in the present invention were prepared as set forth in Scheme 11.

- 50 047314

Scheme 11

In Scheme 11, ring A and substituents X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and m described in the present invention. In some embodiments, R is independently alkyl, heteroalkyl, hydroxyalkyl, or hydrogen, or both R's are taken together to form a substituted or unsubstituted fused 4-, 5-, or 6-membered ring with 1-3 N atoms and 0-2 O atoms or S in the ring.

In some embodiments, compound XI-2 is prepared from compound XI-1 and the amine, NHR2. In some embodiments, compound XI-1 is exposed to carbonyldiimidazole in an appropriate solvent, such as ACN, at an appropriate temperature, such as from about room temperature to about 80° C., for an appropriate period of time to produce a carbamoylimidazole intermediate. In some embodiments, the appropriate time period is from about 2 hours to about 6 hours, or about overnight. In some embodiments, the carbamoylimidazole intermediate is treated with NHR ₂ in a suitable solvent and the reaction is allowed to proceed for an appropriate period of time at an appropriate temperature. In accordance with some embodiments, a suitable solvent is acetonitrile. In some embodiments, a suitable solvent is MeOH, THF, or DCM. In some embodiments, NHR2 is added as a solution in MeOH, THF, or DCM. In some embodiments, NHR ₂ is added neat. In some embodiments, the appropriate period of time at the appropriate temperature is from about 15 minutes to overnight at about room temperature. In some embodiments, the appropriate time period is from about 1 day to about 7 days. In accordance with some embodiments, a suitable temperature is from about room temperature to about 50°C or from about room temperature to about 100°C. In accordance with some embodiments, the amine, NHR ₂ , is provided as a salt. In accordance with some embodiments, the salt is a hydrochloride salt. In some embodiments, if the amine, NHR ₂ , is provided as a hydrochloride salt, then a suitable base, such as H ₃ O-Pr ₂ NEt, is combined with a carbonylimidazole intermediate before adding the hydrochloride salt.

In accordance with some embodiments, compounds are prepared as described in the Examples.

Certain terminology.

Unless otherwise noted, the following terms as used in the present invention are characterized by the definitions provided 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 to be construed as limiting the subject matter described.

As used herein, C1-Cx includes C1- _C2 , C1- _C3 ...C1-Cx. By way of example only, a group designated C1-C4 means that there are from one to four carbon atoms in the fragment, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, K-K-alkyl means that there are from one to four carbon atoms in the alkyl group, 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. An 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, the range of numeric values, such as 1 to 10, refers to each integer in the range represented; for example, from 1 to 10 carbon atoms means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 atoms carbon, although this definition also covers occurrences of the term alkyl where no numerical range is indicated. In accordance with some embodiments, the alkyl is K-^-alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,

- 51 047314 sec-butyl or tert-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

Alkylene group refers to a divalent alkyl group. Any of the above monovalent alkyl groups can be made alkylene by abstraction of the second hydrogen atom from the alkyl. In accordance with some embodiments, the alkylene is a C ₁ -C ₆ alkylene. In other embodiments, the alkylene is a C1-C4 alkylene. In accordance with 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, C.'iC.'3-alkylene). In other embodiments, the alkylene contains one to two carbon atoms (eg, C1C.'2-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, Chi-alkylene). Typical alkylene groups include, but are not limited to -CH2-, -CH( _CH3 ) _- , -C( _CH3 ) _2- , -CH2CH2-, -CH2CH( _CH3 )-, _-CH2C ( _CH3 ) ₂ -, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of the alkyl are replaced with deuterium.

The term alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In accordance with one embodiment, an alkenyl group is characterized by the formula -C(R)=CR ₂ , where R refers to the remaining portions of the alkenyl group, which may be the same or different. In accordance with some embodiments, R is H or alkyl. In some embodiments, 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 accordance with one embodiment, the alkynyl group is characterized by the formula -C^C-R, where R refers to the remaining portions of the alkynyl group. In accordance with some embodiments, R is H or alkyl. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of the alkynyl group include -C^CH. -C CCH3 -C CC1HC1 k -CH2C CH.

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

The term alkylamine refers to an -N(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 (i.e., 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 framework of the ring are all carbon atoms. Thus, the term distinguishes carbocyclic from heterocyclic rings or heterocycles in which the ring framework contains at least one atom that is different from a carbon atom. In accordance with some embodiments, at least one of the two rings of the bicyclic carbocycle is aromatic. In accordance with some embodiments, both rings of the bicyclic carbocycle are aromatic. Carbocycles include 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 accordance with some embodiments, aryl is C ₆ -Clo-aryl. Depending on the structure, the aryl group is monoradical or diradical (ie, an arylene group).

The term cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic group where each of the atoms forming the ring (ie, the backbone atoms) is a carbon atom. In accordance with some embodiments, the cycloalkyls are spirocyclic or bridged compounds. In accordance with some embodiments, the cycloalkyls are optionally fused to an aromatic ring, and

- 52 047314 the point of attachment is at a carbon atom that is not a carbon atom of the aromatic ring. Cycloalkyl groups include groups containing from 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 accordance with some embodiments, the cycloalkyl is a C ₃ -C ₆ -cycloalkyl. In accordance with some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7dimethylbicyclo[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 an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In accordance with one aspect, the fluoroalkyl is a C ₁ -C ₆ -fluoroalkyl.

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

The term heteroalkyl refers to an alkyl group in which one or more skeletal alkyl atoms are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. Heteroalkyl is attached to the moiety at the carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C-C6 heteroalkyl.

The term heteroalkylene refers to a divalent heteroalkyl group.

The term heterocycle or heterocyclic refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing from one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group contains from 3 to 10 atoms in its ring system, and provided that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic connections or bridged connections. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings containing from 3 to 10 atoms in their ring system, and aromatic heterocyclic groups include rings containing from 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, , tietanil, homopiperidinil, oxepanil, tiepanil, oxazepinil, diazepinil, thiazepinil , 1,2,3,6tetrahydropyridinyl, 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, 3azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3 ,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzoC]oxazol-2(3H)-onyl, 1H-benzoC]imidazol- 2(3H)-onyl, benzoC]thiazol-2(3H)-onyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, silt, phthalazinil , 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, the group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). In addition, the group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached ). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In accordance with some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In accordance with 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.

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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 accordance with some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In accordance with some embodiments, the heteroaryl contains 1-4 N atoms on the ring. In accordance with some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms on the ring. In accordance with some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atom, and 0-1 S atom in the ring. In some embodiments, the heteroaryl is C1-C9 heteroaryl. In accordance with some embodiments, the monocyclic heteroaryl is Cl-C ₅ -heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In accordance with 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 accordance with some embodiments, the heterocycloalkyl is fused with aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidin-2,5-dithionyl, pyrrolidine-2,5-dione, silt , pyrrolidinonyl, imidazolidinyl, imidazolidin-2onyl or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of carbohydrates, including without limitation monosaccharides, disaccharides and oligosaccharides. In one aspect, heterocycloalkyl is C ₂ -Clo-heterocycloalkyl. In accordance with another aspect, heterocycloalkyl is C ₄ -C ₁₀ -heterocycloalkyl. In accordance with some embodiments, the heterocycloalkyl contains 0-2 N atoms on the ring. In accordance with some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms on the ring.

The term bond or single bond refers to a chemical bond between two atoms or two fragments if the atoms connected by the bond are considered as part of a larger substructure. In accordance with one aspect, if the group described in the present invention is a link, the control group is absent, thereby allowing the formation of a link between the remaining established groups.

The term fragment refers to a specific segment or functional group of a molecule. Chemical moieties are often shown as chemical units 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). In accordance with certain other embodiments, the optional substituents are separately and independently selected from D, halogen, -CN, -NH2, -Alkyl), -I(alkyl) ₂ , -OH, -CO2H, -OD^alkyl, -C(= O)NH ₂ , -C(=O)NH(alkyl), -C^O^^alkyl^, -S(=O) ₂ NH ₂ , ^(=O) ₂ IN(alkyl), ^(=O ) ₂ I(alkyl) ₂ , -CH2CO2H, -OH^O^alkyl, -CH2C(=O)NH2, -^C^Chalkyl), -C^CRO^^^G -CH2S(=O)2NH2, - ^S^O^NH^^), -CH ₂ S(=O) ₂ N(alkyl) ₂ , alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio , arylthio, alkyl sulfoxide, arylsulfoxide, alkyl sulfone and arylsulfone. The term optionally substituted or substituted means that the control group is optionally substituted with one or more additional group(s) separately and independently selected from D, halogen, -CN, -NH2, -II(alkyl), -I(alkyl) ₂ , -OH, -CO2H, -«^alkyl, -C(=O)NH ₂ , -^^Chalkyl), -C^Zhalkyl)^ -S(=O) ₂ NH ₂ , ^(^^(alkyl ), ^(^U^alkyl)^ alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, arylsulfoxide, alkyl sulfone, and arylsulfone. In accordance with some other embodiments, optional. substituents independently selected from D, halogen, -CN, -NH ₂ , -NH(CH ₃ ), -N(CH ₃ ) ₂ , -OH, -CO ₂ H, -^(CH^alkyl), -C(= O)NH2, -CC^ITO-Cd-alkyl), -C(=O)N(C1-C ₄ -alkyl)2, -S(=O)2NH2,

-S(=O) ₂ NH(Cl-C ₄ -alkyl), -S(=O) ₂ N(Cl-C ₄ -alkyl) ₂ , C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -fluoroalkyl, C1-C ₄ -heteroalkyl, C1-C ₄ -alkoxy, C1-C ₄ -fluoroalkoxy, -SCi-C-halkyl. -S(=O)Cl-C ₄ -alkyl and -S(=O) ₂ C1C ₄ -alkyl. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, _-NH2 , -OH, -NH( _CH3 ), -N( _CH3 ) ₂ , -CH3, -CH2CH3, -CF3, - OCH3 and -OCF3. In accordance with some embodiments, the substituted groups are replaced by one or two preceding groups. In accordance with some embodiments, the substituted groups are replaced by one of the protecting groups. In accordance with some options

- 54 047314 The optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

As used herein, the term acceptable in relation to a formulation, composition or ingredient means that it does not have a persistent adverse effect on the general health of the subject being treated.

In the context of the present invention, the term modulate means interacting with a target, directly or indirectly, to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or enhancing the activity of the target.

In the context of the present invention, the term modulator refers to a molecule that directly or indirectly interacts with a target. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, disruptor, or combinations thereof. In accordance with some embodiments, the modulator is an agonist.

In the context of the present invention, the terms administer, administration, introduction, and the like refer to methods that can be used to ensure delivery of compounds or compositions to the desired site of biological action. These routes include, but are not limited to, 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 routes of administration that can be used for the compounds and methods described herein. In accordance with some embodiments, the compounds and compositions described herein are administered orally.

In the context of the present invention, the terms co-administration or the like cover 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 routes of administration or at the same or different times.

In the context of the present invention, the terms effective amount or therapeutically effective amount refer to a sufficient amount of the administered agent or compound that to some extent alleviates one or more symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of signs, symptoms or causes of disease or any other desired change in a biological system. For example, an effective amount for therapeutic applications is the amount of a composition containing a compound as disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. The appropriate effective amount, if necessary, is determined on a case-by-case basis using methods such as dose escalation studies.

In the context of the present invention, the terms enhance or enhance mean increasing or prolonging either the activity or duration of the desired effect. Thus, with regard to enhancing the action of therapeutic agents, the term enhancement refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on the system. In the context of the present invention, an enhancing effective amount refers to an amount sufficient to enhance the effect of another therapeutic agent in the desired system.

In the context of the present invention, the term pharmaceutical combination means a product that is obtained by 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, eg, a compound described herein or a pharmaceutically acceptable salt and coagent thereof, are administered to a patient simultaneously in the form of a single unit or dose. The term "unfixed combination" means that the active ingredients, for example, a compound described herein, or a pharmaceutically acceptable salt and coagent thereof, are administered to a patient in separate units simultaneously, in parallel or sequentially without any specific intervening time restrictions, wherein such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more active ingredients.

In the context of the present invention, the terms kit and finished product are synonymous.

The term subject or patient includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammals: humans, non-human primates such as chimpanzees and other species of primates and apes, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such such as rabbits, dogs and cats, laboratory animals including rodents such as rats, mice, guinea pigs and the like. In one aspect, the mammal is a human.

In the context of the present invention, the terms treat, treatment or treatment include alleviation, alleviation or reduction of at least one symptom of a disease or condition,

- 55 047314 preventing additional symptoms, suppressing a disease or condition, for example, stopping the progression of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping symptoms of a disease or condition, prophylactically and/or therapeutically.

Pharmaceutical compositions.

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

In accordance with some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method that provides delivery of the compounds to the site of action. These methods include, but are not limited to, delivery by enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and local (including cutaneous, cutaneous, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most appropriate route may depend, for example, on the condition and disorder of the recipient. By way of example only, the compounds described herein can be administered locally to the site in need of treatment, for example, by local infusion during surgery, topical application, such as creams or ointments, injection, catheter or implant. Administration can also be accomplished by direct injection into the affected tissue or organ.

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

Pharmaceutical compositions that can be administered orally include tablets, hard capsules made from gelatin, and soft, sealed capsules made from gelatin and a plasticizer such as glycerin or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in bulk form such as powder or granules, optionally mixed with binders, inert diluents or lubricants, surfactants or dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of a powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration must be in dosages suitable for such administration. Hard capsules may contain the active ingredients in admixture with excipients 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 fatty oils, liquid paraffin or liquid polyethylene glycols. In accordance with some embodiments, stabilizers are added. The pellet cores are provided with suitable coatings. For this purpose, concentrated solutions of Sugars can be used, which may optionally contain acacia gum, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, varnish solutions and suitable organic solvents or mixtures of solvents. Dyes or pigments may be added to tablets or dragee coatings to identify or characterize different dosage combinations of the active compound.

- 56 047314

In accordance with some embodiments, the pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injectable formulations may be presented in unit dosage form, such as ampoules or multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous carrier vehicles, and may contain auxiliary agents 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 solution. water immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the previously described type.

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 solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or carrier media 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 that increase the solubility of the compounds to provide highly concentrated solutions.

Pharmaceutical compositions can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may 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 acacia gum or gum tragacanth.

The pharmaceutical compositions may also be formulated as rectal compositions such as suppositories or retention enemas, for example, containing commonly used suppository bases such as cocoa butter, polyethylene glycol or other glycerides.

Pharmaceutical compositions can be administered topically, that is, by non-systemic administration. This involves applying a compound of the present invention externally 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 penetration through the skin into 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 be from 0.001% to 10% w/w, for example, from 1% to 2% by weight of the formulation.

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 the 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 the 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 can be administered by means of an inhaler or insufflator.

In accordance with some embodiments, a compound disclosed herein is formulated in a manner that achieves delivery of the compound to a specific site in the gastrointestinal tract. For example, a compound disclosed herein is formulated for oral delivery with bioadhesive polymers, pH-sensitive time-sensitive coatings, biodegradable polymers, microbiota-activated systems, and the like to achieve

- 57 047314 delivery of the compound to a specific area of the gastrointestinal tract.

In accordance with some embodiments, a compound disclosed herein is formulated to provide controlled release of the compound. Controlled release refers to the release of a compound of the present invention from the dosage form in which it is included according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, sustained release, pulsatile release, and delayed release profiles. Unlike immediate release compositions, controlled release compositions allow the drug to be delivered to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective drug levels over an extended period of time and thereby provide a longer period of pharmacological response while minimizing side effects compared to traditional rapid release dosage forms. These longer response times provide many inherent benefits that are not achieved with the corresponding short-acting immediate-release formulations.

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

(i) Coating with polymers: The intact molecule can be delivered to the colon without absorption in the upper intestinal tract by coating the drug molecule with suitable polymers that degrade only in the colon.

(ii) Coating with pH-sensitive polymers: Most intestinal and colonic targeted delivery systems are based on coating tablets or pellets that are filled into commonly used hard gelatin capsules. The most commonly used pH-sensitive coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S 100 are copolymers of methacrylic acid and methyl methacrylate.

(iii) Coating with biodegradable polymers;

(iv) Implementation into matrices;

(v) Incorporation into biodegradable matrices and hydrogels;

(vi) Incorporation into pH-sensitive matrices;

(vii) Systems released over time;

(viii) Redox-sensitive polymers;

(ix) Bioadhesive systems;

(x) Microparticle coating;

(xi) Osmotically controlled drug delivery.

Another approach to colon-directed drug delivery or controlled release systems involves embedding the drug in polymer matrices to trap it and release it in the colon. Such matrices can be pH-sensitive or biodegradable. Matrix-based systems, such as multi-matrix (MMX) delayed-release tablets, provide drug release in the colon.

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

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 composition of the type in question, for example, agents suitable for oral administration, may include flavoring agents.

Dosage methods and treatment regimens.

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

- 58 047314 pharmaceutically acceptable solvate, in therapeutically effective quantities.

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 treating diabetes or diabetes-related disorders or conditions, alcoholic or non-alcoholic liver disease, inflammatory bowel conditions, or disorders associated with cell proliferation.

In accordance with certain embodiments, compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, prior therapy, the patient's medical condition, weight and response to medications, and the judgment of the treating physician. Therapeutically effective amounts, if necessary, are determined by methods including, but not limited to, dose escalation and/or dose titration clinical trials.

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

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

In accordance with certain embodiments, when the patient's condition has actually improved, the administered dose of drug is temporarily reduced or temporarily suspended for a certain period of time (eg, drug rest). In specific embodiments, the duration of drug rest ranges from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days or more than 28 days. Dose reductions during drug rest occur, by way of example only, by 10-100%, including, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 only. 75, 80, 85, 90, 95 and 100%.

Immediately after the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, according to specific embodiments, the dose or frequency of administration, or both, is reduced depending on the symptoms to a level at which improvement of the disease, disorder or condition is maintained. However, in certain embodiments, the patient requires periodic treatment 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 its severity, the characteristics (eg, weight, sex) of the subject or host in need of treatment, but is nevertheless determined in accordance with the specific circumstances for a given case, including, for example, the particular agent administered, route of administration, condition to be treated, and subject or host to be treated.

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

In accordance with one embodiment, daily dosages suitable for a compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg body weight. In accordance with some embodiments, the daily dose or amount of active substance in the dosage form is lower

- 59 047314 or higher than the ranges specified herein, based on a number of variables regarding the individual treatment regimen. In various embodiments, daily and unit dosages are varied depending on a number of variables, including, without limitation, the activity of the compound being administered, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the attending physician.

The toxicity and therapeutic efficacy of such therapeutic regimens are determined through standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of LD50 and ED50. The dose relationship between toxic and therapeutic effects represents the therapeutic index and is expressed as the ratio between LD50 and ED50. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and/or a therapeutically effective unit dose amount for use in mammals, including humans. In accordance with some embodiments, the daily dose amount of the compounds described herein is within a circulating concentration range that includes the ED ₅₀ with minimal toxicity. In accordance with certain embodiments, the daily dosage range and/or the amount of a single dose varies within this range depending on the dosage form used and the route of administration used.

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

For any of the above aspects, there are additional embodiments comprising single administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered once daily, or (ii) the compound is administered to the mammal multiple times over the course of one day.

For any of the above aspects, there are additional embodiments comprising multiple administrations of an effective amount of the compound, including additional embodiments in which (i) the compound is administered continuously or intermittently as in a single dose, (ii) the period of time between multiple administrations corresponds to administration every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, (v) the compound is administered to the mammal every 24 hours. In other or alternative embodiments, the method involves a drug rest where administration of the compound is temporarily suspended or the administered dose of the compound is temporarily reduced, and at the end of the drug rest, the dosage of the compound is resumed. In one embodiment, the duration of drug rest varies from 2 days to 1 year.

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

In accordance with one embodiment, the therapeutic efficacy of one of the compounds described herein is enhanced by the administration of an adjuvant (ie, the adjuvant alone has minimal therapeutic effect, but when combined with another therapeutic agent, the overall therapeutic effect for the patient is increased). Or, in accordance with some embodiments, the benefit to a patient is enhanced by administering one of the compounds described herein with another agent (which also includes 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 different aspects of the disease, disorder or condition, being treated, thereby providing greater overall benefit than administering only one of the therapeutic agents.

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

In accordance with certain embodiments, various therapeutically effective doses of the compounds disclosed herein are used in pharmaceutical compositions and/or treatment regimens wherein the compounds disclosed herein are administered in combination with one or more additional agents, such as additional therapists

- 60 047314 commercially effective drug, adjuvant or the like. Therapeutically effective doses of drugs and other agents for use in combination treatment regimens, if necessary, are determined in ways similar to those described above for the active substances themselves. In addition, the methods of prevention/treatment described herein involve the use of metronomic dosing, i.e. providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen includes treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated before, during, or after treatment with a second agent described herein and continued at any time. time during treatment with the second agent or after completion of treatment with the second agent. This also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a triple agent used in combination are administered simultaneously or at different times and/or at increasing or decreasing intervals during the treatment period. Combination treatment also covers intermittent treatment regimens that are started and stopped at different points in time for clinical management purposes.

It will be appreciated that the dosage regimen for treating, preventing, or ameliorating the condition(s) for which relief is desired will be modified according to a variety of factors (e.g., the disease, disorder, or condition suffered by the subject, age, weight, sex, diet and the subject's health status). Thus, in some cases, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

For the combination therapies described herein, dosages of co-administered compounds vary depending on the type of drugs used together, the specific drug used, the disease or condition being treated, etc. In additional embodiments, when coadministered with one or more other therapeutic agents, a compound disclosed herein is administered either simultaneously with one or more other therapeutic agents or sequentially.

In combination therapies, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, multiple therapeutic agents are, by way of example only, presented in one unitary form or in multiple forms (eg, one pill or two separate pills).

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

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

In some cases, the additional therapeutic agent includes a statin, an insulin-sensitizing drug, an insulin secretagogue, an alpha-glucosidase inhibitor, a GLP agonist, a DPP-4 inhibitor (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin, gemigliptin, or dutogliptin), a catecholamine. (such as epinephrine, norepinephrine, or dopamine), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist (such as a thiazolidinedione (TZD) (such as pioglitazone, rosiglitazone, rivoglitazone, or troglitazone), aleglitazar, farglitazar, muraglitazar, or tesaglitazar), or their combination. In some cases, the statin is an HMG-CoA reductase inhibitor. In other cases, 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 its analogues, which

- 61 047314 These promote the production of NAD', a substrate for many enzymatic reactions, including p450, which is a target for FXR (eg, see Yang et al., J. Med. Chem. 50:6458-61, 2007).

In some embodiments, the 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), peroxisome proliferator-activated receptor agonist (PPRAI)-gamma (eg, thiazolidinedione (TZD) (such as pioglitazone, rosiglitazone , rivoglitazone or troglitazone), aleglitazar, farglitazar, muraglitazar or tesaglitazar), or combinations thereof, for the treatment of diabetes 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, a fibrate, vitamins such as niacin, retinoic acid (e.g., 9-cis-retinoic acid), nicotinamide ribonucleoside or analogs thereof, or combinations thereof, for the treatment of diabetes 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, to treat diabetes or a diabetes-related disorder or condition, such as reducing elevated body weight and/or reducing elevated dietary glucose levels.

In accordance with some embodiments, the farnesoid X receptor agonist is administered with at least one additional therapy. In accordance with some embodiments, the at least one additional therapy is a glucose-lowering agent. In accordance with some embodiments, the at least one additional therapy is an anti-obesity agent. In accordance with some embodiments, the at least one additional therapy is selected from, among others, a peroxisome proliferator-activated receptor (PPAR) agonist (gamma, dual, or pan), a dipeptidyl peptidase (IV) inhibitor, a glucagon-like peptide 1 (GLP-I) analogue , insulin or insulin analogue, insulin secretagogue, sodium-dependent glucose transporter 2 (SGLT2) inhibitor, glucophage, human amylin analogue, biguanide, alpha-glucosidase inhibitor, meglitinide, thiazolidinedione and sulfonylurea. In some embodiments, the at least one additional therapy is metformin, sitagliptin, saxagliptin, repaglinide, nateglinide, exenatide, liraglutide, insulin lispro, insulin aspart, insulin glargine, insulin detemir, insulin isophane, and glucagon-like peptide 1, or any combination thereof. In accordance with some embodiments, the at least one additional therapy is a lipid-lowering agent. In accordance with certain embodiments, the at least one additional therapy is administered at the same time as the farnesoid X receptor agonist. In accordance with certain embodiments, the at least one additional therapy is administered less frequently than the farnesoid X receptor agonist. In accordance with certain embodiments, the at least one additional therapy is administered more frequently than the farnesoid X receptor agonist. In certain embodiments, the at least one additional therapy is administered prior to administration of the farnesoid X receptor agonist. In accordance with certain embodiments, the at least one additional therapy is administered after 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 a chemotherapeutic agent, anti-inflammatory agents, radiation therapy, monoclonal antibodies, or combinations thereof.

In accordance with some embodiments, an 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) inhibitor, or a combination thereof.

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

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

In some cases, an FXR agonist is administered in combination with an additional therapeutic agent, such as an antibiotic, a corticosteroid, or an additional anti-inflammatory or immunomodulatory therapy, to treat intestinal conditions associated with inflammation. In some cases, an FXR agonist is administered in combination with metronidazole, vancomycin, fidaxomicin, a corticosteroid, or combinations thereof, to treat intestinal conditions associated with inflammation.

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

In accordance with some embodiments, an FXR agonist is administered in combination with an additional therapeutic agent for the treatment of biliary primary cirrhosis. In accordance with 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, cetuximab, or panitumumab), a chemotherapy agent, FOLFOX, FOLFIRI, CapeOX, 5-FU, leucovorin, regorafenib, irinotecan, oxaliplatin, or combinations thereof, to treat a disorder associated with cell proliferation.

Examples

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

As used above and throughout the specification of the present invention, the following abbreviations, unless otherwise noted, should be understood to have the following meanings:

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asas acetylacetone ACN or MeCN acetonitrile AcOH acetic acid Ace acetyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-dinaphthyl VP benzyl VOS or Vos from/?eot-butylcarbamate iso-Vi iso-butyl tert-V from/?eot-butyl Su CDI cyclohexyl 1,1-carbonyldiimidazole DBA or dba dibenzylideneacetone DCE dichloroethane (C1CH ₂ CH ₂ C1) DCM dichloromethane (CH ₂ C1 ₂ ) DIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-(L ^g ,A-dimethylamino)pyridine DME 1,2-dimethoxyethane DMF L'L'-dimethylformamide DMA L'L'-dimethylacetamide DMPU L',L-dimethylpropylene urea DMSO dimethyl sulfoxide dppf or dppf EDC or EDCI 1,1'-bis(diphenylphosphino)ferrocene A-(3-dimethylaminopropyl)-A-ethylcarbodiimide hydrochloride EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline Eq. equivalent(s) Et ethyl Et ₂ O diethyl ether EtOH ethanol EtOAc ethyl acetate HATU 1 - [bis(dimethylamino)methylene]-1 Η-1,2,3 -triazolo[4,5 -

b]pyridinium 3-oxide hexafluorophosphate

NMRA hexamethylphosphoramide HOBt 1-hydroxybenzotriazole

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HPLC high performance liquid chromatography IBX 2-iodoxybenzoic acid KHMDS Potassium bis(trimethylsilyl)amide NaHMDS sodium bis(trimethylsilyl)amide LiHMDS lithium bis(trimethylsilyl)amide LAH lithium aluminum hydride LCMS liquid chromatography-mass spectrometry 2-MeTHF 2-methyltetrahydrofuran Me methyl MeOH methanol MS mass spectroscopy Ms mesil MTBE methyl ttreoth butyl ether N.B.S. A-bromosuccinimide NMM A-methylmorpholine NMP A-methylpyrrolidin-2-one NMR nuclear magnetic resonance OTf trifluoromethanesulfonate PCC pyridinium chlorochromate P.E. petroleum ether Ph phenyl PPTS pyridium iora toluenesulfonate iso-Pr/i-Pr iso-propyl RP-HPLC high pressure liquid chromatography with reverse phase K.T. room temperature TBS /77/?g/77-butyldimethylsilyl TBAF tetra-n-butylammonium fluoride TV AI tetra-n-butylammonium iodide TEA triethylamine T.F.A. trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMEDA A, A, A, A-tetramethylethylene amine TMS trimethylsilyl T sOH/zkz/?6z-T sOH para-toluenesulfonic acid

Intermediate connection 1.

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

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

1,4-Dioxaspiro[4.5]dec-7-ene-8-boronic acid pinacol ester mixture (25.0 g, 93.9 mmol), 4-iodo-2-methylanisole (28.0 g, 113 mmol) , Pd(dppf)Cl ₂ (1.38 g, 1.89 mmol), dioxane (470 ml) and 1 M Na ₂ CO ₃ (282 ml, 282 mmol) were degassed by ₃ cycles of vacuum and stirred at 50°C in for 2.5 hours and then left to cool to room temperature. The mixture was diluted with EtOAc (500 ml) and washed with

- 65 047314 NaHCO ₃ (2x500 ml). The aqueous layers were back-extracted with EtOAc (200 ml). The combined EtOAc extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 8-(4-methoxy-3-methylphenyl)-1,4-daoxaspiro[4.5 ]dec7-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, 3H), 1, 77 (t, 2H); LCMS: 261.1 [M+H]+.

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

Carbon-supported palladium (10 wt%, 8.08 g, 7.59 mmol) was added to a solution of 8-(4methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (19.8 g, 76.1 mmol) in EtOAc (300 ml) at room temperature under N2. Input _N2 was replaced with an _H2 cylinder. The reaction mixture was stirred for 4.5 hours, filtered through Celite with EtOAc and then concentrated to give 8-(4-methoxy-3-methylphenyl)-1,4dioxaspiro[4.5]decane (18.2 g; ketone content 13% ) as a white solid. ^1H NMR (400 MHz, DMSO-d6): δ 7.00-6.95 (m, 2H), 6.81 (d, 1H), 3.91-3.84 (m, 4H), 3. 73 (s, 3H), 2.49-2.42 (m, 1H), 2.11 (s, 3H), 1.76-1.68 (m, 4H), 1.67-1.55 ( m, 4H); LCMS: 263.1 [M+H]+.

Step 3: 4-(4-methoxy-3-methylphenyl)cyclohexanone.

Formic acid (96%, 14 ml, 356 mmol) and then H ₂ O (2.20 ml, 122 mmol) were added to the 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5] solution decane (18.2 g) in toluene (60 ml) at room temperature under N2 atmosphere. The reaction was heated at 120°C for 4 hours, left to cool to room temperature, and then poured into H ₂ O (200 ml) and toluene (200 ml). The toluene layer was washed (200 ml H ₂ O, followed by 200 ml saturated NaHCO3). The aqueous layers were back-extracted with toluene (100 ml). The combined toluene extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to give 4-(4-methoxy-3methylphenyl)cyclohexanone (15.5 g, 88% in 2 steps) as a white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 7.08-7.03 (m, 2H), 6.84 (d, 1H), 3.74 (s, 3H), 3.00-2, 91 (m, 1H), 2.61-2.51 (m, 2H), 2.282.20 (m, 2H), 2.12 (s, 3H), 2.06-1.98 (m, 2H) , 1.88-1.76 (m, 2H); LCMS: 219.0 [M+H]+.

Step 4: 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene.

A mixture of (methoxymethyl)triphenylphosphonium chloride (35.74 g, 104.3 mmol) and THF (260 ml) under N2 was cooled to -2.2°C in an ice/saline bath. A solution of sodium bis(trimethylsilyl)amide (2 M in THF, 50 mL, 100 mmol) was added dropwise through an addition funnel over 12 min (internal temperature < 0.6°C) followed by rinsing with THF (5 mL). The reaction mixture was stirred for 30 min and then 4-(4-methoxy-3-methylphenyl)cyclohexanone (14.5 g, 66.6 mmol) was added in portions over 5 min (exothermic to 7.3°C). The 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 H ₂ O (400 ml) and toluene (400 ml). The toluene layer was washed (400 ml H ₂ O), dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give 1methoxy-4-(4-(methoxymethylene)cyclohexyl )-2-methylbenzene (15.6 g, 95%) as a pale golden oil. 1H NMR (400 MHz, DMSO-d6): δ 6.99-6.94 (m, 2H), 6.80 (d, 1H), 5.87 (s, 1H), 3.73 (s, 3H ), 3.48 (s, 3H), 2.782.71 (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), 1.721.63 (m, 1H), 1.38-1.23 (m, 2H); LCMS: 247.1 [M+H] ⁺ .

Step 5: 4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde.

Formic acid (96%, 12.5 ml, 331 mmol) and then water (2.5 ml, 139 mmol) were added to a solution of 1-methoxy-4-(4-(methoxymethylene)cyclohexyl)-2-methylbenzene (16 .05 g, 65.15 mmol) in toluene (130 ml) under N2. The reaction was heated at 120°C for 2 hours, left to cool to room temperature, and then poured into 350 ml EtOAc and 350 ml H2O. The organic layer was washed with 350 ml H2O, 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.

Step 6: trans-4-(4-methoxy-3-methylphenyl)cyclohexanecarbaldehyde.

Aqueous sodium hydroxide (3.2 M, 31 mL, 99 mmol) was added to the crude mixture from Step 5 (14.68 g, 63.19 mmol), toluene (60 mL) and ethanol (250 mL) at room temperature. The reaction mixture was stirred for 5.5 hours (equilibrium observed by NMR) and then poured into 350 ml H ₂ O and 350 ml EtOAc. The organic layer was washed with 350 ml H2O and the aqueous layers were back extracted with 150 ml EtOAc. The combined extracts were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by silica gel chromatography (0-5% EtOAc in hexanes) to give trans-4-(4-methoxy-3methylphenyl)cyclohexanecarbaldehyde (10.17 g, 69% ) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 7.01-6.97 (m, 2H), 6.82 (d, 1H), 3.74 (s, 3H ), 2.41-2.27 (m, 2H), 2.12 (s, 3H), 2.03-1.96 (m, 2H), 1.87-1.80 (m, 2H), 1.51-1.39 (m, 2H), 1.35-1.23 (m, 2H); LCMS: 233.0 [M+H]+.

Intermediate 2.

4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

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Step 1: ethyl 4-hydroxy-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate.

n-Butyllithium (2.5 M in hexanes, 60 ml, 150.0 mmol) was added dropwise to a solution of 4-bromo-1methoxy-2-methylbenzene (27.78 g, 138.2 mmol) in THF (300 ml) at -78°C. The mixture was stirred at -78°C for 1 hour and then added dropwise to a solution of ethyl 4-oxocyclohexanecarboxylate (22.34 g, 131.3 mmol) and THF (300 ml) at -78°C. The reaction mixture was stirred at -78°C for 2 hours, added to saturated NH ₄ Cl (600 ml) and then extracted with EtOAc (2x600 ml). The combined organic extracts were washed (400 ml water followed by 400 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give ethyl 4-hydroxy-4-(4-methoxy-3methylphenyl)cyclohexanecarboxylate (18.9 g, 45%) as a yellow oil. ^1H NMR (400 MHz, DMSO- _d6 ): δ 7.11-7.26 (m, 2H), 6.75-6.84 (m, 1H), 4.59-4.64 (m, 1H), 3.98-4.11 (m, 2H), 3.72 (s, 3H), 2.25-2.39 (m, 1H), 2.07-2.13 (s, 3H) , 1.77-1.93 (m, 3H), 1.42-1.75 (m, 5H), 1.11-1.23 (m, 3H); LCMS: 275.2 [M-OH] ⁺ .

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

Boron trifluoride diethyl etherate (24.85 g, 84.03 mmol) was added to a solution of ethyl 4-hydroxy-4-(4methoxy-3-methylphenyl)cyclohexanecarboxylate (18.90 g, 64.64 mmol), allyltrimethylsilane (11.82 g, 103.42 mmol) and CH ₂ Cl ₂ (400 ml) at -78°C. The mixture was stirred at -78°C for 1 hour, stirred at room temperature overnight, and then added to brine (200 ml) and CH ₂ Cl ₂ (200 ml). The organic layer was separated, washed (2x200 ml saturated NaHCO3 and then 200 ml brine), dried (Na ₂ SO ₄ ), filtered and then concentrated. The crude material was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give ethyl 4-allyl-4-(4-methoxy-3methylphenyl)cyclohexanecarboxylate (15 g, 71%) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.00-7.10 (m, 2H), 6.76 (d, 1H), 5.26-5.50 (m, 1H), 4.81- 4.98 (m, 2H), 4.15 (q, 0.5H), 4.03 (q, 1.5H), 3.81 (s, 3H), 2.26-2.42 (m, 3H), 2.21 (s, 3H), 2.15 (d, 1.5H), 1.98 (d, 0.5H), 1.75-1.88 (m, 2.5H), 1 .60-1.72 (m, 0.5H), 1.33-1.55 (m, 3H), 1.27 (t, 0.8H), 1.18 (t, 2.2H); LCMS: 339.3 [M+Na] ⁺ .

Step 3: ethyl 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexane carboxylate.

Osmium tetroxide (0.1 M in tert-butanol, 7.6 mL, 0.76 mmol) was added to a solution of ethyl 4-allyl-4(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (4.81 g, 15. 2 mmol), 4-methylmorpholine-Nooxinda (2.67 g, 22.8 mmol), CH ₃ CN (100 ml) and H2O (25 ml) at 0°C. The reaction mixture was stirred at room temperature overnight and then saturated Na2SO3 (50 ml) was added. The mixture was stirred at RT for 30 min, concentrated, dissolved in water (80 ml) and then extracted with EtOAc (2x100 ml). The organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 1/1) to give ethyl 4-(2,3-dihydroxypropyl)-4-(4methoxy-3-methylphenyl)cyclohexanecarboxylate (5.23 g, 94%) in in the form of yellow oil. 1H NMR (400 MHz, CDC13): δ 7.05-7.16 (m, 2H), 6.78 (d, 1H), 4.06-4.17 (m, 0.5H), 3.95 -4.05 (m, 1.5H), 3.80 (s, 3H), 3.48-3.66 (m, 1H), 3.18-3.32 (m, 2H), 2.40 -2.53 (m, 2H), 2.27-2.37 (m, 1H), 2.19 (s, 3H), 1.80 (t, 3H), 1.32-1.68 (m , 7H), 1.24 (td, 0.8H), 1.17 (t, 2.2H); LCMS: 373.3 [M+Na] ⁺ .

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

Sodium periodate (3.83 g, 17.90 mmol) was added to a solution of ethyl 4-(2,3-dihydroxypropyl)-4-(4methoxy-3-methylphenyl)cyclohexanecarboxylate (5.23 g, 14.9 mmol), THF (70 ml) and H2O (35 ml) at 0°C. The mixture was stirred at room temperature overnight, added to water (50 ml) and extracted with EtOAc (2x100 ml). The organic layers were combined, washed (80 ml water followed by 80 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1) to give ethyl 4-(4-methoxy-3-methylphenyl)-4-(2oxoethyl)cyclohexanecarboxylate (3.95 g, 82%) as yellow oils 1H NMR (400 MHz, CDCl ₃ ): δ 9.289.42 (m, 1H), 7.07-7.19 (m, 2H), 6.79 (d, 1H), 4.15 (q, 0. 5H), 4.04 (q, 1.5H), 3.82 (s, 3H), 2.41-2.52 (m, 3H), 2.33 (s, 1H), 2.21 (s , 3H), 1.75-1.92 (m, 3H), 1.46-1.63 (m, 4H), 1.23-1.31 (t, 0.5H), 1.19 (t , 2.5H); LCMS: 341.3 [M+Na] ⁺ .

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

Sodium borohydride (704 mg, 18.6 mmol) was added to a solution of ethyl 4-(4-methoxy-3-methylphenyl)-4(2-oxoethyl)cyclohexanecarboxylate (3.95 g, 12.41 mmol) and THF (100 ml) at 0°C. The mixture was stirred at 0°C for 1 hour, stirred at room temperature overnight, and then diluted with water (100 ml). The organic solvent was removed under reduced pressure and the aqueous layer was extracted with CH2Cl2 (2x300 ml). Organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 3/1) to give ethyl 4-(2-hydroxyethyl)-4(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (3.11 g, 67%) as yellow oil. 1H NMR (400 MHz, CDCI3): δ 6.96-7.04 (m, 2H), 6.71 (d, 1H), 4.03-4.12 (q, 0.4H), 3.97 (q, 1.6H), 3.74 (s, 3H), 3.28-3.38 (m, 2H), 2.19-2.39 (m, 3H), 2.14 (s, 3H ), 1.71-1.80 (m, 2H), 1.60-1.70 (m, 2H), 1.28-1.50 (m, 4H), 1.17-1.24 (t , 1H), 1.12 (t, 2H); LCMS: 343.2 [M+Na] ⁺ .

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

A solution of triphenylphosphine (4.60 g, 17.54 mmol) and CH2Cl2 (20 ml) was added dropwise to a solution of ethyl 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (2.81 g, 8.77 mmol), CBr ₄

- 67 047314 (4.36 g, 13.16 mmol) and CH2C12 (40 ml) at 0°C. The mixture was stirred at 0°C for 1 hour, stirred at room temperature overnight, and then concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give ethyl 4-(2-bromoethyl)-4-(4-methoxy-3methylphenyl)cyclohexanecarboxylate (2.62 g, 77%) as yellow oils 1H NMR (400 MHz, CDC13): δ 6.96-7.08 (m, 2H), 6.77 (d, 1H), 4.15 (q, 0.3H), 4.03 (q, 1 ,7H), 3.81 (s, 3H), 2.91-3.06 (m, 2H), 2.24-2.41 (m, 3H), 2.15-2.24 (s, 3H ), 1.95-2.06 (m, 2H), 1.77-1.87 (m, 2H), 1.34-1.53 (m, 4H), 1.27 (t, 1H), 1.18(t, 2H); LCMS: 405.1 [M+Na]+.

Step 7: Ethyl 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxylate.

Lithium diisopropylamide (2 M in THF, 4.8 mL, 9.60 mmol) was added dropwise to a solution of ethyl 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarboxylate (1.81 g, 4 .72 mmol), HMPA (4.23 g, 23.61 mmol) and THF (90 ml) at -78°C. The mixture was stirred at -78°C for 3 hours, added to saturated NH ₄ Cl (90 ml) and then extracted with EtOAc (2x150 ml). The combined organic layers were washed (100 ml H2O followed by 100 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 30/1) to give ethyl 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxylate (1.17 g, 82% ) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 6.98-7.05 (m, 2H), 6.69 (d, 1H), 4.05 (q, 2H), 3.73 (s, 3H), 2.14 (s, 3H), 1.70-1.87 (m, 12H), 1.18 (t, 3H); LCMS: 303.3 [M+H]+.

Step 8: (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanol.

Diisobutylaluminum hydride (1 M in toluene, 14 mL, 14.0 mmol) was added to a solution of ethyl 4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carboxylate (1.64 g, 5.42 mmol ) and CH ₂ Cl ₂ (100 ml) at 78°C. The mixture was stirred at -78°C for 1 hour, stirred at RT for 2 hours and then added to ice-cold H2O (80 ml). The pH was adjusted (pH = 6) with 1 N HCl and the mixture was filtered. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2x200 ml). The combined organic layers were washed (100 ml water followed by 100 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 10/1) to give (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanol (1.22 g, 82 %) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 6.99-7.07 (m, 2H), 6.64-6.72 (m, 1H), 3.73 (s, 3H), 3.25 (s , 2H), 2.14 (s, 3H), 1.69-1.81 (m, 6H), 1.40-1.50 (m, 6H); LCMS: 261.2 [M+H] ⁺ .

Step 9: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde.

Pyridinium chlorochromate (1.03 g, 4.78 mmol) was added to a mixture of (4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methanol (621 mg, 2.39 mmol), SiO ₂ (1.93 g, 32.19 mmol) and CH ₂ Cl ₂ (120 ml). The mixture was stirred at RT for 2 hours, filtered through a neutral alumina plug and then concentrated to give 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (601 mg, 93 %) as a white solid. 1H NMR (400 MHz, CDC13): δ 9.48-9.56 (s, 1H), 7.06-7.11 (m, 2H), 6.72-6.78 (m, 1H), 3 .81 (s, 3H), 2.22 (s, 3H), 1.83-1.91 (m, 6H), 1.71-1.80 (m, 6H); LCMS: 259.3 [M+H]+.

The intermediate below was synthesized from 5-bromo-A,A-dimethylpyridin-2-amine by the procedures described for intermediate 2._____________________________________________

Prom. conn. Structure Name [M+N] ⁺ 2.01 l J 1 /7?/l7//c-4-(6-(dimethylamino)pyridin3-yl)cyclohexanecarbaldehyde 259.2

Alternative conditions: Stage 2: 0°C, overnight; stage 3: K ₂ OsO ₄ -2H ₂ O; stage 7: -78°C, 1 hour, then kt., overnight.

Step 9: oxalyl chloride, DMSO, Et ₃ N, -78°C.

Intermediate 3.

4-(4-Methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

Oh oh

Step 1: 1-(1,3-dioxoisoindolin-2-yl)-4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate.

N,N-Diisopropylcarbodiimide (17.98 g, 142.5 mmol) was added to a solution of 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (25 g, 117.8 mmol), 2hydroxyisoindoline-1,3 -dione (19.22 g, 117.8 mmol), DMAP (4.32 g, 35.3 mmol) and CH2C12 (500 ml) at room temperature under N2 atmosphere. The mixture was stirred at RT overnight, washed with H2O (300 mlx2), dried (Na2SO4), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc: 10/1 - 2/1) to give 1 -(1,3-dioxoisoindolin-2-yl)-4-68 047314 methylbicyclo[2.2.2]octane-1,4-dicarboxylate (23 g) as a white solid. 1H NMR (400 MHz, CDCl ₃ ): δ 7.88 (d, 2H), 7.78 (d, 2H), 3.68 (s, 3H), 2.10-2.04 (m, 6H) , 1.93-1.87 (m, 6H); LCMS: 358.1 [M+H]+.

Step 2a: (4-methoxy-3,5-dimethylphenyl)magnesium lithium bromide chloride.

Magnesium (2.37 g, 97.6 mmol) and dry LiCl (4.14 g, 97.6 mmol) were weighed into an oven-dried 250 mL 2-neck flask connected to a dual manifold. The flask was sealed, evacuated and refilled with N2 (3 times). Tetrahydrofuran (70 ml) was added, the mixture was stirred for 15 min, and then DIBAL-H (1 M in toluene, 1.30 ml) was added dropwise at room temperature. The reaction mixture was stirred for 15 min, cooled to 0° C, and then a solution of 5-bromo2-methoxy-1,3-dimethylbenzene (14 g, 65.09 mmol) and THF (70 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours to give (4-methoxy-3,5-dimethylphenyl)magnesium lithium bromide chloride as a gray solution in THF (~140 ml).

Step 2b: bis(4-methoxy-3,5-dimethylphenyl)zinc.

Zinc(II) chloride (1 M THF, 39 ml) was added dropwise to a THF solution of (4-methoxy-3,5dimethylphenyl)magnesium lithium bromide chloride (~140 ml) at room temperature. The mixture was stirred at room temperature for 1 h to obtain bis(4-methoxy-3,5-dimethylphenyl)zinc as a gray solution in THF (~180 ml).

Step 2c: methyl 4-(4-methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octane-1-carboxylate.

A THF solution of bis(4-methoxy-3,5-dimethylphenyl)zinc (~180 ml) was added to a solution of 1-(1,3dioxoisoindolin-2-yl)-4-methylbicyclo[2.2.2]octane-1,4-dicarboxylate (4.9 g, 13.71 mmol), 2-methyl-6(6-methyl-2-pyridyl)pyridine (1.52 g, 8.23 mmol), Ni(acac)2 (1.76 g, 6.86 mmol) and DMF (50 ml) at RT. The mixture was stirred at RT overnight, concentrated to remove organic solvent, and then diluted with EtOAc (500 ml). The organic layer was washed with water (200 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 50/1) to give methyl-4-(4-methoxy-3 ,5-dimethylphenyl)bicyclo[2.2.2]octane-1carboxylate (2.3 g) as a white solid. LCMS: 303.2 [M+H]+

Step 3: (4-(4-methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octan-1-yl)methanol.

DIBAL-H (1 M in toluene, 34 ml) was added to a solution of methyl 4-(4-methoxy-3,5dimethylphenyl)bicyclo[2.2.2]octane-1-carboxylate (3.4 g, 11.24 mmol) and CH ₂ Cl ₂ (30 ml) at -78°C. The mixture was left to warm to RT, stirred at RT overnight, poured into saturated potassium sodium tartrate solution (100 ml), diluted with CH2Cl2 (100 ml), and then stirred at RT for 3 hours The aqueous phase was extracted with CH ₂ Cl ₂ (50 mlx2). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 2/1) to give (4-(4-methoxy-3 ,5dimethylphenyl)bicyclo[2.2.2]octan-1-yl)methanol (2.3 g, 74%) as a brown-black solid. 1H NMR (400 MHz, CDCl ₃ ): δ 6.95 (s, 2H), 3.71 (s, 3H), 3.33 (s, 2H), 2.27 (s, 6H), 1.84 -1.80 (m, 6H), 1.56-1.52 (m, 6H); LCMS: 275.2 [M+H]+.

Step 4: 4-(4-methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde.

Pyridinium chlorochromate (3.61 g, 16.76 mmol) and SiO ₂ (6.80 g, 113.16 mmol) were added to the (4-methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octane solution -1-yl)methanol (2.3 g, 8.38 mmol) and CH ₂ Cl ₂ (20 ml) at RT. The mixture was stirred at RT for 2 hours and then filtered through a neutral plug from aluminum oxide. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 4-(4-methoxy-3,5-dimethylphenyl)bicyclo[2.2.2]octane-1carbaldehyde (1.9 g, 74% yield) as a white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 9.46 (s, 1H), 6.95 (s, 2H), 3.59 (s, 3H), 2.18 (s, 6H), 1 .78-1.74 (m, 6H), 1.69-1.64 (m, 6H); LCMS: 273.1 [M+H] ⁺ .

The intermediates below were synthesized from Intermediate 3 (Step 1) and appropriate starting materials based on the procedures described for Intermediate 3.

Prom. conn. Structure Name [M+N] ⁺ 3.0172 O // W ' O / 4-(6-methoxy-5-methylpyride in-3 yl)bicyclo[2.2.2]octane-1-carbaldehyde 260.1 2 ³ gkt^ ⁰ 4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane-1 carbaldehyde 259.3

Alternative conditions: The Grignard reagent from step 2a was used directly in step 2c (without step 2b). Step 2c: ² Fe(acac)3 (1 equiv. to carboxylate), no ligand, DMPU, THF, rt, overnight; ³ Ni(acac)2(1 equiv. to carboxylate), 6,6'-dimethyl-2,2'-dipyridyl (1.3 equiv. to carboxylate), DMF, 0-35°C, 16 h.

Intermediate 2.

4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

- 69 047314

Step 1: 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol.

series were carried out in parallel: n-BuLi (762 ml, 1.90 mol, 2.5 M in n-hexane) was added dropwise over 1 h to a solution of 4-bromo-1-methoxy-2-methylbenzene (333 g, 1 .66 mol) and dry THF (2 l) at 60°C in an N2 atmosphere. The reaction mixture was stirred at -60°C for 1 hour, and then a solution of 1,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and dry THF (1 L) was added dropwise. within 45 min. The reaction mixture was stirred at -60°C for 1 hour, and then 3 batches were poured into us. aq. NH ₄ Cl (3 l). This mixture was extracted with EtOAc (5 lx2). The combined organic layers were washed with brine (5 L), dried over Na ₂ SO ₄ , filtered, concentrated, and then triturated in n-hexane (1.2 L) at room temperature overnight. The mixture was filtered and the filter cake was washed with cold n-hexane (200 mlx2) and then dried in vacuo to give 8-(4-methoxy-3-methylphenyl)-1,4dioxaspiro[4.5]decan-8-ol (1100 g, 82 %) as a white solid. 1H NMR (400 MHz, CDCl ₃ ): δ 7.30-7.20 (m, 2h), 6.74 (d, 1H), 4.02-3.87 (m, 4H), 3.78 ( s, 3H), 2.18 (s, 3H), 2.15-2.00 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 1H).

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

series were carried out in parallel: BF ₃ -Et ₂ O (376.95 g, 2.65 mol) was added to a solution of 8-(4-methoxy3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (275 g , 0.99 mol), allyltrimethylsilane (180.62 g, 1.58 mol) and dry DCM (3 L) at -65°C under N2 atmosphere. The reaction mixture was stirred at -65°C for 1 hour, and then 4 batches were carefully poured into us. aq. NaHCO ₃ (10 l). This mixture was extracted with DCM (5 lx3). The combined organic layers were washed with brine (5 L), dried over Na ₂ SO ₄ , filtered and concentrated to give 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4dioxaspiro[4.5]decane (1350 g) in the form of a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.17-7.01 (m, 2H), 6.85-6.75 (m, 1H), 5.53-5.37 (m, 1H), 5.01-4.85 (m, 2H), 3.99-3.87 (m, 4H), 3.82 (s, 3H), 2.37-2.29 (m, 1h), 2, 28-2.21 (m, 5H), 2.20-2.10 (m, 2H), 1.82-1.71 (m, 2H), 1.70-1.52 (m, 3H).

Step 3: 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone.

series were carried out in parallel: water (450 ml) and then formic acid (285.95 g, 5.95 mol) were added to a solution of 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[ 4.5]decane (450 g) and THF (1.8 l) at room temperature. The reaction mixture was refluxed overnight, left to cool to room temperature, and then 3 batches were poured into us. aq. NaHCO ₃ (3 l). This mixture was extracted with EA (3 lx3). The combined organic layers were washed with brine (3 L), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 1/0-50/1) to give 4-allyl-4 -(4-methoxy-3-methylphenyl)cyclohexanone (800 g, 69.3% in 2 steps) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.16-7.06 (m, 2H), 6.80-6.73 (m, 1H), 5.48-5.30 (m, 1H), 4.96-4.79 (m, 2H), 3.77 (s, 3H), 2.48-2.35 (m, 2H), 2.32-2.05 (m, 9H), 1, 89-1.77 (m, 2H).

Step 4: 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile.

series were carried out in parallel: tert-BuOK (299.69 g, 2.67 mol) was added portionwise over 1 h (maintaining internal temperature <5°C) to a solution of 4-allyl-4-(4-methoxy-3methylphenyl)cyclohexanone (230 g, 890.25 mmol), Tos-MIC (260.72 g, 1.34 mol) and DME (2 L) at 0°C under N ₂ atmosphere. The mixture was stirred at room temperature for 2 hours, and then 3 batches were poured into us. aq. NH ₄ Cl (5 l). The mixture was extracted with EtOAc (5 Lx2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 1/0-50/1) to give 4-allyl-4-(4 -methoxy-3methylphenyl)cyclohexanecarbonitrile (508 g, 70.6%) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.13-6.99 (m, 2H), 6.83-6.75 (m, 1H), 5.51-5.31 (m, 1H), 5.03-4.85 (m, 2H), 3.84 (s, 3h), 2.58-2.48 (m, 1H), 2.38-2.02 (m, 7H), 1. 98-1.79 (m, 2H), 1.78-1.56 (m, 3H), 1.54-1.40 (m, 1H).

Step 5: 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile.

series were carried out in parallel: NMO (242.66 g, 2.07 mol), and then K ₂ OsO ₄ -2H ₂ O (7.63 g, 20.71 mmol) was added to a solution of 4-allyl-4-(4- methoxy-3-methylphenyl)cyclohexanecarbonitrile (186 g, 690.47 mmol), acetone (2 L) and H ₂ O (250 ml) at 0°C. The reaction was left to warm to room temperature and stirred for 2 hours. 3 batches were poured into us. aq. Na ₂ SO ₃ (4 L) and the mixture was extracted with EtOAc (3 Lx2). The combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 5/1-1/2) to give 4-(2,3-dihydroxypropyl )-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (600 g, 95.4%) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.21-7.01 (m, 2H), 6.87-6.74 (m, 1H), 3.83 (s, 3H), 3.65- 3.49 (m, 1H), 3.35-3.17 (m, 2H), 2.60-2.45 (m, 1H), 2.41-2.11 (m, 5H), 2. 01-1.81 (m, 4h), 1.79-1.38 (m, 6H).

Step 6: 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile.

- 70 047314 series were carried out in parallel: NaIO ₄ (169.20 g, 791.05 mmol) was added portionwise over 30 min (maintaining internal temperature <5°C) to a solution of 4-(2,3-dihydroxypropyl)-4- (4-methoxy3-methylphenyl)cyclohexanecarbonitrile (200 g, 659.21 mmol), THF (2 L) and H ₂ O (1 L) at 0°C. The mixture was stirred at room temperature for 3 hours, and then 3 batches were poured into water (2 L). The mixture was extracted with EtOAc (2 Lx2). The combined organic layers were washed with brine (2 L), dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(4-methoxy-3-methylphenyl)-4-(2oxoethyl)cyclohexanecarbonitrile (510 g) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ): δ 9.439.22 (m, 1H), 7.20-6.99 (m, 2H), 6.87-6.71 (m, 1H), 3.82 ( s, 3H), 2.63-2.48 (m, 2H), 2.46-2.36 (m, 1H), 2.332.13 (m, 4H), 2.02-1.71 (m, 5H), 1.71-1.57 (m, 2H).

Step 7: 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile.

series were carried out in parallel: NaBH ₄ (35.55 g, 939.73 mmol) was added to a solution of 4-(4-methoxy3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile (170 g) and THF (1.7 l) at 0°C in atmosphere N2. The mixture was stirred at room temperature for 3 hours, and then 3 batches were poured into ice water (3 L). This mixture was extracted with EtOAc (1.5 Lx2). The combined organic layers were washed with brine (2 L), dried over Na ₂ SO ₄ , filtered, concentrated to give 4-(2-hydroxyethyl)-4-(4-methoxy-3methylphenyl)cyclohexanecarbonitrile (495 g) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.18-6.97 (m, 2H), 6.88-6.71 (m, 1H), 3.85-3.78 (m, 3H), 3.76-3.70 (m, 1H), 3.44-3.33 (m, 2H), 2.71-2.69 (m, 0.5H), 2.60-2.48 (m , 0.5H), 2.37-2.35 (m, 0.5H), 2.27-2.19 (m, 3H), 2.14-2.12 (m, 0.5H), 1 .96-1.79 (m, 5H), 1.78-1.61 (m, 3H), 1.58-1.45 (m, 1H).

Step 8: 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile.

series were carried out in parallel: a solution of PPh ₃ (316.62 g, 1.21 mol) and DCM (1 L) was added dropwise over 1 hour to a solution of 4-(2-hydroxyethyl)-4-(4-methoxy-3- methylphenyl)cyclohexanecarbonitrile (165 g), CBr ₄ (300.24 g, 905.37 mmol) and DCM (1.5 L) at 0°C under N2 atmosphere. The mixture was stirred at room temperature for 1.5 hours, combined with the other 2 batches and concentrated. The crude product was triturated in MTBE (5 L) at room temperature overnight. The solid was removed by filtration, the cake was washed with MTBE (500 mlx2), the filtrate was concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 30/1) to give 4-(2-bromoethyl)-4-(4-methoxy- 3methylphenyl)cyclohexanecarbonitrile (530 g, 80%) as a white solid. 1H NMR (400 MHz, CDCl ₃ ): δ 7.11-6.96 (m, 2H), 6.86-6.73 (m, 1H), 3.87-3.73 (m, 3H), 3.09-2.93 (m, 2H), 2.78-2.68 (m, 0.5H), 2.62-2.50 (m, 0.5H), 2.38-2.34 (m, 1H), 2.28-2.18 (m, 3H), 2.17-2.10 (m, 2H), 2.08-1.99 (m, 1H), 1.99-1 .79 (m, 3H), 1.77-1.45 (m, 3H).

Step 9: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbonitrile.

series were carried out in parallel: LDA (420 ml, 840 mmol, 2 M in THF) was added dropwise over 1 h to a solution of 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (143 g, 425.26 mmol), HMPA (381.03 g, 2.13 mol) and THF (1430 ml) at -65°C under N2 atmosphere. The mixture was stirred at -65°C for 3 hours and then 3 batches were poured into us. aq. NH ₄ Cl (5 l). This mixture was extracted with EtOAc (3 lx2). The combined organic layers were washed with water (3 L), washed with brine (3 L), dried over Na ₂ SO ₄ , filtered, concentrated and then triturated in EA:hexane (1:30, 775 ml) at r.t. . all night long. The mixture was filtered and the filter cake was washed with EA:hexane (1:30, 150 ml) and dried in vacuo to give 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1carbonitrile (240 g, 73%) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ): δ 7.13-6.98 (m, 2H), 6.83-6.73 (m, 1H), 3.82 (s, 3H), 2.22 ( s, 3H), 2.12-1.98 (m, 6H), 1.94-1.80 (m, 6H).

Step 10: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde.

series were carried out in parallel: DIBAL-H (1 M PhMe, 830 ml, 830 mmol) was added to a solution of 4(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbonitrile (106 g, 415.11 mmol ) in DCM (1 L) at 65°C under N2 atmosphere. The mixture was stirred at -65°C for 1 hour and then 3 batches were poured into us. aq. NaK tartrate (3 L) and diluted with DCM (1.5 L). This mixture was stirred at room temperature for 3 hours. The organic layer was separated and the aqueous phase was extracted with DCM (2 Lx2). The organic layers were combined, washed with brine (3 L), dried over Na ₂ SO ₄ , filtered and concentrated to give 4(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (336 g) in as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.50-9.43 (m, 1H), 7.11-7.00 (m, 2H), 6.83-6.79 (m, 1H) , 3.77-3.68 (m, 3H), 2.18-2.02 (m, 3H), 1.82-1.72 (m, 6H), 1.71-1.60 (m, 6H).

Step 11: Potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanesulfonate.

series were carried out in parallel: aqueous potassium metabisulfite (2 M, 54 ml, 108 mmol) was added over 10 min to a solution of 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (56 g) in THF (300 ml) at 45°C. The mixture was stirred for 3.5 hours at 45°C, left to cool to room temperature, and then stirred at room temperature overnight. 6 batches were filtered, the filter cake was washed with PE (400 ml) and dried in vacuum to obtain potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methanesulfonate (381 g, 81% for 2 stages) as a white solid. 1H NMR (400 MHz, DMSO-d6) 7.12-6.97 (m, 2H), 6.88-6.71 (m, 1H), 4.51 (d, 1H), 3.73 (s , 3H), 3.56 (d, 1H), 2.11 (s, 3H), 1.88-1.56 (m, 12H).

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Step 12: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde.

series were carried out in parallel: saturated aq. Na ₂ CO ₃ (300 ml) was added to a mixture of potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanesulfonate (63.5 g, 167.76 mmol) and DCM (300 ml) at room temperature under N ₂ atmosphere. The mixture was stirred for 1 hour and then 6 batches were poured into a mixture of DCM (1500 ml) and H2O (1500 ml). The organic layer was separated and the aqueous phase was extracted with DCM (1500 mlx3). The combined organic layers were washed with brine (2 L), dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (240.3 g, 92 %) as a white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 9.52-9.41 (m, 1H), 7.14 - 7.02 (m, 2H), 6.84-7.80 (m, 1H ), 3.73 (s, 3H), 2.12 (s, 3H), 1.83-1.72 (m, 6H), 1.71-1.56 (m, 6H); LCMS: 259.1 [M+H]+

Intermediate 4.

(2-Aminopyridin-4-yl)boronic acid

Potassium acetate (47.93 g, 488.4 mmol), Pd(OAc) ₂ (1.04 g, 4.62 mmol) and 2(dicyclohexylphosphino)biphenyl (3.34 g, 9.54 mmol) were added to the solution 4-bromopyridin-2-amine (50 g, 289 mmol), bis(pinacolato)diborone (110.1 g, 433.5 mmol) and dioxane (1000 ml) at RT. The mixture was degassed with 3 cycles of vacuum/N ₂ , heated at 100°C overnight, cooled to room temperature, and then poured into water (1000 ml) to obtain an aqueous suspension. This suspension was washed with EtOAc (500 mlx3) and filtered. The filter cake was washed with H2O (100 ml) and dried in vacuo to give (2aminopyridin-4-yl)boronic acid (25 g, 62%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.57 (d, 1H), 7.09 (s, 1H), 7.01 (d, 1H); LCMS: 139.0 [M+H]+.

Intermediate 5.

4-(1-(1,1,1-trifluoro-methylpropan-yl-pyrazolA-yl-iridin-amine

A mixture of (1,1,1-trifluoro-2-methylpropan-2-yl)hydrazine hydrochloride (27 g, 151.19 mmol), 2-bromoaldehyde (27.4 g, 181.43 mmol) and HOAc (400 ml) was stirred at kt all night. The reaction mixture was adjusted to pH=7 with 1 M NaOH (~400 ml) and then extracted with EtOAc (300 mlx3). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1^20/1) to give 4-bromo-1 -(1,1,1-trifluoro-2-methylpropan-2-yl)N-pyrazole (18 g, 46%) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.64 (s, 1H), 7.52 (s, 1H), 1.81 (s, 6H); LCMS: 257.0 [M+H]+.

Intermediate 6.

4-(2-(tert-Butyl)thiazol-5-yl)pyridin-2-amine

Step 1: 2-(tert-butyl)thiazole.

2-Bromo-1,1-dimethoxyethane (45.06 g, 266.6 mmol) was added to a solution of 2,2-dimethylpropanethioamide (25.0 g, 213 mmol), para-TsOH (4.59 g, 26.6 mmol) and AcOH (50 ml) at room temperature. The mixture was degassed by 3 cycles of vacuum/N ₂ , stirred at 120°C overnight, cooled to room temperature, poured into water (100 ml), and then extracted with ethyl acetate ( 50 mlx3). The organic layers were combined, washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(tert-butyl)thiazole (30 g) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.71 (d, 1H), 7.19 (d, 1H), 1.48 (s, 9H); LCMS: 142.0 [M+H]+.

Step 2: 5-bromo-2-(tert-butyl)thiazole.

N-Bromosuccinimide (75.61 g, 424.8 mmol) was added to a solution of 2-(tert-butyl)thiazole (30 g, 212.4 mmol) and CHCl ₃ (300 ml) at 0°C. The mixture was degassed with 3 cycles of vacuum/ _N2 , stirred at room temperature overnight, diluted with EtOAc (100 ml), and then washed with saturated NaHCO ₃ (30 mlx3). The organic layer _was dried over ( _Na2SO4 ), filtered, concentrated and then purified by column chromatography (petroleum ether/ethyl acetate: 10/3^2/1) to give 5-bromo-2-(tert-butyl)thiazole ( 30 g, 64%) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.57 (s, 1H), 1.43 (s, 9H); LCMS: 220.2 [M+H]+.

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Step 3: 4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-amine.

Pd(dppf)Cl ₂ (5.32 g, 7.27 mmol) was added to a mixture of 5-bromo-2-(tert-butyl)thiazole (16 g, 72.68 mmol), Cs ₂ CO ₃ (71.05 g, 218.05 mmol), intermediate 4 (15.04 g, 109.03 mmol), dioxane (40 ml) and H2O (10 ml) at room temperature under N2. The reaction mixture was degassed with 3 cycles of vacuum/ _N2 , stirred at 80°C overnight, cooled to room temperature, poured into water (100 ml), and then extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/3 - 1/1) to give 4-(2- (tert-butyl)thiazol-5-yl)pyridin-2-amine (8.1 g, 48%) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.11 (s, 1H), 7.91 (d, 1H), 6.78 (d, 1H), 6.60 (s, 1H), 6.03 (s, 2H), 1.40 (s, 9H); LCMS: 234.1 [M+H]+.

Intermediate 7.

4-(2-(tert-Butyl)oxazol-4-yl)pyridin-2-amine

Step 1: 2-bromo-N-methoxy-N-methylisonicotinamide.

A mixture of 2-bromopyridine-4-carboxylic acid (50 g, 247.52 mmol) and CDI (42.14 g, 259.9 mmol) in CH ₂ Cl ₂ (500 ml) was stirred at 25°C for 0.5 h. N-methoxymethanamine hydrochloride (48.29 g, 495.4 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-cold H ₂ O (1000 ml) and extracted with EtOAc (500 mlx2). The organic layer was washed with saturated NaHCO ₃ (200 ml) and brine (300 ml) and then concentrated to give 2-bromo-H-methoxy-Nmethylpyridin-4-carboxamide (60 g, crude) as a brown oil.

Step 2: 1-(2-bromopyridin-4-yl)ethanone.

A solution of methylmagnesium bromide (3 M in ether, 204 ml) was added dropwise at 40°C to a solution of 2bromo-N-methoxy-N-methylpyridine-4-carboxamide (60 g, crude) in THF (500 ml). The mixture was stirred at room temperature for 4 hours, poured into aq. NH ₄ Cl (300 ml) and then extracted with EA (200 mlx3). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , concentrated and then triturated (PE, 200 ml) to give 1-(2-bromo-4-pyridyl)ethanone (40 g, 81 % in two stages) as a white solid. 1H NMR (400 MHz, CDCl ₃ ): δ 8.56 (d, 1H), 7.91 (s, 1H), 7.63 (d, 1H), 2.62 (s, 3H).

Step 3: 2-bromo-1-(2-bromopyridin-4-yl)ethanone.

Bromine (12.4 ml, 240 mmol) was added dropwise to a solution of 1-(2-bromopyridin-4-yl)ethanone (30 g, 149.98 mmol) and HBr (400 ml, 30% in AcOH) at rt. t. The mixture was stirred at room temperature overnight, poured into MTBE (1000 ml) and then filtered. The filter cake was poured into water (300 ml) and EtOAc (300 ml). The mixture was adjusted to pH=8 with saturated NaHCO ₃ and extracted with EtOAc (500 mlx2). The combined organic layers were dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by trituration (MTBE, 150 ml) to give 2-bromo-1-(2-bromopyridin-4-yl)ethanone (36 g, 86 %) as a yellow solid. 1H NMR (400 MHz, CDCl ₃ ): δ 8.60 (d, 1H), 7.95 (s, 1H), 7.72 (d, 1H), 4.38 (s, 2H); LCMS: 278.0 [M+H]+.

Step 4: 4-(2-bromopyridin-4-yl)-2-(tert-butyl)oxazole.

Silver trifluoromethanesulfonate (27.63 g, 107.6 mmol) was added to a mixture of 2-bromo-1-(2bromopyridin-4-yl)ethanone (15 g, 53.8 mmol), pivalamide (7.07 g, 69.9 mmol) and EtOAc (400 ml) at room temperature. The reaction was heated at 80°C for 22 hours, cooled to room temperature, and then poured into H2O (100 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mlx2). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate = 50/1^20/1) to give 4-(2-bromopyridin-4-yl)-2 -(tert-butyl)oxazole (12.5 g, 85%) as a brown oil. 1H NMR (400 MHz, CDCl ₃ ): δ 8.35 (d, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H), 1.44 (s, 9H); LCMS: 281.1 [M+H]+.

Step 5: 4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-amine.

Lithium bis(trimethylsilyl)amide (1 M in THF, 56.8 mL, 56.8 mmol) was added dropwise to a solution of 4-(2-bromopyridin-4-yl)-2-(tert-butyl)oxazole (14, 5 g, 51.6 mmol), XPhos (2.46 g, 5.2 mmol), Pd ₂ (dba) ₃ (2.36 g, 2.58 mmol) and dioxane (400 ml) at room temperature. in an N ₂ atmosphere. The mixture was degassed with 3 vacuum/ _N2 cycles, heated at 100°C overnight, cooled to room temperature, poured into H2O (500 ml), and then extracted with EtOAc (200 ml x 3). The organic layers were dried over Na ₂ SO ₄ , filtered and then concentrated. The crude material was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10/1^0/1) to obtain a substance with impurities, which was triturated with PE/EA = 5:1 (30 ml), filtered and then dried to give 4-(2-(tert-butyl)oxazol-4yl)pyridin-2-amine (7.15 g, 63%) as a yellow solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.53 (s, 1H), 7.89 (d, 1H), 6.82 (s, 1H), 6.78 (d, 1H), 5 .99 (s, 2H), 1.35 (s, 9H); LCMS: 218.1 [M+H] ⁺ .

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Intermediate 8.

4-(1 -(tert-Butyl)-1H-pyrazol-4-yl)pyridin-2-amine

2-Methyltetrahydrofuran (10 ml), Pd(dppf)Cl ₂ and then aq. K ₂ CO ₃ (3 M, 10 ml, 30 mmol) was added to 4-bromopyridin-2-amine (1.87 g, 10.8 mmol) and 1-(tert-butyl)-4-(4,4, 5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-III-pyrazole (2.50 g, 10.0 mmol) into a 40 ml vessel. The reaction was degassed with 3 cycles of vacuum/f, heated at 50°C for 21 hours, and then left to cool to room temperature. The layers were separated and the organic layer was washed with saturated aq. NaK tartrate (25 ml) and then washed with saline (25 ml). The aqueous layers were back-extracted with 2-methyltetrahydrofuran (25 ml). The combined organics were dried ( _MgSO4 ), filtered, concentrated and then dried in vacuo for 1 hour. The crude and MTBE suspension (25 ml) was refluxed for 2 hours, left to cool to room temperature overnight, and then filtered. The filter cake was washed with MTBE (2x3 ml) and then dried in vacuo to give 4-(1-(tert-butyl)-Spirazol-4-yl)pyridin-2-amine (1.15 g, 53%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.27 (s, 1H), 7.86-7.82 (m, 2H), 6.74 (d, 1H), 6.61 (s , 1H), 5.77 (s, 2H), 1.54 (s, 9H); LCMS: 217.1 [M+H]+.

Intermediate 9.

4-(1 -(tert-Pentyl)-III-pyrazol-4-yl)pyridin-2-amine

Step 1: 4-bromo-1-(tert-pentyl)-III-pyrazole.

Concentrated sulfuric acid (3.9 mL, 74.8 mmol) was added to a solution of 4-bromo-Spirazole (10 g, 68.04 mmol) and 2-methylbutan-2-ol (74 mL) at room temperature. The mixture was heated at 100°C for 48 h, concentrated, diluted with H ₂ O (20 ml) and then extracted with ethyl acetate (20 ml). The organic layer was washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate=1/0^200/1) to give 4-bromo-1- (tert-pentyl)-III-pyrazole (5.3 g, 35%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ): δ 7.49 (s, 1H), 7.48 (s, 1H), 1.90-1.84 (m, 2H), 1.54 (s, 6H) , 0.70 (t, 3H).

Step 2: 4-(1-(tert-pentyl)-III-pyrazol-4-yl)pyridin-2-amine.

Pd(dppf)Cl ₂ (1.45 g, 1.98 mmol) was added to a mixture of 4-bromo-1-(tert-pentyl)-III-pyrazole (8.6 g, 39.61 mmol), intermediate 4 (6.56 g, 47.53 mmol), K ₂ CO ₃ (10.95 g, 79.22 mmol), dioxane (90 ml) and H2O (45 ml) at room temperature under N2 atmosphere. The mixture was degassed with 3 vacuum/ _N2 cycles, heated at 80°C for 4 hours, cooled to room temperature, and then poured into H2O (100 ml). The precipitate was filtered off. The filtrate was diluted with ethyl acetate (200 ml) and H2O (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3x200 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, concentrated and then purified by silica gel chromatography (CH2Cl2/CH3OH=100/1^30/1) to obtain 2.7 g of a red solid containing the impurity . Add HCl in CH3OH (4 M, 30 ml). The solution was stirred at room temperature for 2 hours, concentrated, diluted with ethyl acetate (15 ml), and then stirred overnight. The solids were filtered, washed with ethyl acetate (10 ml) and dried to give 4-(1-(tert-pentyl)-N-pyrazol-4-yl)pyridin-2-amine hydrochloride (3.1 g). This substance was dissolved in H2O (5 ml). Aqueous potassium carbonate (2 M, ~8 ml) was slowly added until pH=9-10. The mixture was extracted with ethyl acetate (20 mlx6). The combined organics were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give 4-(1-(tert-pentyl)-III-pyrazol-4-yl)pyridin-2-amine (2. 35 g, 90%) as an off-white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.24 (s, 1H), 7.84-7.83 (m, 2H), 6.75-6.73 (m, 1H), 6. 60 (s, 1H), 5.74 (s, 2H), 1.87-1.81 (m, 2H), 1.52 (s, 6H), 0.62 (t, 3H); LCMS: 231.2 [M+H]+.

The intermediates below were synthesized using the appropriate alcohol or the appropriate intermediate, following the procedures described for intermediate 9.

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Prom. conn. Structure Name [M+N] ⁺ 9.01 nh ₂ /XL ^N-_ \ 4-(1 -(m/tem-butyl)-1 Η- p irazol-3 yl)pyridin-2-amine 217.1 9.02 ¹ ' ² nh ₂ N C |l J , F 4-(1-(1,1,1-trifluoro-2-methylpropan-2yl)-17/-pyrazol-4-yl)pyridin-2-amine 271.1 9.03 ² nh ₂ N'M η 1 4-(1-(3-ethylpentan-3-yl)-177-pyrazol- 4-yl)pyridin-2-amine 259.1 9.04 ³ nh ₂ ml r— 4-(1-(3-methylpentan-3-yl)-177-pyrazol- 4-yl)pyridin-2-amine 245.1 8 ² nh ₂ and / im ^N 4-( 1 -(from/?eot-butyl)-1H- and irazol-4yl)pyridin-2-amine 217.1

Alternative conditions: Stage 1: 30-90°C, 6-18 hours Stage 2: 90°C, overnight; 1Stage 2 only; ² Isolated by trituration with MTBE followed by purification with sgc; ² Isolated by prep-TLC (100% EtOAc) followed by sgc purification.

Intermediate connection 10.

trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarboxylic acid

Step 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 room temperature in an N2 atmosphere (exothermic effect of the reaction up to 32°C). The reaction mixture was stirred at room temperature for 2 hours and then diluted with diethyl ether (300 ml). The organic layer was washed (2x300 ml 1N HCl followed by 300 ml brine), dried (Na ₂ SO ₄ ), filtered and concentrated to give trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 d) in the form of 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).

Step 2: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid.

Potassium carbonate (58.01 g, 419.7 mmol) in H ₂ O (300 ml) was added to a mixture of trans-tert-butyldimethylsilyl-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g crude, 69.6 mmol ), ethanol (1000 ml) and THF (300 ml) at room temperature in an atmosphere of N ₂ . The reaction mixture was stirred at room temperature for 3 hours, concentrated until 300 ml remained, diluted with brine (600 ml), and then acidified to pH 2-3 with 20% NaHSO4 (550 ml). The aqueous layer was extracted with diethyl ether (800 ml). The organic layer was washed (800 ml brine), dried (Na ₂ SO ₄ ), filtered, concentrated and dried under high vacuum (removing sinalol by-products) to give trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid ( 17.3 g, 96% in 2 stages) as a 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).

Intermediate 11.

trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride

- 75 047314

trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarbonyl chloride.

(Chloromethylene)dimethyliminium chloride (34.02 g, 265.78 mmol) was weighed into a 1000 mL round bottom flask (3-neck) and degassed with vacuum/ _N2 (3x) cycles. Toluene (240 ml) was added to the flask and the mixture was cooled (1.3°C) in an ice bath. Anhydrous potassium carbonate* (68.71 g, 497.14 mmol) and intermediate 10 (34.29 g, 132.69 mmol) were added sequentially to the reaction. The ice bath was removed and the mixture was stirred for 35 minutes. Celite (7 g) was added to the reaction and the reaction mixture was then filtered through Celite (70 g, Chemglass 465 ml fritted glass funnel) with toluene washes (3 x 100 ml). This solution (451 g, 8.5% acid chloride, 100% yield, 72 mg/ml) was used directly in the acylation reaction. ^1H NMR (400 MHz, CDCl ₃ ): δ 3.77-3.68 (m, 1H), 2.83-2.74 (m, 1H), 2.31-2.22 (m, 2H) , 2.09-1.99 (m, 2H), 1.76-1.63 (m, 2H), 1.54-1.42 (m, 2H), 1.02 (s, 9H), 0 .20 (s, 6H). *Potassium carbonate was vacuum dried using a heat gun for ~5 min and then left to cool overnight.

Intermediate connection 12.

2,2-Dimethylazetidin-3-ol hydrochloride

Step 1: 2-cyclopropyl-4-(3-nitrophenyl)oxazole.

A solution of 1-benzhydryl-2,2-dimethylazetidin-3-ol (6.03 g, 22.6 mmol) in CH3OH (90 ml) was degassed with 2 vacuum/ _N2 cycles. Aqueous hydrochloric acid (1.0 N, 22 mL, 22 mmol) was added to the reaction, followed by Pd/C (10 wt%, 2.40 g, 2.25 mmol). The reaction mixture was stirred under H ₂ from a balloon at room temperature for 15 hours, filtered through celite and the filter cake was washed with CH3OH (5x20 ml). The filtrate was concentrated, lyophilized and then dried in vacuo to give 2,2dimethylazetidin-3-ol hydrochloride (1.99 g, 64%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 2H), 6.12 (s, 1H), 4.17 (t, 1H), 3.88 (dd, 1H), 3. 54 (dd, 1H), 1.41 (d, 6H).

Intermediate 13.

-((Methylsulfonyl)methyl)azetidine hydrochloride

Step 1: tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate.

Methanesulfonyl chloride (9.8 g, 85.55 mmol) was added to a solution of tert-butyl-3(hydroxymethyl)azetidine-1-carboxylate (10 g, 53.41 mmol) and Et ₃ N (10.81 g, 106. 8 mmol) in CH ₂ Cl ₂ (100 ml) at 0°C in an N2 atmosphere. The reaction was heated to room temperature, stirred for 2 hours, poured into water (200 ml), and then extracted with CH ₂ Cl ₂ (100 ml x 3). The combined organic layers were washed with saturated NaHCO ₃ (100 ml), washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (PE/EA=4/1 - 3/1 ) to give tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (13 g, 83% yield) as a yellow oil. 1H NMR (400 MHz, CDCl ₃ ): δ 4.36 (d, 2H), 4.06 (t, 2H), 3.78-3.67 (m, 2H), 3.06 (s, 3H) , 2.99-2.87 (m, 1H), 1.44 (s, 9H).

Step 2: tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate.

Sodium thiomethylate (36.5 g, 104.2 mmol, 20% purity) was added to a solution of tert-butyl-3(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (13 g, 44.1 mmol) in DMF (150 ml) at room temperature in an atmosphere of N ₂ . The reaction mixture was stirred overnight, poured into water (300 ml) and then extracted with EtOAc (200 ml x 3). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (PE/EA=20/1 -10/1) to give tert-butyl-3- ((methylthio)methyl)azetidine-1-carboxylate (9.86 g, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl ₃ ): δ 4.08-3.97 (m, 2H), 3.62 (d, 2H), 2.82-2.67 (m, 3H), 2.11 ( s, 3H), 1.44 (s, 9H); LCMS: 218.1 [M+H]+.

Step 3: tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate.

3-Chloroperbenzoic acid (14.90 g, 73.38 mmol, 85% purity) was added portionwise to a solution of tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (8.86 g, 36.69 mmol ) in CH ₂ Cl ₂ (90 ml) at 0°C. The reaction mixture was heated to room temperature, stirred at room temperature for 2 hours, and then filtered. The filtrate was diluted with CH ₂ Cl ₂ (100 ml), washed with saturated K ₂ CO ₃ (100 mlx2), washed with saline

- 76 047314 solution (100 ml), dried over Na2SO4, filtered, concentrated, and then purified by chromatography on silica gel (PE/EA = 60/40) to obtain tert-butyl-3-((methylsulfonyl)methyl)azetidine-1carboxylate (6.5 g, 71%) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 4.08-3.90 (m, 2H), 3.80-3.62 (m, 2H), 3.48 (d, 2H), 3 .08-2.88 (m, 4H), 1.37 (s, 9H); LCMS: 272.0 [M+Na]+

Step 4: 3-((Methylsulfonyl)methyl)azetidine hydrochloride.

A mixture of tert-butyl-3-((methylsulfonyl)methyl)azetidine-1-carboxylate (1 g, 4.01 mmol) and HCl (4 M in EtOAc, 20 ml) was stirred at room temperature for 1 hour, and then concentrated to give 3((methylsulfonyl)methyl)azetidine hydrochloride (650 mg) as a white solid. ^1H NMR (400 MHz, DMSO-d6): δ 9.25 (s, 1H), 9.07 (s, 1H), 4.10-3.98 (m, 2H), 3.91-3, 80 (m, 2H), 3.55 (d, 2H), 3.333.20 (m, 1H), 2.99 (s, 3H); LCMS: 150.1 [M+H]+.

Intermediate 14.

6-(1-(tert-Butyl)-1H-pyrazol-4-yl)pyrimidin-4-amine

4-Amino-6-bromopyrimidine (500 mg, 2.87 mmol), 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-ylfN-pyrazole (898 mg , 3.59 mmol) and 1-1'-bis(diphenylphosphinoferrocene dichloropalladium (II) (105 mg, 0.144 mmol) were weighed in a 20 mL microwave irradiation vessel. 1,4Dioxane (3.92 mL) and aqueous potassium carbonate (2.2 M, 3.92 mL, 8.62 mmol) was added to the vessel. The reaction mixture was heated under microwave irradiation at 150°C for 15 min. The aqueous layer was pipetted off and EtOAc (20 mL) followed by Celite. and Na ₂ SO ₄ was added to the organic layer. The organic layer was filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in CH ₂ Cl ₂ then 0-12% CH ₃ OH in CH ₂ Cl ₂ ) to obtain. 6-(1-(tert-butyl)-1H-pyrazol-4yl)pyrimidin-4-amine (484 mg, 77%) as a purple solid. ^1H NMR (400 MHz, DMSOd6): δ 8.33 ( s, 2H), 7.93 (s, 1H), 6.71 (br, 2H), 6.59 (d, 1H), 1.55 (s, 9H); ]+.

The intermediates below were synthesized from the corresponding amino/halogen(hetero)aromatic starting material and 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-A pyrazole by the procedure described for intermediate 14.

Prom. conn. Structure Name [M+N] ⁺ 14.01 nh ₂ iAn ΗΪ NV b= _N ' \ 4-(1 -(tert-butyl)-1 H-and irazol-4yl)pyrimidin-2-amine 217.9 14.02 νη ₂ A / 1 NV 6-(1 -(tert-butyl)-1 H-and irazol-4yl)pyrazin-2-amine 218.0 14.03 ο-? 6-( 1 -(tert-butyl)-1 H-and irazol-4yl)pyridin-2-amine 217.0 14.04 νη ₂ ίίη , ^Ν 5-( 1 -(tert-butyl)-1R-pyrazol-4yl)pyride in-3-amine 217.1 14.05 ο 2-( 1 -(tert-butyl)-1 H-and irazol-4yl)pyridin-4-amine 217.0 14.06 νη ₂ Ν' ^χ Χ| η .1, F ^ _Ν '\ 4-( 1 -(tert-butyl)-1 H-and irazol-4yl)-5-fluoropyridin-2-amine 235.1

Alternative conditions: 160°C, 20 min; DME/2.2 MK ₂ CO ₃ (1:1 or 1.5:1); Dioxane/2.2 M K2CO3

- 77 047314 (2:1).

Intermediate 15.

4-(4-(tert-Butyl)-III-imidazol-1-yl)pyridin-2-amine

Step 1: 4-(tert-butyl)-1H-imidazole.

A mixture of 1-bromo-3,3-dimethylbutan-2-one (15 g, 83.77 mmol) and formamide (84.75 g, 1.88 mol) was stirred at 170°C for 5 hours, left to cool to t., poured into water (200 ml) and then extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ , filtered and then concentrated to give 4-(tert-butyl)-shimidazole (8 g) as a yellow oil, which was used immediately in the next step. LCMS: 125.2 [M+H]+.

Step 2: 4-(4-(tert-butyl)-III-imidazol-1-yl)-2-chloropyridine.

Potassium carbonate (18.92 g, 136.89 mmol) was added to a solution of 4-tert-butyl-III-imidazole (8 g, 54.76 mmol), 2-chloro-4-fluoropyridine (14.41 g, 109. 52 mmol) and NMP (80 ml) at RT. The mixture was stirred at 100°C overnight, left to cool to RT, poured into water (200 ml) and then extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (300 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 70/30) to give 4-(4-(tert-butyl )-III-imidazol-1-yl)-2-chloropyridine (4 g, 31%) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.50 (d, 1H), 8.44 (d, 1H), 7.97 (d, 1H), 7.80 (dd, 1H), 7 .72 (d, 1H), 1.25 (s, 9H); LCMS: 236.1 [M+H] ⁺ .

Step 3: 4-(4-(tert-butyl)-III-imidazol-1-yl)pyridin-2-amine.

Lithium bis(trimethylsilyl)amide (1 M in THF, 31.2 ml) was added to a solution of 4-(4-(tert-butyl)-Shimidazol-1-yl)-2-chloropyridine (3.5 g, 14.85 mmol), Pd ₂ (dba) ₃ (543.9 mg, 0.59 mmol), XPhos (566.2 mg, 1.19 mmol) and dioxane (100 ml) at room temperature under N2 atmosphere. The mixture was degassed with 3 cycles _of vacuum, stirred at 100°C overnight, left to cool to room temperature, poured into water (100 ml), and then extracted with EtOAc (3x200 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/EtOAc = 30/70) to give impurities (2.1 g) , which was further purified by reverse phase HPLC (water (10 mM NH ₄ HCO ₃ )/CH ₃ CN) to give 4-(4(tert-butyl)-III-imidazol-1-yl)pyridin-2-amine ( 1.36 g, 71%) as a brown solid. 1H

NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.95 (d, 1H), 7.35 (s, 1H), 6.80 (dd, 1H), 6.60 ( s, 1H), 6.10 (s, 2H), 1.24 (s, 9H); LCMS: 217.1 [M+H] ⁺ .

The intermediate below was synthesized from 2-chloro-4-fluoropyridine and 3-(tert-butyl)-III15.01 pyrazole based on the procedures described for intermediate 15, steps 2-3.

Prom. Conn.

Structure Name [M+N] ⁺ V 4-(3 -(thyret-butyl)-1R-pyrazol-1 yl)pyridin-2-amine 217.1

Connection 1.

trans-4-((4-(2-(tert-Butyl)thiazol-5-yl)pyridin-2-yl)(((trans)-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl (tetrahydro-2H-pyran-4-yl)carbamate

Step 1: 4-(2-(tert-butyl)thiazol-5-yl)X-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)pyridin-2-amine.

Intermediate 1 (1.0 g, 4.30 mmol) and then sodium triacetoxyborohydride (1.33 g, 6.26 mmol) were added to a solution of intermediate 6 (913 mg, 3.91 mmol) in CH ₂ Cl ₂ (12 ml) at 0°C. The ice/water bath was removed. The reaction mixture was stirred at room temperature overnight and then diluted with EtOAc (15 ml). The organic layer was washed with 3.0 M K ₂ CO ₃ (20 ml), washed with brine (20 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-50% EtOAc in CH ₂ Cl ₂ ). Residual AcOH was noted, thus the product fractions were

- 78 047314 centered, diluted with EtOAc (20 ml), washed with 3.0 M K ₂ CO ₃ (20 ml), washed with saline (20 ml), dried (Na ₂ SO ₄ ), filtered and then concentrated to give 4 -(2-(tert-butyl)thiazol-5-yl)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)pyridin-2-amine (1.34 g, 76%) in as a beige solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.11 (s, 1H), 7.95 (d, 1H), 7.026.96 (m, 2H), 6.83-6.69 (m, 1H), 6.75-6.69 (m, 2H), 6.65 (s, 1H), 3.76 (s, 3H), 3.15 (t, 2H), 2.42-2.32 (m, 1H), 2.11 (s, 3H), 1.93-1.75 (m, 4H), 1.65-1.52 (m, 1H), 1.46-1.32 (m , 11H), 1.15-1.02 (m, 2H); LCMS: 450.3 [M+H]+.

Step 2: trans-N-(4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)Ni((trans-4-(4 -methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide.

Intermediate 11 (10.4 mL, 70.6 mg/mL, 2.66 mmol) was added to a mixture of 4-(2-(tert-butyl)thiazol-5-yl)-N-((trans-4-(4- methoxy-3-methylphenyl)cyclohexyl)methyl)pyridin-2-amine (600 mg, 1.33 mmol), DMAP (165 mg, 1.33 mmol), triethylamine (744 μl, 5.33 mmol) and toluene (2 .5 ml) at room temperature. The reaction was heated at 80°C overnight. Additional intermediate 11 (10.4 mL, 70.6 mg/mL, 2.66 mmol) was added. The reaction was heated at 80°C for 2 hours, left to cool to room temperature, diluted with EtOAc (30 ml), washed with 1.0 M KH ₂ PO ₄ (15 ml), washed with saline (30 ml), dried ( Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-20% EtOAc in hexanes) to give trans-H-(4-(2-(tert-butyl)thiazol-5-yl)pyridine -2-yl)-4((tert-butyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (566 mg, 61%) as a white foam. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.53 (d, 1H), 8.46 (s, 1H), 7.73 (s, 1H), 7.62 (dd, 1H), 6.97-6.91 (m, 2H), 6.81-6.76 (m, 1H), 3.74-3.68 (m, 5H), 3.58-3.47 (m, 1H ), 2.48-2.15 (m, 2H), 2.08 (s, 3H), 1.83-1.68 (m, 8H), 1.52-1.39 (m, 12H), 1.35-1.20 (m, 2H), 1.19-0.92 (m, 4H), 0.81 (s, 9H), 0.00 (s, 6H); LCMS: 690.6 [M+H]+.

Step 3: trans-H-(4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(4-methoxy3-methylphenyl) cyclohexyl)methyl)cyclohexanecarboxamide.

Aqueous hydrochloric acid (1 N, 1.27 mL, 1.27 mmol) was added to the solution of trans-N-(4(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)-4-( (tertbutyldimethylsilyl)oxy)-N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl) cyclohexanecarboxamide (562 mg, 0.82 mmol), THF (3 ml) and CH ₃ OH (3 ml ) at 0°C. The reaction mixture was stirred at RT for 1 hour, diluted with EtOAc (15 ml), washed with saturated NaHCO ₃ (10 ml), washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated, and then purified by silica gel chromatography (0-100% EtOAc in CH ₂ Cl ₂ ) to obtain trans-N-(4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)-4-hydroxy- N-((trans-4-(4-methoxy-3-methylphenyl)cyclohexyl)methyl)cyclohexanecarboxamide (406 mg, 86%) as a white foam. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.53 (d, 1H), 8.46 (s, 1H), 7.73 (s, 1H), 7.61 (dd, 1H), 6 .97-6.91 (m, 2H), 6.80-6.75 (m, 1H), 4.45 (d, 1H), 3.74-3.68 (m, 5H), 3.33 -3.25 (m, 1H), 2.38-2.25 (m, 1H), 2.22-2.12 (m, 1H), 2.08 (s, 3H), 1.82-1 .68 (m, 8H), 1.50-1.38 (m, 12H), 1.32-1.20 (m, 2H), 1.09-0.95 (m, 2H), 0.95 -0.80 (m, 2H); LCMS: 576.4 [M+H]+.

Step 4: trans-4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy-3methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl(tetrahydro-2H-pyran-4-yl)carbamate.

Solution of trans-H-(4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)-4-hydroxy-N-((trans-4-(4-methoxy-3methylphenyl)cyclohexyl) methyl) cyclohexanecarboxamide (220 mg, 0.38 mmol), CDI (97 mg, 0.60 mmol) and CH3CN (8 ml) were heated at 80°C overnight and then cooled to room temperature. Aminotetrahydropyran (34 µl, 0.34 mmol) was added to a portion of the CH3CN solution (0.45 mL, 0.085 mmol) and the mixture was stirred at room temperature overnight. Additional 4-aminotetrahydropyran (34 μL, 0.34 mmol) was added and the mixture was stirred at room temperature for 1 day. Additional 4-aminotetrahydropyran (9 μL, 0.09 mmol) was added and the mixture was stirred at room temperature for another day. The reaction mixture was diluted with EtOAc (10 ml), washed with saturated NaHCO ₃ (10 ml), washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-10% CH ₃ OH in CH ₂ Cl ₂ ) to give trans-4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl)((trans-4-(4-methoxy- 3methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl (tetrahydro-2H-pyran-4-yl)carbamate (51 mg, 86%) as a white foam. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.53 (d, 1H), 8.46 (s, 1H), 7.74 (s, 1H), 7.61 (dd, 1H), 7 .08-7.02 (d, 1H), 6.96-6.91 (m, 2H), 6.80-6.75 (m, 1H), 4.45 (d, 1H), 3.81 -3.68 (m, 7H), 3.49-3.38 (m, 1H), 3.33-3.25 (t, 2H), 2.38-2.25 (m, 2H), 2 .08 (s, 3H), 1.93-1.60 (m, 10H), 1.57-1.40 (m, 12H), 1.39-1.20 (m, 4H), 1.09 -0.95 (m, 4H); LCMS: 703.5 [M+H]+.

The compounds below were synthesized from the corresponding intermediates and the corresponding amines based on the procedures described for compound 1.

- 79 047314

Conn. Structure Name [M+N] ⁺ 1.01 O £y''' ⁴ⁿ '\ ^/4 | O 'HuAkh'· ¹ _N J\ \Ζ-, _Ο Λ _Ν _ xAk mfy-k ^ ^he trans-4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl) (((trans)-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3 hydroxyazetidine-1 carboxylate 675.2 1.02 <k/ trans-4-((4-(2-(tert-butyl)thiazol-5-yl)pyridin-2-yl) (((trans)-4-(4-methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl) cyclohexyl-3 hydroxy-2,2-dimethylase etidine1-carboxylate 703.5

- 80 047314

1.03 O _ 1 1 1 II and _ ^N |1 \ Jx ^x JL i / L JL o |ί ^he from/?a//c-4-((4-(2-(t/?eot-butyl) thiazol-5-yl)pyridin-2-yl) (((from/?ans)-4-(4 -methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4hydroxypiperidine-1 carboxylate 703.5 1.04 O <^ ^X ]'^N ^x4 S ^x ^ ^X | O ^ _O AU ^° ⁿ ^-0 ' from/?a//c-4-((4-(2-(t/?eot-butyl)oxazol-4-yl)pyridin-2-yl) (((from/?ans)-4-(4 -methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 hydroxyazetidine-1 carboxylate 659.5 1.05 o ι^>·^^Ν' ^Λ4 γ ^/χ > o /Ci Ύ;'°, ^Λ Ά V-4- ^ΟΗ from/?a//c-4-((4-(2-(t/?eot-butyl)oxazol-4-yl)pyridin-2-yl) (((from/?ans)-4-(4 -methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 hydroxy-2,2-dimethylase etidine1-carboxylate 687.5 1.06 ο | ^χΖΧ >''' ^Λ '^Ν' ^Α ν ^ΧΧ4 ] Ο ^Ν |1 ^^ ^,?ζ/ο/ ^ ^ν/ £ X £χχ£ -Ν / Ιχ £χ ο (f /—\ - ^ΟΗ ^ο ^ζ ' from/?a//c-4-((4-(2-(t/?eot-butyl)oxazol-4-yl)pyridin-2-yl) (((from/?ans)-4-(4 -methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4hydroxypiperidine-1 carboxylate 687.5

- 81 047314

1.07 w °C IZ ъ from/?ans-4-((4-(2-(from/?eot-butyl) oxazol-4-yl)pyridin-2-yl) (((from/?sh/s)-4-(4- methoxy-3 methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl (tetrahydro-2R-pyran-4yl)carbamate 687.6 1.08 O . 1 J 1 1 J А N^4 N-Ч DD DD / А™ ° 1 , ^Ν \ ^Х trans-4-((4-( 1 -(from/?eot-butyl)1//-pyrazol-4-yl)pyridin-2-yl) ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-3 - Hydroxyazetidine-1 carboxylate 658.5 1.09 ¥ °Ч D/ < ъ / trans-4-((4-( 1 -(ot/?eot-butyl)1//-pyrazol-4-yl)pyridin-2-yl) ((trans-4-(4-methoxy-3 methylphenyl)cyclohexyl )methyl )carbamoyl)cyclohexyl-3 hydroxy-2,2-dimethylase etidine1-carboxylate 686.5 1.10 o ί ^χ ^· ^,Λ '^Ν ^χΑ4 γ ^/χ Ί o DDD^—νΧι Il j / L 1 *^N ' trans-4-((4-( 1 -(from/?eot-butyl)1//-pyrazol-4-yl)pyridin-2-yl) ((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl-4hydroxypiperidine-1 - carboxylate 686.6

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trans-4-((4-( 1 -(tert-butyl)- 1//-pyrazol-4-yl)pyridin-2-yl) O ο ((/7//76///6-4-(4-methoxy-3 - 1.11 ' O / nV η Ί U ⁴ N- Η methylphenyl)cyclohexyl)methyl)carbamoyl)cyclohexyl(tetrahydro-2//-pyran-4-yl)carbamate 4-((4-( 1 -(/77/?v/77-butyl)-1Hpyrazol-4-yl)-5 -fluoropyr idin-2- 686.6 ABOUT yl)((4-(4-methoxy-3 - 1.12 o D Ρ Ν- ο JJ ΌΗ methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)carbamoyl) 702.4 F (////76///6-ci cloxyl)-3 - Hydroxyazetidine-1 carboxylate 4-((2-( 1 -(/77/76777-butyl)-1H- pyrazol-4-yl)pyridin-4-yl)((4- ABOUT Ο (4-methoxy-3-methylphenyl) 1.13 CL N Ρ^Ν- π •Ο^Ν- ΌΗ bicyclo [2.2.2] octan-1 -yl) methyl) carbamoyl)(/77/?b///c-cyclohexyl)-3-hydroxyazetidine-1 carboxylate 4-((5-( 1 -(/77/76777-butyl)-1H- pyrazol-4-yl)pyr idin-3-yl)((4- 684.5 ABOUT (4-methoxy-3-methylphenyl) 1.14 (ίη ρ ⁴ Ν- Ο JJ ΌΗ bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)(/?///b///b- 684.5 cyclohexyl)-3 hydroxyazetidine-1 carboxylate 4-((6-( 1 -(tre from-butyl)-1H- pyrazol-4-yl)pyridin-2-yl)((4- ABOUT ο (4-methoxy-3-methylphenyl) 1.15 ' O / όΐ Γ, ^Ν ' Η ΌΗ bicyclo [2.2.2] octan-1 -yl) methyl) carbamoyl)(/7///b///b-cyclohexyl)-3-hydroxyazetidine-1 carboxylate 684.5

Alternative conditions: Stage 1: 0-45°C; 15-21 hours; In some cases, 1 equiv was added. AcOH. Stage 2: temperature -80°C; 1-20 h; CH ₂ Cl ₂ as a solvent; In some cases, DMAP was not used; 2 equiv. intermediate 11 was usually sufficient. Stage 3: THF/CH ₃ OH (1:1 or 2:1); 1-2.5 hours; In some cases, additional HPLC purification is necessary. Stage 4a: temperature -80°C; 2-16 hours; In some cases, more than 1.5 equiv. CDI is required for complete conversion to acylmidazole. Stage 4b: 2 hours-5 days; iso-Pr2\E1 (2 equiv. relative to the amine) was added if the amine was an HCl salt.

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Connection 2.

4-((4-(2-(tert-Butyl)oxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan1-yl)methyl )carbamoyl)(trans-cyclohexyl)(3-hydroxypropyl)carbamate o

Step 1: 4-(2-(tert-butyl)oxazol-4-yl)-K-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)pyridin-2 -amine.

Methanol (4.0 mL) and acetic acid (38 μL, 0.61 mmol) were added to intermediate 2 (523 mg, 2.02 mmol) and intermediate 7 (398 mg, 1.83 mmol) in a 40 ml. The mixture was stirred at 60°C for 3 hours and cooled to room temperature. 2-methylpyridine borane complex (196 mg, 1.83 mmol) was added. The reaction mixture was stirred at RT for 63 hours, diluted with EtOAc (10 ml), washed with saturated NH ₄ Cl (10 ml), washed with saturated NaHCO ₃ (10 ml), washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-40% EtOAc in hexanes) to give 4-(2-(tert-butyl)oxazol4-yl)-M-((4-(4 -methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine (685 mg, 81%) as a white foam. ^1H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.91 (d, 1H), 7.26-7.07 (m, 2H), 6.97 (s, 1H), 6.82 (d, 1H), 6.72 (dd, 1H), 6.53 (t, 1H), 3.73 (s, 3H), 3.13 (d, 2H), 2, 11 (s, 3H), 1.75-1.69 (m, 6H), 1.57-1.50 (m, 6H), 1.37 (s, 9H); LCMS: 460.4 [M+H]+.

Step 2: trans-M-(4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)-M-((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide.

Dichloromethane (7.0 mL) and triethylamine (831 μL, 5.96 mmol) were added to 4-(2-(tert-butyl)oxazol-4yl)-M-((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-amine (685 mg, 1.49 mmol) and intermediate 10 (462 mg, 1.79 mmol) into a 40 ml vial. Cyclic anhydride of 1-propylphosphonic acid (T3P 50+% w/w dissolved in CH ₂ Cl ₂ , 1.90 g, 2.98 mmol) was weighed into a separate vessel and then added to the reaction. Dichloromethane (2 ml) was added to the T3P vessel and this solution was added to the reaction. The reaction mixture was stirred at RT for 15 hours, washed with water (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-15% EtOAc in hexanes) to obtain trans-N-(4-(2-(tert-butyl)oxazol-4yl)pyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)-M-((4-(4-methoxy-3methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (995 mg, 95%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.53 (d, 1H), 7.77 (s, 1H), 7.67 (d, 1H), 7. 02-6.97 (m, 2H), 6.76 (d, 1H), 3.75 (s, 2H), 3.71 (s, 3H), 3.59-3.47 (m, 1H) , 2.36-2.20 (m, 1H), 2.08 (s, 3H), 1.80-1.70 (m, 4H), 1.651.57 (m, 6H), 1.52-1 .42 (2H), 1.41-1.17 (m, 15H), 1.04-0.90 (m, 2H), 0.81 (s, 9H), 0.14 (s, 6H); LCMS: 700.1 [M+H] ⁺ .

Step 3: trans-M-(4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3methylphenyl)bicyclo[ 2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide.

Aqueous hydrochloric acid (1 N, 2.12 mL, 2.12 mmol) was added to the solution of trans-M-(4(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)-4-( (tert-butyldimethylsilyl)oxy)-N-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (990 mg, 1.41 mmol), CH3OH (5, 0 ml) and THF (5.0 ml) at 0°C. The ice/water bath was removed. The reaction mixture was stirred at RT for 1 hour, cooled in an ice/water bath, diluted with saturated NaHCO ₃ (7 ml), and then extracted with EtOAc (10 ml). The organic layer was washed with brine (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated, and then purified by silica gel chromatography (0-50% EtOAc in CH ₂ Cl ₂ ), then (0-5% CH3OH in CH ₂ Cl ₂ ) to obtain trans-M-(4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)-4hydroxy-N-((4-(4-methoxy-3- methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (727 mg, 87%) as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.53 (d, 1H), 7.78 (s, 1H), 7.67 (d, 1H), 7. 02-6.97 (m, 2H), 6.76 (d, 1H), 4.44 (d, 1H), 3.73 (s, 2H), 3.70 (s, 3H), 3.33 -3.26 (m, 1H), 2.332.15 (m, 1H), 2.08 (s, 3H), 1.80-1.67 (m, 4H), 1.65-1.54 (m , 6H), 1.49-1.32 (m, 17H), 0.94-0.78 (m, 2H); LCMS: 586.4 [M+H] ⁺ .

Step 4: 4-((4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl) (trans-cyclohexyl) (3 hydroxypropyl)carbamate.

A solution of trans-M-(4-(2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3methylphenyl)bicyclo[2.2. 2]octan-1-yl)methyl)cyclohexanecarboxamide (100 mg, 0.17 mmol), CDI (42 mg, 0.26 mmol) and CH3CN (1 ml) were heated at 80°C overnight and then cooled to t. 3-Amino-1propanol (26 µl, 0.34 mmol) was added to a portion of the CH3CN solution (0.5 ml, 0.085 mmol). The mixture was stirred at RT for 4 hours, diluted with EtOAc (10 ml), washed with saturated NaHCO ₃ (10 ml),

- 84 047314 washed with saline (10 ml), dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-5.5% CH3OH in CH2Cl2) to give 4-((4-( 2-(tert-butyl)oxazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)(trans-cyclohexyl)( 3-Hydroxypropyl)carbamate (53 mg, 91%) as a white foam. ^1H NMR (400 MHz, DMSO-d6): δ 8.85 (s, 1H), 8.54 (d, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7 .02-6.97 (m, 2H), 6.91 (t, 0.90H), 6.77 (d, 1H), 6.67-6.59 (m, 0.10H), 4.40 -4.32 (m, 2H), 3.75 (s, 2H), 3.70 (s, 3H), 3.39-3.31 (m, 2H), 3.01-2.95 (m , 2H), 2.36-2.25 (m, 1H), 2.08 (s, 3H), 1.92-1.75 (m, 4H), 1.65-1.57 (m, 6H ), 1.55-1.42 (m, 4H), 1.41-1.31 (m, 15H), 1.08-0.93 (m, 2H); LCMS: 687.5 [M+H]+.

The compounds below were synthesized from the corresponding intermediates and the corresponding amines based on the procedures described for compound 2.________________________

Conn. Structure Name [M+N] ⁺ 2.01 o X 1 J Lie / GA-° ^N Η- 4-((4-(2-(tert-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( tra//scyclohexyl)-3-hydroxy-3-methylazetidine-1-carboxylate 715.2

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2.02 0 0 Λ J kl S / ⁿ 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)(/?7/l7//scyclohexyl)-(3-hydroxypropyl) carbamate 703.0 2.03 \,ρ ω; d'° 4 m o'o / 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)(/?7/l7//scyclohexyl)-3 -(methyl sulfonyl) azetidine-1-carboxylate 763.2 2.04 Chh 4 m o / o / 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)(/?7/l7//scyclohexyl)-oxetane-3 ylcarbamate 701.4 2.05 o nA 4AcXn^\ s. JI Λ JX i / L J. O ^OH A-N \ 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl) cyclohexyl-4- hydroxypiperide mn-trans-1 carboxylate 729.4 2.06 ο ο JfVJ 1 LJ 1 on UCH Λi ^Ν ^λ 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)cyclohexyl(2- hydroxyethyl)/??/l7//s-carbamate 689.2

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2.07 O o νΑι ^^ο'^ν-'-ά JI JL II « . V-A_x-\/OH - ₀ AZ CHL^. =~ N ^x 4-((4-(2-(ot/?eot-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)(/7?/l7//scyclohexyl)-3-(2-hydroxyethoxy) azetidine-1-carboxylate 745.2 2.08 O O ₄ . UU ALJA U AJ UCs / ^nhi N ⁴ 4-((4-(2-(/77/?e/77-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl )methyl)carbamoyl)(tt7/?sh/scyclohexyl)(3-hydroxy-3 methylbutyl)carbamate 731.4 2.09 HA o ' o / 4-((4-(2-(/77/?e/77-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl )methyl)carbamoyl)cyclohexyl-3 - (dimethylamino)pyrrolidine trans-1-carboxylate 742.6 2.10 / o / w A °>o ^.2 Ί O X (A)-4-((4-(2-(/7?/7g/7?-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2. 2] octan1 -yl)methyl)carbamoyl)cyclohexyl-2- (hydroxymethyl)azetide and n-/7?/7<7//c-1 carboxylate 715.5 2.11 o l ” ^he \<у\/ \„AA / ° ^L ^s >\ ^O ^x (A)-4-((4-(2-(/77/7<?/77-butyl)oxazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2. 2] octan-1 -yl)methyl)carbamoyl)cyclohexyl-2- (hydroxymethyl)azetide and n-/7?/7<7//c-1 carboxylate 699.5

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2.12 o O nA AA _O A x L JAA n / <A° ⁿ ^~o ⁴ 4-((4-(2-(otreot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( t/l7//scyclohexyl)-3-hydroxy-3 methylazetidine-1-carboxylate 699.3 2.13 / o/o <> X°>o "A yW O \ 4-((4-(2-(otreot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( t/l7//scyclohexyl)-3 -(methyl sulfonyl) azetidine-1-carboxylate 747.3 2.14 o o d Ch-t U I / 4-((4-(2-(otreot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( t/l7//scyclohexyl)-3-(2-hydroxyethoxy) azetidine-1-carboxylate 729.1 2.15 t A X ' o / 4-((4-(2-(otreot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( t/l7//scyclohexyl)-3 -(hydroxymethyl) azetidine-1-carboxylate 699.6 2.16 o X/T\X\J ыХ\ \Х Х^/Х _К |--^\ / II 1 । N ° 7 / ^N ^о ⁴ 4-((4-(2-(otreot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)cyclohexyl -3-(dimethylamino)pyrrole ide in-traps-1-carboxylate 726.6

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2.17 ABOUT O \ A JL Ν / £ ο ιί Ά\ '—ο ' 4-((4-(2-(t/?eot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl) cyclohexyl-4- Hydroxypiperide IP-trans-1 carboxylate 713.4 2.18 ο rXy ^X ^N' ^J \ ^/ X Ο ι~- _ο ι U ι Zl· -JU ULn / ^Η 4-((4-(2-(ot/?eot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl)(/77/l7//scyclohexyl)-oxetane-3 ylcarbamate 685.4 2.19 ο ΎΎ^ A ^U 'A~ ^OH - _ο α>'Ху^ ^-ο ⁴ 4-((4-(2-(/77/?е/77-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl )methyl)carbamoyl)cyclohexyl(2- hydroxyethyl)/7?/7<7//c'-carbamate 673.2 2.20 / ⁰ / ο x < ¹ )=ο τζ 0 X 4-((4-(2-(/77/?е/77-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl )methyl)carbamoyl)(/7?/7<7//c'cyclohexyl)(3-hydroxy-3 methylbutyl)carbamate 715.3 2.21 X Ο ι 2*^ °4 4/ > ο ' ο / (S)-4-((4-(l -(/ttreot-butyl)- 1Hpyrazol-4-yl)pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo [2.2.2] octane -1 -yl)methyl)carbamoyl)cyclohexyl-2- (hydroxymethyl)azetide and n-/77/7<7//c-1 carboxylate 698.5

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2.22 o ΦΑ'Ν'γΑ O 1 1 J l ^Ν || Ν^\ II J Г II, lAoh аФ ^x A' ^x 4-((4-(1 -(/7?/7с/7?-butyl)-1 Η- p-irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2 .2] octan-1 -yl)methyl)carbamoyl) (/77/V7//C-cyclohexyl)-3-hydrox and 3-methyl azetide in-1-carboxylate 698.5 2.23 o ιΑ'/Α'Ν'Α'Α ^ο xx) 1 LJ 1 ^Ν |1 ⁴ -'7 T , ^N \ ° ° ^x 4-((4-(1 -(/ttreot-butyl)-1H- and irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl) (/77/76///C-cyclohexyl)-3 (methylsulfonyl)azetidine-1carboxylate 746.6 2.24 / ABOUT / A7 J0 1 / /F o •'L )=o F O=sl=O / 4-((4-(1 -(/ttreot-butyl)-1 Η- p-irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl)carbamoyl) (/77/76///C-cyclohexyl)-3 - ((methylsulfonyl)methyl)azetidine 1-carboxylate 760.6 2.25 O o ύ °CH a A / 4-((4-(1 -(/ttreot-butyl)-1H- and irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl) (/77/76///C-cyclohexyl)-3 -(2hydroxyethoxy)azetidine-1 carboxylate 728.5

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2.26 ό ΛΑ 'o / 4-((4-(1 -(/7?/7<?/7?-butyl)-1/7-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo [2.2.2] octan-1 -yl)methyl)carbamoyl)cyclohexyl-3 - (dimethylamino)pyrrolidine trans-1-carboxylate 725.6 2.27 / O / Oh dd o M )=o 0 O I 4-((4-(1 -(/7?/7<?/7?-butyl)- 177-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2 .2] octan-1 -yl)methyl)carbamoyl)cyclohexyl-4- hydroxypiperide in-traps-1 carboxylate 712.6 2.28 ΖΙ °H A/ / 4-((4-(1 -(ot/?eot-butyl)- 177-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl)carbamoyl) (trans-cyclohexyl)oxetane-3 ylcarbamate 684.6 2.29 / o / o A /A o M >O ΧΖ th 4-((4-(1 -(ot/?eot-butyl)- 177-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl)carbamoyl) cyclohexyl-/7?/l7//c(tetrahydro2//-thiopyran-4-yl)carbamate 728.2 2.30 o vA nA <A<A^°n II Ί G II N ^X 4-((4-(1 -(/tgret-butyl)-177-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3 -methylphenyl)bicyclo[2.2.2]octan-1 -yl )methyl)carbamoyl)cyclohexyl(2- hydroxyethyl)/7?/7<7//s-carbamate 672.6

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2.31 / ⁰ / О ζ· I / 0 A >o IZ 0 X 4-((4-(1 -(tert-butyl)-1 Η- p irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl) (t/7<7//c-cyclohexyl)(3 hydroxypropyl)carbamate 686.5 2.32 / o / Jk /Ά o m >=o xz O X 4-((4-(1 -(tert-butyl)-1R-pyrazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octan-1-yl) methyl)carbamoyl) (t/7<7//c-cyclohexyl)(3-hydrox and 3-methylbutyl)carbamate 714.6 2.33 X 0 °C L/ ' o / (//)-4-((4-(1 -(tert-butyl')- 1Hpyrazol-4-yl)pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo [2.2.2] octan-1yl)methyl)carbamoyl) CI CLOHEXIL-/77/7<7//C'-3 hydroxypyrrolidine-1 carboxylate 698.6 2.34 X 0 δ °Ч А о ' о / (5)-4-((4-( 1 -(tert-butyl)- 1Hpyrazol-4-yl)pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1yl)methyl)carbamoyl) cyclohexyl-/7?/7<7//c-3 hydroxypyrrolidine-1 carboxylate 698.6

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2.35 / O / ABOUT 1 * O >o £ o t 4-((4-(3 -(m/tem-butyl)-1R-pyrazol1-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl)carbamoyl)cyclohexyl-/i/?ts-3 hydroxyazetidine-1-carboxylate 684.2 2.36 / °/o 1 * >o o t 4-((6-( 1 -(t/?eth-butyl)- 177-pyrazol4-yl)pyrimidin-4-yl)((4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl) carbamoyl)(trsh/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 685.6 2.37 I O b O— ' o / 4-((6-( 1 -(t/?e/i-butyl)-1R-pyrazol4-yl)pyrimidin-4-yl)((4-(4methoxy-3,5-dimethylphenyl)bicyclo[2.2.2 ]octan-1 -yl)methyl) carbamoyl)(t/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 699.5

Alternative conditions: Stage 1a: 60-65°C; 3-69 h; In some cases, 1 equivalent was used. AcOH. Stage 1b: 0-40°C, 15-24 hours Stage 2: temperature -40°C; 15-63 hours; In some cases, more equiv. T3P, intermediate 10 and Et ₃ N were required for complete conversion; In some cases DMAP was used. Stage 3: 1-19 hours Stage 4a: temperature -80°C, 3.5-19 hours; In some cases, more than 1.5 equiv. CDI is required for complete conversion to acylimidazole. Stage 4b: temperature -50°C; 2-96 h; isoPr ₂ NEt (2 equiv. relative to the amine) was added if the amine was an HCl salt.

The compound below was synthesized from compound 2.29 using NaIO ₄ , THF, H ₂ O, 0-50°C, 37 h.

Conn. Structure Name [M+N] ⁺ 2.38 about JL. -O K / O [ ^s ' II \ l II . n (1 r,4r)-4-((4-( 1 -(t/?eth-butyl)-177pyrazol-4-yl)pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo [ 2.2.2] octan-1 -yl)methyl) carbamoyl)cyclohexyl( 1 - otetrahydro-2//-thiopyran-4yl)carbamate oxide 744.6

The compound below was synthesized from compound 2.29 using meta-CPBA, CH ₂ Cl ₂ , 0°C -k. t., 4 hours

Conn. Structure Name [M+N] ⁺ 2.39 •A /k o -F >0 ΤΖ U II ⁰ 0 4-((4-(1 -(ot/?eot-butyl)-\Hpyrazol-4-yl)pyridin-2-yl)((4(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1yl)methyl)carbamoyl) cycloge k<ml-trans-(1,1dioxidotetrahydro-2/7thiopyran-4-yl)carbamate 760.5

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Connection 3.

4-((4-(1-(tert-Butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-trans-1carboxylate

Step 1: 4-(1-(tert-butyl)-III-pyrazol-4-yl)-H-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan1-yl)methyl) pyridine-2-amine.

Intermediate 2 (199 mg, 0.77 mmol) and intermediate 8 (200 mg, 0.925 mmol) were suspended in CH ₃ OH (4 ml). Acetic acid (13.2 µl, 0.23 mmol) was added. The reaction mixture was heated in a 60°C oil bath for 4 hours and allowed to cool to room temperature. 2Methylpyridine borane complex (82 mg, 0.77 mmol) was added. The reaction mixture was stirred at RT for 16 hours, diluted with 20 ml saturated NH ₄ Cl, and then extracted with 20 ml EtOAc. The organic layer was washed with 20 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (20-80% EtOAc in hexanes) to give 4-(1-(tert-butyl)-1H-pyrazole -4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)purugin-2amine (255 mg, 72%) as off-white foam. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.26 (s, 1H), 7.86 (d, 1H), 7.84 (s, 1H), 7.09-7.04 (m , 2H), 6.80 (d, 1H), 6.70 (s, 1H), 6.68 (d, 1H), 6.16 (t, 1H), 3.72 (s, 3H), 3 .11 (d, 2H), 2.12 (s, 3H), 1.77-1.67 (m, 6H), 1.59-1.47 (m, 15H); LCMS: 459.6 [M+H]+.

Step 2: trans^-P-PCHt-bu'tylES-pyrazolA-ylShchiridinG-i.tsP-Ctretbutyldimethylsilyl)oxy)-N((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl )methyl)cyclohexanecarboxamide.

4-(1-(tert-butyl)-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)pyridin-2 α-amine (250 mg, 0.545 mmol) and DMAP (69 mg, 0.57 mmol) were combined in toluene (1 ml). Triethylamine (0.3 mL, 2.15 mmol) and then intermediate 11 (4.4 mL, 71 mg/mL, 1.12 mmol) were added at RT. The reaction was heated at 80°C for 2 h , left to cool to room temperature, diluted with 5 ml of 1 M K2HPO4, and then extracted with 20 ml of EtOAc. The organic layer was washed with 20 ml brine, _dried ( _Na2SO4 ), filtered, concentrated and then purified by silica gel chromatography (10-25% EtoAc in hexanes) to give trans-NH-C-St-butylES-pyrazolChil )pyridin-2-yl)-4-((tert-butyldimethylsilyl)oxy)-N((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)cyclohexanecarboxamide (308 mg, 81%) in the form of white foam. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.61 (s, 1H), 8.40 (d, 1H), 8.15 (s, 1H), 7.73 (s, 1H), 7 .58 (d, 1H), 7.02-6.96 (m, 2H), 6.76 (d, 1H), 3.75-3.68 (m, 5H), 3.56-3.45 (m, 1H), 2.31-2.20 (m, 1H), 2.08 (s, 3H), 1.80-1.68 (m, 4H), 1.66-1.52 (m , 15H), 1.50-1.29 (m, 8H), 0.98-0.84 (m, 2H), 0.79 (s, 9H), -0.02 (s, 6H); LCMS: 699.6 [M+H]+. Note: Compound 3, Step 2 can also be synthesized based on the procedure for Compound 2, Step 2.

Step 3: trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy3-methylphenyl) )bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide.

Aqueous hydrochloric acid (1 N, 0.65 ml, 0.65 mmol) was added to the solution of trans-N(4(1 -(tert-butyl)-1H-pyrazol-4-yl)purugin-2-yl)-4 -((tert-butyldumethylsilyl)oxy)-N-((4-(4-methoxy-3 methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (303 mg, 0.433 mmol) in THF (1 .3 ml) and CH ₃ OH (1.3 ml) at 0°C. The reaction mixture was stirred at room temperature for 2.5 hours, cooled to 0°C in an ice/water bath, diluted with 20 ml saturated NaHCO3, and then extracted with 20 ml EtOAc. The organic layer was washed with 20 mL saturated NaHCO3, washed with 20 mL brine, dried ( _Na2SO4 ), filtered, concentrated, and then purified by silica gel chromatography (0-5% CH3OH in _CH2Cl2 ) to give trans-N-(4 -(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxyN((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane- 1-yl)methyl)cyclohexanecarboxamide (214 mg, 85%) as a white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 8.61 (s, 1H), 8.41 (d, 1H), 8.15 (s, 1H), 7.74 (s, 1H), 7 .58 (d, 1H), 7.03-6.96 (m, 2H), 6.76 (d, 1H), 3.75-3.67 (m, 5H), 3.32-3.23 (m, 1H), 2.28-2.17 (m, 1H), 2.08 (s, 3H), 1.80-1.67 (m, 4H), 1.64-1.52 (m , 16H), 1.46-1.31 (m, 8H), 0.89-0.74 (m, 2H); LCMS: 585.7 [M+H]+.

Step 4: 4-((4-( 1 -(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3 methylphenyl)bicyclo [2.2.2] octan-1 -yl)methyl)carbamoyl)cyclohexyl-3-hydroxyazetidine-trans-1 carboxylate.

A mixture of trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3methylphenyl)bicyclo [2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide (100 mg, 0.171 mmol), CDI (42 mg, 0.26 mmol) and CH3CN (1 ml) were heated at 80°C for 2 h and then was left to cool to rt. 3-Hydroxyazetidine hydrochloride (37 mg, 0.34 mmol) and then iso-Pr ₂ NEt (0.12 ml, 0.68 mmol) was added to part of this solution (0.5 ml, 0.09 mmol) at room temperature. The reaction mixture was stirred at room temperature.

- 94 047314 for 20 hours, diluted with 10 ml EtoAc, washed with 10 ml saturated NaHCO ₃ , washed with 10 ml brine, dried (Na ₂ SO ₄ ), filtered, concentrated and then purified by silica gel chromatography (0-50% EtOAc in CH ₂ Cl ₂ and then 0-10% CH3OH in CH ₂ Cl ₂ ) to give 4-((4-(1-(tert-butyl)-III-pyrazol-4-yl)pyridin-2-yl)(( 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate (51 mg, 87%) as a white foam. ¹ HNMR (400 MHz, DMSO-d ₆ ): δ 8.62 (s, 1H), 8.41 (d, 1H), 8.16 (s, 1H), 7.75 (s, 1H), 7 .58 (d, 1H), 7.036.95 (m, 2H), 6.76 (d, 1H), 5.63 (d, 1H), 4.40-4.29 (m, 2H), 4. 01-3.94 (m, 2H), 3.76-3.67 (m, 5H), 3.59-3.52 (m, 2H), 2.36-2.25 (m, 1H), 2.08 (s, 3H), 1.89-1.74 (m, 4H), 1.65-1.53 (m, 15H), 1.52-1.39 (m, 2H), 1, 39-1.30 (m, 6H), 1.06-0.91 (m, 2H); LCMS 684.6 [M+H]+.

The compounds below were synthesized from the corresponding intermediates based on the procedures described for compound 3.__________________________________________________________

3.01 O . Jew 1 LJ Jl 1 J Jl Ί IL JL / ^H L=n' ^x 4-((4-(1 -(tert-butyl)-1 Η- p irazol4-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane-1 - yl)methyl)carbamoyl)cyclohexyl(tetrahydro-27/-pyran4-yl)t/?w/s-carbamate 712.6 3.02 o II\L II. LA.oh e _N '\ 4-((4-(1 -(tert-butyl)-1 Η- p irazol4-yl)pyridin-2-yl)(trans(4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl)carbamoyl)(from/?w/s-cyclohexyl)-3(hydroxymethyl)azetidine-1 carboxylate 698.5 3.03 / o/o tfy' \ * o >o P 0 I 4-((4-(1 -(tert-butyl)-1H- and irazol4-yl)pyridin-2-yl)((4-(4-methoxy3 -methylphenyl)bicyclo[2.2.2]octan-1 -yl )methyl)carbamoyl) (trans-cyclohexyl)-3 hydroxypyrrolidine-1 carboxylate 698.5 3.04 I o d °=< f' / o / 4-((4-(1 -(tert-butyl)-1H- and irazol4-yl)pyridin-2-yl)((4-(4-methoxy3,5 - dimethyl phenyl)bicyclo [2.2.2] octan-1-yl)methyl)carbamoyl) (trans-cyclohexyl)-3 hydroxyazetidine-1-carboxylate 698.6 3.05 / o / =O & 1 4 V >0 R o I 4-((4-(1 -(tert-butyl)-III-pyrazol4-yl)pyridin-2-yl)((4-(6-methoxy5 -methylpyridin-3-yl)bicyclo [2.2.2]octan-1-yl)methyl) carbamoyl)(/7//l7//s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 685.6

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3.06 / -z \=z w A Ί )=o R O I 4-((4-(1 -(mpem-butyl)-III-pyrazol4-yl)pyridin-2-yl)((4-(6(dimethylamino)pyridin-3 yl)bicyclo [2.2.2] octane -1 yl)methyl)carbamoyl)(tra//scyclohexyl)-3-hydroxyase etidine1-carboxylate 684.6 3.07 I o d o ' o / 4-((4-(2-(tert-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)cyclohexyl -trbts-3 hydroxyazetidine-1-carboxylate 701.8 3.08 O lM ι 1 J 1 „ II J Lie / Η- 4-((4-(2-(tert-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl)( tra//scyclohexyl)-3 -(hydroxymethyl) azetidine-1-carboxylate 715.2 3.09 Ο Ο <^Ο ΤΜ JL LJ ji 1 j . JU ULs / ⁿ Ν ^χ 4-((4-(2-(tert-butyl)thiazol-5yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl) cyclohexyl(tetrahydro-2//-pyran4-yl)trbts-carbamate 729.9 3.10 Ο χχΙ 1 1 J 1 ^1< ^γγΛ ^ ^ΟΗ 4-((4-(2-(tert-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl)carbamoyl) cyclohexyl-3-hydrox iazetide intrans-1-carboxylate 685.3

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3.11 / O / ABOUT X °с ' >° IZ th 4-((4-(2-(ot/?eot-butyl)oxazol-4yl)pyridin-2-yl)((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan1 -yl)methyl) carbamoyl) cyclohexyl(tetrahydro-2H-pyran4-yl)o/?w/s-carbamate 713.1 3.12 / o/o h 1 * /X o >° o I 4-((6-(1 -(ot/?eot-butyl)-1 R-p-irazol4-yl)pyrazin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octane -1 -yl)methyl)carbamoyl) (trans-cyclohexyl)-3 hydroxyazetidine-1-carboxylate 685.5 3.13 o UCH 1 1 J 1 DD / and _he T 1, ^N \“ 4-((6-(1 -(ot/?eot-butyl)-1R-pyrazol4-yl)pyrazin-2-yl)((4-(4-methoxy3,5 - dimethyl phenyl)bicyclo [2.2. 2] octan-1 -yl)methyl)carbamoyl) (trans-cyclohexyl)-3 hydroxyazetidine-1-carboxylate 699.2 3.14 o XU 1 1 J 1 VT/U n^n Η 1 ill . ''qUO/_he\, ^N \ ^X 4-((4-(1 -(from/?eot-butyl)-1R-pyrazol4-yl)pyrimidin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1 -yl)methyl) carbamoyl)(from/?w/s-cyclohexyl)-3hydroxyazetidine-1-carboxylate 685.6 3.15 I O d °4 Mz ' o / 4-((4-(1 -(ot/?eot-butyl)-1R-pyrazol4-yl)pyrimidin-2-yl)((4-(4methoxy-3,5-d immethylphenyl)bicyclo[2.2.2] octan-1yl)methyl)carbamoyl)(/??/l7//scyclohexyl)-3 - hydroxyase etidine1-carboxylate 699.6

Alternative conditions: Stage 1a: temperature -60°C; 3-24 hours; In some cases, 1 equivalent was used. AcOH. Stage 1b: temperature -30°C; 16 hours-4 days. Stage 2: toluene/CH ₂ C1 ₂ (2:1) as solvent; 0-80°C; 15 min-5 h; In some cases, DMAP was not used. Stage 3: 1-5 hours; In some cases, 6 equiv was used. drive HCl. Stage 4a: In some cases, more than 1.5 eq. CDI is required for complete conversion to acylimidazole; temperature -80°C; 1-18 hours. Stage 4b: 1.5 hours-5 days; iso-Pr ₂ NEt is typically added before the amine; iso-Pr ₂ NEt was not used if the amine is a free base.

Connection 4.

4-(((4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4-(1-(tert-pentyl)-1H-pyrazol-4yl)pyridin- 2-yl)carbamoyl)cyclohexyl-trans-3-hydroxyazetidine-1-carboxylate

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Step 1: H-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2|octan-1-yl)methyl)-4-(1-(tert-pentyl)-1Hpyrazol-4 -yl) pyridine-2-amine.

Sodium triacetoxyborohydride (689.1 mg, 3.25 mmol) was added to a solution of intermediate 2 (420.0 mg, 1.63 mmol), intermediate 9 (449.3 mg, 1.95 mmol) and 1,2- dichloroethane (10 ml) at 0°C in an N2 atmosphere. The mixture was left stirring at room temperature overnight, diluted with saturated NaHCO ₃ (20 ml) and then extracted with CH2C12 (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated, and then purified by silica gel chromatography (CH ₂ Cl ₂ /CH ₃ OH=80/1^50/1) to obtain N -((4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-4-( 1 -(tert-peptyl)-1H-pyrazol-4-yl)pyridin-2amine ( 600 mg, 78%) as a red solid. 'H NMR (400 MHz, CDCl ₃ ): δ 7.86-7.82 (m, 3H), 7.11 (s, 1H), 7.09 (s, 1H), 6.80-6.63 (m, 3H), 6.60-6.55 (m, 1H), 3.81 (s, 3H), 3.10 (d, 2H), 2.22 (s, 3H), 1.981.90 ( m, 2H), 1.84-1.83 (m, 5H), 1.65-1.62 (m, 13H), 0.76-0.67 (m, 3H).

Step 2: tert-4-((tert-butyldimethylsilyl)oxy)-H-((4-(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-H-(4-( 1-(tert-pentyl)-1H-pyrazol-4-yl)pyridin-2yl)cyclohexanecarboxamide.

A solution of propylphosphine anhydride (50% purity in EtOAc, 1.4 ml, 2.28 mmol) was added to the mixture of N((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl )-4-(1-(tert-pentyl)-1H-pyrazol-4yl)pyridin-2-amine (400.0 mg, 0.85 mmol), Et ₃ N (0.48 ml, 3.39 mmol) , DMAP (31.0 mg, 0.25 mmol), intermediate 10 (415.5 mg, 4.61 mmol) and CH2Cl2 (10 ml). The mixture was stirred at 40°C for 3 hours, poured into water (10 ml), and then extracted with CH ₂ Cl ₂ (10 ml x 4). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered, concentrated, and then purified by silica gel chromatography (CH ₂ Cl ₂ /CH ₃ OH = 200/1 ^ 150/1) to obtain tert4 -((tert-butyldimethylsilyl)oxy)-H-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-H(4-(1-(tert- pentyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide (700 mg, 77%) as a red solid. Ή NMR (400 MHz, CDC13): δ 8.43 (d, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.30-7.27 (m, 2H), 7.04-7.02 (m, 2H),7.72 (d, 1H), 3.80-3.79 (m, 1H), 3.78 (s, 3H), 3.60-3, 55(m, 2H), 2.32-2.18 (m, 2H), 2.05 (s, 3H), 2.00-1.96 (m, 15 H), 1.82 (s, 6H ), 1.73-1.64 (m, 4H), 1.04-1.12 (m, 2H), 0.89-0.87 (m, 9H), 0.79-0.75 (m , 3H), 0.064 (s, 6H); LCMS: 713.6 [M+H]+.

Step 3: tert-4-hydroxy-H-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-H-(4(1 -(tert-pentyl) )-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide.

Aqueous hydrochloric acid (1 M, 0.56 mL, 0.56 mmol) was added dropwise to the solution of tert-4-((tert-butyldimethylsilyl)oxy)-H-((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1yl)methyl)-H-(4-(1-(tert-pentyl)-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexanecarboxamide (400 mg, 0.56 mmol ), THF (5 ml) and CH3OH (5 ml) at 0°C. The mixture was stirred at RT for 4 hours, poured into saturated NaHCO ₃ (20 ml), and then extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered, concentrated and then purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/0^3/1) to give tert-4-hydroxy -H-((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)-H-(4-(1-(tretpentyl)-1H-pyrazol-4-yl )pyridin-2-yl)cyclohexanecarboxamide (370 mg, 63%) as a white solid. Ή NMR (400 MHz, DMSO-d^: δ 8.59 (s, 1H), 8.41 (d, 1H), 8.16 (s, 1H), 7.73 (s, 1H), 7. 58 (d, 1H), 7.01-6.95 (m, 2H), 6.72 (d, 1H), 4.41 (d, 1H), 3.71-3.70 (m, 5H) , 3.33-3.32 (m, 1H), 2.24-2.22 (m, 1H), 2.08 (s, 3H), 1.88-1.86 (m, 2H), 1 .62-1.60 (m, 4H), 1.58-1.54 (m, 12H), 1.37-1.34 (m, 8H), 0.83-0.80 (m, 2H) , 0.65 (t, 3H); LCMS: 599.4 [M+H]+.

Step 4: tert-4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4-(1-(tert-pentyl)1H-pyrazol- 4-yl)pyridin-2-yl)carbamoyl)cyclohexyl-3-hydroxyazetidine-1-carboxylate.

1,1'-Carbonyldiimidazole (60.9 mg, 0.37 mmol) was added at room temperature to a solution of tert-4-hydroxy-N((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2] octan-1-yl)methyl)-H-(4-(1-(tert-pentyl)-1H-pyrazol-4yl)pyridin-2-yl)cyclohexanecarboxamide (150.0 mg, 0.25 mmol) and CH3CN ( 5 ml). The mixture was stirred at 80°C overnight and cooled to room temperature. N,N-diisopropylethylamine (71.2 mg, 0.55 mmol) was added followed by azetidin-3-ol hydrochloride (54.9 mg, 0.50 mmol). The mixture was stirred at room temperature overnight, poured into H2O (10 ml) and then extracted with ethyl acetate (10 ml x 4). The organic layer was washed with brine (10 ml), dried over Na2SO4, filtered, concentrated and then purified by pre-HPLC (water (0.04% HCl)-CH ₃ CN) to give tert-4-(((4 -(4-methoxy-3methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4-(1-(tert-pentyl)-1H-pyrazol-4-yl)pyridin-2yl)carbamoyl)cyclohexyl- 3-hydroxyazetidine-1-carboxylate (80.5 mg, 45%). 'H NMR (400 MHz,

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DMSO- _d6 ): δ 8.59 (s, 1H), 8.40 (d, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.58 (d, 1H ), 7.00-6.97 (m, 2H), 6.76 (d, 1H), 5.75-5.73 (m, 1H), 4.74-4.35 (m, 2H), 3.99-3.95 (m, 2H), 3.72-3.70 (m, 5H), 3.57-3.54 (m, 2H), 2.33-2.22 (m, 1H ), 2.08 (s, 3H), 2.88-2.84 (m, 6H), 1.62-1.57 (m, 7h), 1.54 (s, 6H), 1.38- 1.37 (m, 1H), 1.36-1.34 (m, 6H), 1.07-0.91 (m, 2H), 0.65 (t, 3H); LCMS: 698.5 [M+H]+.

The compounds below were synthesized from the corresponding intermediates based on the procedures described for compound 4.__________________________________________________________

Conn. Structure Name [M+N] ⁺ 4.01 About wvXA _N X L-—Α _ο Α _ν ^. II JL II, \South-on 4-(((4-(4-methoxy-3 - methyl phenyl)bicyclo[2.2.2]octan-1yl)methyl)(4-( 1 -(tert-pentyl)- Shpirazol-4-yl)pyridin-2-yl)carbamoyl)cyclohexyl-trsh/s- 3 hydroxy-3-methyl azetide in-1 carboxylate 712.4 4.02 / ABOUT / O u A O T 4-(((4-(4-methoxy-3 - methyl phenyl)bicyclo [2.2.2] octan-1yl)methyl)(4-( 1 -(tert-pentyl)- 1Hpyrazol-4-yl)pyridin-2-yl) carbamoyl)cyclohexyl-/and/> sh/s-4hydroxypiperidine-1-carboxylate 726.5 4.03 °u xz 0 T 4-(((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2] octan-1 -yl)methyl)(4(1 -(tert-pentyl)-1H- and irasol-4yl)pyridine -2-yl)carbamoyl) cyclohexyl-ot/?sh/s-(3 hydroxypropyl)carbamate 700.5

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4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4(1 -(3-methylpentan-3-yl)- 1Hpyrazol-4-yl )pyridin-2-yl) carbamoyl) cyclohexyl-/7?/l7//c'-3 hydroxyazetidine-1-carboxylate 4-(((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2] octane -1 -yl)methyl)(4(1 -(3-methylpentan-3-yl)- 1Hpyrazol-4-yl)pyridin-2-yl) carbamoyl) cyclohexyl-/7?/7<7//с'- 3 hydroxy-3-methyl azetide in-1 carboxylate

4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4(1 -(3-methylpentan-3-yl)- 1Hpyrazol-4-yl )pyridin-2yl)carbamoyl)cyclohexyl-/7?/7<7//c4-hydroxypiperidine-1 carboxylate

4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4(1 -(3-methylpentan-3-yl)- 1Hpyrazol-4-yl )pyridin-2yl)carbamoyl)cyclohexyl-/7?/7<7//с(3-hydroxypropyl)carbamate 4-((4-( 1 -(3-ethylpentan-3-yl)- 1Hpyrazol-4-yl) pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl-/7?/7<7//c'-3 hydroxyazetidine -1-carboxylate

712.5

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4.09 О n > о 11 JLH , f IA / / r OH ° \ N— V= _N ' ^XF 4-(((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)(4(1-(1,1,1-trifluoro-2-methylpropan-2yl) - 1//-pyrazol-4-yl)pyr idin-2yl)carbamoyl)cyclohexyl-t/g///c3 -hydroxyazetidine-1-carboxylate 738.5 4.10 ¹ X O d A o ' o / 4-((4-( 1 -(tert-butyl)-1 H-and irazol3-yl)pyridin-2-yl)((4-(4-methoxy3-methylphenyl)bicyclo[2.2.2]octan1 -yl) methyl)carbamoyl) cyclohexyl-trsh/s-3 hydroxyazetidine-1-carboxylate 684.6 4.11 ¹ / o / Τ' °)=o d o X 4-((4-(4-(otreot-butyl)-1Nimidazol-1-yl)pyridin-2-yl)((4-(4methoxy-3-methylphenyl)bicyclo [2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl-trans-3 hydroxyazetidine-1-carboxylate 684.6

Alternative conditions: stage 2: ¹ He used DMAP; all night long. Stage 3: 1-4 hours. Stage 4a: 3.5 hours-all night; 50-80°C; In some cases more than 1.5 equiv was needed. CDI for complete conversion to acylimidazole; Stage 4b: 1 hour-all night; Iso-P^Net was not used if the amine was the free base.

Example A-1. Parenteral pharmaceutical composition.

To prepare a parenteral pharmaceutical composition suitable for injection (subcutaneous, intravenous), 1-1000 mg of a compound described in the present invention, or a pharmaceutically acceptable salt or solvate thereof, was dissolved in sterile water and then mixed with 10 ml of 0.9% sterile saline solution. Optionally, a suitable buffer is added, as well as an optional acid or base to adjust the pH value. The mixture was included in a dosage unit 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, is added to water (with optional solubilizer(s), optional buffer(s), and taste masking adjuvants) with providing 20 mg/ml solution.

Example A-3. Oral tablet.

A tablet was prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight microcrystalline cellulose, 1-10% by weight low-substituted hydroxypropylcellulose, and 1-10% by weight magnesium stearate or other appropriate aids. The 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 prepare a pharmaceutical composition for oral delivery, 10-500 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder mixture. The mixture is 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 closed.

Example A-5. Gel composition for topical use.

To prepare a pharmaceutical gel composition for topical use, a compound described herein, or a pharmaceutically acceptable salt thereof, was mixed with hydroxypro

- 101 047314 pilcellulose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then included in containers, such as tubes, that are suitable for topical administration.

Example B-1. In Vitro FXR Assay (TK).

Sowing.

CV-1 cells were seeded at a density of 2,000,000 cells in a T175 flask with DMEM + 10% FBS, double charcoal stripped, and incubated at 37°C in 5% CO2 for 18 h (O/N).

Transfection.

After 18 h of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% double charcoal-stripped serum. In a polypropylene tube, 2500 μl of OptiMEM (Life Technologies, cat. no. 31985-062) was combined with expression plasmids for hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP. The tube was then shaken for a short period of time and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP from Roche, catalog no. 06 366 236 001) was added to the OptiMEM/plasmid mixture, vortexed and incubated at room temperature for 20 minutes. After incubation, the transfection reagent/DNA mixture complex was added to the cells in a T175 flask and the cells were incubated at 37°C in 5% CO2 for 18 h (O/N).

Tested connections.

Compounds were serially diluted in DMSO and added to transfected CV-1 cells. The cells were then incubated for 18 hours. The next day, the cells were lysed and examined for luminescence.

Representative data for exemplary compounds disclosed herein are given in Table. 2.

table 2

Compound TK hFXR: EC50 1 ++ 1.01 ++ 1.02 ++ 1.03 ++ 1.04 ++ 1.05 ++ 1.06 ++ 1.07 ++ 1.08 ++ 1.09 +++ 1,Yu ++ 1,I ++ 1.12 +++ 1.13 ++

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4.08

4.09 +++

4.10

4.11 '+++' means EC50 <0.01 µM, '++' means 5 EC 0 >0.01 µM and <1 µM.

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

Sowing.

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

Transfection.

After 18 h of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% double charcoal-stripped serum. In a polypropylene tube, 2500 μl of OptiMEM (Life Technologies, cat. no. 31985-062) was combined with expression plasmids for hFXR, hRXR, hSHP-luc, and pCMX-YFP. The tube was then shaken for a short period of time and incubated at room temperature for 5 minutes. Transfection reagent (X-tremeGENE HP from Roche, catalog no. 06 366 236 001) was added to the OptiMEM/plasmid mixture, vortexed and incubated at room temperature for 20 minutes. After incubation, the transfection reagent/DNA mixture complex was added to the cells in a T175 flask and the cells were incubated at 37°C in 5% CO2 for 18 h (O/N).

Tested connections.

Compounds were serially diluted in DMSO and added to transfected CV-1 cells. The cells were then incubated for 18 h.

The next day, cells were lysed and examined for luminescence.

Example B-3. Study of NASH activity (STZ model).

NASH was induced in C57BL/6 males by a single subcutaneous injection of 200 μg STZ 2 days after birth followed by ad libitum high-fat feeding (HFD) after 4 weeks of age. While the HFD was continued, doses of compounds were administered over 4-8 weeks to determine the effect on NASH. Fasting glucose was measured throughout the study using a portable glucose meter. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglyceride (TG) were measured using a clinical chemistry analyzer. TG content in liver tissue was measured using a Triglyceride E-test kit (Wako, Tokyo, Japan). Histological analysis of liver sections was performed on tissue embedded in Tissue-TEK O.C.T., flash frozen in liquid nitrogen and stored at -80°C. Sections were cut (5 μm), air dried, and fixed in acetone. For hematoxylin and eosin staining, liver sections were pretreated with Bouin's solution and then stained with hematoxylin and eosin solution. The degree of liver fibrosis (zone-3) was assessed using Sirius red staining.

Example B-4. Study of NASH activity (AMLN model).

NASH was induced in C57BL/6 males 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 maintained on this diet for 29 weeks. After 26 weeks of nutritional induction, liver biopsies were performed for initial histological assessment 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 administered FXR agonists daily by gavage for 8 weeks. At the end of the study, a liver biopsy was performed to evaluate liver steatosis and fibrosis by examining tissue sections stained with H and E and Sirius red, respectively. Total collagen content in the liver was measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Triglyceride and total cholesterol contents in liver homogenates were measured in single measurements using a Cobas C-111 autoanalyzer with a commercial kit (Roche Diagnostics, Germany) according to the manufacturer's instructions.

Example B-5. CCl ₄ fibrosis model.

Fibrosis was induced in male BALB/c mice by administering CCl ₄ times every two weeks via intraperitoneal injection. CCl ₄ was obtained in oil at a ratio of 1:1 and administered intraperitoneally in an amount of 1 ml/kg. After 2-4 weeks of fibrosis induction, compounds were administered daily by gavage for 2-6 weeks of treatment, while CCl ₄ was continued. At the end of the study, the liver was fixed in formaldehyde and stained with Sirius red for histopathological assessment of fibrosis. Total collagen content was measured by colorimetric determination of hydroxyproline residues by acid hydrolysis of collagen. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using a clinical chemistry analyzer.

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Example B-6. Model of intrahepatic cholestasis.

Experimental intrahepatic cholestasis induced by administration of 17a-ethinyl estradiol (E2) to rodents is a widely used in vivo model to study the mechanisms involved in estrogen-induced cholestasis. Intrahepatic cholestasis was induced in adult male mice by subcutaneous injection of 10 mg kg 17a-ethinyl estradiol (E2) daily for 5 days. Testing of FXR ligands was performed by administering the compounds during the induction of cholestasis by E2. Cholestatic effects were quantified by assessing liver-to-body weight ratios and measuring total serum bile acid and alkaline phosphatase levels using reagents and controls from Diagnostic Chemicals Ltd. and Cobas Mira plus CC analyzer (Roche Diagnostics). For histology and mitosis measurements, liver samples from each mouse were fixed in 10% neutral buffered formalin. Sections 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-7. Direct regulation of the target gene.

Direct regulation of target genes by FXR ligands was assessed by dosing mice with compounds either at time points or chronically and collecting tissues at various time points after dosing. RNA was isolated from tissues such as ileum and liver and reverse transcribed to cDNA for qPCR analysis of genes known from the literature to be directly and indirectly regulated by FXR, such as SHP, BSEP, IBABP, FGF15, CYP7A1, CYP8B1 and C3.

Example B-8. Study of PK in mice.

The plasma pharmacokinetics of any of the compounds described herein as a test drug were measured after a single bolus intravenous and oral administration to mice (CD-1, C57BL and diet-induced obese mice). The test drug was prepared intravenously in a solution of DMSO, PEG400, hydroxypropyl-β-cyclodextrin (HPeCD) and administered (eg at a dose of 3 ml/kg) at selected dose levels. The oral formulation was prepared in appropriate oral dosing media (vegetable oils, PEG400, Solutol, citrate buffer, or carboxymethylcellulose) and administered at a dose volume of 5 ~ 10 ml/kg at selected dose levels. Blood samples (approximately 0.15 ml) were collected by cheek pouch method at predetermined time intervals after intravenous or oral dosing into tubes containing EDTA. Plasma was isolated by centrifuging the blood at 10,000 g for 5 minutes, and aliquots were transferred into a 96-well plate and stored at 60°C or lower until analysis.

Test drug calibration standards were prepared by diluting the DMSO stock solution with DMSO over a range of concentrations. Aliquots of calibration standards in DMSO were combined with plasma from naïve mice such that the final concentrations of calibration standards in plasma were 10-fold lower than the calibration standards in DMSO. Plasma samples for PK assessment were combined with blank DMSO to match the matrix. Calibration standards and samples for PK measurements were combined with ice-cold acetonitrile containing the analytical internal standard and centrifuged at 1850 g for 30 min at 4°C. Supernatant fractions were analyzed by LC/MS/MS and quantified using a calibration curve. Pharmacokinetic parameters (area under the curve (AUC), _Cmax , _Tmax , half-life (T1 _/2 ), clearance (CL), volume of distribution at steady state ( _Vdss ) and mean residence time (MRT)) were calculated using non-compartmental analysis using Microsoft Excel (version 2013).

Example B-9. Rat model ANIT.

The compound described herein was evaluated in a chronic cholestasis treatment model over a dose range (eg, at doses ranging from 0.01 to 100 mg/kg). This model was used to evaluate the suitability of using FXR agonists, such as the compound described herein, for the treatment of cholestatic liver diseases such as bile acid malabsorption (eg, primary or secondary hologenic diarrhea), bile reflux gastritis, collagenous colitis, lymphocytic colitis, inflammatory bowel disease, unspecified colitis, Alagille syndrome, biliary atresia, ductopenic liver graft rejection, graft-versus-host disease associated with bone marrow or stem cell transplantation, fibrocystic degeneration of the liver, and liver disease associated with parenteral nutrition.

Rats were administered alpha-naphthylisothiocyanate (ANIT) (0.1% w/w) in the diet for 3 days prior to treatment with a compound described herein at a range of doses (e.g., at doses ranging from 0.01 to 100 mg/kg). The control group without cholestasis was fed a standard diet without ANIT and served as control animals without cholestasis (Control). After 14 days of oral dosing, rat serum was analyzed for analyte levels. LLQ, lower limit of quantitation. Mean ± SEM; n = 5.

Levels of indicators of hepatobiliary damage were measured in rat serum, such as elevated levels of circulating aspartate aminotransferase (AST), alanine aminotransferase

- 106 047314 (ALT), bilirubin and bile acids. Exposure to ANIT caused severe cholestasis and hepatocellular damage. A compound that improves many of these parameters is useful in the treatment of the above diseases or conditions.

Decreased hepatic bile acid accumulation, increased biliary excretion of bile acids, and inhibition of bile acid synthesis are consistent with the pharmacologic action of an FXR agonist. Improvement in conjugated serum bilirubin (a direct measure of liver function) indicates resolution of cholestasis with improved excretion of bile acids.

In addition, an assay was performed to determine 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 circulation and signals the liver to suppress the expression of CYP7A1 synergistically with SHP. The direct FXR-dependent induction of FGF15/19 along with the anticholestatic properties of FGF15/19 makes it a useful serum biomarker for detecting targeted FXR agonist interactions.

Serum FGF15 levels were quantified using the FGF15 Meso Scale Discovery (MSD) assay. For example, a mouse anti-FGF15 antibody from R&D Systems (AF6755) was used in the assay as both capture and detection antibodies. MSD SULFO-TAG NHS ester was used to tag the anti-FGF15 antibody. Standard 96-well MSD plates were coated with FGF15 capture antibodies and the plates were blocked with MSD Blocker A reagent (R93AA-2). After washing the plate with PBS + 0.05% Tween 20, MSD 4 was added to each well and incubated for 30 min. 25 μl of calibrator or sample dilutions (serum or EDTA plasma) were added to each well and incubated with shaking at room temperature.

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

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of the present invention and the scope of the appended claims.

Example B-10. Mouse model of chronic DSS colitis.

Chronically dextran sulfate sodium (DSS) induced mice were used to test the therapeutic potential of compounds against inflammatory bowel disease (IBD). Chronic colitis was induced by administering DSS to mice in drinking water. For example, 2% DSS in drinking water for 5 days and regular drinking water for 5 days, then this cycle of administration was repeated two more times with higher concentrations of DSS, 2.5% and 3%, respectively, for a total of three cycles. Colitis developed approximately after the first cycle of DSS administration, which was monitored by body weight loss, stool consistency, and rectal bleeding. The FXR agonist was tested by administering to mice simultaneously with the initiation of 2% DSS with water. Alternatively, FXR agonist testing was performed after the first cycle of 2% DSS with water and plain water. During the period of administration of the FXR agonist to mice, therapeutic effects were monitored by monitoring body weight, stool consistency, and rectal bleeding. After euthanasia, disease progression and FXR agonist effects were further quantified by measuring colon weight and length, colon histology using H and E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of disease-associated genes.

Example B-11. Mouse model of colitis with adoptive T cell transfer.

The T cell adoptive transfer colitis model has been accepted as a relevant mouse model of human inflammatory bowel disease (IBD). To induce colitis in this model, a population of CD4 T cells was isolated from the spleen of donor mice, then the high CD4+CD45RB T cell subpopulation was purified by cell sorting using flow cytometry. The purified CD4+CD45RB high T cell subset was injected into the peritoneal cavity of SCID recipient mice. Colitis developed approximately three to six weeks after T-cell transfer, which was monitored by body weight loss (although body weight loss can be variable), loose stool, or bloody diarrhea. FXR agonist testing was initiated concomitantly with the injection of a purified CD4+CD45RB high T cell subset into SCID recipient mice. Alternatively, the FXR agonist was administered two or three weeks after T cell transfer, when the model had already developed colitis. During the period of administration of the FXR agonist to mice, therapeutic effects were monitored by monitoring body weight, stool consistency, and rectal bleeding. After euthanasia, disease progression and FXR agonist effects were further quantified by measuring colon weight and length, colon and ileal histology using H and E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of genes associated with disease.

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Example B-12. Mdrla-/- mouse model.

The Mdrla-/- mouse model is a model of spontaneous colitis that is being used to test new therapeutics for the treatment of human IBD. Loss of the Mdr1a gene in this model results in disruption of intestinal barrier function, leading to increased infiltration of intestinal bacteria and subsequent colitis. Under proper housing conditions, Mdr1a −/− mice developed colitis at approximately 8–13 weeks of age. During disease progression, the Disease Activity Index (DAI), which summarizes clinical observation scores of rectal prolapse, stool consistency, and rectal bleeding, was used to monitor disease. FXR agonist testing was initiated early in the disease, typically with a DAI value of less than 1.0. Alternatively, FXR agonist administration was started when colitis had already developed, usually when the DAI value was greater than 2.0. The therapeutic effects of the FXR agonist were monitored by measuring DAI, and testing was stopped when the desired disease severity was achieved, typically at a DAI value of approximately 5.0. After euthanasia, disease progression and FXR agonist effects were further quantified by measuring colon weight and length, colon histology using H and E staining for inflammation and structural changes in the mucosa, and protein and RNA expression of disease-associated genes.

The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of the present invention and the scope of the appended claims.

Claims (11)

1. A compound of formula (I') or a pharmaceutically acceptable salt thereof: Where: ring A represents X ¹ represents N; X ⁵ , X ⁶ and X ⁷ each represent CR ⁷ ; R ¹ represents C1- _C4 alkoxy; X ² represents CR ² ; R ² represents C1- _C4 alkyl; X ³ represents CR ³ ; R ³ represents H, C1-C ₄ alkyl; each X ⁴ represents CH; R ⁴ and R ⁵ are taken together to form a bridge, which is -CH2CH2-; L missing; each R ⁷ is independently selected from H and halogen; R ⁸ represents C ₄ -C ₈ -alkyl or C ₄ -C ₈ -haloalkyl; R ⁹ represents H; R ¹⁰ is -OC(=O)N(R ¹² )(R ¹³ ); R ¹¹ represents H; R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 4-, 5- or 6-membered heterocycloalkyl ring substituted with 1, 2 or 3 groups selected from -OH, -N(C1-C4-alkyl) 2, C1C6-alkyl, -S(=O)2(C1-C4-alkyl), -C1-C4-alkyl-S(=O)2(C1-C4-alkyl), -C1-C6-alkyl-OR ¹⁷ and -O-C1-C ₆ -alkylOR ¹⁷ ; R represents H or CpC ₆ -alkyl; m represents 0; and n represents 0. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is characterized by the structure of formula (Ia') or a pharmaceutically acceptable salt thereof: - 108 047314 Formula (la’). 3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein X ⁵ , X ⁶ and X ⁷ are CH. 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, where R ⁸ represents -C(CH ₃ ) ₃ . 5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, where R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a 4-membered or 5-membered heterocycloalkyl ring substituted with 1 or 2 groups, selected from -OH, -N(C ₁ -C ₄ -αalkyl) ₂ and C ₁ -C ₆ -alkyl. 6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ represents ^he 7. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, where R ¹⁰ represents is itself 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein X ³ represents CH. 9. The connection according to claim 1, which is: or a pharmaceutically acceptable salt thereof. 10. Connection selected from: - 109 047314 - 110 047314 - 111 047314 or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition containing a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.