Combinations with benzodioxole as GLP-1R agonists for use in the treatment of NASH / NAFLD and related diseases

Description

FIELD OF THE INVENTION

[0001] The invention relates to combinations for use in methods for treating nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease.BACKGROUND OF THE INVENTION

[0002] Nonalcoholic steatohepatitis (NASH) is a clinical and histological subset of non-alcoholic fatty liver disease (NAFLD, defined as presence of >5% hepatic steatosis) that is associated with increased all cause mortality, cirrhosis and end stage liver disease, increased cardiovascular mortality, and increased incidence of both liver related and non liver related cancers (Sanyal et al, Hepatology 2015;61(4):1392-1405). NAFLD is the most common cause of chronic liver disease in the Western world. It is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, NASH, fibrosis, cirrhosis, end stage liver disease, and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of NAFLD / NASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, a substantial portion do. At the present time, treatment options are limited to lifestyle modification including exercise and diet (EASL-EASD-EASO Clinical Practice Guidelines, J. Hepatol. 2016;64(6):1388-1402).

[0003] Alterations in lipid metabolism have been hypothesized to contribute to the molecular pathogenesis of NAFLD and NASH. Steatosis is a necessary but not sufficient component of the pathogenesis of NASH (Day C, and James O., Hepatology. 1998; 27(6):1463-6). Consistent with this, multiple studies have demonstrated that the severity of steatosis predicts the risk of concomitant steatohepatitis as well as the risk of progression to cirrhosis (Sorensen et al, Lancet. 1984; 2(8397): 241-4; Wanless I and Lentz J, Hepatology 1990;12(5):1106-10; Reeves H, et al, J. Hepatol. 1996; 25(5): 677-83). Hepatic steatosis is a consequence of an imbalance in TG production / uptake into the liver and clearance / removal (Cohen JC, et al, Science. 2011; 332(6037):1519-1523). It is hypothesized that reducing steatosis, the metabolic driver underpinning the development of NAFLD / NASH, will result in subsequent improvements in hepatic inflammation and fibrosis.

[0004] Savage, et al., demonstrated that ACC1 and ACC2 are both involved in regulating fat oxidation in hepatocytes while ACC1, the dominant isoform in rat liver, is the sole regulator of fatty acid synthesis. Furthermore, in their model, combined reduction of both isoforms is required to significantly lower hepatic malonyl-CoA levels, increase fat oxidation in the fed state, reduce lipid accumulation, and improve insulin action in vivo. Thus, hepatic ACC1 and ACC2 inhibitors may be useful in the treatment of NAFLD and hepatic insulin resistance. See, Savage, D. B., et al., "Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2" J. Clin. Invest. 2006;116(3):817-24. See also, Oh, W., et al., "Glucose and fat metabolism in adipose tissue of acetyl-CoA carboxylase 2 knockout mice" PNAS, 102(5) 1384-1389 (2005).

[0005] Acetyl-CoA Carboxylase (ACC) play a key role in regulating lipid metabolism. ACC catalyzes an essential and rate limiting step in the process of de novo lipogenesis (DNL) (Saggerson D, Annu. Rev. Nutr. 2008; 28:253-72.). Further, ACC also regulates mitochondrial beta-oxidation of fatty acids through allosteric regulation of the enzyme carnitine palmitoyltransferase 1 (CPT1) (Saggerson, 2008; Waite M, and Wakil SJ. J. Biol. Chem. 1962;237:2750-2757.). Emerging data also suggest that suppression of DNL through ACC inhibition may directly reduce inflammation by restraining the formation of the inflammatory interleukin-17 (IL-17) secreting T-cells of the T helper 17 lineage (Th17 cells) and favoring the development of anti-inflammatory FoxP3(+) regulatory T (Treg) cells (Berod L, et al. Nat. Med. 2014; 20(11): 1327-33). Recently, ACC inhibtion has also been shown to suppress primary human hepatic stellate cell activation in-vitro and reduce hepatic fibrosis in rat models (Ross et al, Abstract PS-132 Journal of Hepatology 2019 vol. 70 page e86).

[0006] Inhibition of ACC activity is hypothesized to be beneficial to patients with NASH by at least three independent mechanisms. As summarized above, humans with NAFLD show marked elevations in hepatic DNL and normalization of this increased flux through pharmacologic hepatic ACC inhibition is hypothesized to reduce steatosis. Consistent with this, ACC inhibitors have been shown to inhibit DNL. In addition, the effect of ACC inhibtions to increase fatty acid oxidation may also contribute to reduce liver fat content.. See Griffith DA, et al. J. Med. Chem. 2014;57(24):10512-10526; Kim CW, et al. Cell Metab. 2017;26, 394-406; Stiede K,, et al. Hepatology. 2017;66(2):324-334; Lawitz EJ, et al. Clin Gastroenterol Hepatol. 2018 (https: / / doi.org / 10.1016 / j.cgh.2018.04.042). In addition, inhibition of DNL in IL-17 secreting T-cells is expected to suppress hepatic inflammation by restraining the formation of the inflammatory Th17 cells (Berod et al., 2014), a pathway that may be important in NASH pathogenesis (Rau M, et al. J. Immunol. 2016;196(1):97-105), and favoring the development of anti-inflammatory Treg cells. Further, ACC inhibition may reduce stellate cell activation and fibrosis (Ross et al., 2019)

[0007] 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid is a selective ACC inhibitor and was prepared as the free acid in Example 9 of U.S. Patent No. 8,859,577, which is the U.S. national phase of International Application No. PCT / IB2011 / 054119. Crystal forms of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid, including an anhydrous mono-tris form (Form 1) and a trihydrate of the mono-tris salt (Form 2), are described in International PCT Application No. PCT / IB2018 / 058966.

[0008] Triglycerides or triacylglycerols (TG) represent a major form of energy storage in mammals. TG's are formed by the sequential esterification of glycerol with three fatty acids of varying chain lengths and degrees of saturation (Coleman, R. A., and Mashek, D. G. 2011. Chem. Rev. 111: 6359-6386). TG synthesized in the intestine or liver are packaged into chylomicrons or very low-density lipoprotein (VLDL), respectively, and exported to peripheral tissues where they are hydrolysed to their constituent fatty acids and glycerol by lipoprotein lipase (LPL). The resultant non-esterified fatty acids (NEFA) can either be metabolised further to produce energy or reesterified and stored.

[0009] Under normal physiological conditions, the energy-dense TG remains sequestered in various adipose depots until there is a demand for its release, whereupon, it is hydrolyzed to glycerol and free fatty acids which are then released into the blood stream. This process is tightly regulated by the opposing actions of insulin and hormones such as catecholamines which promote the deposition and mobilization of TG stores under various physiological conditions. In the post-prandial setting, insulin acts to inhibit lipolysis, thereby, restraining the release of energy in the form of NEFA and ensuring the appropriate storage of dietary lipids in adipose depots. However, in patients with type 2 diabetes, the ability of insulin to suppress lipolysis is impaired and NEFA flux from adipocytes is inappropriately elevated. This, in turn, results in increased delivery of lipid to tissues such as muscle and liver. In the absence of energetic demand the TG and other lipid metabolites, such as diacylglycerol (DAG) can accumulate and cause a loss of insulin sensitivity (Erion, D. M., and Shulman, G. I. 2010. Nat Med 16: 400-402). Insulin resistance in muscle is characterized by reduced glucose uptake and glycogen storage, whilst in the liver, loss of insulin signaling gives rise to dysregulated glucose output and overproduction of TG-rich VLDL, a hallmark of type 2 diabetes (Choi, S. H., and Ginsberg, H. N. 2011. Trends Endocrinol. Metab. 22: 353-363). Elevated secretion of TG-enriched VLDL, so called VLDL1 particles, is thought to stimulate the production of small, dense low-density lipoprotein (sdLDL), a proatherogenic subfraction of LDL that is associated with elevated risk of coronary heart disease (St-Pierre, A. C.et.al. 2005. Arterioscler. Thromb. Vasc. Biol. 25: 553-559).

[0010] In mammals, two diacylglycerol acyltransferases (DGAT) enzymes (DGAT1 and DGAT2) have been characterized. Although these enzymes catalyze the same enzymatic reaction, their respective amino acid sequences are unrelated and they occupy distinct gene families. Mice harboring a disruption in the gene encoding DGAT1 are resistant to diet-induced obesity and have elevated energy expenditure and activity (Smith, S. J. et. al., 2000. Nat Genet 25: 87-90). Dgat1- / - mice exhibit dysregulated postaborpative release of chylomicrons and accumulate lipid in the enterocytes (Buhman, K. K. et.al. 2002. J. Biol. Chem. 277: 25474-25479). The metabolically favorable phenotype observed in these mice is suggested to be driven by loss of DGAT1 expression in the intestine (Lee, B., et.al. 2010. J. Lipid Res. 51: 1770-1780). Importantly, despite a defect in lactation in female Dgat1- / - mice, these animals retain the capacity to synthesize TG suggesting the existence of additional DGAT enzymes. This observation and the isolation of a second DGAT from the fungus Mortierella rammaniana led to the identification and characterization of DGAT2 (Yen, C. L. et.al. 2008. J. Lipid Res. 49: 2283-2301).

[0011] DGAT2 is highly expressed in liver and adipose, and unlike DGAT1, exhibits exquisite substrate specificity for DAG (Yen, C.L., 2008). Deletion of the DGAT2 gene in rodents results in defective intraunterine growth, severe lipemia, impaired skin barrier function, and early postnatal death (Stone, S. J. et.al. 2004. J. Biol. Chem. 279: 11767-11776). Due to the lethality caused by loss of DGAT2, much of our understanding of the physiological role of DGAT2 derives from studies performed with antisense oligonucleotides (ASO) in rodent models of metabolic disease. In this setting, inhibition of hepatic DGAT2 resulted in improvements in plasma lipoprotein profile (decrease in total cholesterol and TG) and a reduction of hepatic lipid burden which was accompanied by improved insulin sensitivity and whole-body glucose control (Liu, Y. et.al. 2008. Biochim. Biophys. Acta 1781: 97-104; Choi, C. S. et.al. 2007. J. Biol. Chem. 282: 22678-22688; Yu, X. X. et.al. 2005. Hepatology 42: 362-371). Although the molecular mechanisms underlying these observations are not fully elucidated, it is clear that suppression of DGAT2 results in a down-regulation of the expression of multiple genes encoding proteins involved in lipogensis, including sterol regulatory element-binding proteins 1c (SREBP1c) and stearoyl CoA-desaturase 1 (SCD1) (Choi, 2007; Yu, 2005). In parallel, oxidative pathways are induced as evidenced by increased expression of genes such as carnitine palmitoyl transfersase 1 (CPT1) (Choi, 2007). The net result of these changes is to decrease the levels of hepatic DAG and TG lipid which, in turn, leads to improved insulin responsiveness in the liver. Furthermore, DGAT2 inhibition suppresses hepatic VLDL TG secretion and reduction in circulating cholesterol levels. Finally, plasma apolipoprotein B (APOB) levels were suppressed, possibly due to decreased supply of TG for lipidation of the newly synthesized APOB protein (Liu, 2008; Yu, 2005). The beneficial effects of DGAT2 inhibition on both glycemic control and plasma cholesterol profile suggest that this target might be valuable in the treatment of metabolic disease (Choi, 2007). In addition, the observation that suppression of DGAT2 activity results in reduced hepatic lipid accumulation suggests that inhibitors of this enzyme might have utility in the treatment of NASH.

[0012] (S)-2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide [including its crystalline solid forms (Form 1 and Form 2)] is a DGAT2 inhibitor described in Example 1 of U.S. Patent No. 10,071,992.

[0013] Ketohexokinase (KHK) is the principal enzyme in fructose metabolism and catalyzes the conversion of fructose to fructose-1-phosphate (F1P). KHK is expressed as two alternative mRNA splice variants, denoted KHKa and KHKc, resulting from alternative splicing of the third exon. The affinity and capacity of KHKc for fructose phosphorylation is much greater than KHKa as evidenced by a much lower Km (Ishimoto, Lanaspa et al., PNAS 109, 4320-4325, 2012). While KHKa is ubiquitously expressed, the expression of KHKc is highest in the liver, kidney and intestines, the primary sites of fructose metabolism in the body (Diggle CP, et al. (2009) J Histochem Cytochem 57:763-774; Ishimoto, Lanaspa, et al., PNAS 109, 4320-4325, 2012). Additionally, loss of function mutations have been reported in humans and termed Essential Fructosuria (OMIM #229800), with no adverse effects except the appearance of fructose in the urine after ingestion of the sugar.

[0014] A more severe condition involved in fructose metabolism is Hereditary Fructose Intolerance (HFI, OMIM #229600) which is caused by defects in aldolase B (GENE: ALDOB) which is the enzyme responsible for breaking down F1P and is immediately downstream of the KHK step in the pathway (Bouteldja N, et. al, J. Inherit. Metab. Dis. 2010 Apr;33(2):105-12; Tolan, DR, Hum Mutat. 1995;6(3):210-8; http: / / www.omim.org / entry / 229600). It is a rare disorder which affects an estimated 1 in 20,000 people, and mutations result in accumulation of F1P, depletion of ATP, and increase in uric acid, the combination of which causes hypoglycemia, hyperuricemia, and lactic acidosis, among other metabolic derangements. HFI impairs the body's ability to metabolize dietary fructose resulting in acute symptoms such as vomiting, severe hypoglycemia, diarrhea, and abdominal distress, leading to long term growth defects, liver and kidney damage and potentially death (Ali M et al, J. Med. Genet. 1998 May:35(5):353-65). Patients generally suffer through the first years of life prior to diagnosis, and the only course of treatment is avoiding fructose in the diet. This is made challenging by the presence of this macronutrient in a majority of food items. In addition to physical symptoms, many patients experience emotional and social isolation as a consequence of their unusual diet, and constantly struggle to adhere to strict dietary limitations (HFI-INFO Discussion Board, http: / / hfiinfo.proboards.com. Accessed 14 December 2015). Even when they appear non-symptomatic, some patients develop NAFLD and kidney disease, which underscores the inadequacy of self-imposed dietary restriction as the only treatment option, and the high unmet medical need for this condition.

[0015] In hyperglycemic conditions, endogenous fructose production occurs through the polyol pathway, a pathway by which glucose is converted to fructose with sorbitol as an intermediate. The activity of this pathway increases with hyperglycemia. In these studies, the authors demonstrated that the KHK null mice were protected from glucose induced weight gain, insulin resistance and hepatic steatosis suggesting that under hyperglycemic conditions, endogenously produced fructose may contribute to insulin resistance and hepatic steatosis (Lanaspa, M.A., et al., Nature Comm. 4, 2434, 2013). Therefore, the inhibition of KHK is anticipated to benefit many diseases where alterations of either or both of endogenous or ingested fructose are involved.

[0016] [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid (including a crystalline free acid form thereof) is a ketohexokinase inhibitor and is described in Example 4 of U.S. Patent No. 9,809,579.

[0017] Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, Type 2 diabetes mellitus, also known as,T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). These may be grouped into six major classes, each acting through a different primary mechanism: (A) Insulin secretogogues, including sulphonyl-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hypoglycemia. (F) sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit reabsorption of glucose in the kidneys and thereby lower glucose levels in the blood. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0018] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, the drugs for T2DM have limited efficacy and do not address the most important problems, the declining β-cell function and the associated obesity.

[0019] Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.

[0020] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia and nonalcoholic fatty liver disease (NAFLD).

[0021] NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of NAFLD / NASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, a substantial portion does.

[0022] GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17 (2): 93-102).

[0023] In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal post-prandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

[0024] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1, liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients such as those with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

[0025] 2-[(4-{6-[(4-Cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically salt thereof [such as its 2-amino-2-(hydroxymethyl)propane-1,3-diol salt, also known as its tris salt] is a GLP-1R agonist described in U.S. Patent No.10,208,019 (see Example 4A-01 of the patent).

[0026] Additional GLP-1R agonists that are useful for the present invention are described in U.S. Provisional Patent Application No. 62 / 684,696 filed June 13, 2018, and U.S. Provisional Patent Application No. 62 / 846,944 filed May 13, 2019.

[0027] The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and is primarily expressed in the liver, kidney and intestine (see, e.g., Seol et al. (1995) Mol. Endocrinol. 9:72-85 and Forman et al. (1995) Cell 81:687-693). It functions as a heterodimer with the retinoid X receptor (RXR) and binds to response elements in the promoters of target genes to regulate gene transcription. The FXR-RXR heterodimer binds with highest affinity to an inverted repeat-1 (IR-1) response element, in which consensus receptor-binding hexamers are separated by one nucleotide. FXR is part of an interrelated process, in that FXR is activated by bile acids (the end product of cholesterol metabolism) (see, e.g., Makishima et al. (1999) Science 284: 1362-1365, Parks et al. (1999) Science 284:1365-1368, Wang et al. (1999) Mol. Cell. 3:543-553), which serve to inhibit cholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem. 275:39313-39317.

[0028] FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis and lipogenesis. (Crawley, Expert Opinion Ther. Patents (2010), 20(8): 1047-1057). In addition to the treatment of dyslipidemia, multiple indications for FXR have been described, including treatment of liver disease, diabetes, vitamin D-related diseases, drug-induced side effects and hepatitis. (Crawley, supra). While advances have been made in the development of novel FXR agonists, significant room for improvement remains.

[0029] The FXR agonist Tropifexor or a pharmaceutically acceptable salt thereof is described in, e.g., Example 1-1B of U.S. Patent No. 9,150,568. The chemical name of Tropifexor is 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid.

[0030] In view of the above, there exists a need for medicaments, for example, oral medicaments, containing combination of GLP-1R agonist and ACC1 and / or ACC2 inhibitors; combination of GLP-1R agonist and DGAT2 inhibitor; combination of GLP-1R agonist and KHK inhibitor; and / or combination of GLP-1R agonist and FXR agonist to treat diseases or disorders including NAFLD, and NASH. The specific combinations for use in treating diseases and conditions described herein satisfy the existing need.

[0031] WO-2019 / 239319 and WO-2018 / 109607 both disclose benzimidazoles and aza analogues thereof which are said to be GLP-1 receptor agonists.SUMMARY OF THE INVENTION

[0032] The invention relates to combinations for use in methods for treating nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease.

[0033] One embodiment (Embodiment A) of the present invention provides a combination comprising (1) GLP-1R agonist and (2) 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the method results in the reduction of at least one point in severity of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring systems, reducing the level of serum markers of nonalcoholic steatohepatitis activity, reducing nonalcoholic steatohepatitis disease activity or reducing the medical consequences of nonalcoholic steatohepatitis in a patient.

[0035] One embodiment (Embodiment D) of the present invention provides a combination comprising (1) GLP-1R agonist and (2) [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the method results in the reduction of at least one point in severity of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring systems, reducing the level of serum markers of nonalcoholic steatohepatitis activity, reducing nonalcoholic steatohepatitis disease activity or reducing the medical consequences of nonalcoholic steatohepatitis in a patient.

[0037] One embodiment (Embodiment G), the present invention provides a combination comprising (1) GLP-1R agonist and (2) (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the method results in the reduction of at least one point in severity of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring systems, reducing the level of serum markers of nonalcoholic steatohepatitis activity, reducing nonalcoholic steatohepatitis disease activity or reducing the medical consequences of nonalcoholic steatohepatitis in a patient.

[0039] One embodiment (Embodiment J) of the present invention provides a combination comprising (1) GLP-1R agonist and (2) 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the method results in the reduction of at least one point in severity of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring systems, reducing the level of serum markers of nonalcoholic steatohepatitis activity, reducing nonalcoholic steatohepatitis disease activity or reducing the medical consequences of nonalcoholic steatohepatitis in a patient.

[0041] Any one of the combinations for use in a method of treating of the invention described here may further optionally comprise at least one other pharmaceutical agent.

[0042] In some embodiments, the at least one other pharmaceutical agent (in the combination for use in a method of treating of the invention) is selected from the group consisting of an acetyl-CoA carboxylase- (ACC) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor, an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a PPARγ agonist, a PPAR α / γ agonist, a biguanide, a glucagon-like peptide 1 (GLP-1) modulator, liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl peptidease IV (DPP-IV) inhibitor, an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa), insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, SGLT2 inhibitors, a glucagon receptor modulator, GPR119 modulators, FGF21 derivatives or analogs, TGR5 receptor modulators, GPBAR1 receptor modulators, GPR40 agonists, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors, inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g. PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including IL1beta, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, choesterol absorption inhibitors, PCSK9 modulators, cholesteryl ester transfer protein inhibitors and modulators of RXRalpha.

[0043] In some embodiments, the at least one other pharmaceutical agent (in the combination for use in a method of treating of the invention) is selected from the group consisting of cysteamine or a pharmaceutically acceptable salt thereof, cystamine or a pharmaceutically acceptable salt thereof, an anti-oxidant compound, lecithin, vitamin B complex, a bile salt preparations, an antagonists of Cannabinoid-1 (CB1) receptor, an inverse agonists of Cannabinoid-1 (CB1) receptor, a peroxisome proliferator-activated receptor) activity regulators, a benzothiazepine or benzothiepine compound, an RNA antisense construct to inhibit protein tyrosine phosphatase PTPRU, a heteroatom-linked substituted piperidine and derivatives thereof, an azacyclopentane derivative capable of inhibiting stearoyl-coenzyme alpha delta-9 desaturase, acylamide compound having secretagogue or inducer activity of adiponectin, a quaternary ammonium compound, Glatiramer acetate, pentraxin proteins, a HMG-CoA reductase inhibitor, n-acetyl cysteine, isoflavone compound, a macrolide antibiotic, a galectin inhibitor, an antibody, or any combination of thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] FIG. 1 is a characteristic x-ray powder diffraction pattern showing crystalline Form 1 of Example DGAT2i Compound (Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)). FIG. 2 is a characteristic x-ray powder diffraction pattern showing crystalline Form 2 of Example DGAT2i Compound (Vertical Axis: Intensity (CPS); Horizontal Axis: Two theta (degrees)). FIG. 3 shows an illustrative PXRD pattern of Form 1 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) carried out on a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. FIG. 4 shows an illustrative Raman spectra of Form 1 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) collected using a Nicolet NXR FT-Raman accessory attached to the FT-IR bench. FIG. 5 shows an illustrative 13< C ssNMR pattern of Form 1 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) conducted on a Bruker-BioSpin CPMAS probe positioned into a Bruker-BioSpin Avance III 500 MHz ( 1< H frequency) NMR spectrometer. FIG. 6 shows an illustrative PXRD pattern of Form 2 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) carried out on a Bruker AXS D4 Endeavor diffractometer equipped with a Cu radiation source. FIG. 7 shows an illustrative Raman spectra of Form 2 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) collected using a Nicolet NXR FT-Raman accessory attached to the FT-IR bench. FIG. 8 shows an illustrative 13< C ssNMR pattern of Form 2 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) conducted on a Bruker-BioSpin CPMAS probe positioned into a Bruker-BioSpin Avance III 500 MHz ( 1< H frequency) NMR spectrometer. FIG. 9 shows an illustrative single crystal structure of Form 2 of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (Example ACCi compound) . FIG. 10 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on plasma triglyceride levels in Western diet fed Sprague Dawley rats, measured at the fed state. FIG. 11 summarizes the effects of oral administration as monotherapy and in combination 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on plasma triglyceride levels in Western diet fed Sprague Dawley rats measured at the fasted state. FIG. 12 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on SREBP-1 nuclear localization in Western diet fed rats. FIG. 13 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on hepatic lipogenic gene expression in Western diet fed rats, specifically acetyl-CoA carboxylase (ACC1). FIG. 14 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on hepatic lipogenic gene expression in Western diet fed rats, specifically fatty acid synthase (FASN). FIG. 15 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on hepatic lipogenic gene expression in Western diet fed rats, specifically sterol-CoA desaturase (SCD1). FIG. 16 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on hepatic lipogenic gene expression in Western diet fed rats, specifically sterol regulatory element-binding protein 1c (SREBP-1c). FIG. 17 summarizes the effect of administration of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide as monotherapy and in combination on hepatic lipogenic gene expression in Western diet fed rats, specifically proprotein convertase subtilisin / kexin type 9 (PCSK9). FIG. 18 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on hepatic triglyceride levels in Western diet fed Sprague Dawley rats. Figure 19 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on elasticity of the liver, a marker of hepatic inflammation and fibrosis, in choline deficient and high fat diet (CDAHFD) fed Male Wistar Hann rats. Figure 20 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on hepatic alpha smooth actin (SMA) immunohistochemisrty, a marker of myofibroblast activation and fibrogenesis, in CDAHFD fed Male Wistar Hann rats. Figure 21 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on hepatic Picosirius red staining in CDAHFD fed Male Wistar Hann rats. Figure 22 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on hepatic alpha smooth actin (SMA) gene expression in CDAHFD fed Male Wistar Hann rats. Figure 23 summarizes the effects of oral administration as monotherapy and in combination of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide on hepatic collagen 1A1 gene expression in CDAHFD fed Male Wistar Hann rats. Figure 24 represents an observed powder X-ray diffraction pattern for an anhydrous (anhydrate) crystal form (Form 1) of tris salt of compound Example 7. Figure 25 represents an observed powder X-ray diffraction pattern for an anhydrous (anhydrate) crystal form (Form A) of tris salt of compound Example 10. DETAILED DESCRIPTION OF THE INVENTION

[0045] The invention may be understood more readily by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein.

[0046] It is to be understood that this invention is not limited to specific synthetic methods of making that may of course vary. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings: As used herein in the specification, "a" or "an" may mean one or more. As used herein in the claim(s), when used in conjunction with the word "comprising", the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

[0047] The term "about" refers to a relative term denoting an approximation of plus or minus 10% of the nominal value it refers, in one embodiment, to plus or minus 5%, in another embodiment, to plus or minus 2%. For the field of this disclosure, this level of approximation is appropriate unless the value is specifically stated to require a tighter range.

[0048] "Compounds" when used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The expression "prodrug" refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form). Exemplary prodrugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of the invention include but are not limited to those having a carboxyl moiety wherein the free hydrogen is replaced by (C 1 -C 4 )alkyl, (C 2 -C 7 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C 1 -C 2 )alkylamino(C 2 -C 3 )alkyl (such as β-dimethylaminoethyl), carbamoyl-(C 1 -C 2 )alkyl, N,N-di(C 1 -C 2 )alkylcarbamoyl-(C 1 -C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2 -C 3 )alkyl.

[0049] As used herein, an arrowhead , or wavy line, denotes a point of attachment of a substituent to another group.

[0050] "Patient" refers to warm blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and humans. A "mammal" is a patient.

[0051] By "pharmaceutically acceptable" is meant that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0052] As used herein, the following terms have the general meaning for administration of pharmaceutical agetns: QD means once daily and BID means twice daily.

[0053] As used herein, the expressions "reaction-inert solvent" and "inert solvent" refer to a solvent or a mixture thereof which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.

[0054] As used herein, the term "selectivity" or "selective" refers to a greater effect of a compound in a first assay, compared to the effect of the same compound in a second assay. For example, in "gut selective" compounds, the first assay is for the half life of the compound in the intestine and the second assay is for the half life of the compound in the liver.

[0055] "Therapeutically effective amount" means an amount of all pharmalogical agents in the combination therapy described herein that treats the particular disease, condition, or disorder described herein.

[0056] The term "treating", "treat" or "treatment" as used herein embraces preventative, i.e., prophylactic; palliative treatment, i.e., relieve, alleviate, or slow the progression of the patient's disease (or condition) or any tissue damage associated with the disease (or condition); and reversal where the patient's disease (or condition) is not only alleviated but any tissue damage associated with the disease (or condition) is placed in a better state then when treatment was initiated. This latter could occur, for example and not limitation, from any one or more of the following: demonstration of NASH resolution and / or from an improvement in the fibrosis score based on liver biopsy; lower incidence of progression to cirrhosis, hepatocellular carcinoma, and / or other liver related outcomes; a reduction or improvement of the level of serum or imaging based markers of nonalcoholic steatohepatitis activity; reduction or improvement of nonalcoholic steatohepatitis disease activity; or reduction in the medical consequences of nonalcoholic steatohepatitis.

[0057] It appears that the administration of an ACC inhibitor may have positive effects to lower hepatic TGs and potentially other beneficiall effects on treatment of NASH. Increases in circulating TG levels has been reported to be a mechanistic consequence of hepatic ACC inhibition (Kim et al, 2017), though doses of ACC inhibitors that only partially inhibit DNL may not produce elevations in circulating TGs (Bergman et al., (2018) J. of Hepatology, Volume 68, S582). It has been discovered that administration of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid, optionally administered as a pharmaceutically acceptable salt, has a potential to result in elevations in circulating TGs (generally measured from plasma) in Western diet fed Sprague Dawley rats as was observed in human subjects.

[0058] The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless specified otherwise, it is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the invention. In addition, the invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention.

[0059] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine (DEA) or isopropylamine. Concentration of the eluent affords the enriched mixture.

[0060] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g. hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.

[0061] Where the compounds of the invention possess two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations R and S refer respectively to each stereogenic center in ascending numerical order (1, 2, 3, etc.) according to the conventional IUPAC number schemes for each molecule. Where the compounds of the invention possess one or more stereogenic centers and no stereochemistry is given in the name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including the racemic form.

[0062] It is also possible that the intermediates and compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.

[0063] Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0064] Included within the scope of the claimed compounds invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[0065] The invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0066] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2< H and 3< H, carbon, such as 11< C, 13< C and 14< C, chlorine, such as 31< Cl, fluorine, such as 18< F, iodine, such as 123< I, 124< I and 125< I, nitrogen, such as 13< N and 15< N, oxygen, such as 15< O, 17< O and 18< O, phosphorus, such as 32< P, and sulphur, such as 35< S.

[0067] Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3< H, and carbon-14, i.e. 14< C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0068] Substitution with heavier isotopes such as deuterium, i.e. 2< H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0069] Substitution with positron emitting isotopes, such as 11< C, 18< F, 15< O and 13< N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0070] Isotopically-labelled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

[0071] The compounds of the invention may be isolated and used per se, or when possible, in the form of its pharmaceutically acceptable salt. The term "salts" refers to inorganic and organic salts of a compound of the invention. These salts can be prepared in situ during the final isolation and purification of a compound, or by separately treating the compound with a suitable organic or inorganic acid or base and isolating the salt thus formed. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, (i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate, hexafluorophosphate, benzene sulfonate, tosylate, formate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, borate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.

[0072] The invention also relates to base addition salts of the compounds of the invention. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., lithium, potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. See e.g. Berge, et al. J. Pharm. Sci. 66, 1-19 (1977).

[0073] Certain compounds of the invention may exist in more than one crystal form (generally referred to as "polymorphs"). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the invention followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

[0074] Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). A preparation of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide is presented in Example 1 of US 2018-0051012A1. A preparation of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid is in Example 9 of US 8,859,577.GLP-1R agonist / ACCi combination

[0075] Embodiment A relates to combinations of a GLP-1R agonist and the ACC inhibitor 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.

[0076] Embodiment A5 is a further embodiment of Embodiment A, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof. In a further embodiment, the GLP-1R agonist is a pharmaceutically acceptable salt.

[0077] Embodiment A6 is a further embodiment of Embodiment A5, wherein the pharmaceutically acceptable salt is a tris salt.

[0078] Embodiment A7 is a further embodiment of Embodiment A or Embodiment A5, wherein the 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or pharmaceutically acceptable salt thereof is 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid.

[0079] Embodiment A8 is a further embodiment of Embodiment A7, wherein the 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid is a crystal form.

[0080] Embodiment A9 is a further embodiment of Embodiment A8, wherein the ratio of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and 2-amino-2-(hydroxymethyl)propane-1,3-diol in the crystal form is 1:1.

[0081] Embodiment A10 is a further embodiment of Embodiment A8 or A9, wherein the crystal form is an anhydrous crystal form.

[0082] Embodiment A11 is a further embodiment of Embodiment A10, wherein the anhydrous crystal form has a PXRD pattern comprising peaks at diffraction angles of 9.6, 10.7, and 11.3 2Θ, + 0.2° 2Θ.

[0083] Embodiment A12 is a further embodiment of Embodiment A10 or A11, wherein the anhydrous crystal form has a Raman spectrum comprising peak shifts at 1511, 1561, and 1615 cm -1< , ± 2 cm -1< .

[0084] Embodiment A13 is a further embodiment of any one of Embodiments A10 to A12, wherein the anhydrous crystal form has a 13< C ssNMR spectrum comprising chemical shifts at 22.9, 146.2, and 161.9 ppm, ± 0.2 ppm.

[0085] Embodiment A14 is a further embodiment of Embodiment A13, wherein the anhydrous crystal form has an analytical parameter selected from the group consisting of a Raman spectrum comprising peak shifts at 1511 and 1615 cm -1< , ± 2 cm -1< , and a 13< C ssNMR spectrum comprising at least one chemical shift at 22.9, 146.2, or 161.9 ppm, ± 0.2 ppm.

[0086] Embodiment A15 is a further embodiment of Embodiment A8 or A9, wherein the crystal form is a trihydrate crystal form.

[0087] Embodiment A16 is a further embodiment of Embodiment A15, wherein the trihydrate crystal form has a PXRD pattern comprising peaks at diffraction angles of 8.4, 9.0, and 10.5 2Θ, ± 0.2° 2Θ.

[0088] Embodiment A17 is a further embodiment of Embodiment A15 or A16, wherein the trihydrate crystal form has a Raman spectrum comprising peak shifts at 1507, 1557, and 1610 cm -1< , ± 2 cm -1< .

[0089] Embodiment A18 is a further embodiment of any one of Embodiment A15 to A17, wherein the trihydrate crystal form has a 13< C ssNMR spectrum comprising chemical shifts at 19.2, 149.5, and 163.8 ppm, ± 0.2 ppm.

[0090] Embodiment A19 is a further embodiment of Embodiment A18, wherein the trihydrate crystal form has an analytical parameter selected from the group consisting of a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2Θ, ± 0.2° 2Θ, a Raman spectrum comprising peak shifts at 1557 and 1610 cm -1< , ± 2 cm -1< , and a 13< C ssNMR spectrum comprising at least one chemical shift at 19.2, 149.5, or 163.8 ppm, ± 0.2 ppm.

[0091] Embodiment A20 is a further embodiment of Embodiment A18, wherein the trihydrate crystal form has an analytical parameter selected from the group consisting of a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2Θ, ± 0.2° 2Θ, and a Raman spectrum comprising at least one peak shift at 1507, 1557, or 1610 cm -1< , ± 2 cm -1< .

[0092] Embodiment A21 is a further embodiment of Embodiment A18, wherein the trihydrate crystal form has an analytical parameter selected from the group consisting of a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2Θ, ± 0.2° 2Θ, and a 13< C ssNMR spectrum comprising at least one chemical shift at 19.2, 149.5, or 163.8 ppm, ± 0.2 ppm.

[0093] Embodiment A22 is a further embodiment of Embodiment A or any one of Embodiments A5 to A12, the composition further comprises at least one other pharmaceutical agent.

[0094] Embodiment A23 is a further embodiment of Embodiment A22, wherein the at least one other pharmaceutical agent is selected from the group consisting of an acetyl-CoA carboxylase-(ACC) inhibitor, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea, a meglitinide, an α-amylase inhibitor, an α-glucoside hydrolase inhibitor, an α-glucosidase inhibitor, a PPARγ agonist, a PPAR α / γ agonist, a biguanide, a glucagon-like peptide 1 (GLP-1) modulator, liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, SIRT-1 activator, a dipeptidyl peptidease IV (DPP-IV) inhibitor, an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa), insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, a VPAC2 receptor agonist, SGLT2 inhibitors, a glucagon receptor modulator, GPR119 modulators, FGF21 derivatives or analogs, TGR5 receptor modulators, GPBAR1 receptor modulators, GPR40 agonists, GPR120 modulators, high affinity nicotinic acid receptor (HM74A) activators, SGLT1 inhibitors, inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g. PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors, inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including IL1beta, HMG-CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, choesterol absorption inhibitors, PCSK9 modulators, cholesteryl ester transfer protein inhibitors and modulators of RXRalpha.

[0095] Each of the GLP-1R agonist and the ACC inhibitor be can present in a same composition or in separate compositions. The combined amount of the GLP-1R agonist and the ACC inhibitor is therapeutically effective for the methods decribed herein. Even when the GLP-1R agonist and the ACC inhibitor are present in separate compositions, they can be administered simultaneously or sequentially; and when they are administered sequentially, they can be administered in any order.GLP-1R agonist / KHKi combination

[0096] Embodiment D relates to combinations of a GLP-1R agonist and the KHKi inhibitor [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or a pharmaceutically acceptable salt thereof.

[0097] Embodiment D5 is a further embodiment of Embodiment D, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof. In a further embodiment, the GLP-1R agonist is a pharmaceutically acceptable salt.

[0098] Embodiment D6 is a further embodiment of Embodiment D5, wherein the pharmaceutically acceptable salt is a tris salt. In some further embodiments, the tris salt is a crystal form, for example, as one described herein.

[0099] Embodiment D7 is a further embodiment of any one of Embodiment D or Embodiments D5 to D6, wherein the [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or a pharmaceutically acceptable salt thereof is [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

[0100] Embodiment D8 is a further embodiment of Embodiment D7, wherein the [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid is a crystal form.

[0101] Embodiment D9 is a further embodiment of Embodiment D8, wherein the crystal form has a PXRD pattern comprising peaks at diffraction angles of 9.0, 10.4, 15.0, and 21.4 2Θ, ± 0.2° 2Θ.

[0102] Embodiment D10 is a further embodiment of Embodiment D8, wherein the crystal form has a PXRD pattern comprising peaks at diffraction angles of 9.0, 15.0 19.6, 21.4, and 26.5 2Θ, ± 0.20 2Θ.

[0103] Embodiment D11 is a further embodiment of Embodiment D8, wherein the crystal form has a PXRD pattern comprising peaks at diffraction angles of 10.4, 11.5, 15.0, 19.6, and 26.5 2Θ, ± 0.20 2Θ.

[0104] Embodiment D12 is a further embodiment of any one of Embodiment D or Embodiments D5 to D11, wherein the composition further comprises at least one other pharmaceutical agent.

[0105] Each of the GLP-1R agonist and the KHK inhibitor be can present in a same composition or in separate compositions. The combined amount of the GLP-1R agonist and the KHK inhibitor is therapeutically effective for the methods decribed herein. Even when the GLP-1R agonist and the KHK inhibitor are present in separate compositions, they can be administered simultaneously or sequentially; and when they are administered sequentially, they can be administered in any order.GLP-1R agonist / DGAT2 inhibitor combination

[0106] Embodiment G relates to combinations of a GLP-1R agonist and the DGAT2 inhibitor (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[0107] Embodiment G5 is a further embodiment of Embodiment G, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof. In a further embodiment, the GLP-1R agonist is a pharmaceutically acceptable salt.

[0108] Embodiment G6 is a further embodiment of Embodiment G5, wherein the pharmaceutically acceptable salt is a tris salt. In some further embodiments, the tris salt is a crystal form, for example, as one described herein.

[0109] Embodiment G7 is a further embodiment of any one of Embodiment G or Embodiments G5 to G6, wherein the (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof is (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide.

[0110] Embodiment G8 is a further embodiment of Embodiment G7, wherein the (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide is a crystal form.

[0111] Embodiment G9 is a further embodiment of Embodiment G8, wherein the crystal form has a PXRD pattern comprising peaks at diffraction angles of 5.3, 7.7, 15.4 2Θ, ± 0.2° 2Θ (Form 1).

[0112] Embodiment G10 is a further embodiment of Embodiment G8, wherein the crystal form has a PXRD pattern comprising peaks at diffraction angles of 6.5, 9.3, 13.6 2Θ, ± 0.2° 2Θ (Form 2).

[0113] Embodiment G11 is a further embodiment of any one of Embodiment G or Embodiments G5 to G10, wherein the composition further comprises at least one other pharmaceutical agent.

[0114] Each of the GLP-1R agonist and the DGAT2 inhibitor be can present in a same composition or in separate compositions. The combined amount of the GLP-1R agonist and the DGAT2 inhibitor is therapeutically effective for the methods decribed herein. Even when the GLP-1R agonist and the DGT2 inhibitor are present in separate compositions, they can be administered simultaneously or sequentially; and when they are administered sequentially, they can be administered in any order.GLP-1R agonist / FXR agonist combination

[0115] Embodiment J relates to combinations of a GLP-1R agonist and the FXR agonist 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (also known as Tropifexor) or a pharmaceutically acceptable salt thereof.

[0116] Embodiment J5 is a further embodiment of Embodiment J, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-Cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-Chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof. In a further embodiment, the GLP-1R agonist is a pharmaceutically acceptable salt.

[0117] Embodiment J6 is a further embodiment of Embodiment J5, wherein the pharmaceutically acceptable salt is a tris salt. In some further embodiments, the tris salt is a crystal form, for example, as one described herein.

[0118] Embodiment J7 is a further embodiment of any one of Embodiment J or Embodiments J5 to J6, wherein the 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid.

[0119] Embodiment J8 is a further embodiment of any one of Embodiment J or Embodiments J5 to J7, wherein the composition further comprises at least one other pharmaceutical agent.

[0120] Each of the GLP-1R agonist and the FXR agonist be can present in a same composition or in separate compositions. The combined amount of the GLP-1R agonist and the FXR agonist is therapeutically effective for the methods decribed herein. Even when the GLP-1R agonist and the FXR agonist are present in separate compositions, they can be administered simultaneously or sequentially; and when they are administered sequentially, they can be administered in any order.COMBINATION AGENTS

[0121] The compounds in the combinations for use in a method of treating of the invention can be administered separately or together as separate agents or in a fixed-dose comibination or in combination with one or more additional therapeutic agents. When administered in combination, each component may be administered at the same time (i.e. simultaneously) or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Thus, the methods of treatment described herein include use of combination agents to adiminister two or more agents in combination.

[0122] The combination agents are administered to a patient or mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of the compounds of the invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to treat the desired disease / condition.

[0123] Examples of suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors). Suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE)-10 inhibitor, an AMPK activator, a sulfonylurea (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), a meglitinide, an α-amylase inhibitor (e.g., tendamistat, trestatin and AL-3688), an α-glucoside hydrolase inhibitor (e.g., acarbose), an α-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARγ agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), a PPAR α / γ agonist (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) modulator such as an agonist (e.g., exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta ®< ), albiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds disclosed by Zhang, S., et al., Drug Discovery Today, 12(9 / 10), 373-381 (2007)), SIRT-1 activator (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (e.g., those in WO2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, glucokinase activators (GKa) such as those described in WO2010103437, WO2010103438, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor (e.g. GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), Ertugliflozin, ASP-1941, THR1474, TS-071, ISIS388626 and LX4211 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al. Annual Reports in Medicinal Chemistry 2008, 43, 119-137, GPR119 modulators, particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al. et al., Current Opinion in Investigational Drugs 2009, 10(4)359-364, TGR5 (also termed GPBAR1) receptor modulators, particularly agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777, GPR40 agonists, such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including but not limited to TAK-875, GPR120 modulators, particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative listing of anti-diabetic agents that can be combined with the compounds of the invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611. Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and / or CCR5, inhibitors of PKC isoforms (e.g. PKCα, PKCβ, PKCγ), inhibitors of fatty acid synthetase, inhibitors of serine palmitoyl transferase, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including IL1beta, modulators of RXRalpha. In addition suitable anti-diabetic agents include mechanisms listed by Carpino, P.A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51.

[0124] Suitable anti-obesity agents include 11β-hydroxy steroid dehydrogenase-1 (11β-HSD type 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, β 3 adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), PYY 3-36 (including analogs thereof), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as Axokine ™< available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP / ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, the combination of naltrexone with buproprion and the like.

[0125] Preferred anti-obesity agents for use in the combination aspects of the invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005 / 116034 or US Publication No. 2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY 3-36 (as used herein "PYY 3-36 " includes analogs, such as peglated PYY 3-36 e.g., those described in US Publication 2006 / 0178501), opioid antagonists (e.g., naltrexone), the combination of naltrexone with buproprion, oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin ®< ), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta ®< ), AOD-9604 (CAS No. 221231-10-3), phentermine and topiramate (trade name: Qsymia), and sibutramine. Preferably, compounds of the invention and combination therapies are administered in conjunction with exercise and a sensible diet.

[0126] The combinations for use in a method of treating of the invention may be used in combination with cholesterol modulating agents (including cholesterol lowering agents) such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP / Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase / squalene cyclase inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant or an agent such as mipomersen.

[0127] Examples of suitable cholesterol / lipid lowering agents and lipid profile therapies include: HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors; and cholesteryl ester transfer protein inhibitors. Other atherosclerotic agents include PCSK9 modulators.

[0128] In another embodiment, the combinations for use in a method of treating of the invention may be co-administered with agents for the treatment of non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD), such as Orlistat, TZDs and other insulin sensitizing agents, FGF21 analogs, Metformin, Omega-3-acid ethyl esters (e.g. Lovaza), Fibrates, HMG CoA-reductase Inhibitors, Ezitimbe, Probucol, Ursodeoxycholic acid, TGR5 agonists, FXR agonists, Vitamin E, Betaine, Pentoxifylline, CB1 antagonists, Carnitine, N-acetylcysteine, Reduced glutathione, lorcaserin, the combination of naltrexone with buproprion, SGLT2 Inhibitors, Phentermine, Topiramate, Incretin (GLP and GIP) analogs and Angiotensin-receptor blockers.

[0129] In another embodiment, the additional pharmaceutical agent is selected from the group consisting of cysteamine or a pharmaceutically acceptable salt thereof, cystamine or a pharmaceutically acceptable salt thereof, an anti-oxidant compound, lecithin, vitamin B complex, a bile salt preparations, an antagonists of Cannabinoid-1 (CB1) receptor, an inverse agonists of Cannabinoid-1 (CB1) receptor, a peroxisome proliferator-activated receptor) activity regulators, a benzothiazepine or benzothiepine compound, an RNA antisense construct to inhibit protein tyrosine phosphatase PTPRU, a heteroatom-linked substituted piperidine and derivatives thereof, an azacyclopentane derivative capable of inhibiting stearoyl-coenzyme alpha delta-9 desaturase, acylamide compound having secretagogue or inducer activity of adiponectin, a quaternary ammonium compound, Glatiramer acetate, pentraxin proteins, a HMG-CoA reductase inhibitor, n-acetyl cysteine, isoflavone compound, a macrolide antibiotic, a galectin inhibitor, an antibody, or any combination of thereof.

[0130] Additional therapeutic agents include anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, thrombolytic or fibrinolytic agents, anti-arrythmic agents, anti-hypertensive agents, calcium channel blockers (L-type and T-type), cardiac glycosides, diruetics, mineralocorticoid receptor antagonists, NO donating agents such as organonitrates, NO promoting agents such as phosphodiesterase inhibitors, cholesterol / lipid lowering agents and lipid profile therapies, anti-diabetic agents, anti-depressants, anti-inflammatory agents (steroidal and non-steroidal), anti-osteoporosis agents, hormone replacement therapies, oral contraceptives, anti-obesity agents, anti-anxiety agents, antiproliferative agents, anti-tumor agents, anti-ulcer and gastroesophageal reflux disease agents, growth hormone and / or growth hormone secretagogues, thyroid mimetics (including thyroid hormone receptor antagonist), anti-infective agents, anti-viral agents, anti-bacterial agents, and anti-fungal agents.

[0131] Agents used in an ICU setting are included, for example, dobutamine, dopamine, dpinephrine, nitroglycerin, nitroprusside etc.

[0132] Combination agents useful for treating vasculitis are included, for example, azathioprine, cyclophosphamide, mycophenolate, mofetil, rituximab etc.

[0133] In another embodiment, the invention provides a combination for use in a method of treating wherein an additional agent (the third agent) is at least one agent selected from a factor Xa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent. Exemplary factor Xa inhibitors include apixaban and rivaroxaban. Examples of suitable anti-coagulants for use in combination with the compounds of the invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin).

[0134] In another preferred embodiment the additional (the third agent) is at least one agent selected from warfarin, dabigatran, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase.

[0135] A preferred third agent is at least one anti-platelet agent. Especially preferred anti-platelet agents are aspirin and clopidogrel.

[0136] The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function, for example by inhibiting the aggregation, adhesion or granular secretion of platelets. Agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA) and COX-2 inhibitors such as CELEBREX or piroxicam are preferred. Other suitable platelet inhibitory agents include Ilb / Illa antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g., Pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

[0137] The term anti-platelet agents (or platelet inhibitory agents), as used herein, is also intended to include ADP (adenosine diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors P 2 Y 1 and P 2 Y 12 , with P 2 Y 12 being even more preferred. Preferred P 2 Y 12 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use.

[0138] The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and / or the granular secretion of plasminogen activator inhibitor-1 and / or serotonin) and / or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, dabigatran, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. The term thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, denote agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor VIIa inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

[0139] Examples of suitable anti-arrythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K +< channel openers such as I Ach inhibitors, and I Kur inhibitors (e.g., compounds such as those disclosed in WO01 / 40231).

[0140] The combinations for use in a method of treating of the invention may be used in combination with antihypertensive agents and such antihypertensive activity is readily determined by those skilled in the art according to standard assays (e.g., blood pressure measurements). Examples of suitable anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265); Dual ET / All antagonist (e.g., compounds disclosed in WO 00 / 01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrates). An exemplary antianginal agent is ivabradine.

[0141] Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine and mybefradil.

[0142] Examples of suitable cardiac glycosides include digitalis and ouabain.

[0143] In one embodiment, the combinations for use in a method of treating of the invention may be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (such as LASIX ™< ), torsemide (such as DEMADEX ™< ), bemetanide (such as BUMEX ™< ), and ethacrynic acid (such as EDECRIN ™< ); (b) thiazide-type diuretics such as chlorothiazide (such as DIURIL ™< , ESIDRIX ™< or HYDRODIURIL ™< ), hydrochlorothiazide (such as MICROZIDE ™< or ORETIC ™< ), benzthiazide, hydroflumethiazide (such as SALURON ™< ), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOL ™< ); (c) phthalimidine-type diuretics such as chlorthalidone (such as HYGROTON ™< ), and metolazone (such as ZAROXOLYN ™< ); (d) quinazoline-type diuretics such as quinethazone; and (e) potassium-sparing diuretics such as triamterene (such as DYRENIUM ™< ), and amiloride (such as MIDAMOR ™< or MODURETlC ™< ).

[0144] In another embodiment, the combinations for use in a method of treating of the invention may be co-administered with a loop diuretic. In still another embodiment, the loop diuretic is selected from furosemide and torsemide. In still another embodiment, the compounds of the invention may be co-administered with furosemide. In still another embodiment, the compounds of the invention may be co-administered with torsemide which may optionally be a controlled or modified release form of torsemide.

[0145] In another embodiment, the combinations for use in a method of treating of the invention may be co-administered with a thiazide-type diuretic. In still another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In still another embodiment, the compounds of the invention may be co-administered with chlorothiazide. In still another embodiment, the compounds of the invention may be co-administered with hydrochlorothiazide.

[0146] In another embodiment, the combinations for use in a method of treating of the invention may be co-administered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic is chlorthalidone. Examples of suitable mineralocorticoid receptor antagonists include sprionolactone and eplerenone. Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

[0147] Those skilled in the art will recognize that the combinations for use in a method of treating of this invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments including PCI, stenting, drug eluting stents, stem cell therapy and medical devices such as implanted pacemakers, defibrillators, or cardiac resynchronization therapy.

[0148] The dosage of each therapeutic agent, e.g., the GLP-1R agonist described herein, and any additional therapeutic agent, is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired. In general, the dosage range of each therapeutic agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day. However, some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like. The determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.

[0149] According to the invention, a compound and at least one additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition. In the combination aspect of the invention, the combination for use in a method of treating of the invention and at least one other pharmaceutical agent (e.g., another anti-obesity agent,) may be administered either separately or in a pharmaceutical composition comprising both. It is generally preferred that such administration be oral.

[0150] When a combination of compounds are administered together, such administration may be sequential in time or simultaneous. Simultaneous administration of drug combinations is generally preferred. For sequential administration, a compound of the invention and the additional pharmaceutical agent may be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous. When compounds are administered sequentially, the administration of each may be by the same or by different methods.

[0151] According to the invention, a combination is preferably administered in the form of a pharmaceutical composition. Accordingly, compounds can be administered to a patient separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or inhalant).

[0152] The compounds can be administered alone but will generally be administered in an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.

[0153] The pharmaceutical composition comprises a compound or compounds in an amount generally in the range of from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1%, 2% or 3% to less than 50% such as about 25%, 30% or 35%.

[0154] Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known to those skilled in this art. For examples, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore Md. 20.sup.th ed. 2000.

[0155] Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers or diluents (including solvents and vehicles) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. A prefrerred carrier is Miglyol.RTM. brand caprylic / capric acid ester with glycerine or propylene glycol (e.g., Miglyol.RTM. 812, Miglyol.RTM. 829, Miglyol.RTM. 840) available from Condea Vista Co., Cranford, N.J. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0156] These compositions for parenteral injection may also contain excipients such as preserving, wetting, emulsifying, and dispersing agents. Prevention of microorganism contamination of the compositions can be accomplished with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

[0157] Solid dosage forms for oral administration include capsules, tablets, chews, lozenges, pills, powders, and multi-particulate preparations (granules). In such solid dosage forms, a compound of the invention or a combination is admixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include materials such as sodium citrate or dicalcium phosphate and / or (a) one or more fillers or extenders (e.g., microcrystalline cellulose (available as Avicel.TM. from FMC Corp.) starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, betacyclodextrin, polyethylene glycol, medium chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide and the like); (b) one or more binders (e.g., carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like); (c) one or more humectants (e.g., glycerol and the like); (d) one or more disintegrating agents (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, sodium lauryl sulphate, sodium starch glycolate (available as Explotab.TM.from Edward Mendell Co.), crosslinked polyvinyl pyrrolidone, croscarmellose sodium A-type (available as Ac-di-sol.TM.), polyacrilin potassium (an ion exchange resin) and the like); (e) one or more solution retarders (e.g., paraffin and the like); (f) one or more absorption accelerators (e.g., quaternary ammonium compounds and the like); (g) one or more wetting agents (e.g., cetyl alcohol, glycerol monostearate and the like); (h) one or more adsorbents (e.g., kaolin, bentonite and the like); and / or (i)one or more lubricants (e.g., talc, calcium stearate, magnesium stearate, stearic acid, polyoxyl stearate, cetanol, talc, hydrogenated caster oil, sucrose esters of fatty acid, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycols, sodium lauryl sulfate and the like). In the case of capsules and tablets, the dosage forms may also comprise buffering agents.

[0158] Solid compositions of a similar type may also be used as fillers in soft or hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0159] Solid dosage forms such as tablets, dragees, capsules, and granules may be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may also contain opacifying agents, and can also be of such composition that they release the compound of the invention and / or the additional pharmaceutical agent in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The drug may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0160] For tablets, the active agent will typically comprise less than 50% (by weight) of the formulation, for example less than about 10% such as 5% or 2.5% by weight. The predominant portion of the formulation comprises fillers, diluents, disintegrants, lubricants and optionally, flavors. The composition of these excipients is well known in the art. Frequently, the fillers / diluents will comprise mixtures of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and di-calcium phosphate. The filler / diluent mixtures typically comprise less than 98% of the formulation and preferably less than 95%, for example 93.5%. Preferred disintegrants include Ac-di-sol.TM., Explotab.TM., starch and sodium lauryl sulphate. When present a disintegrant will usually comprise less than 10% of the formulation or less than 5%, for example about 3%. A preferred lubricant is magnesium stearate. When present a lubricant will usually comprise less than 5% of the formulation or less than 3%, for example about 1%.

[0161] Tablets may be manufactured by standard tabletting processes, for example, direct compression or a wet, dry or melt granulation, melt congealing process and extrusion. The tablet cores may be mono or multi-layer(s) and can be coated with appropriate overcoats known in the art.

[0162] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the compound of the invention or the combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyole.RTM. (available from CONDEA Vista Co., Cranford, N.J.), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0163] Besides such inert diluents, the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0164] Oral liquid forms include solutions, wherein the active compound is fully dissolved. Examples of solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride-based systems. Glyceryl- and glyceride-based systems may include, for example, the following branded products (and corresponding generic products): Captex.TM. 355 EP (glyceryl tricaprylate / caprate, from Abitec, Columbus Ohio), Crodamol.TM. GTC / C (medium chain triglyceride, from Croda, Cowick Hall, UK) or Labrafac.TM. CC (medium chain triglyides, from Gattefosse), Captex.TM. 500P (glyceryl triacetate i.e. triacetin, from Abitec), Capmul.TM. MCM (medium chain mono- and diglycerides, fromAbitec), Migyol.TM. 812 (caprylic / capric triglyceride, from Condea, Cranford N.J.), Migyol.TM. 829 (caprylic / capric / succinic triglyceride, from Condea), Migyol.TM. 840 (propylene glycol dicaprylate / dicaprate, from Condea), Labrafil.TM. M1944CS (oleoyl macrogol-6 glycerides, from Gattefosse), Peceol.TM. (glyceryl monooleate, from Gattefosse) and Maisine.TM. 35-1 (glyceryl monooleate, from Gattefosse). Of particular interest are the medium chain (about C.sub.8 to C.sub.10) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95% or 99%. Adjuvants and additives may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers and solubilizers.

[0165] Suspensions, in addition to the compound or combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0166] Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound or a combination with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thereby releasing the active component(s).

[0167] Dosage forms for topical administration include ointments, creams, lotions, powders and sprays. The drugs are admixed with a pharmaceutically acceptable excipient, diluent or carrier, and any preservatives, buffers, or propellants that may be required.

[0168] When compounds are poorly soluble in water, e.g., less than about 1 .mu.g / mL, liquid compositions in solubilizing, non-aqueous solvents such as the medium chain triglyceride oils discussed above are a preferred dosage form for these compounds.

[0169] Solid amorphous dispersions, including dispersions formed by a spray-drying process, are also a preferred dosage form for poorly soluble compounds. By "solid amorphous dispersion" is meant a solid material in which at least a portion of the poorly soluble compound is in the amorphous form and dispersed in a water-soluble polymer. By "amorphous" is meant that the poorly soluble compound is not crystalline. By "crystalline" is meant that the compound exhibits long-range order in three dimensions of at least 100 repeat units in each dimension. Thus, the term amorphous is intended to include not only material which has essentially no order, but also material which may have some small degree of order, but the order is in less than three dimensions and / or is only over short distances. Amorphous material may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC).

[0170] Preferably, at least a major portion (i.e., at least about 60 wt %) of the poorly soluble compound in the solid amorphous dispersion is amorphous. The compound can exist within the solid amorphous dispersion in relatively pure amorphous domains or regions, as a solid solution of the compound homogeneously distributed throughout the polymer or any combination of these states or those states that lie intermediate between them. Preferably, the solid amorphous dispersion is substantially homogeneous so that the amorphous compound is dispersed as homogeneously as possible throughout the polymer. As used herein, "substantially homogeneous" means that the fraction of the compound that is present in relatively pure amorphous domains or regions within the solid amorphous dispersion is relatively small, on the order of less than 20 wt %, and preferably less than 10 wt % of the total amount of drug.

[0171] Water-soluble polymers suitable for use in the solid amorphous dispersions should be inert, in the sense that they do not chemically react with the poorly soluble compound in an adverse manner, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. 1-8). The polymer can be neutral or ionizable, and should have an aqueous-solubility of at least 0.1 mg / mL over at least a portion of the pH range of 1-8.

[0172] Water-soluble polymers suitable for use with the invention may be cellulosic or non-cellulosic. The polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

[0173] Exemplary water-soluble polymers include hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl methyl cellulose phthalate (HPMCP), carboxy methyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO, also known as poloxamers), and mixtures thereof. Especially preferred polymers include HPMCAS, HPMC, HPMCP, CMEC, CAP, CAT, PVP, poloxamers, and mixtures thereof. Most preferred is HPMCAS. See European Patent Application Publication No. 0 901 786 A2.

[0174] The solid amorphous dispersions may be prepared according to any process for forming solid amorphous dispersions that results in at least a major portion (at least 60%) of the poorly soluble compound being in the amorphous state. Such processes include mechanical, thermal and solvent processes. Exemplary mechanical processes include milling and extrusion; melt processes including high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes including non-solvent precipitation, spray coating and spray drying. See, for example, the following U.S. Patents: Nos. 5,456,923 and 5,939,099, which describe forming dispersions by extrusion processes; Nos. 5,340,591 and 4,673,564, which describe forming dispersions by milling processes; and Nos. 5,707,646 and 4,894,235, which describe forming dispersions by melt congeal processes. In a preferred process, the solid amorphous dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0 901 786 A2. In this process, the compound and polymer are dissolved in a solvent, such as acetone or methanol, and the solvent is then rapidly removed from the solution by spray drying to form the solid amorphous dispersion. The solid amorphous dispersions may be prepared to contain up to about 99 wt % of the compound, e.g., 1 wt %, 5 wt %, 10 wt %, 25 wt %, 50 wt %, 75 wt %, 95 wt %, or 98 wt % as desired.

[0175] The solid dispersion may be used as the dosage form itself or it may serve as a manufacturing-use-product (MUP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is an aqueous suspension of a 1:1 (w / w) compound / HPMCAS-HF spray-dried dispersion containing 2.5 mg / mL of compound in 2% polysorbate-80. Solid dispersions for use in a tablet or capsule will generally be mixed with other excipients or adjuvants typically found in such dosage forms. For example, an exemplary filler for capsules contains a 2:1 (w / w) compound / HPMCAS-MF spray-dried dispersion (60%), lactose (fast flow) (15%), microcrystalline cellulose (e.g., Avicel.sup.(R0-102) (15.8%), sodium starch (7%), sodium lauryl sulfate (2%) and magnesium stearate (1%).

[0176] The HPMCAS polymers are available in low, medium and high grades as Aqoa.sup.(R)-LF, Aqoat.sup.(R)-MF and Aqoat.sup.(R)-HF respectively from Shin-Etsu Chemical Co., LTD, Tokyo, Japan. The higher MF and HF grades are generally preferred.

[0177] The following paragraphs describe exemplary formulations, dosages, etc. useful for non-human animals. The administration of a combination described herein can be effected orally or non-orally.

[0178] An amount of each of the components in a combination described herein, together or in combination with an another agent is administered such that an effective dose is received. Generally, a daily dose that is administered orally to an animal is between about 0.01 and about 1,000 mg / kg of body weight, e.g., between about 0.01 and about 300 mg / kg or between about 0.01 and about 100 mg / kg or between about 0.01 and about 50 mg / kg of body weight, or between about 0.01 and about 25 mg / kg, or about 0.01 and about 10 mg / kg or about 0.01 and about 5 mg / kg.

[0179] Conveniently, a compound or combination can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

[0180] Conveniently, a compound or combination can also be added directly to the feed, as such, or in the form of an animal feed supplement, also referred to as a premix or concentrate. A premix or concentrate of the compound in an excipient, diluent or carrier is more commonly employed for the inclusion of the agent in the feed. Suitable excipients, diluents or carriers are liquid or solid, as desired, such as water, various meals such as alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, urea, bone meal, and mineral mixes such as are commonly employed in poultry feeds. A particularly effective excipient, diluent or carrier is the respective animal feed itself; that is, a small portion of such feed. The carrier facilitates uniform distribution of the compound in the finished feed with which the premix is blended. Preferably, the compound is thoroughly blended into the premix and, subsequently, the feed. In this respect, the compound may be dispersed or dissolved in a suitable oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then blended with the carrier. It will be appreciated that the proportions of compound in the concentrate are capable of wide variation since the amount of the compound in the finished feed may be adjusted by blending the appropriate proportion of premix with the feed to obtain a desired level of compound.

[0181] High potency concentrates may be blended by the feed manufacturer with proteinaceous carrier such as soybean oil meal and other meals, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, the animals are permitted to consume the usual diet. Alternatively, such concentrated supplements may be added directly to the feed to produce a nutritionally balanced, finished feed containing a therapeutically effective level of a compound of the invention. The mixtures are thoroughly blended by standard procedures, such as in a twin shell blender, to ensure homogeneity.

[0182] If the supplement is used as a top dressing for the feed, it likewise helps to ensure uniformity of distribution of the compound across the top of the dressed feed.

[0183] Drinking water and feed effective for increasing lean meat deposition and for improving lean meat to fat ratio are generally prepared by mixing a compound of the invention with a sufficient amount of animal feed to provide from about 10 -3< to about 500 ppm of the compound in the feed or water.

[0184] The preferred medicated swine, cattle, sheep and goat feed generally contain from about 1 to about 400 grams of a compound of the invention (or combination) per ton of feed, the optimum amount for these animals usually being about 50 to about 300 grams per ton of feed.

[0185] The preferred poultry and domestic pet feeds usually contain about 1 to about 400 grams and preferably about 10 to about 400 grams of a compound of the invention (or combination) per ton of feed.

[0186] For parenteral administration in animals, the compound or combination may be prepared in the form of a paste or a pellet and administered as an implant, usually under the skin of the head or ear of the animal in which increase in lean meat deposition and improvement in lean meat to fat ratio is sought.

[0187] Paste Formulations may be prepared by dispersing the drug in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

[0188] Pellets containing a therapeutically effective amount of each of the components in a combination described herein, with a diluent such as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium or calcium stearate, may be added to improve the pelleting process.

[0189] It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increase in lean meat deposition and improvement in lean meat to fat ratio desired. Moreover, implants may also be made periodically during the animal treatment period in order to maintain the proper drug level in the animal's body.

[0190] The invention has several advantageous veterinary features. For the pet owner or veterinarian who wishes to increase leanness and / or trim unwanted fat from pet animals, the instant invention provides the means by which this may be accomplished. For poultry, beef and swine breeders, utilization of the method of the invention yields leaner animals that command higher sale prices from the meat industry.EXAMPLES

[0191] Examples described below which do not fall within the scope of the claims are included for reference purposes only.

[0192] Unless specified otherwise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England) and Tyger Scientific (Princeton, NJ). Certain common abbreviations and acronyms have been employed which may include: AcOH (acetic acid), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), CDI (1,1'-carbonyldiimidazole), DCM (dichloromethane), DEA (diethylamine), DIPEA (N,N-diisopropylethylamine), DMAP (4-dimethylaminopyridine), DMF (N,N'-dimethylformamide), DMSO (dimethylsulfoxide), EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide), Et 2 O (diethyl ether), EtOAc (ethyl acetate), EtOH (ethanol), G or g (gram), HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium), HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluoro phosphate), HOBT (1-hydroxybenzotriazole), H or h (hour), IPA (isopropyl alcohol), KHMDS (potassium hexamethyldisilazane), MeOH (methanol), L or l (liter), mL (milliliter) MTBE (tert-butyl methyl ether), mg (milligram), NaBH(OAc) 3 (sodium triacetoxyborohydride), NaHMDS (sodium hexamethyldisilazane), NMP (N-methylpyrrolidone), RH (relative humidity), RT or rt (room temperature which is the same as ambient temperature (about 20 to 25 °C)), SEM ([2-(Trimethylsilyl)ethoxy]methyl), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), and T 3 P (propane phosphonic acid anhydride).

[0193] 1< H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million (ppm) relative to the residual proton signal in the deuterated solvent (CHCl 3 at 7.27 ppm; CD 2 HOD at 3.31 ppm) and are reported using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

[0194] ssNMR means solid-state NMR.

[0195] PXRD means Powder X-ray Diffraction.

[0196] The term "substantially the same" when used to describe X-ray powder diffraction patterns is mean to include patterns in which peaks are within a standard deviation of + / - 0.2° 2Θ.

[0197] As used herein, the term "substantially pure" with reference to a particular crystalline form means that the crystalline form includes less than 10%, preferably less than 5%, preferably less than 3%, preferably less than 1% by weight of any other physical form of the same compound.

[0198] Reactions were performed in air or, when oxygen- or moisture-sensitive reagents or intermediates were employed, under an inert atmosphere (nitrogen or argon). When appropriate, reaction apparatuses were dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal ™< products from Aldrich Chemical Company, Milwaukee, Wisconsin or DriSolv ™< products from EMD Chemicals, Gibbstown, NJ) were employed. Commercial solvents and reagents were used without further purification. When indicated, reactions were heated by microwave irradiation using Biotage Initiator or Personal Chemistry Emrys Optimizer microwaves. Reaction progress was monitored using thin layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS) analyses. TLC was performed on pre-coated silica gel plates with a fluorescence indicator (254 nm excitation wavelength) and visualized under UV light and / or with I 2 , KMnO 4 , CoCl 2 , phosphomolybdic acid, and / or ceric ammonium molybdate stains. LCMS data were acquired on an Agilent 1100 Series instrument with a Leap Technologies autosampler, Gemini C18 columns, MeCN / water gradients, and either TFA, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using Waters ZQ mass spectrometer scanning in both positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were acquired on an Agilent 1100 Series instrument using Gemini or XBridge C18 columns, MeCN / water gradients, and either TFA or ammonium hydroxide modifiers. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP 6890 injector, HP-1 column (12 m×0.2 mm×0.33 µm), and helium carrier gas. The sample was analyzed on an HP 5973 mass selective detector scanning from 50 to 550 Da using electron ionization. Purifications were performed by medium performance liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-packed Isco RediSep or Biotage Snap silica cartridges. Chiral purifications were performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar instruments; ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and CO 2 mixtures with MeOH, EtOH, iPrOH, or MeCN, alone or modified using TFA or iPrNH 2 . UV detection was used to trigger fraction collection.

[0199] Mass spectrometry data are reported from LCMS analyses. Mass spectrometry (MS) was performed via atmospheric pressure chemical ionization (APCI), electrospray Ionization (ESI), electron impact ionization (EI) or electron scatter (ES) ionization sources. Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography-mass spectrometry (GCMS) instrumentation. The symbol denotes that the chlorine isotope pattern was observed in the mass spectrum. Proton nuclear magnetic spectroscopy ( 1< H NMR) chemical shifts are given in parts per million downfield from tetramethylsilane and were recorded on on 300, 400, 500, or 600 MHz Varian spectrometers. Chemical shifts are expressed in parts per million (ppm, δ) referenced to the deuterated solvent residual peaks. The peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analytical instrument as described above. Optical rotation data were acquired on a PerkinElmer model 343 polarimeter using a 1 dm cell. Silica gel chromatography was performed primarily using a medium pressure Biotage or ISCO systems using columns pre-packaged by various commercial vendors including Biotage and ISCO. Microanalyses were performed by Quantitative Technologies Inc. and were within 0.4% of the calculated values.

[0200] Unless otherwise noted, chemical reactions were performed at room / ambient temperature (about 23 degrees Celsius).

[0201] The compounds and intermediates described below generally were named using the naming convention provided with ChemBioDraw Ultra, Version 12.0 (CambridgeSoft Corp., Cambridge, Massachusetts). The naming convention provided with ChemBioDraw Ultra, Version 12.0 are well known by those skilled in the art and it is believed that the naming convention provided with ChemBioDraw Ultra, Version 12.0 generally comports with the IUPAC (International Union for Pure and Applied Chemistry) recommendations on Nomenclature of Organic Chemistry and the CAS Index rules. Unless noted otherwise, all reactants were obtained commercially without further purifications or were prepared using methods known in the literature.

[0202] Chiral separations were used to separate enantiomers or diastereomers of some intermediates during the preparation of the compounds of the invention. When chiral separation was done, the separated enantiomers were designated as ENT-1 or ENT-2 (or DIAST-1 or DIAST-2), according to their order of elution. In some embodiments, enantiomers designated as ENT-1 or ENT-2 can be used as starting materials to prepare other enantiomers or diastereomers. In such situations, the resulting enantiomers prepared are designated as ENT-X1 and ENT-X2, respectively, according to their starting materials; similarly, the diastereomers prepared are designated as DIAST-X1 and DIAST-X2, respectively, (or DIAST-according to their starting materials. DIAST-Y and DIAST-Z nomenclature is used similarly, in syntheses employing multiple intermediates.

[0203] For compounds with two chiral centers, the stereoisomers at each stereocenter were separated at different times. The designation of ENT-1 or ENT-2 (or DIAST-1 or DIAST-2) of an intermediate or an example refers to the order of elution for the separation done at that step. It is recognized that when stereoisomers at a chiral center are separated in a compound with two or more centers, the separated enantiomers are diastereomers of each other. By way of example, but not limitation, Examples 15 and 16 have two chiral centers. The chiral center of the cyclopropyl moiety was separated when intermediate C36 was separated into ENT-1, giving intermediate P17, and ENT-2, giving intermediate P18. P18 was then used in preparing C70, which had one stereoisomer enriched at the cyclopropyl chiral carbon and a mixture of stereoisomers at the dioxolane carbon. C70 was then separated into DIAST-Y1 at the dioxolane carbon, giving intermediate C71, and DIAST-Y2 at the dioxolane carbon, giving intermediate C72, where these intermediates are enriched in a single stereoisomer. C71 was then used to prepare Example 15, which is identified by name as 2-{6-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-6-azaspiro[2.5]oct-1-yl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid, DIAST-X1, trifluoroacetate salt [from P18 via C71]. In these preparations, after a mixture is subjected to separation procedures, the chiral center is identified with "abs" near that center, with the understanding that the separated enantiomers may not be enantiomerically pure. Typically, the enriched enantiomer at each chiral center is >90% of the isolated material. Preferably, the enriched enantiomer at each center is >98% of the mixture.

[0204] In some examples, the optical rotation of an enantiomer was measured using a polarimeter. According to its observed rotation data (or its specific rotation data), an enantiomer with a clockwise rotation was designated as the (+)-enantiomer and an enantiomer with a counter-clockwise rotation was designated as the (-)-enantiomer. Racemic compounds are indicated either by the absence of drawn or described stereochemistry, or by the presence of (+ / -) adjacent to the structure; in this latter case, indicated stereochemistry represents the relative (rather than absolute) configuration of the compound's substituents.

[0205] Reactions proceeding through detectable intermediates were generally followed by LCMS, and allowed to proceed to full conversion prior to addition of subsequent reagents. For syntheses referencing procedures in other Examples or Methods, reaction conditions (reaction time and temperature) may vary. In general, reactions were followed by thin-layer chromatography or mass spectrometry, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents / gradients were chosen to provide appropriate R f s or retention times. All starting materials in these Preparations and Examples are either commercially available or can be prepared by methods known in the art or as described herein.

[0206] The terms "concentrated", "evaporated", and "concentrated in vacuo" refer to the removal of solvent at reduced pressure on a rotary evaporator with a bath temperature less than 60°C. The abbreviation "min" and "h" stand for "minutes" and "hours" respectively. The term "TLC" refers to thin layer chromatography, "room temperature or ambient temperature" means a temperature between 18 to 25°C, "GCMS" refers to gas chromatography-mass spectrometry, "LCMS" refers to liquid chromatography-mass spectrometry, "UPLC" refers to ultra performance liquid chromatography and "HPLC" refers to high pressure liquid chromatography, "SFC" refers to supercritical fluid chromatography.

[0207] Hydrogenation may be performed in a Parr Shaker under pressurized hydrogen gas, or in Thales-nano H-Cube flow hydrogenation apparatus at full hydrogen and a flow rate between 1-2 mL / min at specified temperature.

[0208] HPLC, UPLC, LCMS, GCMS, and SFC retention times were measured using the methods noted in the procedures.PREPARATION OF INTERMEDIATES AND EXAMPLES Preparation P1 tert-Butyl 4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P1)

[0209] Step 1. Synthesis of 2-bromo-6-[(4-chloro-2-fluorophenyl)(hydroxy)methyl]phenol (C1).

[0210] This experiment was carried out in two batches of the same scale. n-Butyllithium (2.5 M solution in hexanes; 32.8 mL, 82.0 mmol) was slowly added to a -70 °C solution of 1-bromo-4-chloro-2-fluorobenzene (17.2 g, 82.1 mmol) in diethyl ether (100 mL), while the temperature of the reaction mixture was maintained below -60 °C. After the reaction mixture had been stirred at -70 °C for 20 minutes, a solution of 3-bromo-2-hydroxybenzaldehyde (5.5 g, 27 mmol) in diethyl ether (100 mL) was slowly added, while the reaction temperature was maintained below -60 °C. After a further 1 hour of stirring at -70 °C, the reaction was quenched by addition of aqueous ammonium chloride solution (50 mL) at -70 °C, and the resulting mixture was diluted with water (100 mL). The two batches were combined at this point and extracted with ethyl acetate (400 mL); the organic layer was washed with saturated aqueous sodium chloride solution (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 7% ethyl acetate in petroleum ether) afforded C1 as a white solid. Combined yield: 15.7 g, 47.4 mmol, 88%. 1< H NMR (400 MHz, chloroform-d) δ 7.44 (dd, J = 8.0, 1.5 Hz, 1H), 7.37 (dd, J = 8.1, 8.1 Hz, 1H), 7.15 (br dd, J = 8.5, 2.1 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.80 (dd, J = 7.8, 7.8 Hz, 1H), 6.78 (s, 1H), 6.31 (d, J = 4.8 Hz, 1H), 3.02 (br d, J = 4.9 Hz, 1H).Step 2. Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxole (C2).

[0211] To a solution of C1 (15.7 g, 47.4 mmol) in methanol (450 mL) was added a solution of sodium periodate (25.4 g, 119 mmol) in water (105 mL), and the reaction mixture was stirred at 30 °C for 16 hours, whereupon it was concentrated in vacuo. After the residue had been diluted with dichloromethane (500 mL), it was washed with water (500 mL). The dichloromethane solution was then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: petroleum ether) provided C2 as a white solid. Yield: 10.0 g, 30.3 mmol, 64%. The following 1< H NMR data was obtained from an experiment carried out in the same manner but on smaller scale. 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.67 - 7.61 (m, 2H), 7.50 (s, 1H), 7.43 (brdd, J = 8, 2 Hz, 1H), 7.09 (dd, J = 8.3, 1.1 Hz, 1H), 7.01 (dd, J = 7.9, 1.1 Hz, 1H), 6.86 (dd, J = 8.1, 8.1 Hz, 1H).Step 3. Synthesis of tert-butyl 4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (C3).

[0212] A reaction flask containing a suspension of C2 (8.00 g, 24.3 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.01 g, 29.1 mmol), sodium carbonate (5.15 g, 48.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) [Pd(dppf)Cl 2 ; 888 mg, 1.21 mmol] in 1,4-dioxane (80 mL) and water (32 mL) was evacuated and charged with nitrogen. This evacuation cycle was repeated twice, and then the reaction mixture was stirred at 90 °C for 16 hours. After removal of solvent in vacuo, the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 4.3% ethyl acetate in petroleum ether) provided the product, which was combined with material from a similar reaction carried out using C2 (2.00 g, 6.07 mmol) to afford C3 as a light-yellow gum. Combined yield: 10.3 g, 23.8 mmol, 78%. 1< H NMR (400 MHz, chloroform-d) δ 7.53 (dd, J = 8.3, 7.8 Hz, 1H), 7.23 - 7.16 (m, 3H), 6.88 - 6.83 (m, 2H), 6.81 - 6.76 (m, 1H), 6.34 - 6.28 (br m, 1H), 4.10 - 4.05 (m, 2H), 3.61 (br dd, J = 6, 5 Hz, 2H), 2.59 - 2.50 (br m, 2H), 1.48 (s, 9H).Step 4. Synthesis of tert-butyl 4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P1).

[0213] A solution of C3 (10.3 g, 23.8 mmol) and tris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 1.54 g, 1.66 mmol) in methanol (100 mL) was stirred at 50 °C under hydrogen (45 psi) for 18 hours. The reaction mixture was then filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure and subjected to silica gel chromatography (Gradient: 0% to 9% ethyl acetate in petroleum ether). The resulting material was combined with that from a similar reaction carried out using C3 (1.67 g, 3.87 mmol) to afford P1 as a colorless gum. Combined yield: 10.3 g, 23.7 mmol, 86%. LCMS m / z 456.1 [M+Na +< ]. 1< H NMR (400 MHz, chloroform-d) δ 7.52 (dd, J = 8.5, 7.6 Hz, 1H), 7.23 - 7.17 (m, 2H), 7.16 (s, 1H), 6.83 (dd, J = 7.8, 7.8 Hz, 1H), 6.78 - 6.69 (m, 2H), 4.35 - 4.10 (br m, 2H), 2.89 - 2.71 (m, 3H), 1.89 - 1.77 (m, 2H), 1.77 - 1.63 (m, 2H), 1.47 (s, 9H).Preparation P2 tert-Butyl 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P2)

[0214] Step 1. Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxole (C4).

[0215] To a solution of 3-bromobenzene-1,2-diol (330 g, 1.75 mol) in toluene (1.5 L) were added 1-(4-chloro-2-fluorophenyl)ethanone (316 g, 1.83 mol) and p-toluenesulfonic acid (6.02 g, 35.0 mmol). The reaction apparatus was fitted with a Dean-Stark trap, and the reaction mixture was heated at 140 °C for 60 hours, whereupon the solution was concentrated in vacuo and purified using silica gel chromatography (Eluent: petroleum ether); C4 was obtained as a mixture of yellow oil and solid. Yield: 158 g, 460 mmol, 26%. 1< H NMR (400 MHz, chloroform-d): δ 7.54 (dd, J = 8.4, 8.4 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.95 (dd, J = 7.9, 1.4 Hz, 1H), 6.75 (dd, component of ABX pattern, J = 7.8, 1.4 Hz, 1H), 6.70 (dd, component of ABX pattern, J = 7.9, 7.9 Hz, 1H), 2.11 (d, J = 1.1 Hz, 3H).Step 2. Synthesis of tert-butyl 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (C5).

[0216] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (62 g, 200 mmol) and sodium carbonate (100 g, 940 mmol) were added to a solution of C4 (58.0 g, 169 mmol) in 1,4-dioxane (600 mL). After addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.0 g, 8.2 mmol), the reaction mixture was heated to 90 °C and stirred for 16 hours. Water (500 mL) was then added, and the resulting mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (2 x 500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 9% ethyl acetate in petroleum ether) provided C5 as a yellow oil. Yield: 56.0 g, 126 mmol, 75%. 1< H NMR (400 MHz, chloroform-d) δ 7.50 (dd, J = 8.2, 8.2 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.83 - 6.77 (m, 2H), 6.74 (dd, component of ABX pattern, J = 5.4, 3.6 Hz, 1H), 6.39 - 6.33 (br m, 1H), 4.14 - 4.08 (m, 2H), 3.70 - 3.56 (m, 2H), 2.66 - 2.45 (m, 2H), 2.07 (d, J = 1.1 Hz, 3H), 1.50 (s, 9H).Step 3. Synthesis of tert-butyl 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P2).

[0217] To a solution of C5 (56.0 g, 126 mmol) in methanol (200 mL) was added tris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 8.10 g, 8.75 mmol), and the reaction mixture was heated to 50 °C for 18 hours under hydrogen (45 psi). It was then cooled to 25 °C and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, and purified twice using silica gel chromatography (First column - Gradient: 0% to 9% ethyl acetate in petroleum ether; Second column - Gradient: 0% to 2% ethyl acetate in petroleum ether), affording P2 as a yellow solid. Yield: 37.0 g, 82.6 mmol, 66%. LCMS m / z 392.1 [(M - 2-methylprop-1-ene)+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 7.51 (dd, J = 8.3, 8.0 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.77 (dd, component of ABC pattern, J = 7.8, 7.8 Hz, 1H), 6.70 (dd, component of ABC pattern, J = 7.7, 1.3 Hz, 1H), 6.66 (dd, component of ABC pattern, J = 7.8, 1.3 Hz, 1H), 4.37 - 4.13 (br m, 2H), 2.92 - 2.73 (m, 3H), 2.05 (d, J = 1.1 Hz, 3H), 1.90 - 1.63 (m, 4H), 1.49 (s, 9H).Preparation P3 4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, p-toluenesulfonate salt (P3)

[0218] Step 1. Isolation of tert-butyl 4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (C6) and tert-butyl 4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (C7).

[0219] Separation of P2 (75.2 g, 168 mmol) into its component enantiomers was carried out via SFC (supercritical fluid chromatography)_[Column: Chiral Technologies Chiralpak AD-H, 5 µm; Mobile phase: 4:1 carbon dioxide / (2-propanol containing 0.2% 1-aminopropan-2-ol)]. The first-eluting compound was designated as C6, and the second-eluting enantiomer as C7. The indicated absolute configurations were assigned on the basis of a single-crystal X-ray structure determination carried out on C8, which was derived from C6 (see below). C6 - Yield: 38.0 g, 84.8 mmol, 50%. Retention time 3.64 minutes [Column: Chiral Technologies Chiralpak AD-H, 4.6 x 250 mm, 5 µm; Mobile phase A: carbon dioxide; Mobile phase B: 2-propanol containing 0.2% 1-aminopropan-2-ol; Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8.00 minutes; Flow rate: 3.0 mL / minute; Back pressure: 120 bar]. C7 - Yield: 36.8 g, 82.2 mmol, 49%. Retention time 4.19 minutes (Analytical SFC conditions identical to those used for C6). Step 2. Synthesis of 4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, p-toluenesulfonate salt (P3).

[0220] A solution of C7 (1.62 g, 3.62 mmol) in ethyl acetate (36 mL) was treated with p-toluenesulfonic acid monohydrate (791 mg, 4.16 mmol) and heated at 45 °C. After 23 hours, the reaction mixture was allowed to cool to room temperature and the solid was collected via filtration. It was rinsed with a mixture of ethyl acetate and heptane (1:1, 2 x 15 mL) to afford P3 as a white solid. Yield: 1.37 g, 2.63 mmol, 73%. LCMS m / z 348.1 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (v br s, 1H), 8.29 (v br s, 1H), 7.65 - 7.55 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H), 6.88 - 6.81 (m, 2H), 6.75 - 6.68 (m, 1H), 3.42 - 3.33 (m, 2H), 3.11 - 2.93 (m, 3H), 2.29 (s, 3H), 2.03 (s, 3H), 1.98 - 1.82 (m, 4H).Conversion of C6 to 4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, methanesulfonate salt (C8) for determination of absolute stereochemistry

[0221]

[0222] p-Toluenesulfonic acid (377 mg, 2.19 mmol) was added to a solution of C6 (490 mg, 1.09 mmol) in ethyl acetate (5.5 mL), and the reaction mixture was stirred at room temperature overnight. After dilution with additional ethyl acetate, the reaction mixture was washed sequentially with aqueous sodium bicarbonate solution, water, and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Yield: 375 mg, 1.08 mmol, 99%. 1< H NMR (400 MHz, methanol-d 4 ) δ 7.59 (dd, J = 8.3. 8.3 Hz, 1H), 7.27 (dd, J = 10.9, 2.0 Hz, 1H), 7.20 (br dd, J = 8.4, 2.1 Hz, 1H), 6.81 - 6.75 (m, 1H), 6.74 - 6.67 (m, 2H), 3.18 - 3.09 (m, 2H), 2.88 - 2.77 (m, 1H), 2.77 - 2.67 (m, 2H), 2.02 (d, J = 0.7 Hz, 3H), 1.85 - 1.73 (m, 4H).

[0223] A 0.1 M solution of this free base (4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine) in ethyl acetate was prepared and subjected to a salt screen. Only the methanesulfonate salt formation is described here. A mixture of methanesulfonic acid (25 µL, 39 µmol) and the solution of substrate (0.1 M; 0.25 mL, 25 µmol) was stirred overnight. Sufficient methanol was then added to dissolve the solid present, and ethyl acetate (3 mL) was added. The resulting solution was allowed to evaporate slowly, without stirring, to afford crystals of C8; one of these was used for the single crystal X-ray structure determination described below.Single-crystal X-ray structural determination of C8 Single Crystal X-Ray Analysis

[0224] Data collection was performed on a Bruker D8 Quest diffractometer at room temperature. Data collection consisted of omega and phi scans.

[0225] The structure was solved by intrinsic phasing using SHELX software suite in the orthorhombic class space group P2 1 2 1 2 1 . The structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters.

[0226] Formation of the methanesulfonate salt was confirmed via N1_H1X_O4 proton transfer.

[0227] The hydrogen atoms located on nitrogen and oxygen were found from the Fourier difference map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms.

[0228] Analysis of the absolute structure using likelihood methods (Hooft, 2008) was performed using PLATON (Spek). The results indicate that the absolute structure has been correctly assigned; the method calculates that the probability that the structure is correct is 100%. The Hooft parameter is reported as 0.02 with an esd of 0.0012 and the Parson's parameter is reported as 0.07 with an esd of 0.009. The absolute configuration at C7 was confirmed as (R).

[0229] The asymmetric unit is comprised of one molecule of the protonated free base of C8 and one molecule of deprotonated methanesulfonic acid. The final R-index was 4.6%. A final difference Fourier revealed no missing or misplaced electron density.

[0230] Pertinent crystal, data collection, and refinement information is summarized in Table A. Atomic coordinates, bond lengths, bond angles, and displacement parameters are listed in Tables B - D.Software and References

[0231] SHELXTL, Version 5.1, Bruker AXS, 1997. PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13. MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M. Towler, and J. van de Streek, J. Appl. Cryst. 2006, 39, 453-457. OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341. R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008, 41, 96-103. H. D. Flack, Acta Cryst. 1983, A39, 867-881. Table A. Crystal data and structure refinement for C8. Empirical formulaC 20 H 23 ClFNO 5 SFormula weight443.90Temperature296(2) KWavelength1.54178 ÅCrystal systemOrthorhombicSpace groupP2 1 2 1 2 1 Unit cell dimensionsa = 6.5348(5) Åα = 90°b = 9.3688(7) Åβ = 90°c = 35.214(3) Åγ = 90°Volume2155.9(3) Å 3< Z4Density (calculated)1.368 Mg / m 3< Absorption coefficient2.823 mm -1< F(000)928Crystal size0.480 x 0.100 x 0.040 mm 3< Theta range for data collection2.509 to 70.483°Index ranges-7<=h<=7, -11<=k<=8, -42<=I<=42Reflections collected16311Independent reflections4035 [R int = 0.0638]Completeness to theta = 67.679°99.0%Absorption correctionEmpiricalRefinement methodFull-matrix least-squares on F 2< Data / restraints / parameters4035 / 2 / 271Goodness-of-fit on F 2< 0.832Final R indices [I>2σ(I)]R1 = 0.0463, wR2 = 0.1227R indices (all data)R1 = 0.0507, wR2 = 0.1294Absolute structure parameter-0.003(18)Extinction coefficient0.0051(6)Largest diff. peak and hole0.256 and -0.305 e.Å -3< Table B. Atomic coordinates (x 10 4< ) and equivalent isotropic displacement parameters (Å 2< x 10 3< ) for C8. U(eq) is defined as one-third of the trace of the orthogonalized U ij< tensor. xyzU(eq)S(1)3842(2)9910(1)5317(1)57(1)Cl(1)-1625(2)-718(1)6588(1)80(1)O(1)6138(4)3727(3)6876(1)53(1)F(1)639(5)3071(4)7503(1)89(1)O(2)3445(4)5043(3)7117(1)57(1)O(4)2909(6)11013(4)5082(1)78(1)O(3)3708(7)10299(4)5708(1)83(1)N(1)10461(5)2909(4)5493(1)56(1)C(9)5652(6)4826(4)6629(1)44(1)C(1)3361(7)1662(4)6697(1)53(1)C(6)2957(6)2523(4)7012(1)49(1)C(10)4075(6)5613(4)6776(1)47(1)C(14)6628(6)5138(4)6294(1)47(1)O(5)5833(7)9578(4)5179(1)96(1)C(15)8265(6)4182(4)6130(1)49(1)C(5)1105(7)2270(5)7190(1)59(1)C(16)7309(6)3048(5)5874(1)54(1)C(2)1971(7)670(4)6567(1)55(1)C(4)-286(7)1288(5)7080(1)64(1)C(7)4448(6)3667(4)7142(1)52(1)C(13)5876(8)6374(5)6113(1)60(1)C(11)3359(7)6819(4)6602(1)57(1)C(8)5296(8)3485(6)7537(1)64(1)C(19)9905(7)4976(6)5902(1)67(1)C(17)8902(7)2063(5)5702(1)59(1)C(12)4316(8)7178(5)6263(1)65(1)C(3)150(7)497(4)6756(1)56(1)C(18)11476(7)3977(6)5738(1)73(1)C(20)2328(14)8399(7)5260(2)117(3) Table C. Bond lengths [Å] and angles [°] for C8. S(1)-O(5)1.423(4)C(4)-C(3)1.389(6)S(1)-O(3)1.428(3)C(4)-H(4)0.9300S(1)-O(4)1.458(3)C(7)-C(8)1.506(6)S(1)-C(20)1.738(6)C(13)-C(12)1.373(7)Cl(1)-C(3)1.729(5)C(13)-H(13)0.9300O(1)-C(9)1.385(4)C(11)-C(12)1.388(7)O(1)-C(7)1.449(4)C(11)-H(11)0.9300F(1)-C(5)1.367(4)C(8)-H(8A)0.9600O(2)-C(10)1.376(4)C(8)-H(8B)0.9600O(2)-C(7)1.449(4)C(8)-H(8C)0.9600N(1)-C(18)1.478(6)C(19)-C(18)1.505(7)N(1)-C(17)1.486(5)C(19)-H(19A)0.9700N(1)-H(1X)0.99(2)C(19)-H(19B)0.9700N(1)-H(1Y)0.97(2)C(17)-H(17A)0.9700C(9)-C(10)1.369(5)C(17)-H(17B)0.9700C(9)-C(14)1.375(5)C(12)-H(12)0.9300C(1)-C(2)1.378(6)C(18)-H(18A)0.9700C(1)-C(6)1.395(5)C(18)-H(18B)0.9700C(1)-H(1)0.9300C(20)-H(20A)0.9600C(6)-C(5)1.384(6)C(20)-H(20B)0.9600C(6)-C(7)1.519(6)C(20)-H(20C)0.9600C(10)-C(11)1.369(5)C(14)-C(13)1.409(6)O(5)-S(1)-O(3)116.2(3)C(14)-C(15)1.509(5)O(5)-S(1)-O(4)110.1(2)C(15)-C(16)1.527(5)O(3)-S(1)-O(4)109.9(2)C(15)-C(19)1.531(6)O(5)-S(1)-C(20)107.6(4)C(15)-H(15)0.9800O(3)-S(1)-C(20)106.6(3)C(5)-C(4)1.351(7)O(4)-S(1)-C(20)105.9(4)C(16)-C(17)1.518(6)C(9)-O(1)-C(7)105.0(3)C(16)-H(16A)0.9700C(10)-O(2)-C(7)105.2(3)C(16)-H(16B)0.9700C(18)-N(1)-C(17)112.3(3)C(2)-C(3)1.372(6)C(18)-N(1)-H(1X)107(3)C(2)-H(2)0.9300C(17)-N(1)-H(1X)113(3)C(18)-N(1)-H(1Y)113(3)C(1)-C(2)-H(2)120.3C(17)-N(1)-H(1Y)103(3)C(5)-C(4)-C(3)117.5(4)H(1X)-N(1)-H(1Y)108(4)C(5)-C(4)-H(4)121.2C(10)-C(9)-C(14)124.1(3)C(3)-C(4)-H(4)121.2C(10)-C(9)-O(1)109.6(3)O(1)-C(7)-O(2)105.7(3)C(14)-C(9)-0(1)126.3(3)O(1)-C(7)-C(8)108.7(3)C(2)-C(1)-C(6)121.9(4)O(2)-C(7)-C(8)108.8(3)C(2)-C(1)-H(1)119.0O(1)-C(7)-C(6)108.7(3)C(6)-C(1)-H(1)119.0O(2)-C(7)-C(6)108.6(3)C(5)-C(6)-C(1)115.3(4)C(8)-C(7)-C(6)115.8(3)C(5)-C(6)-C(7)123.0(3)C(12)-C(13)-C(14)122.4(4)C(1)-C(6)-C(7)121.7(4)C(12)-C(13)-H(13)118.8C(9)-C(10)-C(11)122.1(4)C(14)-C(13)-H(13)118.8C(9)-C(10)-O(2)110.3(3)C(10)-C(11)-C(12)115.6(4)C(11)-C(10)-O(2)127.5(4)C(10)-C(11)-H(11)122.2C(9)-C(14)-C(13)113.6(4)C(12)-C(11)-H(11)122.2C(9)-C(14)-C(15)122.1(3)C(7)-C(8)-H(8A)109.5C(13)-C(14)-C(15)124.2(3)C(7)-C(8)-H(8B)109.5C(14)-C(15)-C(16)110.4(3)H(8A)-C(8)-H(8B)109.5C(14)-C(15)-C(19)114.1(3)C(7)-C(8)-H(8C)109.5C(16)-C(15)-C(19)108.4(3)H(8A)-C(8)-H(8C)109.5C(14)-C(15)-H(15)107.9H(8B)-C(8)-H(8C)109.5C(16)-C(15)-H(15)107.9C(18)-C(19)-C(15)112.2(4)C(19)-C(15)-H(15)107.9C(18)-C(19)-H(19A)109.2C(4)-C(5)-F(1)117.2(4)C(15)-C(19)-H(19A)109.2C(4)-C(5)-C(6)125.0(4)C(18)-C(19)-H(19B)109.2F(1)-C(5)-C(6)117.9(4)C(15)-C(19)-H(19B)109.2C(17)-C(16)-C(15)112.2(3)H(19A)-C(19)-H(19B)107.9C(17)-C(16)-H(16A)109.2N(1)-C(17)-C(16)110.1(3)C(15)-C(16)-H(16A)109.2N(1)-C(17)-H(17A)109.6C(17)-C(16)-H(16B)109.2C(16)-C(17)-H(17A)109.6C(15)-C(16)-H(16B)109.2N(1)-C(17)-H(17B)109.6H(16A)-C(16)-H(16B)107.9C(16)-C(17)-H(17B)109.6C(3)-C(2)-C(1)119.4(4)H(17A)-C(17)-H(17B)108.2C(3)-C(2)-H(2)120.3C(13)-C(12)-C(11)122.1(4)C(1)-C(2)-H(2)120.3C(13)-C(12)-H(12)118.9C(11)-C(12)-H(12)118.9C(2)-C(3)-C(4)120.8(4)H(18A)-C(18)-H(18B)108.2C(2)-C(3)-Cl(1)119.6(3)S(1)-C(20)-H(20A)109.5C(4)-C(3)-Cl(1)119.6(3)S(1)-C(20)-H(20B)109.5N(1)-C(18)-C(19)109.9(3)H(20A)-C(20)-H(20B)109.5N(1)-C(18)-H(18A)109.7S(1)-C(20)-H(20C)109.5C(19)-C(18)-H(18A)109.7H(20A)-C(20)-H(20C)109.5N(1)-C(18)-H(18B)109.7H(20B)-C(20)-H(20C)109.5C(19)-C(18)-H(18B)109.7

[0232] Symmetry transformations used to generate equivalent atoms. Table D. Anisotropic displacement parameters (Å 2< x 10 3< ) for C8. The anisotropic displacement factor exponent takes the form: -2π 2< [h 2< a* 2< U 11< + ... + 2 h k a* b* U 12< ].U 11< U 22< U 33< U 23< U 13< U 12< S(1)73(1)48(1)48(1)-2(1)7(1)-1(1)CI(1)81(1)78(1)81(1)-8(1)1(1)-8(1)O(1)54(1)50(1)56(1)14(1)10(1)17(1)F(1)83(2)103(2)79(2)-40(2)38(2)-6(2)O(2)66(2)49(1)54(1)2(1)11(1)18(1)O(4)87(2)84(2)64(2)19(2)17(2)21(2)O(3)122(3)80(2)47(1)-3(1)7(2)-13(2)N(1)47(2)73(2)48(2)7(2)3(1)11(2)C(9)51(2)38(2)44(2)2(1)-7(1)2(2)C(1)63(2)46(2)50(2)5(2)21(2)13(2)C(6)55(2)47(2)45(2)5(1)11(2)19(2)C(10)55(2)39(2)46(2)-5(1)-4(2)6(2)C(14)54(2)46(2)42(2)0(1)-9(2)-5(2)O(5)88(2)88(3)113(3)-24(2)13(2)21(2)C(15)47(2)61(2)40(2)3(2)-3(1)-2(2)C(5)60(2)62(2)54(2)-6(2)19(2)13(2)C(16)43(2)53(2)65(2)-4(2)8(2)-6(2)C(2)72(3)49(2)45(2)2(2)16(2)14(2)C(4)57(2)68(3)65(2)-3(2)23(2)6(2)C(7)54(2)50(2)51(2)7(2)12(2)16(2)C(13)81(3)54(2)46(2)9(2)-4(2)4(2)C(11)70(3)46(2)54(2)-8(2)-14(2)17(2)C(8)69(3)71(3)51(2)4(2)4(2)15(2)C(19)54(2)78(3)70(3)-13(2)2(2)-25(2)C(17)54(2)57(2)67(2)-3(2)8(2)3(2)C(12)96(3)43(2)56(2)5(2)-14(2)13(2)C(3)64(2)52(2)52(2)4(2)2(2)14(2)C(18)43(2)103(4)73(3)7(3)3(2)-18(2)C(20)153(7)87(4)110(5)-14(4)-6(5)-57(5) Preparation of P3, di-p-toluoyl-L-tartrate salt 4-[(25)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, di-p-toluoyl-L-tartrate salt (P3, di-p-toluoyl-L-tartrate salt).

[0233]

[0234] A solution of C13, free base (519 mg, 1.49 mmol) and di-p-toluoyl-L-tartaric acid (278 mg, 0.719 mmol) in acetonitrile (7.5 mL) was stirred at 50 °C for 1.5 hours. The mixture was allowed to cool to room temperature at 0.2 °C / minute. After 15 hours at room temperature, the mixture was heated to 65 °C and charged with acetonitrile (15 mL). The mixture was allowed to cool to room temperature at 0.2 °C / minute. After 15 hours at room temperature, the mixture was heated to 54 °C. After 3 hours, the solid was collected by filtration, and dried in a vacuum oven at 35 °C under nitrogen, providing P3, di-p-toluoyl-L-tartrate salt as a white solid (217 mg, 0.296 mmol, 20%, 82% ee).

[0235] A solution of P3, di-p-toluoyl-L-tartrate salt (217 mg, 0.296 mmol, 82% ee) in acetonitrile (8.0 mL) at 50 °C was allowed to cool to room temperature at 0.2 °C / minute. After 15 hours, the solid was collected by filtration, and dried in a vacuum oven at 35 °C under nitrogen, providing P3, di-p-toluoyl-L-tartrate salt as a white solid (190 mg, 0.259 mmol, 88%, 88% ee). LCMS m / z 348.1 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.9 - 8.5 (br s, 2H), 7.79 (d, J = 8.1 Hz, 4H), 7.64 - 7.54 (m, 2H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.26 (d, J = 8.0 Hz, 4H), 6.87 - 6.78 (m, 2H), 6.69 (dd, J = 6.7, 2.5 Hz, 1H), 5.58 (s, 2H), 3.37 - 3.28 (m, 2H, assumed; partially obscured by water peak), 3.05 - 2.89 (m, 3H), 2.33 (s, 6H), 2.02 (s, 3H), 1.92 - 1.80 (m, 4H). Retention time: Peak 1 (4.97 minutes, minor) and Peak 2 (5.31 minutes, Major) {Column: Chiralpak IC-U 3.0 x 50 mm, 1.6 µm; Mobile phase A: carbon dioxide; Mobile phase B: 0.1% isopropylamine in methanol; Gradient: 10% B for 5.00 minutes, then 45% B for 0.6 minutes; Flow rate: 1.7 mL / minute; Back pressure: 130 bar}.Preparation P4 tert-Butyl 4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P4)

[0236]

[0237] A suspension of P2 (2.00 g, 4.46 mmol), zinc cyanide (734 mg, 6.25 mol), zinc (70.1 mg, 1.07 mmol), 1,1'-bis(diphenylphosphino)ferrocene (dppf; 198 mg, 0.357 mmol) and tris(dibenzylideneacetone)dipalladium(0) (164 mg, 0.179 mmol) in N,N-dimethylacetamide (20 mL) was stirred at 120 °C for 16 hours, whereupon it was filtered. The filtrate was mixed with water (50 mL) and extracted with ethyl acetate (3 x 50 mL); the combined organic layers were then washed sequentially with water (30 mL) and with saturated aqueous sodium chloride solution (20 mL), and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) afforded a solid, which was treated with acetonitrile (15 mL) and water (15 mL) and subjected to lyophilization. This provided P4 as a light yellow solid. Yield: 1.17 g, 2.67 mmol, 60%. LCMS m / z 461.3 [M+Na +< ]. 1< H NMR (400 MHz, chloroform-d) 7.71 (dd, J = 7.7, 7.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (dd, J = 10.0, 1.5 Hz, 1H), 6.79 (dd, component of ABC pattern, J = 7.7, 7.6 Hz, 1H), 6.72 (dd, component of ABC pattern, J = 7.8, 1.3 Hz, 1H), 6.68 (dd, component of ABC pattern, J = 7.8, 1.3 Hz, 1H), 4.37 - 4.14 (br m, 2H), 2.91 - 2.73 (m, 3H), 2.07 (d, J = 1.1 Hz, 3H), 1.89 - 1.62 (m, 4H), 1.49 (s, 9H).Preparations P5 and P6 4-Bromo-2-phenyl-1,3-benzodioxole, ENT-1 (P5) and 4-Bromo-2-phenyl-1,3-benzodioxole, ENT-2 (P6)

[0238] Step 1. Synthesis of 2-bromo-6-[hydroxy(phenyl)methyl]phenol (C9).

[0239] Phenyllithium (1.9 M solution in 1-butoxybutane; 78.5 mL, 149 mmol) was slowly added to a -70 °C solution of 3-bromo-2-hydroxybenzaldehyde (10.0 g, 49.7 mmol) in tetrahydrofuran (70 mL), at a rate that maintained the reaction temperature below -60 °C. The resulting suspension was stirred at -70 °C for 1 hour, and then allowed to warm to room temperature overnight, whereupon it was poured into a 0 °C aqueous ammonium chloride solution (30 mL). This mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) provided C9 as a yellow solid. Yield: 6.11 g, 21.9 mmol, 44%. 1< H NMR (400 MHz, chloroform-d) δ 7.45 - 7.28 (m, 6H), 7.22 - 7.18 (m, 1H), 7.06 (br d, J = 7.7 Hz, 1H), 6.77 (dd, J = 7.9, 7.8 Hz, 1H), 6.06 (br s, 1H), 2.89 (br s, 1H).Step 2. Synthesis of 4-bromo-2-phenyl-1,3-benzodioxole (C10).

[0240] To a solution of C9 (6.11 g, 21.9 mmol) in methanol (370 mL) was added a solution of sodium periodate (11.7 g, 54.7 mmol) in water (175 mL). The reaction mixture was stirred at 30 °C for 40 hours, whereupon most of the methanol was removed via concentration in vacuo. The resulting mixture was extracted with dichloromethane (5 x 100 mL), and the combined organic layers were washed sequentially with aqueous sodium sulfite solution (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Eluent: petroleum ether) provided C10 as a colorless oil. Yield: 4.50 g, 16.2 mmol, 74%. LCMS m / z 278.5 (bromine isotope pattern observed) [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 7.62 - 7.57 (m, 2H), 7.49 - 7.43 (m, 3H), 7.04 (s, 1H), 7.00 (dd, J = 8.0, 1.4 Hz, 1H), 6.79 (dd, component of ABX pattern, J = 7.8, 1.4 Hz, 1H), 6.75 (dd, component of ABX pattern, J = 7.9, 7.8 Hz, 1H).Step 3. Isolation of 4-bromo-2-phenyl-1,3-benzodioxole, ENT-1 (P5) and 4-bromo-2-phenyl-1,3-benzodioxole, ENT-2 (P6).

[0241] The enantiomers comprising C10 (5.00 g, 18.0 mmol) were separated using SFC [Column: Chiral Technologies ChiralCel OD, 10 µm; Mobile phase: 3:1 carbon dioxide / (methanol containing 0.1% ammonium hydroxide)]. The first-eluting enantiomer was designated as ENT-1 (P5), and the second-eluting enantiomer as ENT-2 (P6); both were obtained as yellow oils. P5 Yield: 2.20 g, 7.94 mmol, 44%. LCMS m / z 277.0 (bromine isotope pattern observed) [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 7.63 - 7.55 (m, 2H), 7.51 - 7.42 (m, 3H), 7.04 (s, 1H), 7.00 (dd, J = 8.0, 1.3 Hz, 1H), 6.80 (dd, component of ABX pattern, J = 7.8, 1.4 Hz, 1H), 6.75 (dd, component of ABX pattern, J = 7.9, 7.8 Hz, 1H). Retention time 3.28 minutes (Column: Chiral Technologies ChiralCel OD-H, 4.6 x 150 mm, 5 µm; Mobile phase A: carbon dioxide; Mobile phase B: methanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 5.5 minutes; Flow rate: 2.5 mL / minute). P6 Yield: 2.00 g, 7.22 mmol, 40%. LCMS m / z 276.9 (bromine isotope pattern observed) [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 7.63 - 7.55 (m, 2H), 7.50 - 7.42 (m, 3H), 7.04 (s, 1H), 7.00 (dd, J = 8.0, 1.4 Hz, 1H), 6.80 (dd, component of ABX pattern, J = 7.8, 1.4 Hz, 1H), 6.75 (dd, component of ABX pattern, J = 7.9, 7.9 Hz, 1H). Retention time 3.73 minutes (Analytical conditions identical to those used for P5). Preparation P7 tert-Butyl 4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P7)

[0242] Step 1. Synthesis of 2-(4-bromo-2-methyl-1,3-benzodioxol-2-yl)-5-chloropyridine (C11).

[0243] A mixture of 5-chloro-2-ethynylpyridine (1.80 g, 13.1 mmol), 3-bromobenzene-1,2-diol (2.47 g, 13.1 mmol), and triruthenium dodecacarbonyl (167 mg, 0.261 mmol) in toluene (25 mL) was degassed for 1 minute and then heated at 100 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and filtered through a pad of diatomaceous earth; the filtrate was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 1% ethyl acetate in petroleum ether) to provide C11 as a yellow oil. Yield: 1.73 g, 5.30 mmol, 40%. LCMS m / z 325.6 (bromine-chlorine isotope pattern observed) [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.63 (dd, J = 2.4, 0.7 Hz, 1H), 7.71 (dd, component of ABX pattern, J = 8.4, 2.4 Hz, 1H), 7.60 (dd, component of ABX pattern, J = 8.4, 0.7 Hz, 1H), 6.97 (dd, J = 8.0, 1.4 Hz, 1H), 6.76 (dd, component of ABX pattern, J = 7.8, 1.4 Hz, 1H), 6.72 (dd, component of ABX pattern, J = 8.0, 7.8 Hz, 1H), 2.10 (s, 3H).Step 2. Synthesis of tert-butyl 4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]-3,6-dihydropyridine-1(2H)-carboxylate (C12).

[0244] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (388 mg, 0.530 mmol) was added to a suspension of C11 (1.73 g, 5.30 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.64 g, 5.30 mmol), and cesium carbonate (5.18 g, 15.9 mmol) in 1,4-dioxane (35 mL) and water (6 mL). The reaction mixture was stirred at 90 °C for 4 hours, whereupon it was diluted with ethyl acetate (30 mL) and water (5 mL). The organic layer was concentrated in vacuo and the residue was subjected to silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether), affording C12 as a yellow gum. Yield: 1.85 g, 4.31 mmol, 81%. LCMS m / z 451.0+ [M+Na +< ]. 1< H NMR (400 MHz, chloroform-d) δ 8.62 (dd, J = 2.5, 0.8 Hz, 1H), 7.69 (dd, component of ABX pattern, J = 8.4, 2.4 Hz, 1H), 7.57 (dd, component of ABX pattern, J = 8.4, 0.8 Hz, 1H), 6.84 - 6.79 (m, 2H), 6.78 - 6.73 (m, 1H), 6.39 - 6.33 (br m, 1H), 4.13 - 4.07 (m, 2H), 3.68 - 3.58 (m, 2H), 2.60 - 2.51 (br m, 2H), 2.07 (s, 3H), 1.49 (s, 9H).Step 3. Synthesis of tert-butyl 4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (P7).

[0245] A solution of C12 (2.61 g, 6.08 mmol) and tris(triphenylphosphine)rhodium(I) chloride (Wilkinson's catalyst; 563 mg, 0.608 mmol) in methanol (100 mL) was degassed under vacuum and then purged with hydrogen; this evacuation-purge cycle was carried out a total of three times. The reaction mixture was then stirred at 60 °C under hydrogen (50 psi) for 16 hours, whereupon it was filtered. The filtrate was concentrated in vacuo, and the residue was purified using silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether); the resulting material was combined with material from a similar hydrogenation carried out on C12 (110 mg, 0.256 mmol) to provide P7 as a light-yellow gum. Combined yield: 2.05 g, 4.76 mmol, 75%. LCMS m / z 431.3 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.62 (d, J = 2.3 Hz, 1H), 7.69 (dd, component of ABX pattern, J = 8.4, 2.4 Hz, 1H), 7.57 (d, half of AB quartet, J = 8.4 Hz, 1H), 6.79 (dd, component of ABC pattern, J = 7.8, 7.7 Hz, 1H), 6.72 (dd, component of ABC pattern, J = 7.8, 1.3 Hz, 1H), 6.68 (br d, component of ABC pattern, J = 7.9 Hz, 1H), 4.32 - 4.12 (br m, 2H), 2.91 - 2.73 (m, 3H), 2.05 (s, 3H), 1.90 - 1.62 (m, 4H), 1.48 (s, 9H).Preparations P8 and P9 tert-Butyl 4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate, ENT-1 (P8) and tert-Butyl 4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidine-1-carboxylate, ENT-2 (P9)

[0246]

[0247] Separation of P7 (500 mg, 1.16 mmol) into its component enantiomers was effected using SFC {Column: Phenomenex Lux Amylose-1, 5 µm; Mobile phase: 9:1 carbon dioxide / [2-propanol containing 0.2% (7 M ammonia in methanol)]}. The first-eluting enantiomer was designated as ENT-1 (P8), and the second-eluting enantiomer as ENT-2 (P9). P8 Yield: 228 mg, 0.529 mmol, 46%. Retention time 4.00 minutes {Column: Phenomenex Lux Amylose-1, 4.6 x 250 mm, 5 µm; Mobile phase A: carbon dioxide; Mobile phase B: [2-propanol containing 0.2% (7 M ammonia in methanol)]; Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8.00 minutes; Flow rate: 3.0 mL / minute; Back pressure: 120 bar}. P9 Yield: 229 mg, 0.531 mmol, 46%. Retention time 4.50 minutes (Analytical conditions identical to those used for P8). Preparation P10 {4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetic acid (P10)

[0248] Step 1. Synthesis of 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, p-toluenesulfonate salt (C13).

[0249] A solution of P2 (5.0 g, 11 mmol) and p-toluenesulfonic acid (4.81 g, 27.9 mmol) in ethyl acetate (100 mL) was stirred at 60 °C for 2 hours, whereupon it was concentrated in vacuo to afford C13 as a yellow gum. This material was taken directly into the following step. LCMS m / z 347.9 [M+H] +< .Step 2. Synthesis of ethyl {4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetate (C14).

[0250] Potassium carbonate (7.71 g, 55.8 mmol) and ethyl bromoacetate (1.86 g, 11.2 mmol) were added to a solution of C13 (from the previous step; ≤11 mmol) in acetonitrile (150 mL), and the reaction mixture was stirred at 55 °C for 16 hours. It was then filtered, and the filtrate was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) to afford C14 as a yellow gum. By 1< H NMR analysis, this material was not entirely pure. Yield: 3.57 g, 8.23 mmol, 75% over 2 steps. 1< H NMR (400 MHz, chloroform-d), C14 peaks only: δ 7.52 (dd, J = 8.4, 8.0 Hz, 1H), 7.17 - 7.07 (m, 2H), 6.77 (dd, component of ABC pattern, J = 7.8, 7.8 Hz, 1H), 6.72 - 6.67 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.27 (s, 2H), 3.07 (m, 2H), 2.70 (tt, J = 12.1, 3.8 Hz, 1H), 2.35 (ddd, J = 11.5, 11.5, 2.7 Hz, 2H), 2.04 (d, J = 1.1 Hz, 3H), 2.02 - 1.76 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H).Step 3. Synthesis of {4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}acetic acid (P10).

[0251] A solution of C14 (3.57 g, 8.23 mmol) and aqueous sodium hydroxide solution (3 M; 13.7 mL, 41.1 mmol) in a mixture of methanol (80 mL) and tetrahydrofuran (40 mL) was stirred at 25 °C for 16 hours. After removal of solvents in vacuo, the aqueous residue was acidified to pH 7 by addition of 1 M hydrochloric acid, and then extracted with a mixture of dichloromethane and methanol (10:1, 2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide P10 as a yellow solid. Yield: 2.95 g, 7.27 mmol, 88%. LCMS m / z 406.2 [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 7.61 (dd, J = 8.3, 8.3 Hz, 1H), 7.29 (dd, J = 10.9, 2.0 Hz, 1H), 7.22 (ddd, J = 8.4, 2.0, 0.8 Hz, 1H), 6.82 (dd, component of ABC pattern, J = 8.3, 7.1 Hz, 1H), 6.78 - 6.72 (m, 2H), 3.65 - 3.54 (br m, 2H), 3.51 (s, 2H), 3.04 - 2.88 (m, 3H), 2.23 - 2.07 (m, 2H), 2.07 - 1.93 (m, 2H), 2.04 (d, J = 1.1 Hz, 3H).Preparation P11 Methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P11)

[0252] Step 1. Synthesis of methyl 3-[(2-methoxyethyl)amino]-4-nitrobenzoate (C15).

[0253] To a colorless solution of methyl 3-fluoro-4-nitrobenzoate (50 g, 250 mmol) in tetrahydrofuran (400 mL) was added triethylamine (40.7 g, 402 mmol, 55.8 mL) followed by addition of 2-methoxyethanamine (30.2 g, 402 mmol) in tetrahydrofuran (100 mL), drop-wise, at room temperature. The resultant yellow solution was stirred at 55 °C for 18 hours. The solution was cooled to room temperature and concentrated under reduced pressure to remove tetrahydrofuran. The resultant yellow solid was dissolved in ethyl acetate (800 mL) and washed with saturated aqueous ammonium chloride solution (250 mL). The aqueous phase was separated and extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 250 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield C15 (60.2 g, 94%) as a yellow solid. 1< H NMR (600 MHz, chloroform-d) δ 8.23 (d, 1H), 8.17 (br s, 1H), 7.58 (d, 1H), 7.25 (dd, 1H), 3.95 (s, 3H), 3.69-3.73 (m, 2H), 3.56 (m, 2H), 3.45 (s, 3H); LCMS m / z 255.4 [M+H] +< .Step 2. Synthesis of methyl 4-amino-3-[(2-methoxyethyl)amino]benzoate (C16).

[0254] To solution of C15 (30 g, 118 mmol) in methanol (500 mL) was added Pd / C (10 g, 94 mmol). This reaction was stirred at room temperature under 15 psi hydrogen for 18 hours. The black suspension was filtered through diatomaceous earth and the filter cake was washed with methanol (500 mL). The combined filtrates were concentrated in vacuo to give C16 (26.5 g, quantitative) as a brown oil, which solidified on standing. 1< H NMR (400 MHz, chloroform-d) δ 7.48 (dd, 1H), 7.36 (d, 1H), 6.69 (d, 1H), 3.87 (s, 3H), 3.77 (br s, 2H), 3.68 (t, 2H), 3.41 (s, 3H), 3.32 (t, 2H); LCMS m / z 224.7 [M+H] +< .Step 3. Synthesis of methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P11).

[0255] To a solution of C16 (5.00 g, 22.3 mmol) in tetrahydrofuran (100 mL) was added 2-chloro-1,1,1-trimethoxyethane (3.31 mL, 24.6 mmol), followed by p-toluenesulfonic acid monohydrate (84.8 mg, 0.446 mmol). The reaction mixture was heated at 45 °C for 5 hours, whereupon it was concentrated in vacuo; the residual oil was dissolved in ethyl acetate (10 mL) and heated until a solution formed. This was slowly stirred while cooling to room temperature overnight. The precipitate was collected via filtration and washed with heptane to afford P11 as a gray solid. Yield: 5.73 g, 20.3 mmol, 91%. 1< H NMR (600 MHz, chloroform-d) δ 8.12 (br s, 1H), 8.01 (br d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 4.52 (t, J = 5.1 Hz, 2H), 3.96 (s, 3H), 3.74 (t, J = 5.1 Hz, 2H), 3.28 (s, 3H).Step 4. Synthesis of methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, hydrochloride salt (P11, HCl salt).

[0256] A solution of C16 (5.0 g, 24 mmol) in 1,4-dioxane (100 mL) was heated to 100 °C, a solution of chloroacetic anhydride (4.1 g, 24.5 mmol) in 1,4-dioxane (60 mL) was added via addition funnel over a period of 10 hours, and the reaction mixture was stirred for another 12 hours at 100 °C. The following day, the reaction was cooled to room temperature and the 1,4-dioxane was removed under reduced pressure. The crude reaction mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was separated, dried over sodium sulfate, and filtered. A solution of 4 M hydrogen chloride in 1,4-dioxane (1.1 equiv.) was added to the ethyl acetate solution with constant stirring. The hydrochloride salt of P11 precipitated out as a pale yellow solid. The suspension was stirred for 1 hour and the hydrochloride salt of P11 was then collected by filtration to give a yellow solid (6.1 g, 86%). 1< H NMR (600 MHz, CD 3 OD) δ 8.64 (s, 1H), 8.30 (d, 1H), 7.92 (d, 1H), 5.32 (s, 2H), 4.84 (m, 2H), 3.99 (s, 3H), 3.83 (t, 2H), 3.31 (s, 3H). LCMS m / z 283.2 [M+H] +< .Preparation P12 Methyl 1-(2-methoxyethyl)-2-(piperazin-1-ylmethyl)-1H-benzimidazole-6-carboxylate (P12)

[0257] Step 1. Synthesis of methyl 2-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (C17).

[0258] Compound P11 (1.59 g, 5.62 mmol) was added to a 15 °C mixture of tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) and potassium carbonate (2.97 g, 21.5 mmol) in acetonitrile (15 mL), and the reaction mixture was stirred at 55 °C for 12 hours. It was then combined with a similar reaction carried out using P11 and tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol), and the mixture was filtered. After the filtrate had been concentrated in vacuo, the residue was purified via chromatography on silica gel (Gradient: 0% to 60% ethyl acetate in petroleum ether) to provide C17 as a pale yellow solid. Combined yield: 2.30 g, 5.32 mmol, 83%. LCMS m / z 433.0 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.12 (d, J = 1.5 Hz, 1H), 7.96 (dd, J = 8.4, 1.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 4.58 (t, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.46 - 3.37 (br m, 4H), 3.28 (s, 3H), 2.54 - 2.44 (br m, 4H), 1.45 (s, 9H).Step 2. Synthesis of methyl 1-(2-methoxyethyl)-2-(piperazin-1-ylmethyl)-1H-benzimidazole-6-carboxylate (P12).

[0259] To a solution of C17 (2.30 g, 5.32 mmol) in dichloromethane (80 mL) was added a solution of hydrogen chloride in ethyl acetate (20 mL). The reaction mixture was stirred at 20 °C for 2 hours, whereupon it was concentrated in vacuo. The residue was diluted with water (20 mL), adjusted to a pH of 9 to 10 by addition of saturated aqueous sodium bicarbonate solution, and extracted with a mixture of ethyl acetate and methanol (10:1, 15 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford P12 as a pale yellow solid. Yield: 1.68 g, 5.05 mmol, 95%. LCMS m / z 332.8 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.13 (br s, 1H), 7.96 (br d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 4.59 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 2H), 3.75 (t, J = 5.5 Hz, 2H), 3.29 (s, 3H), 2.87 (t, J = 4.8 Hz, 4H), 2.50 (br m, 4H).Preparation P13 6-Bromo-2-(chloromethyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine (P13)

[0260] Step 1. Synthesis of 5-bromo-N-(2-methoxyethyl)-2-nitropyridin-3-amine (C18).

[0261] A solution of 5-bromo-3-fluoro-2-nitropyridine (400 mg, 1.81 mmol) and 2-methoxyethanamine (408 mg, 5.43 mmol) in tetrahydrofuran (10 mL) was stirred at 25 °C for 2 hours, whereupon it was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford C18 as a yellow solid. Yield: 430 mg, 1.56 mmol, 86%.Step 2. Synthesis of 5-bromo-N 3< -(2-methoxyethyl)pyridine-2,3-diamine (C19).

[0262] A solution of C18 (430 mg, 1.56 mmol), ammonium chloride (833 mg, 15.6 mmol), and iron powder (870 mg, 15.6 mmol) in a mixture of methanol (10 mL) and water (2 mL) was stirred at 80 °C for 30 minutes. The resulting suspension was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL); the combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide C19 as a brown solid. Yield: 350 mg, 1.42 mmol, 91%. 1< H NMR (400 MHz, chloroform-d) δ 7.63 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 4.33 - 4.19 (br s, 2H), 3.65 (dd, J = 5.6, 4.6 Hz, 2H), 3.40 (s, 3H), 3.22 (br t, J = 5 Hz, 2H).Step 3. Synthesis of 6-bromo-2-(chloromethyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine (P13).

[0263] A solution of C19 (400 mg, 1.63 mmol) in 1,4-dioxane (8 mL) was treated with chloroacetyl chloride (0.284 mL, 3.57 mmol) and stirred at room temperature until LCMS analysis indicated complete conversion of C19 to the intermediate amide. After removal of the 1,4-dioxane in vacuo, the residue was dissolved in trifluoroacetic acid (8 mL) and heated at 80 °C for 18 hours, whereupon the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was dissolved in ethyl acetate (50 mL) and neutralized by addition of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) afforded P13 as a solid. Yield: 176 mg, 0.578 mmol, 35%. LCMS m / z 306.1 (bromine-chlorine isotope pattern observed) [M+H] +< . 1< H NMR (600 MHz, chloroform-d) δ 8.58 (br s, 1H), 7.89 (br s, 1H), 4.92 (s, 2H), 4.44 (t, J = 5.0 Hz, 2H), 3.71 (t, J = 5.0 Hz, 2H), 3.28 (s, 3H).Preparation P14 Methyl 2-{[4-(2,3-dihydroxyphenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P14)

[0264] Step 1. Synthesis of [(3-bromobenzene-1,2-diyl)bis(oxymethanediyloxyethane-2,1-diyl)]bis(trimethylsilane) (C20 ).

[0265] This reaction was carried out in two batches of identical scale. N,N-Diisopropylethylamine (37.8 mL, 217 mmol) was added drop-wise to a solution of 3-bromobenzene-1,2-diol (10.0 g, 52.9 mmol) in tetrahydrofuran (300 mL). After the mixture had been stirred for 10 minutes at 20 °C, [2-(chloromethoxy)ethyl](trimethyl)silane (19.2 mL, 108 mmol) was added drop-wise over 5 minutes, and stirring was continued for 16 hours at room temperature (18 °C). N,N-Diisopropylethylamine (27.6 mL, 158 mmol) was again added, followed by drop-wise addition of [2-(chloromethoxy)ethyl](trimethyl)silane (14.0 mL, 79.1 mmol) at room temperature (18 °C). After another 2.5 hours at room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. At this point, the crude products from the two batches were combined and purified using silica gel chromatography (Gradient: 0% to 7% ethyl acetate in petroleum ether), to afford C20 as a colorless oil. By 1< H NMR analysis, this material was not entirely pure. Combined yield: 22.9 g, 50.9 mmol, 48%. 1< H NMR (400 MHz, chloroform-d), C20 peaks only: δ 7.19 (dd, J = 8.1, 1.5 Hz, 1H), 7.12 (dd, J = 8.3, 1.4 Hz, 1H), 6.90 (dd, J = 8.2. 8.2 Hz, 1H), 5.26 - 5.19 (m, 4H), 4.00 - 3.92 (m, 2H), 3.80 - 3.73 (m, 2H), 1.00 - 0.91 (m, 4H), 0.03 (s, 9H), 0.00 (s, 9H).Step 2. Synthesis of tert-butyl 4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (C21).

[0266] A reaction vessel containing a suspension of C20 (6.11 g, 13.6 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5.04 g, 16.3 mmol), aqueous sodium carbonate solution (1 M; 40.8 mL, 40.8 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (497 mg, 0.679 mmol) in 1,4-dioxane (100 mL) was evacuated and charged with nitrogen. This evacuation cycle was repeated twice, and then the reaction mixture was stirred at 85 °C for 16 hours, whereupon the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 8% methanol in dichloromethane) provided C21 as a yellow oil. Yield: 5.47 g, 9.91 mmol, 73%. 1< H NMR (600 MHz, chloroform-d) δ 7.10 (br d, J = 8.2 Hz, 1H), 6.98 (dd, J = 7.9, 7.9 Hz, 1H), 6.81 (br d, J = 7.7 Hz, 1H), 5.79 (br s, 1H), 5.23 (s, 2H), 5.07 (s, 2H), 4.03 (br s, 2H), 3.83 - 3.74 (m, 4H), 3.59 (br s, 2H), 2.52 (br s, 2H), 1.49 (s, 9H), 1.01 - 0.89 (m, 4H), 0.01 (s, 9H), 0.01 (s, 9H).Step 3. Synthesis of tert-butyl 4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidine-1-carboxylate (C22).

[0267] A solution of C21 (12.5 g, 22.6 mmol) in methanol (300 mL) was treated with 10% palladium on carbon (2.94 g, 2.76 mmol) and hydrogenated for 16 hours at 40 psi and 25 °C. LCMS analysis at this point indicated conversion to the product: LCMS m / z 576.0 [M+Na +< ]. After the reaction mixture had been filtered, and the filter cake had been washed with methanol (2 x 100 mL), the combined filtrates were concentrated in vacuo to afford C22 as a colorless oil. Yield: 11.2 g, 20.1 mmol, 89%. 1< H NMR (400 MHz, chloroform-d) δ 7.05 - 6.97 (m, 2H), 6.83 (dd, J = 6.9, 2.5 Hz, 1H), 5.22 (s, 2H), 5.13 (s, 2H), 4.38 - 4.10 (br m, 2H), 3.90 - 3.82 (m, 2H), 3.81 - 3.73 (m, 2H), 3.22 (tt, J = 12.2, 3.5 Hz, 1H), 2.79 (br dd, J = 12.8, 12.8 Hz, 2H), 1.78 (br d, J = 13 Hz, 2H), 1.65 - 1.52 (m, 2H), 1.48 (s, 9H), 1.04 - 0.91 (m, 4H), 0.03 (s, 9H), 0.00 (s, 9H).Step 4. Synthesis of 4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidine (C23).

[0268] To a room temperature (15 °C) solution of C22 (7.23 g, 13.0 mmol) in dichloromethane (90 mL) was added 2,6-dimethylpyridine (2.39 g, 22.3 mmol), followed by drop-wise addition of trimethylsilyl trifluoromethanesulfonate (3.80 g, 17.1 mmol). The reaction mixture was stirred at 15 °C for 16 hours, whereupon additional 2,6-dimethylpyridine (909 mg, 8.48 mmol) and trimethylsilyl trifluoromethanesulfonate (1.45 g, 6.52 mmol) were added. After stirring at room temperature (15 °C) for another 5 hours, LCMS analysis of the reaction mixture indicated the presence of product: LCMS m / z 454.1 [M+H] +< . The reaction mixture was concentrated in vacuo, and the residue was washed sequentially with aqueous ammonium chloride solution (3 x 100 mL) and saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford C23 as a brown oil (6.6 g). This material was taken directly to the following step.Step 5. Synthesis of methyl 2-{[4-(2,3-bis{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (C24).

[0269] To a solution of C23 (from the previous step; 6.6 g, ≤13 mmol) in acetonitrile (150 mL) was added P11 (3.08 g, 10.9 mmol), followed by potassium carbonate (10.1 g, 73.1 mmol), and the reaction mixture was stirred at room temperature (15 °C) for 16 hours. LCMS analysis at this point indicated the presence of the product: LCMS m / z 700.2 [M+H] +< . The reaction mixture was filtered, and the filtrate was concentrated in vacuo; purification via silica gel chromatography (Gradient: 34% to 56% ethyl acetate in petroleum ether) afforded C24 as a yellow oil. Yield: 5.4 g, 7.7 mmol, 59% over 2 steps. 1< H NMR (400 MHz, chloroform-d) δ 8.16 - 8.12 (m, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.04 - 6.96 (m, 2H), 6.86 (dd, J = 6.7, 2.6 Hz, 1H), 5.21 (s, 2H), 5.12 (s, 2H), 4.63 (t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.93 - 3.83 (m, 4H), 3.80 - 3.72 (m, 4H), 3.31 (s, 3H), 3.17 - 3.06 (m, 1H), 2.99 (br d, J = 11.2 Hz, 2H), 2.35 - 2.22 (m, 2H), 1.81 (br d, half of AB quartet, J = 12.6 Hz, 2H), 1.75 - 1.61 (m, 2H), 1.04 - 0.91 (m, 4H), 0.05 (s, 9H), -0.01 (s, 9H).Step 6. Synthesis of methyl 2-{[4-(2,3-dihydroxyphenyl)piperidin-1-yl]methyl}-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (P14).

[0270] A solution of hydrogen chloride in 1,4-dioxane (4 M; 96 mL, 384 mmol) was added to a room temperature (18 °C) solution of C24 (6.40 g, 9.14 mmol) in 1,4-dioxane (120 mL). After completion of the addition, the reaction mixture was stirred at room temperature (18 °C) for 16 hours, combined with a similar reaction carried out using C24 (1.00 g, 1.43 mmol), and concentrated in vacuo. The residue was treated with a mixture of dichloromethane and methanol (20:1, 150 mL) and stirred at room temperature (18 °C) for 1 hour, whereupon the solid (4.85 g) was collected via filtration. This material was treated with water (100 mL), and the mixture was adjusted to a pH of 7 to 8 by addition of aqueous sodium bicarbonate solution, stirred at room temperature (18 °C) for 30 minutes, and filtered. The filter cake was washed with water (2 x 20 mL), then mixed with methanol (100 mL) and concentrated in vacuo. The resulting material was treated with petroleum ether (100 mL) and stirred at room temperature (18 °C) for 30 minutes. After filtration, the filter cake was mixed with toluene (30 mL) and concentrated in vacuo to provide P14 as a gray solid. Combined yield: 2.92 g, 6.64 mmol, 63%. LCMS m / z 440.1 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d, J = 1.6 Hz, 1H), 7.81 (dd, J = 8.5, 1.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 6.64 - 6.51 (m, 3H), 4.63 (t, J = 5.3 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.75 (t, J = 5.3 Hz, 2H), 3.22 (s, 3H), 2.97 - 2.78 (m, 3H), 2.18 (br dd, J = 11, 11 Hz, 2H), 1.75 - 1.64 (m, 2H), 1.64 - 1.49 (m, 2H).Preparation P15 Methyl 2-(chloromethyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (P15)

[0271]

[0272] This entire sequence was carried out on large scale. In general, before reactions, as well as after addition of reagents, reactors were evacuated to -0.08 to -0.05 MPa and then filled with nitrogen to normal pressure. This process was generally repeated 3 times, and then oxygen content was assessed to ensure that it was ≤1.0%. For the processes of extraction and washing of organic layers, mixtures were generally stirred for 15 to 60 minutes and then allowed to settle for 15 to 60 minutes before separation of layers.Step 1. Synthesis of (2S)-2-[(benzyloxy)methyl]oxetane (C25).

[0273] This reaction was carried out in three batches of approximately the same scale. A 2000 L glass-lined reactor was charged with 2-methylpropan-2-ol (774.7 kg). Potassium tert-butoxide (157.3 kg, 1402 mol) was added via a solid addition funnel, and the mixture was stirred for 30 minutes. Trimethylsulfoxonium iodide (308.2 kg, 1400 mol) was then added in the same manner, and the reaction mixture was heated at 55 °C to 65 °C for 2 to 3 hours, whereupon (2S)-2-[(benzyloxy)methyl]oxirane (92.1 kg, 561 mol) was added at a rate of 5 to 20 kg / hour. After the reaction mixture had been maintained at 55 °C to 65 °C for 25 hours, it was cooled to 25 °C to 35 °C, and filtered through diatomaceous earth (18.4 kg). The filter cake was rinsed with tert-butyl methyl ether (3 x 340 kg), and the combined filtrates were transferred to a 5000 L reactor, treated with purified water (921 kg), and stirred for 15 to 30 minutes at 15 °C to 30 °C. The organic layer was then washed twice using a solution of sodium chloride (230.4 kg) in purified water (920.5 kg), and concentrated under reduced pressure (≤ -0.08 MPa) at ≤45 °C. n-Heptane (187 kg) was added, and the resulting mixture was concentrated under reduced pressure (≤ -0.08 MPa) at ≤45 °C; the organic phase was purified using silica gel chromatography (280 kg), with sodium chloride (18.5 kg) on top of the column. The crude material was loaded onto the column using n-heptane (513 kg), and then eluted with a mixture of n-heptane (688.7 kg) and ethyl acetate (64.4 kg). The three batches were combined, providing C25 as an 85% pure light yellow oil (189.7 kg, 906 mmol, 54%). 1< H NMR (400 MHz, chloroform-d), C25 peaks only: δ 7.40 - 7.32 (m, 4H), 7.32 - 7.27 (m, 1H), 4.98 (dddd, J = 8.1, 6.7, 4.9, 3.7 Hz, 1H), 4.72 - 4.55 (m, 4H), 3.67 (dd, component of ABX pattern, J = 11.0, 4.9 Hz, 1H), 3.62 (dd, component of ABX pattern, J = 11.0, 3.7 Hz, 1H), 2.72 - 2.53 (m, 2H).Step 2. Synthesis of (2S)-oxetan-2-ylmethanol (C26).

[0274] 10% Palladium on carbon (30.7 kg) was added through an addition funnel to a 10 °C to 30 °C solution of 85% pure C25 (from previous step; 185.3 kg, 884.8 mol) in tetrahydrofuran (1270 kg) in a 3000 L stainless steel autoclave reactor. The addition funnel was rinsed with purified water and tetrahydrofuran (143 kg), and the rinses were added to the reaction mixture. After the reactor contents had been purged with nitrogen, they were similarly purged with hydrogen, increasing the pressure to 0.3 to 0.5 MPa and then venting to 0.05 MPa. This hydrogen purge was repeated 5 times, whereupon the hydrogen pressure was increased to 0.3 to 0.4 MPa. The reaction mixture was then heated to 35 °C to 45 °C. After 13 hours, during which the hydrogen pressure was maintained at 0.3 to 0.5 MPa, the mixture was vented to 0.05 MPa, and purged five times with nitrogen, via increasing the pressure to 0.15 to 0.2 MPa and then venting to 0.05 MPa. After the mixture had been cooled to 10 °C to 25 °C, it was filtered, and the reactor was rinsed with tetrahydrofuran (2 x 321 kg). The filter cake was soaked twice with this rinsing liquor and then filtered; concentration at reduced pressure (≤ -0.06 MPa) was carried out at ≤40 °C, affording C26 (62.2 kg, 706 mol, 80%) in tetrahydrofuran (251 kg)Step 3. Synthesis of (2S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (C27).

[0275] 4-(Dimethylamino)pyridine (17.5 kg, 143 mol) was added to a 10 °C to 25 °C solution of C26 (from the previous step; 62.2 kg, 706 mol) in tetrahydrofuran (251 kg) and triethylamine (92.7 kg, 916 mol) in dichloromethane (1240 kg). After 30 minutes, p-toluenesulfonyl chloride (174.8 kg, 916.9 mol) was added in portions at intervals of 20 to 40 minutes, and the reaction mixture was stirred at 15 °C to 25 °C for 16 hours and 20 minutes. Purified water (190 kg) was added; after stirring, the organic layer was washed with aqueous sodium bicarbonate solution (prepared using 53.8 kg of sodium bicarbonate and 622 kg of purified water), and then washed with aqueous ammonium chloride solution (prepared using 230 kg of ammonium chloride and 624 kg of purified water). After a final wash with purified water (311 kg), the organic layer was filtered through a stainless steel Nutsche filter that had been preloaded with silica gel (60.2 kg). The filter cake was soaked with dichloromethane (311 kg) for 20 minutes, and then filtered; the combined filtrates were concentrated at reduced pressure (≤ -0.05 MPa) and ≤40 °C until 330 to 400 L remained. Tetrahydrofuran (311 kg) was then added, at 15 °C to 30 °C, and the mixture was concentrated in the same manner, to a final volume of 330 to 400 L. The tetrahydrofuran addition and concentration was repeated, again to a volume of 330 to 400 L, affording a light yellow solution of C27 (167.6 kg, 692 mmol, 98%) in tetrahydrofuran (251.8 kg). 1< H NMR (400 MHz, chloroform-d), C27 peaks only: δ 7.81 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.91 (ddt, J = 8.0, 6.7, 3.9 Hz, 1H), 4.62 - 4.55 (m, 1H), 4.53 - 4.45 (m, 1H), 4.14 (d, J = 3.9 Hz, 2H), 2.75 - 2.63 (m, 1H), 2.60 - 2.49 (m, 1H), 2.44 (s, 3H).Step 4. Synthesis of (2S)-2-(azidomethyl)oxetane (C28).

[0276] N,N-Dimethylformamide (473 kg), sodium azide (34.7 kg, 534 mol), and potassium iodide (5.2 kg, 31 mol) were combined in a 3000 L glass-lined reactor at 10 °C to 25 °C. After addition of C27 (83.5 kg, 344.6 mol) in tetrahydrofuran (125.4 kg), the reaction mixture was heated to 55 °C to 65 °C for 17 hours and 40 minutes, whereupon it was cooled to 25 °C to 35 °C, and nitrogen was bubbled from the bottom valve for 15 minutes. tert-Butyl methyl ether (623 kg) and purified water (840 kg) were then added, and the resulting aqueous layer was extracted twice with tert-butyl methyl ether (312 kg and 294 kg). The combined organic layers were washed with purified water (2 x 419 kg) while maintaining the temperature at 10 °C to 25 °C, affording C28 (31.2 kg, 276 mol, 80%) in a solution of the above organic layer (1236.8 kg).Step 5. Synthesis of 1-[(2S)-oxetan-2-yl]methanamine (C29).

[0277] 10% Palladium on carbon (3.7 kg) was added through an addition funnel to a 10 °C to 30 °C solution of C28 [from the previous step; 1264 kg (31.1 kg of C28, 275 mol)] in tetrahydrofuran (328 kg) in a 3000 L stainless steel autoclave reactor. The addition funnel was rinsed with tetrahydrofuran (32 kg), and the rinse was added to the reaction mixture. After the reactor contents had been purged with nitrogen, they were similarly purged with hydrogen, increasing the pressure to 0.05 to 0.15 MPa and then venting to 0.03 to 0.04 MPa. This hydrogen purge was repeated 5 times, whereupon the hydrogen pressure was increased to 0.05 to 0.07 MPa. The reaction temperature was increased to 25 °C to 33 °C, and the hydrogen pressure was maintained at 0.05 to 0.15 MPa for 22 hours, while exchanging the hydrogen every 3 to 5 hours. The mixture was then purged five times with nitrogen, via increasing the pressure to 0.15 to 0.2 MPa and then venting to 0.05 MPa. After filtration, tetrahydrofuran (92 kg and 93 kg) was used to wash the reactor and then soak the filter cake. The combined filtrates were concentrated at reduced pressure (≤ -0.07 MPa) and ≤45 °C, affording C29 (18.0 kg, 207 mol, 75%) in tetrahydrofuran (57.8 kg). 1< H NMR (400 MHz, DMSO-d 6 ), C29 peaks only: δ 4.62 (ddt, J = 7.6, 6.6, 5.1 Hz, 1H), 4.49 (ddd, J = 8.6, 7.3, 5.6 Hz, 1H), 4.37 (dt, J = 9.1, 5.9 Hz, 1H), 2.69 (d, J = 5.1 Hz, 2H), 2.55 - 2.49 (m, 1H), 2.39 (m, 1H).Step 6. Synthesis of methyl 4-nitro-3-{[(2S)-oxetan-2-ylmethyl]amino)benzoate (C30 ).

[0278] Potassium carbonate (58.1 kg, 420 mol) was added to a solution of methyl 3-fluoro-4-nitrobenzoate (54.8 kg, 275 mol) in tetrahydrofuran (148 kg) in a 100 L glass-lined reactor, and the mixture was stirred for 10 minutes. A solution of C29 (29.3 kg, 336 mol) in tetrahydrofuran (212.9 kg) was added, and the reaction mixture was stirred at 20 °C to 30 °C for 12 hours, whereupon ethyl acetate (151 kg) was added, and the mixture was filtered through silica gel (29 kg). The filter cake was rinsed with ethyl acetate (150 kg and 151 kg), and the combined filtrates were concentrated at reduced pressure (≤ -0.08 MPa) and ≤45 °C to a volume of 222 to 281 L. After the mixture had been cooled to 10 °C to 30 °C, n-heptane (189 kg) was added, stirring was carried out for 20 minutes, and the mixture was concentrated at reduced pressure (≤ -0.08 MPa) and ≤45 °C to a volume of 222 L. n-Heptane (181 kg) was again added into the mixture at a reference rate of 100 to 300 kg / hour, and stirring was continued for 20 minutes. The mixture was sampled until residual tetrahydrofuran was ≤5% and residual ethyl acetate was 10% to 13%. The mixture was heated to 40 °C to 45 °C and stirred for 1 hour, whereupon it was cooled to 15 °C to 25 °C at a rate of 5 °C to 10 °C per hour, and then stirred at 15 °C to 25 °C for 1 hour. Filtration using a stainless steel centrifuge provided a filter cake, which was rinsed with a mixture of ethyl acetate (5.0 kg) and n-heptane (34 kg), and then stirred with tetrahydrofuran (724 kg) at 10 °C to 30 °C for 15 minutes; filtration provided a yellow solid largely composed of C30 (57.3 kg, 210 mol, 76%). 1< H NMR (400 MHz, DMSO-d 6 ) 8.34 (t, J = 5.8 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.13 (dd, J = 8.9, 1.8 Hz, 1H), 4.99 (dddd, J = 7.7, 6.7, 5.3, 4.1 Hz, 1H), 4.55 (ddd, J = 8.6, 7.3, 5.8 Hz, 1H), 4.43 (dt, J = 9.1, 6.0 Hz, 1H), 3.87 (s, 3H), 3.67 - 3.61 (m, 2H), 2.67 (dddd, J = 11.1, 8.6, 7.7, 6.2 Hz, 1H), 2.57 - 2.47 (m, 1H).Step 7. Synthesis of methyl 2-(chloromethyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (P15).

[0279] A solution of C30 (from the previous step; 51.8 kg, 190 mol) in tetrahydrofuran (678 kg), in a 3000 L autoclave reactor, was treated with 10% palladium on carbon (5.2 kg) at 10 °C to 30 °C. The addition pipe was rinsed with tetrahydrofuran (46 kg) and the rinse was added to the reaction mixture. After the reactor contents had been purged with nitrogen, they were similarly purged with hydrogen, increasing the pressure to 0.1 to 0.2 MPa and then venting to 0.02 to 0.05 MPa. This hydrogen purge was repeated 5 times, whereupon the hydrogen pressure was increased to 0.1 to 0.25 MPa. The reaction mixture was stirred at 20 °C to 30 °C, and every 2 to 3 hours, the mixture was purged with nitrogen three times, and then purged with hydrogen five times; after each final hydrogen exchange, the hydrogen pressure was increased to 0.1 to 0.25 MPa. After 11.25 hours total reaction time, the reaction mixture was vented to normal pressure, and purged five times with nitrogen, via increasing the pressure to 0.15 to 0.2 MPa and then venting to 0.05 MPa. It was then filtered, and the filter cake was rinsed twice with tetrahydrofuran (64 kg and 63 kg); the combined rinse and filtrate were concentrated under reduced pressure (≤ -0.08 MPa) and ≤40 °C to a volume of 128 to 160 L. Tetrahydrofuran (169 kg) was added, and the mixture was again concentrated to a volume of 128 to 160 L; this process was repeated a total of 4 times, affording a solution of the intermediate methyl 4-amino-3-{[(2S)-oxetan-2-ylmethyl]amino}benzoate.

[0280] Tetrahydrofuran (150 kg) was added to this solution, followed by 2-chloro-1,1,1-trimethoxyethane (35.1 kg, 227 mol) and p-toluenesulfonic acid monohydrate (1.8 kg, 9.5 mol). After the reaction mixture had been stirred for 25 minutes, it was heated at 40 °C to 45 °C for 5 hours, whereupon it was concentrated under reduced pressure to a volume of 135 to 181 L. 2-Propanol (142 kg) was added, and the mixture was again concentrated to a volume of 135 to 181 L, whereupon 2-propanol (36.5 kg) and purified water (90 kg) were added, and stirring was continued until a solution was obtained. This was filtered with an in-line liquid filter, and then treated with purified water (447 kg) at a reference rate of 150 to 400 kg / hour at 20 °C to 40 °C. After the mixture had been cooled to 20 °C to 30 °C, it was stirred for 2 hours, and the solid was collected via filtration with a centrifuge. The filter cake was rinsed with a solution of 2-propanol (20.5 kg) and purified water (154 kg); after drying, P15 was obtained as a white solid (32.1 kg, 109 mol, 57%). 1< H NMR (400 MHz, chloroform-d) δ 8.14 - 8.11 (m, 1H), 8.01 (dd, J = 8.5, 1.1 Hz, 1H), 7.79 (br d, J = 8.6 Hz, 1H), 5.26 - 5.18 (m, 1H), 5.04 (s, 2H), 4.66 - 4.58 (m, 2H), 4.53 (dd, component of ABX pattern, J = 15.7, 2.7 Hz, 1H), 4.34 (dt, J = 9.1, 6.0 Hz, 1H), 3.96 (s, 3H), 2.82 - 2.71 (m, 1H), 2.48 - 2.37 (m, 1H).Preparation P16 Methyl 2-(chloromethyl)-1-methyl-1H-benzimidazole-6-carboxylate (P16)

[0281]

[0282] Methyl 4-amino-3-(methylamino)benzoate (206 mg, 1.14 mmol) was dissolved in 1,4-dioxane (11.5 mL) and treated with chloroacetyl chloride (109 µL, 1.37 mmol). The mixture was stirred at 100 °C for 3 hours and cooled to room temperature. Triethylamine (0.8 mL, 7 mmol) and heptane (10 mL) were added and filtered. The filtrate was concentrated under reduced pressure and the crude material was purified by chromatography on silica gel (Eluent: 40% ethyl acetate in heptane) to afford 120 mg of P16 (44%). 1< H NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 8.01 (d, 1H), 7.78 (d, 1H), 4.87 (s, 2H), 3.97 (s, 3H), 3.94 (s, 3H); LCMS m / z 239.1 [M+H] +< .Preparations P17 and P18 Methyl 2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-1 (P17) and Methyl 2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-2 (P18)

[0283] Step 1. Synthesis of tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (C31).

[0284] A solution of potassium tert-butoxide (65.9 g, 587 mmol) in tetrahydrofuran (500 mL) was added to a 0 °C solution of ethyl (diethoxyphosphoryl)acetate (132 g, 589 mmol) in tetrahydrofuran (500 mL), and the resulting suspension was stirred at 0 °C for 1 hour, whereupon it was cooled to -50 °C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (90.0 g, 452 mmol) in tetrahydrofuran (1.5 L) was added drop-wise at -50 °C, and the reaction mixture was subsequently allowed to slowly warm to 20 °C, and then to stir for 16 hours at 20 °C. After addition of water (1 L), the mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2 x 800 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting material was washed several times with petroleum ether (200 mL) to provide C31 as a white solid. Yield: 95.0 g, 353 mmol, 78%. 1< H NMR (400 MHz, chloroform-d) δ 5.71 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.55 - 3.43 (m, 4H), 2.94 (br t, J = 5.5 Hz, 2H), 2.28 (br t, J = 5.5 Hz, 2H), 1.47 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H).Step 2. Synthesis of 6-tert-butyl 1-ethyl 6-azaspiro[2. 5]octane-1, 6-dicarboxylate (C32).

[0285] To a solution of trimethylsulfoxonium iodide (140 g, 636 mmol) in dimethyl sulfoxide (800 mL) was added potassium tert-butoxide (71.2 g, 634 mmol) in one portion at 20 °C. After the reaction mixture had been stirred at 20 °C for 1.5 hours, a solution of C31 (95.0 g, 353 mmol) in dimethyl sulfoxide (800 mL) was added drop-wise, and stirring was continued at 20 °C for 16 hours. Saturated aqueous sodium chloride solution (2.0 L) was then added; the resulting mixture was neutralized by addition of ammonium chloride, and extracted with ethyl acetate (3.0 L). The combined organic layers were washed sequentially with water (2 x 1.0 L) and with saturated aqueous sodium chloride solution (2.0 L), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluent: 10:1 petroleum ether / ethyl acetate) afforded C32 as a yellow oil. 1< H NMR analysis indicated that extraneous aliphatic material was present. Yield: 80 g, 280 mmol, 79%. 1< H NMR (400 MHz, chloroform-d), C32 peaks only: δ 4.19 - 4.09 (m, 2H), 3.55 - 3.39 (m, 3H), 3.27 (ddd, J = 13.0, 7.0, 4.5 Hz, 1H), 1.76 - 1.64 (m, 2H), 1.56 (dd, J = 8.0, 5.5 Hz, 1H, assumed; partially obscured by water peak), 1.47 (s, 9H), 1.47 - 1.37 (m, 2H), 1.27 (t, J = 7.0 Hz, 3H), 1.17 (dd, J = 5.0, 5.0 Hz, 1H), 0.93 (dd, J = 8.0, 4.5 Hz, 1H).Step 3. Synthesis of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-1-carboxylic acid (C33).

[0286] To a mixture of C32 (80 g, 280 mmol) in tetrahydrofuran (500 mL) and water (500 mL) was added lithium hydroxide monohydrate (37.4 g, 891 mmol) in one portion. The reaction mixture was stirred at 25 °C for 16 hours, whereupon it was diluted with water (600 mL) and washed with ethyl acetate (3 x 300 mL). The organic layers were discarded, and the aqueous layer was acidified to pH 3 to 4 by addition of 6 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 600 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with petroleum ether (300 mL) provided C33 as a white solid. Yield: 42.0 g, 164 mmol, 59%. LCMS m / z 278.2 [M+Na +< ]. 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.15 - 12.03 (br s, 1H), 3.43 - 3.25 (m, 3H, assumed; partially obscured by water peak), 3.23 - 3.12 (m, 1H), 1.64 - 1.50 (m, 2H), 1.52 (dd, J = 7.5, 5.5 Hz, 1H), 1.39 (s, 9H), 1.39 - 1.28 (m, 2H), 0.96 - 0.88 (m, 2H).Step 4. Synthesis of tert-butyl 1-({4-(methoxycarbonyl)-2-[(2-methoxyethyl)amino]phenyl}carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (C34).

[0287] A solution of C33 (570 mg, 2.23 mmol), C16 (500 mg, 2.23 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 1.27 g, 3.34 mmol) in N,N-dimethylformamide (10 mL) was stirred at 30 °C for 30 minutes, whereupon triethylamine (902 mg, 8.91 mmol) was added, and stirring was continued at 30 °C for 16 hours. The reaction mixture was then poured into water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 x 50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 1:1 petroleum ether / ethyl acetate) afforded C34 as a brown oil, which was taken directly into the following step.Step 5. Synthesis of methyl 2-[6-(tert-butoxycarbonyl)-6-azaspiro[2.5]oct-1-yl]-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (C35).

[0288] A solution of C34 (from the previous step, ≤2.23 mmol) in acetic acid (15 mL) was stirred at 50 °C for 16 hours, whereupon it was concentrated in vacuo to provide C35 as a brown oil. This material was used directly in the next step. LCMS m / z 444.1 [M+H] +< .Step 6. Synthesis of methyl 2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (C36).

[0289] Trifluoroacetic acid (5 mL) was added to a solution of C35 (from the previous step; ≤2.23 mmol) in dichloromethane (10 mL), and the reaction mixture was stirred at 25 °C for 2 hours. After removal of solvents in vacuo, the residue was basified via addition of saturated aqueous potassium carbonate solution (40 mL), and extracted with a mixture of dichloromethane and methanol (10:1, 3 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and subjected to silica gel chromatography (Eluent: 10:1:0.1 dichloromethane / methanol / concentrated ammonium hydroxide) to afford C36 as a yellow solid. Yield: 640 mg, 1.86 mmol, 83% over three steps. LCMS m / z 344.1 [M+H] +< .Step 7. Isolation of methyl 2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-1 (P17) and methyl 2-(6-azaspiro[2.5]oct-1-yl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-2 (P18).

[0290] Separation of C36 (630 mg, 1.83 mmol) into its component enantiomers was carried out using SFC [Column: Chiral Technologies Chiralpak AD, 10 µm; Mobile phase: 55:45 carbon dioxide / (ethanol containing 0.1% ammonium hydroxide)]. The first-eluting peak was designated as ENT-1 (P17), and the second-eluting enantiomer as ENT-2 (P18); both were isolated as pale yellow solids. P17 Yield: 300 mg, 0.874 mmol, 48%. LCMS m / z 344.1 [M+H] +< . Retention time: 5.10 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6 x 150 mm, 3 µm; Mobile phase A: carbon dioxide; Mobile phase B: ethanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 5.5 minutes, then held at 40% B for 3.0 minutes; Flow rate: 2.5 mL / minute). P18 Yield: 240 mg, 0.699 mmol, 38%. LCMS m / z 344.1 [M+H] +< . Retention time: 7.35 minutes (Analytical conditions identical to those used for P17). Preparation P19 Methyl 4-amino-3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}benzoate (P19)

[0291] Step 1. Synthesis of methyl 3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}-4-nitrobenzoate (C37).

[0292] Triethylamine (3.65 mL, 26.2 mmol) was added to a solution of methyl 3-fluoro-4-nitrobenzoate (1.00 g, 5.02 mmol) and 1-(1-ethyl-1H-imidazol-5-yl)methanamine, dihydrochloride salt (1.00 g, 5.05 mmol) in a mixture of tetrahydrofuran (12 mL) and methanol (8 mL). The reaction mixture was stirred at 60 °C for 40 hours, whereupon it was concentrated in vacuo and purified using silica gel chromatography (Gradient: 0% to 2% methanol in dichloromethane) to afford C37 as an orange solid. Yield: 1.27 g, 4.17 mmol, 83%. 1< H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 8.8 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.68 (d, J = 1.7 Hz, 1H), 7.57 (br s, 1H), 7.33 (dd, J = 8.8, 1.7 Hz, 1H), 7.11 (br s, 1H), 4.53 (d, J = 4.9 Hz, 2H), 3.99 (q, J = 7.3 Hz, 2H), 3.95 (s, 3H), 1.47 (t, J = 7.3 Hz, 3H).Step 2. Synthesis of methyl 4-amino-3-{[(1-ethyl-1H-imidazol-5-yl)methyl]amino}benzoate (P19).

[0293] A mixture of wet palladium on carbon (144 mg) and C37 (412 mg, 1.35 mmol) in methanol (13 mL) was stirred under a balloon of hydrogen for 16 hours at 25 °C. The reaction mixture was then filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to afford P19 as a gray solid. Yield: 340 mg, 1.24 mmol, 92%. 1< H NMR (400 MHz, methanol-d 4 ) δ 7.66 (br s, 1H), 7.38 - 7.29 (m, 2H), 6.97 (br s, 1H), 6.67 (d, J = 7.9 Hz, 1H), 4.35 (s, 2H), 4.11 (q, J = 7.3 Hz, 2H), 3.81 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H).Preparation P20 Methyl 4-amino-3-(methylamino)benzoate (P20 )

[0294] Step 1. Synthesis of methyl 3-(methylamino)-4-nitrobenzoate (D1).

[0295] To a solution of methyl 3-fluoro-4-nitrobenzoate (5.10 g, 25.6 mmol) in tetrahydrofuran (60 mL) was added methylamine (38.4 mL, 76.8 mmol, 2 M in tetrahydrofuran), drop-wise, over 10 minutes. The pale yellow solution turned deep orange immediately upon addition and was stirred for 2 hours at room temperature. The reaction mixture was then diluted with diethyl ether (100 mL) and the organic layer was washed sequentially with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 5.26 g of methyl 3-(methylamino)-4-nitrobenzoate (98%) as a deep orange solid. LCMS m / z 211.1 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.22 (d, J = 8.9 Hz, 1H), 8.00 (br s, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.25 (dd, J = 8.9, 1.7 Hz, 1H, assumed; partially obscured by solvent peak), 3.95 (s, 3H), 3.09 (d, J = 5.1 Hz, 3H).Step 2. Synthesis of methyl 4-amino-3-(methylamino)benzoate (P20 ).

[0296] A solution of D1 (5.26 g, 25.0 mmol) in ethanol (150 mL) was added to a 500 mL Parr ®< bottle previously charged with 10% palladium on carbon (50% water; 1 g). The mixture was shaken under 50 psi hydrogen atmosphere for 1 hour at room temperature, whereupon it was filtered and the filter cake was rinsed with ethanol (100 mL). The filtrate was concentrated under reduced pressure to yield 4.38 g of P20 (97%) as an off-white solid. LCMS m / z 181.1 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 7.46 (dd, J = 8.0, 1.9 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H), 3.72 (br s, 2H), 3.21 (br s, 1H), 2.91 (s, 3H).Preparations P21 and P22 5-Bromo-N 3< -methylpyridine-2,3-diamine (P21) and 5-Bromo-N 3< ,6-dimethylpyridine-2,3-diamine (P22)

[0297] Intermediate P21 was synthesized according to the literature procedure (Choi, J. Y. et al. J. Med. Chem. 2012, 55, 852-870). Intermediate P22 was synthesized using the same method.Preparation P23 Methyl 2-(chloromethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate (P23)

[0298] Step 1. Synthesis of methyl 3-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-4-nitrobenzoate (D2).

[0299] To a colorless solution of methyl 3-fluoro-4-nitrobenzoate (1.0 g, 5.0 mmol) in N,N-dimethylformamide (10 mL) was slowly added 1-(1-methyl-1H-imidazol-5-yl)methanamine (670 mg, 6.0 mmol) and triethylamine (762 mg, 7.53 mmol). The reaction mixture was stirred at 60 °C for 16 hours, whereupon it was poured into water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Eluent: 20% methanol in dichloromethane). The obtained yellow solid was triturated with 30:1 petroleum ether / ethyl acetate to deliver D2 (1.2 g, 82%) as a yellow solid. LCMS m / z 290.9 [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.25 (d, J = 8.9 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.70 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.34 (dd, J = 8.9, 1.7 Hz, 1H), 7.12 (s, 1H), 4.54 (d, J = 5.0 Hz, 2H), 3.96 (s, 3H), 3.67 (s, 3H).Step 2. Synthesis of methyl 4-amino-3-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}benzoate (D3).

[0300] To a suspension of D2 (5.46 g, 18.8 mmol) in methanol (160 mL) was added wet 10% palladium on carbon (1 g). The mixture was stirred under 1 atmosphere of hydrogen for 36 hours at 20 °C. The reaction mixture was filtered and the filter cake was rinsed with methanol (200 mL). The filtrate was concentrated under reduced pressure to deliver D3 (4.8 g, 98%) as a brown solid. LCMS m / z 260.9 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 7.56 (s, 1H), 7.18 (br d, J = 8.1 Hz, 1H), 7.12 (br s, 1H), 6.87 (s, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.50 (s, 2H), 4.84 (t, J = 5.2 Hz, 1H), 4.23 (d, J = 5.0 Hz, 2H), 3.73 (s, 3H), 3.63 (s, 3H).Step 3. Synthesis of methyl 2-(hydroxymethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate (D4).

[0301] A mixture of D3 (780 mg, 3.00 mmol) and 2-hydroxyacetic acid (342 mg, 4.49 mmol) in 1,3,5-trimethylbenzene (8 mL) was stirred at 140 °C for 14 hours and at 25 °C for 48 hours. The clear yellow solution was decanted off to give a brown residue that was dissolved in methanol (50 mL) and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Eluent: 20% methanol in dichloromethane) to provide D4 (318 mg, 35%) as a yellow foam. LCMS m / z 300.9 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.13 - 8.11 (m, 1H), 7.83 (dd, J = 8.4, 1.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 6.58 (s, 1H), 5.69 (s, 2H), 4.75 (s, 2H), 3.84 (s, 3H), 3.53 (s, 3H).Step 4. Synthesis of methyl 2-(chloromethyl)-1-[(1-methyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylate (P23).

[0302] To a suspension of D4 (500 mg, 1.66 mmol) in dichloromethane (10 mL) and N,N-dimethylformamide (3 mL) was added thionyl chloride (990 mg, 0.60 mL, 8.32 mmol), drop-wise, at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The resultant brown residue was triturated with dichloromethane (10 mL). The solids were collected by filtration and rinsed with dichloromethane (5 mL) to provide P23 (431 mg, 73%) as an off-white solid. LCMS m / z 318.9 [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 9.17 (s, 1H), 8.31 (s, 1H), 7.93 (br d, J = 8.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.11 (s, 1H), 5.92 (s, 2H), 5.13 (s, 2H), 3.87 (s, 3H), 3.87 (s, 3H).Preparation P24 5-Chloro-2-(chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine (P24)

[0303] Step 1. Synthesis of 6-chloro-N-methyl-3-nitropyridin-2-amine (D5).

[0304] To a suspension of 2,6-dichloro-3-nitropyridine (200 g, 1.04 mol) and Na 2 CO 3 (132 g, 1.24 mol) in ethanol (1 L) was added a solution of methylamine in tetrahydrofuran (2.0 M; 622 mL,1.24 mol), drop-wise, at 0 °C via syringe. After completion of the addition, the reaction mixture was stirred at 18 °C for 6 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a yellow solid. The crude material was purified by silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) to afford D5 (158 g, 81% yield) as a yellow solid. 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (br s, 1H), 8.41 (d, J = 8.6 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H).Step 2. Synthesis of 6-chloro-N 2< -methylpyridine-2,3-diamine (D6).

[0305] To a mixture of D5 (15.8 g, 84.2 mmol) in acetic acid (100 mL) was added iron powder (15.4 g, 276 mmol). The reaction mixture was stirred at 80 °C for 3 hours, whereupon it was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (2 x 100). The combined organic layers were concentrated under reduced pressure and the crude material was purified by silica gel chromatography (Eluent: 1:1 ethyl acetate / petroleum ether) to afford D6 (8.40 g, 63% yield) as a brown solid. 1< H NMR (400 MHz, chloroform-d) δ 6.79 (d, J = 7.7 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 3.00 (s, 3H).Step 3. Synthesis of 5-chloro-2-(chloromethyl)-3-methyl-3H-imidazo[4,5-b]pyridine (P24).

[0306] To a solution of D6 (50.0 g, 317 mmol) in 1,4-dioxane (1.2 L) was added chloroacetyl chloride (55.5 mL, 698 mmol) and the reaction mixture was stirred at 15 °C for 50 minutes. It was then concentrated under reduced pressure to give a brown solid, which was taken up in trifluoroacetic acid (1.2 L) and stirred at 80 °C for 60 hours. The mixture was concentrated under reduced pressure to give a brown oil, which was diluted with ethyl acetate (1 L) and neutralized by addition of saturated aqueous sodium bicarbonate solution. When carbon dioxide evolution subsided, the layers were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Gradient: 10% to 25% ethyl acetate in petroleum ether) to afford P24 (61.0 g, 79% yield) as a yellow solid. LCMS m / z 215.7 (dichloro isotope pattern observed) [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 3.84 (s, 3H).Examples 1 and 2 2-({4-[2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid, ENT-X1, trifluoroacetate salt (1) [from C39]; and 2-({4-[2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid, ENT-X2, trifluoroacetate salt (2) [from C40 ]

[0307] Step 1. Synthesis of methyl 2-(f4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate (C38).

[0308] This experiment was carried out in two batches of identical scale. A reaction vessel containing a mixture of C2 (500 mg, 1.52 mmol), P12 (530 mg, 1.59 mmol), [2',6'-bis(propan-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (Ruphos; 142 mg, 0.304 mmol), tris(dibenzylideneacetone)dipalladium(0) (139 mg, 0.152 mmol), and cesium carbonate (1.48 g, 4.54 mmol) in toluene (15 mL) was evacuated and charged with nitrogen. This evacuation cycle was repeated twice, whereupon the reaction mixture was stirred at 100 °C for 16 hours, combined with the second batch, and filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography (Gradient: 0% to 60% ethyl acetate in petroleum ether) followed by preparative thin-layer chromatography (Eluent: 1:1 petroleum ether / ethyl acetate) to afford C38 as a pale yellow solid. Combined yield: 600 mg, 1.03 mmol, 34%. LCMS m / z 581.0+ [M+H] +< .Step 2. Isolation of methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-1 (C39) and methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylate, ENT-2 (C40 ).

[0309] Separation of C38 (780 mg, 1.34 mmol) into its component enantiomers was effected using SFC [Column: Chiral Technologies Chiralpak AD, 10 µm; Mobile phase: 3:2 carbon dioxide / (ethanol containing 0.1% ammonium hydroxide)]. The first-eluting enantiomer, designated as ENT-1 (C39), was obtained as a white solid. Yield: 282 mg, 0.485 mmol, 36%. LCMS m / z 581.0 [M+H] +< . Retention time 1.90 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6 x 50 mm, 3 µm; Mobile phase A: carbon dioxide; Mobile phase B: ethanol containing 0.05% diethylamine; Gradient: 5% B for 0.20 minutes, then 5% to 40% B over 1.4 minutes, then held at 40% B for 1.05 minutes; Flow rate: 4.0 mL / minute).

[0310] The second-eluting enantiomer, designated as ENT-2, (C40), was subjected to a second purification using SFC [Column: Chiral Technologies Chiralpak AD, 10 µm; Mobile phase: 3:2 carbon dioxide / (ethanol containing 0.1% ammonium hydroxide)]. This provided C40 as a pale brown solid. Yield: 280 mg, 0.482 mmol, 36%. LCMS m / z 581.0 [M+H] +< . Retention time 2.18 minutes (Analytical conditions identical to those used for C39). Step 3. Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid, ENT-X1, trifluoroacetate salt (1) [from C39].

[0311] Aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was added to a solution of C39 (70 mg, 0.12 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was again added, and stirring was continued for an additional 20 hours. The reaction mixture was then adjusted to pH 7 via addition of 1 M hydrochloric acid, and subsequently concentrated in vacuo to remove methanol and tetrahydrofuran. The residue was adjusted to a pH of 5 to 6 by addition of trifluoroacetic acid and then purified via reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobile phase B: acetonitrile; Gradient: 30% to 60% B) to afford 1 as a white solid. Yield: 40.5 mg, 59.5 µmol, 50%. LCMS m / z 567.0+ [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 8.37 (br s, 1H), 8.07 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.0, 8.0 Hz, 1H), 7.34 (dd, J = 10.2, 2.0 Hz, 1H), 7.30 (br dd, J = 8.3, 2.0 Hz, 1H), 7.22 (s, 1H), 6.87 (dd, J = 8.1, 8.1 Hz, 1H), 6.63 (br d, J = 8 Hz, 1H), 6.60 (br d, J = 8 Hz, 1H), 4.70 (s, 2H), 4.65 (t, J = 4.8 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.59 - 3.42 (m, 8H), 3.29 (s, 3H).Step 4. Synthesis of 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperazin-1-yl}methyl)-1-(2-methoxyethyl)-1H-benzimidazole-6-carboxylic acid, ENT-X2, trifluoroacetate salt (2) [from C40 ].

[0312] Aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was added to a solution of C40 (69 mg, 0.12 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL). After the reaction mixture had been stirred at 25 °C for 16 hours, aqueous lithium hydroxide solution (2 M; 0.30 mL, 0.60 mmol) was again added, and stirring was continued for an additional 20 hours. The reaction mixture was adjusted to pH 7 via addition of 1 M hydrochloric acid, and then concentrated in vacuo to remove methanol and tetrahydrofuran. The residue was adjusted to a pH of 5 to 6 by addition of trifluoroacetic acid and subsequently purified via reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobile phase B: acetonitrile; Gradient: 30% to 60% B) to afford 2 as a white solid. Yield: 22.9 mg, 33.6 µmol, 28%. LCMS m / z 567.0+ [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 8.40 - 8.35 (m, 1H), 8.07 (dd, J = 8.6, 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.0, 8.0 Hz, 1H), 7.35 (dd, J = 10.2, 2.0 Hz, 1H), 7.31 (br dd, J = 8, 2 Hz, 1H), 7.22 (s, 1H), 6.87 (dd, J = 8.3, 8.0 Hz, 1H), 6.63 (br d, J = 8 Hz, 1H), 6.60 (br d, J = 8 Hz, 1H), 4.68 (s, 2H), 4.65 (t, J = 4.9 Hz, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.57 - 3.40 (m, 8H), 3.29 (s, 3H).Example 3 2-({4-[2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid, trifluoroacetate salt (3)

[0313] Step 1. Synthesis of 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine (C13, free base).

[0314] To a solution of P2 (300 mg, 0.670 mmol) in ethyl acetate (3.5 mL) was added p-toluenesulfonic acid monohydrate (318 mg, 1.67 mmol). The reaction mixture was stirred at 60 °C for 1 hour, whereupon it was basified by addition of saturated aqueous potassium carbonate solution (20 mL) and extracted with a mixture of dichloromethane and methanol (10:1, 3 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide C13, free base, as a brown solid. Yield: 230 mg, 0.661 mmol, 99%.Step 2. Synthesis of 6-bromo-2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine (C41).

[0315] A suspension of C13 , free base (130 mg, 0.374 mmol), P13 (130 mg, 0.427 mmol), and potassium carbonate (172 mg, 1.24 mmol) in acetonitrile (2 mL) was stirred at 50 °C for 16 hours. The reaction mixture was then purified using preparative thin-layer chromatography (Eluent: ethyl acetate) to afford C41 as a brown oil. Yield: 114 mg, 0.185 mmol, 49%. LCMS m / z 617.1 (bromine-chlorine isotope pattern observed) [M+H] +< .Step 3. Synthesis of methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate (C42).

[0316] A solution of C41 (114 mg, 0.185 mmol), 1,3-bis(diphenylphosphino)propane (15.3 mg, 37.1 µmol), palladium(II) acetate (8.3 mg, 37 µmol), and triethylamine (187 mg, 1.85 mmol) in a mixture of methanol (5 mL) and N,N-dimethylformamide (1 mL) was stirred at 80 °C under carbon monoxide (50 psi) for 16 hours. After the reaction mixture had been diluted with ethyl acetate (50 mL), it was washed with saturated aqueous sodium chloride solution (2 x 50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification using preparative thin-layer chromatography (Eluent: ethyl acetate) provided C42 as a colorless oil. Yield: 60.0 mg, 0.101 mmol, 55%. LCMS m / z 617.2 (chlorine isotope pattern observed [M+Na +< ].Step 4. Synthesis of 2-([4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid, trifluoroacetate salt (3).

[0317] To a solution of C42 (60.0 mg, 0.101 mmol) in methanol (2.0 mL) was added aqueous sodium hydroxide solution (3 M; 1.0 mL, 3.0 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. It was then adjusted to pH 7 by addition of 1 M hydrochloric acid, and extracted with a mixture of dichloromethane and methanol (10:1, 3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified using reversed-phase HPLC (Column: Boston Green ODS, 5 µm; Mobile phase A: 0.1% trifluoroacetic acid in water; Mobile phase B: acetonitrile; Gradient: 10% to 95% B) to afford 3 as a white solid. Yield: 29.6 mg, 42.6 µmol, 42%. LCMS m / z 581.0 [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 9.13 (d, J = 1.9 Hz, 1H), 8.74 (d, J = 1.9 Hz, 1H), 7.63 (dd, J = 8.3, 8.3 Hz, 1H), 7.30 (dd, J = 10.9, 2.0 Hz, 1H), 7.24 (ddd, J = 8.4, 2.0, 0.7 Hz, 1H), 6.89 - 6.84 (m, 1H), 6.82 - 6.77 (m, 2H), 4.98 - 4.89 (m, 2H, assumed; largely obscured by water peak), 4.64 (t, J = 4.8 Hz, 2H), 4.04 - 3.92 (br m, 2H), 3.75 (dd, J = 5.4, 4.2 Hz, 2H), 3.51 - 3.39 (m, 2H), 3.31 (s, 3H), 3.19 - 3.06 (m, 1H), 2.41 - 2.24 (m, 2H), 2.24 - 2.12 (m, 2H), 2.06 (d, J = 1.0 Hz, 3H).Examples 4 and 5 Ammonium 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (4) and Ammonium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl)methyl)-I-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (5)

[0318] Step 1. Synthesis of 4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine, trifluoroacetate salt (C43).

[0319] To a solution of P1 (300 mg, 0.691 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.3 mL). The reaction mixture was stirred at 29 °C for 2 hours, whereupon it was concentrated in vacuo to afford C43 as a brown oil, which was used directly in the following step.Step 2. Synthesis of methyl 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C44) and methyl 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C45).

[0320] To a solution of C43 (from the previous step, ≤0.691 mmol) in acetonitrile (10 mL) was added P15 (204 mg, 0.692 mmol), followed by potassium carbonate (956 mg, 6.92 mmol). The reaction mixture was stirred at 29 °C for 16 hours, whereupon it was filtered; the filtrate was concentrated in vacuo to give a residue, which was purified by preparative thin-layer chromatography (Eluent: 2:1 petroleum ether / ethyl acetate) to provide a mixture of the diastereomeric products as a yellow gum (178 mg). Separation into the two products was carried out via SFC [Column: Chiral Technologies ChiralCel OD, 5 µm; Mobile phase: 55:45 carbon dioxide / (methanol containing 0.1% ammonium hydroxide)]. The first-eluting diastereomer, obtained as a yellow oil, was designated as C44. Yield: 44.3 mg, 74.8 µmol, 11% over 2 steps. LCMS m / z 592.1 [M+H] +< . Retention time 4.26 minutes (Column: Chiral Technologies ChiralCel OD-3, 4.6 x 100 mm, 3 µm; Mobile phase A: carbon dioxide; Mobile phase B: methanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 4.5 minutes, then held at 40% B for 2.5 minutes; Flow rate: 2.8 mL / minute).

[0321] The second-eluting diastereomer was subjected to a second purification via SFC [Column: Chiral Technologies ChiralCel OD, 5 µm; Mobile phase: 3:2 carbon dioxide / (methanol containing 0.1% ammonium hydroxide)], providing the second-eluting diastereomer as a colorless oil, which was designated as C45. Yield: 38 mg, 64 µmol, 9% over 2 steps. LCMS m / z 592.1 [M+H] +< . Retention time 4.41 minutes (Analytical conditions identical to those used for C44 ).

[0322] The indicated absolute stereochemistries at the dioxolane were assigned via potency correlation of 5 with a sample of 5, free acid synthesized from intermediate C48; the absolute stereochemistry of that intermediate was determined via single-crystal X-ray structure determination (see below) of C49, a hemisulfate salt of C48. Step 3. Synthesis of ammonium 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl}piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (4 ).

[0323] Aqueous lithium hydroxide solution (2 M; 0.80 mL, 1.6 mmol) was added to a solution of C44 (44.3 mg, 74.8 µmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL), and the reaction mixture was stirred at 26 °C for 3 hours. It was then adjusted to pH 7 by addition of trifluoroacetic acid, and the resulting mixture was concentrated in vacuo and purified using reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile; Gradient: 30% to 50% B) to afford 4 as a white solid. Yield: 26.6 mg, 44.7 µmol, 60%. LCMS m / z 578.0+ [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 8.31 (d, J = 1.4 Hz, 1H), 7.96 (dd, J = 8.5, 1.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.0, 8.0 Hz, 1H), 7.34 (dd, J = 10.1, 2.0 Hz, 1H), 7.29 (br dd, J = 8.3, 2.0 Hz, 1H), 7.20 (s, 1H), 6.86 - 6.79 (m, 1H), 6.77 (br dd, component of ABC pattern, J = 7.9, 1.3 Hz, 1H), 6.73 (dd, component of ABC pattern, J = 7.5, 1.4 Hz, 1H), 5.29 - 5.18 (m, 1H), 4.9 - 4.78 (m, 1H, assumed; partially obscured by water peak), 4.68 (dd, J = 15.3, 2.7 Hz, 1H), 4.54 (td, J = 8.0, 5.9 Hz, 1H), 4.44 (dt, J = 9.2, 5.9 Hz, 1H), 4.02 (AB quartet, J AB = 13.9 Hz, Δν AB = 49.0 Hz, 2H), 3.18 - 3.08 (m, 1H), 3.05 - 2.96 (m, 1H), 2.81 - 2.68 (m, 2H), 2.56 - 2.45 (m, 1H), 2.45 - 2.30 (m, 2H), 2.03 - 1.88 (m, 2H), 1.88 - 1.79 (m, 2H).Step 4. Synthesis of ammonium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl}piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (5 ).

[0324] Aqueous lithium hydroxide solution (2 M; 0.80 mL, 1.6 mmol) was added to a solution of C45 (38 mg, 64 µmol) in a mixture of methanol (1 mL) and tetrahydrofuran (1 mL), and the reaction mixture was stirred at 24 °C for 2.5 hours. It was then adjusted to pH 7 by addition of 1 M hydrochloric acid, and the resulting mixture was concentrated in vacuo and purified using reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile; Gradient: 29% to 49% B), providing 5 as a white solid. Yield: 27.9 mg, 46.9 µmol, 73%. LCMS m / z 577.9 [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ) δ 8.32 (d, J = 1.4 Hz, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.0, 8.0 Hz, 1H), 7.34 (dd, J = 10.2, 2.0 Hz, 1H), 7.29 (br dd, J = 8.3, 2.0 Hz, 1H), 7.20 (s, 1H), 6.85 - 6.80 (m, 1H), 6.77 (dd, component of ABC pattern, J = 8.0, 1.3 Hz, 1H), 6.73 (dd, component of ABC pattern, J = 7.5, 1.4 Hz, 1H), 5.30 - 5.20 (m, 1H), 4.9 - 4.79 (m, 1H, assumed; partially obscured by water peak), 4.68 (dd, J = 15.4, 2.7 Hz, 1H), 4.62 - 4.54 (m, 1H), 4.44 (dt, J = 9.2, 5.9 Hz, 1H), 4.02 (AB quartet, J AB = 13.9 Hz, Δν AB = 44.6 Hz, 2H), 3.18 - 3.09 (m, 1H), 3.06 - 2.97 (m, 1H), 2.80 - 2.67 (m, 2H), 2.55 - 2.30 (m, 3H), 2.02 - 1.78 (m, 4H).Alternate Synthesis of Example 5, free acid 2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid (5, free acid )

[0325] Step 1. Isolation of tert-butyl 4-[(2R)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (C46 ) and tert-butyl 4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine-1-carboxylate (C47 ).

[0326] Separation of P1 (10 g, 23 mmol) into its component enantiomers was carried out using reversed-phase HPLC [Column: Phenomenex Lux Amylose-1, 5 µm; Mobile phase: 9:1 carbon dioxide / (2-propanol containing 0.2% 1-aminopropan-2-ol)]. The first-eluting enantiomer was designated as C46, and the second-eluting enantiomer as C47; both were obtained as colorless oils. The absolute stereochemistries indicated for C46 and C47 were assigned based on a single-crystal X-ray structure determination carried out on C49, which was synthesized from C47 (see below). C46 Yield: 4.47 g, 10.3 mmol, 45%. Retention time: 3.98 minutes [Column: Phenomenex Lux Amylose-1, 4.6 x 250 mm, 5 µm; Mobile phase A: carbon dioxide; Mobile phase B: 2-propanol containing 0.2% 1-aminopropan-2-ol; Gradient: 5% B for 1.00 minute, then 5% to 60% B over 8.00 minutes; Flow rate: 3.0 mL / minute; Back pressure: 120 bar]. C47 Yield: 4.49 g, 10.3 mmol, 45%. Retention time: 4.32 minutes (Analytical SFC conditions identical to those used for C46 ). Step 2. Synthesis of 4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine (C48 ).

[0327] p-Toluenesulfonic acid monohydrate (566 mg, 2.98 mmol) was added to a solution of C47 (1.12 g, 2.58 mmol) in ethyl acetate (26 mL). After the reaction mixture had been heated at 45 °C for 16 hours, it was concentrated in vacuo, dissolved in ethyl acetate, and washed with saturated aqueous sodium bicarbonate solution. The aqueous layers were extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure, affording C48 as a foamy white solid (947 mg), LCMS m / z 334.0+ [M+H] +< . A portion of this material, which still contained some p-toluenesulfonic acid, was used in the synthesis of C50 below.

[0328] A second portion of the foamy white solid (440 mg) was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 15 mL); the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford C48 (350 mg) as a colorless oil that no longer contained p-toluenesulfonic acid. Adjusted yield: 350 mg, 1.05 mmol, 88%. 1< H NMR (400 MHz, chloroform-d) δ 7.53 (dd, J = 8.4, 7.8 Hz, 1H), 7.22 - 7.13 (m, 3H), 6.87 - 6.80 (m, 1H), 6.79 - 6.71 (m, 2H), 3.23 - 3.14 (m, 2H), 2.86 - 2.69 (m, 3H), 1.90 - 1.68 (m, 4H).Step 3. Synthesis of 4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidine, hemisulfate salt (C49 ).

[0329] A 0.1 M solution of C48 (the colorless oil from above) in ethyl acetate was prepared and subjected to a salt screen. Only the sulfate salt formation is described here. A mixture of sulfuric acid (25 µmol) and the solution of substrate (0.1 M, 250 µL, 25 µmol) was heated to 45 °C for 1 hour, allowed to cool to room temperature, and stirred for 15 hours. The resulting suspension was treated with methanol (approximately 150 µL) until a solution formed; this was allowed to slowly evaporate overnight, until approximately 50 µL of solvent remained. One of the resulting crystals was analyzed by single-crystal X-ray structure determination, establishing the absolute stereochemistry as that shown.Single-crystal X-ray structural determination of C49 Single Crystal X-Ray Analysis

[0330] Data collection was performed on a Bruker D8 Venture diffractometer at room temperature. Data collection consisted of omega and phi scans. The structure was solved by intrinsic phasing using SHELX software suite in the triclinic class space group P1. The structure was subsequently refined by the full-matrix least squares method. All non-hydrogen atoms were found and refined using anisotropic displacement parameters. The hydrogen atoms located on nitrogen were found from the Fourier difference map and refined with distances restrained. The remaining hydrogen atoms were placed in calculated positions and were allowed to ride on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms. The asymmetric unit is comprised of two molecules of protonated C48, one molecule of doubly deprotonated sulfuric acid, and one molecule full occupancy water. Thus, the structure is a hemisulfate salt and hemihydrate. The chlorofluorophenyl ring is disordered and modeled with occupancy of 60 / 40, with the ring flipped over two positions. Analysis of the absolute structure using likelihood methods (Hooft, 2008) was performed using PLATON (Spek). The results indicate that the absolute structure has been correctly assigned; the method calculates that the probability that the structure is correct is 100.0. The Hooft parameter is reported as 0.061 with an esd of 0.004 and the Parson's parameter is reported as 0.063 with an esd of 0.005. The final R-index was 3.1%. A final difference Fourier revealed no missing or misplaced electron density. Pertinent crystal, data collection, and refinement information is summarized in Table E. Atomic coordinates, bond lengths, bond angles, and displacement parameters are listed in Tables F - H. Software and References

[0331] SHELXTL, Version 5.1, Bruker AXS, 1997. PLATON, A. L. Spek, J. Appl. Cryst. 2003, 36, 7-13. MERCURY, C. F. Macrae, P. R. Edington, P. McCabe, E. Pidcock, G. P. Shields, R. Taylor, M. Towler, and J. van de Streek, J. Appl. Cryst. 2006, 39, 453-457. OLEX2, O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, and H. Puschmann, J. Appl. Cryst. 2009, 42, 339-341. R. W. W. Hooft, L. H. Straver, and A. L. Spek, J. Appl. Cryst. 2008, 41, 96-103. H. D. Flack, Acta Cryst. 1983, A39, 867-881. Table E. Crystal data and structure refinement for C49. Empirical formulaC 36 H 38 Cl 2 F 2 N 2 O 9 SFormula weight783.64Temperature296(2) KWavelength1.54178 ÅCrystal systemTriclinicSpace groupP1Unit cell dimensionsa = 5.9095(2) Åα = 86.5910(10)°b = 6.1712(2) Åβ = 89.3680(10)°c = 25.6096(8) Åγ = 75.7680(10)°Volume903.68(5) Å 3< Z1Density (calculated)1.440 Mg / m 3< Absorption coefficient2.743 mm -1< F(000)408Crystal size0.380 x 0.120 x 0.080 mm 3< Theta range for data collection3.458 to 72.096°Index ranges-7<=h<=7, -7<=k<=7, -31<=l<=31Reflections collected24619Independent reflections6399 [R int = 0.0323]]Completeness to theta = 67.679°96.6%Absorption correctionEmpiricalRefinement methodFull-matrix least-squares on F 2< Data / restraints / parameters6399 / 9 / 495Goodness-of-fit on F 2< 1.014Final R indices [I>2σ(I)]R1 = 0.0305, wR2 = 0.0805R indices (all data)R1 = 0.0310, wR2 = 0.0810Absolute structure parameter0.058(4)Extinction coefficientn / aLargest diff. peak and hole0.167 and -0.184 e.Å -3< Table F. Atomic coordinates (x 10 4< ) and equivalent isotropic displacement parameters (Å 2< x 10 3< ) for C49. U(eq) is defined as one-third of the trace of the orthogonalized U ij< tensor. xyzU (eq)S(1)8968(1)2512(1)4774(1)33(1)Cl(1)2534(3)7001 (5)9863(1)161(1)F(1)9192(9)7761(7)8721(2)95(1)C(1)7533(7)6719(7)8821(1)72(1)C(2)6041(9)7355(8)9230(2)92(1)C(3)4428(8)6206(10)9350(2)93(2)C(4)4276(8)4392(9)9082(2)86(1)C(5)5801(7)3784(7)8678(1)69(1)C(6)7444(6)4930(5)8533(1)56(1)Cl(1')2534(3)7001 (5)9863(1)161(1)F(1')6045(13)1811(12)8450(3)95(1)C(1')5801(7)3784(7)8678(1)69(1)C(2')4276(8)4392(9)9082(2)86(1)C(3')4428(8)6206(10)9350(2)93(2)C(4')6041(9)7355(8)9230(2)92(1)C(5')7533(7)6719(7)8821(1)72(1)C(6')7444(6)4930(5)8533(1)56(1)Cl(2)-2047(5)12265(3)154(1)157(1)F(2)-2662(7)5436(7)1220(2)92(1)C(19)-1591(6)7059(7)1154(1)68(1)C(20)-2327(8)8653(9)752(2)88(1)C(21)-1157(9)10260(8)665(2)88(1)C(22)728(9)10361(7)964(2)80(1)C(23)1431(6)8731(6)1364(1)65(1)C(24)274(5)7058(5)1472(1)54(1)Cl(2')-2047(5)12265(3)154(1)157(1)F(2')3433(15)8441(16)1630(4)92(1)C(19')1431(6)8731(6)1364(1)65(1)C(20')728(9)10361(7)964(2)80(1)C(21')-1157(9)10260(8)665(2)88(1)C(22')-2327(8)8653(9)752(2)88(1)C(23')-1591(6)7059(7)1154(1)68(1)C(24')274(5)7058(5)1472(1)54(1)N(1)4370(3)2950(4)5713(1)41(1)N(2)4133(4)8236(3)4386(1)42(1)O(1)10923(4)2331(5)8233(1)77(1)O(2)7874(4)3730(4)7651(1)64(1)O(3)1766(4)6201(4)2352(1)64(1)O(4)2966(5)3591(4)1729(1)75(1)O(5)9024(3)2305(3)4214(1)50(1)O(6)7650(4)989(3)5024(1)63(1)O(7)11358(3)1934(4)4982(1)64(1)O(8)7789(3)4827(3)4909(1)46(1)O(1W)10276(4)6879(4)5537(1)54(1)C(7)9086(6)4293(6)8090(1)63(1)C(8)9234(4)1745(5)7490(1)44(1)C(9)11056(5)930(6)7834(1)54(1)C(10)12654(5)-1059(6)7768(1)62(1)C(11)12316(5)-2213(6)7338(1)58(1)C(12)10459(4)-1405(5)6994(1)47(1)C(13)8826(4)623(4)7066(1)38(1)C(14)6762(4)1637(4)6711(1)37(1)C(15)7243(4)3516(4)6343(1)42(1)C(16)5126(4)4639(4)6009(1)44(1)C(17)3883(5)1105(5)6056(1)50(1)C(18)5997(4)-38(4)6386(1)41(1)C(25)996(6)5296(6)1900(1)60(1)C(26)3848(5)4738(4)2505(1)45(1)C(27)4542(6)3183(5)2133(1)52(1)C(28)6579(6)1567(5)2178(1)56(1)C(29)7932(6)1577(5)2620(1)56(1)C(30)7236(5)3123(5)2992(1)51(1)C(31)5126(5)4786(4)2944(1)42(1)C(32)4261(4)6474(4)3352(1)39(1)C(33)6145(5)7543(5)3544(1)51(1)C(34)5139(5)9272(4)3932(1)50(1)C(35)2313(5)7116(5)4227(1)49(1)C(36)3263(4)5420(4)3826(1)42(1) Table G. Bond lengths [Å] and angles [°] for C49. S(1)-O(5)1.4463(18)S(1)-O(7)1.4668(19)S(1)-O(6)1.475(2)S(1)-O(8)1.4863(18)Cl(1)-C(3)1.731(4)F(1)-C(1)1.314(6)C(1)-C(6)1.375(5)C(1)-C(2)1.374(6)C(2)-C(3)1.343(8)C(2)-H(2)0.9300C(3)-C(4)1.369(8)C(4)-C(5)1.373(6)C(4)-H(4)0.9300C(5)-C(6)1.370(5)C(5)-H(5)0.9300C(6)-C(7)1.493(5)Cl(1')-C(3')1.731(4)F(1')-C(1')1.357(8)C(1')-C(6')1.370(5)C(1')-C(2')1.373(6)C(2')-C(3')1.369(8)C(2')-H(2')0.9300C(3')-C(4')1.343(8)C(4')-C(5')1.374(6)C(4')-H(4')0.9300C(5')-C(6')1.375(5)C(5')-H(5')0.9300C(6')-C(7)1.493(5)Cl(2)-C(21)1.739(4)F(2)-C(19)1.312(5)C(19)-C(24)1.378(5)C(19)-C(20)1.378(6)C(20)-C(21)1.348(7)C(20)-H(20)0.9300C(21)-C(22)1.375(7)C(22)-C(23)1.384(6)C(22)-H(22)0.9300C(23)-C(24)1.385(5)C(23)-H(23)0.9300C(24)-C(25)1.485(5)Cl(2')-C(21')1.739(4)F(2')-C(19')1.340(9)C(19')-C(20')1.384(6)C(19')-C(24')1.385(5)C(20')-C(21')1.375(7)C(20')-H(20')0.9300C(21')-C(22')1.348(7)C(22')-C(23')1.378(6)C(22')-H(22')0.9300C(23')-C(24')1.378(5)C(23')-H(23')0.9300C(24')-C(25)1.485(5)N(1)-C(17)1.480(4)N(1)-C(16)1.480(3)N(1)-H(1X)0.95(2)N(1)-H(1Y)0.97(2)N(2)-C(34)1.483(4)N(2)-C(35)1.487(4)N(2)-H(2X)0.96(2)N(2)-H(2Y)0.99(2)O(1)-C(9)1.368(4)O(1)-C(7)1.445(4)O(2)-C(8)1.373(3)O(2)-C(7)1.443(3)O(3)-C(26)1.380(3)O(3)-C(25)1.440(3)O(4)-C(27)1.369(4)O(4)-C(25)1.447(4)O(1W)-H(1WX)0.93(2)O(1W)-H(1WY)0.94(2)C(7)-H(7)0.9800C(8)-C(9)1.374(4)C(8)-C(13)1.376(4)C(9)-C(10)1.370(5)C(10)-C(11)1.387(5)C(10)-H(10)0.9300C(11)-C(12)1.390(4)C(11)-H(11)0.9300C(12)-C(13)1.400(4)C(12)-H(12)0.9300C(13)-C(14)1.514(3)C(14)-C(18)1.518(3)C(14)-C(15)1.528(3)C(14)-H(14)0.9800C(15)-C(16)1.518(3)C(15)-H(15A)0.9700C(15)-H(15B)0.9700C(16)-H(16A)0.9700C(16)-H(16B)0.9700C(17)-C(18)1.513(4)C(17)-H(17A)0.9700C(17)-H(17B)0.9700C(18)-H(18A)0.9700C(18)-H(18B)0.9700C(25)-H(25)0.9800C(26)-C(31)1.367(4)C(26)-C(27)1.379(3)C(27)-C(28)1.363(4)C(28)-C(29)1.394(5)C(28)-H(28)0.9300C(29)-C(30)1.376(4)C(29)-H(29)0.9300C(30)-C(31)1.408(4)C(30)-H(30)0.9300C(31)-C(32)1.514(3)C(32)-C(33)1.527(4)C(32)-C(36)1.524(3)C(32)-H(32)0.9800C(33)-C(34)1.510(4)C(33)-H(33A)0.9700C(33)-H(33B)0.9700C(34)-H(34A)0.9700C(34)-H(34B)0.9700C(35)-C(36)1.515(3)C(35)-H(35A)0.9700C(35)-H(35B)0.9700C(36)-H(36A)0.9700C(36)-H(36B)0.9700O(5)-S(1)-O(7)109.68(13)O(5)-S(1)-O(6)109.65(13)O(7)-S(1)-O(6)109.45(15)O(5)-S(1)-O(8)111.22(11)O(7)-S(1)-O(8)109.11(11)O(6)-S(1)-O(8)107.69(11)F(1)-C(1)-C(6)118.6(4)F(1)-C(1)-C(2)119.1(4)C(6)-C(1)-C(2)122.1(4)C(3)-C(2)-C(1)118.9(4)C(3)-C(2)-H(2)120.5C(1)-C(2)-H(2)120.5C(2)-C(3)-C(4)121.6(4)C(2)-C(3)-Cl(1)119.3(4)C(4)-C(3)-Cl(1)119.1(5)C(3)-C(4)-C(5)118.2(5)C(3)-C(4)-H(4)120.9C(5)-C(4)-H(4)120.9C(6)-C(5)-C(4)122.4(4)C(6)-C(5)-H(5)118.8C(4)-C(5)-H(5)118.8C(5)-C(6)-C(1)116.7(3)C(5)-C(6)-C(7)122.7(3)C(1)-C(6)-C(7)120.6(3)F(1')-C(1')-C(6')114.7(4)F(1')-C(1')-C(2')122.1(5)C(6')-C(1')-C(2')122.4(4)C(3')-C(2')-C(1')118.2(5)C(3')-C(2')-H(2')120.9C(1')-C(2')-H(2')120.9C(4')-C(3')-C(2')121.6(4)C(4')-C(3')-Cl(1')119.3(4)C(2')-C(3')-Cl(1')119.1(5)C(3')-C(4')-C(5')118.9(4)C(3')-C(4')-H(4')120.5C(5')-C(4')-H(4')120.5C(6')-C(5')-C(4')122.1(4)C(6')-C(5')-H(5')118.9C(4')-C(5')-H(5')118.9C(1')-C(6')-C(5')116.7(3)C(1')-C(6')-C(7)122.7(3)C(5')-C(6')-C(7)120.6(3)F(2)-C(19)-C(24)119.3(4)F(2)-C(19)-C(20)118.1(4)C(24)-C(19)-C(20)122.5(4)C(21)-C(20)-C(19)118.4(4)C(21)-C(20)-H(20)120.8C(19)-C(20)-H(20)120.8C(20)-C(21)-C(22)122.4(4)C(20)-C(21)-Cl(2)118.9(4)C(22)-C(21)-Cl(2)118.7(4)C(21)-C(22)-C(23)117.8(4)C(21)-C(22)-H(22)121.1C(23)-C(22)-H(22)121.1C(22)-C(23)-C(24)122.0(4)C(22)-C(23)-H(23)119.0C(24)-C(23)-H(23)119.0C(19)-C(24)-C(23)116.8(3)C(19)-C(24)-C(25)120.3(3)C(23)-C(24)-C(25)122.9(3)F(2')-C(19')-C(20')123.5(5)F(2')-C(19')-C(24')113.9(5)C(20')-C(19')-C(24')122.0(4)C(21')-C(20')-C(19')117.8(4)C(21')-C(20')-H(20')121.1C(19')-C(20')-H(20')121.1C(22')-C(21')-C(20')122.4(4)C(22')-C(21')-Cl(2')118.9(4)C(20')-C(21')-Cl(2')118.7(4)C(21')-C(22')-C(23')118.4(4)C(21')-C(22')-H(22')120.8C(23')-C(22')-H(22')120.8C(24')-C(23')-C(22')122.5(4)C(24')-C(23')-H(23')118.7C(22')-C(23')-H(23')118.7C(23')-C(24')-C(19')116.8(3)C(23')-C(24')-C(25)120.3(3)C(19')-C(24')-C(25)122.9(3)C(17)-N(1)-C(16)112.6(2)C(17)-N(1)-H(1X)110.7(19)C(16)-N(1)-H(1X)108(2)C(17)-N(1)-H(1Y)108(2)C(16)-N(1)-H(1Y)112.4(19)H(1X)-N(1)-H(1Y)105(3)C(34)-N(2)-C(35)112.2(2)C(34)-N(2)-H(2X)109.7(19)C(35)-N(2)-H(2X)109.7(19)C(34)-N(2)-H(2Y)107.7(19)C(35)-N(2)-H(2Y)110.8(19)H(2X)-N(2)-H(2Y)107(3)C(9)-O(1)-C(7)106.0(2)C(8)-O(2)-C(7)105.9(2)C(26)-O(3)-C(25)105.9(2)C(27)-O(4)-C(25)105.7(2)H(1WX)-O(1W)-H(1WY)105(4)O(2)-C(7)-O(1)106.5(3)O(2)-C(7)-C(6)110.4(3)O(1)-C(7)-C(6)111.2(3)O(2)-C(7)-C(6')110.4(3)O(1)-C(7)-C(6')111.2(3)O(2)-C(7)-H(7)109.6O(1)-C(7)-H(7)109.6C(6)-C(7)-H(7)109.6C(9)-C(8)-O(2)110.0(2)C(9)-C(8)-C(13)123.4(2)O(2)-C(8)-C(13)126.6(2)O(1)-C(9)-C(10)128.1(3)O(1)-C(9)-C(8)110.1(3)C(10)-C(9)-C(8)121.7(3)C(9)-C(10)-C(11)116.3(3)C(9)-C(10)-H(10)121.8C(11)-C(10)-H(10)121.8C(10)-C(11)-C(12)122.0(3)C(10)-C(11)-H(11)119.0C(12)-C(11)-H(11)119.0C(11)-C(12)-C(13)121.3(3)C(11)-C(12)-H(12)119.4C(13)-C(12)-H(12)119.4C(8)-C(13)-C(12)115.3(2)C(8)-C(13)-C(14)119.8(2)C(12)-C(13)-C(14)124.9(2)C(13)-C(14)-C(18)114.2(2)C(13)-C(14)-C(15)111.38(19)C(18)-C(14)-C(15)108.70(19)C(13)-C(14)-H(14)107.4C(18)-C(14)-H(14)107.4C(15)-C(14)-H(14)107.4C(16)-C(15)-C(14)111.7(2)C(16)-C(15)-H(15A)109.3C(14)-C(15)-H(15A)109.3C(16)-C(15)-H(15B)109.3C(14)-C(15)-H(15B)109.3H(15A)-C(15)-H(15B)107.9N(1)-C(16)-C(15)109.9(2)N(1)-C(16)-H(16A)109.7C(15)-C(16)-H(16A)109.7N(1)-C(16)-H(16B)109.7C(15)-C(16)-H(16B)109.7H(16A)-C(16)-H(16B)108.2N(1)-C(17)-C(18)110.94(19)N(1)-C(17)-H(17A)109.5C(18)-C(17)-H(17A)109.5N(1)-C(17)-H(17B)109.5C(18)-C(17)-H(17B)109.5H(17A)-C(17)-H(17B)108.0C(17)-C(18)-C(14)110.6(2)C(17)-C(18)-H(18A)109.5C(14)-C(18)-H(18A)109.5C(17)-C(18)-H(18B)109.5C(14)-C(18)-H(18B)109.5H(18A)-C(18)-H(18B)108.1O(3)-C(25)-O(4)106.6(2)O(3)-C(25)-C(24')111.0(3)O(4)-C(25)-C(24')109.4(3)O(3)-C(25)-C(24)111.0(3)O(4)-C(25)-C(24)109.4(3)O(3)-C(25)-H(25)109.9O(4)-C(25)-H(25)109.9C(24)-C(25)-H(25)109.9C(31)-C(26)-C(27)123.2(3)C(31)-C(26)-O(3)127.3(2)C(27)-C(26)-O(3)109.5(2)C(28)-C(27)-O(4)127.7(2)C(28)-C(27)-C(26)121.9(3)O(4)-C(27)-C(26)110.3(2)C(27)-C(28)-C(29)116.3(2)C(27)-C(28)-H(28)121.9C(29)-C(28)-H(28)121.9C(30)-C(29)-C(28)121.8(3)C(30)-C(29)-H(29)119.1C(28)-C(29)-H(29)119.1C(29)-C(30)-C(31)121.7(3)C(29)-C(30)-H(30)119.2C(31)-C(30)-H(30)119.2C(26)-C(31)-C(30)115.1(2)C(26)-C(31)-C(32)121.5(2)C(30)-C(31)-C(32)123.4(2)C(31)-C(32)-C(33)113.3(2)C(31)-C(32)-C(36)111.48(19)C(33)-C(32)-C(36)108.02(19)C(31)-C(32)-H(32)107.9C(33)-C(32)-H(32)107.9C(36)-C(32)-H(32)107.9C(34)-C(33)-C(32)110.5(2)C(34)-C(33)-H(33A)109.6C(32)-C(33)-H(33A)109.6C(34)-C(33)-H(33B)109.6C(32)-C(33)-H(33B)109.6H(33A)-C(33)-H(33B)108.1N(2)-C(34)-C(33)110.6(2)N(2)-C(34)-H(34A)109.5C(33)-C(34)-H(34A)109.5N(2)-C(34)-H(34B)109.5C(33)-C(34)-H(34B)109.5H(34A)-C(34)-H(34B)108.1N(2)-C(35)-C(36)110.71(19)N(2)-C(35)-H(35A)109.5C(36)-C(35)-H(35A)109.5N(2)-C(35)-H(35B)109.5C(36)-C(35)-H(35B)109.5H(35A)-C(35)-H(35B)108.1C(35)-C(36)-C(32)111.9(2)C(35)-C(36)-H(36A)109.2C(32)-C(36)-H(36A)109.2C(35)-C(36)-H(36B)109.2C(32)-C(36)-H(36B)109.2H(36A)-C(36)-H(36B)107.9

[0332] Symmetry transformations used to generate equivalent atoms. Table H. Anisotropic displacement parameters (Å 2< x 10 3< ) for C49. The anisotropic displacement factor exponent takes the form: -2π 2< [h 2< a* 2< U 11< + ... + 2 h k a* b* U 12< ].U 11< U 22< U 33< U 23< U 13< U 12< S(1)32(1)32(1)32(1)-3(1)-2(1)-1(1)Cl(1)107(1)258(2)90(1)-63(1)19(1)19(1)F(1)111(2)91(2)98(2)-30(2)6(2)-46(2)C(1)81(2)71 (2)60(2)-20(2)-16(2)-6(2)C(2)100(3)92(3)74(3)-42(2)-16(2)7(2)C(3)70(2)134(4)53(2)-27(2)-7(2)19(3)C(4)71(2)116(3)67(2)0(2)-1(2)-16(2)C(5)75(2)70(2)59(2)-11(2)-7(2)-10(2)C(6)65(2)54(2)42(1)-8(1)-18(1)-1(1)Cl(1')107(1)258(2)90(1)-63(1)19(1)19(1)F(1')111(2)91(2)98(2)-30(2)6(2)-46(2)C(1')75(2)70(2)59(2)-11 (2)-7(2)-10(2)C(2')71(2)116(3)67(2)0(2)-1(2)-16(2)C(3')70(2)134(4)53(2)-27(2)-7(2)19(3)C(4')100(3)92(3)74(3)-42(2)-16(2)7(2)C(5')81(2)71(2)60(2)-20(2)-16(2)-6(2)C(6')65(2)54(2)42(1)-8(1)-18(1)-1(1)Cl(2)243(2)110(1)80(1)12(1)-39(1)26(1)F(2)88(2)106(2)93(2)-12(2)-22(2)-44(2)C(19)62(2)77(2)62(2)-26(2)-12(2)-5(2)C(20)85(3)98(3)66(2)-20(2)-31(2)10(2)C(21)117(3)74(3)51(2)-11 (2)-10(2)18(2)C(22)104(3)70(2)60(2)-9(2)8(2)-8(2)C(23)58(2)73(2)60(2)-13(2)-3(1)-6(2)C(24)50(2)60(2)47(2)-23(1)-4(1)-2(1)Cl(2')243(2)110(1)80(1)12(1)-39(1)26(1)F(2')88(2)106(2)93(2)-12(2)-22(2)-44(2)C(19')58(2)73(2)60(2)-13(2)-3(1)-6(2)C(20')104(3)70(2)60(2)-9(2)8(2)-8(2)C(21')117(3)74(3)51(2)-11 (2)-10(2)18(2)C(22')85(3)98(3)66(2)-20(2)-31(2)10(2)C(23')62(2)77(2)62(2)-26(2)-12(2)-5(2)C(24')50(2)60(2)47(2)-23(1)-4(1)-2(1)N(1)30(1)59(1)32(1)-3(1)-4(1)-7(1)N(2)49(1)38(1)37(1)-11(1)-5(1)0(1)O(1)58(1)107(2)55(1)-23(1)-26(1)6(1)O(2)64(1)66(1)50(1)-21(1)-23(1)12(1)O(3)66(1)62(1)52(1)-27(1)-19(1)11(1)O(4)92(2)64(1)56(1)-32(1)-20(1)10(1)O(5)62(1)51(1)34(1)-5(1)-2(1)-9(1)O(6)76(1)43(1)70(1)-4(1)32(1)-14(1)O(7)45(1)68(1)69(1)-29(1)-22(1)13(1)O(8)45(1)35(1)53(1)-9(1)-4(1)2(1)O(1W)56(1)50(1)51(1)-3(1)-12(1)1(1)C(7)68(2)73(2)45(2)-12(1)-14(1)-12(2)C(8)38(1)51(1)36(1)-4(1)-3(1)0(1)C(9)42(1)76(2)39(1)-1(1)-9(1)-4(1)C(10)38(1)87(2)48(2)10(1)-8(1)6(1)C(11)45(1)60(2)55(2)9(1)2(1)13(1)C(12)41(1)46(1)47(1)0(1)3(1)0(1)C(13)34(1)43(1)34(1)2(1)-1(1)-4(1)C(14)30(1)44(1)31(1)-4(1)-1(1)0(1)C(15)41(1)38(1)45(1)0(1)-12(1)-7(1)C(16)44(1)43(1)39(1)-3(1)-6(1)4(1)C(17)39(1)73(2)42(1)-1(1)-3(1)-23(1)C(18)41(1)46(1)39(1)-4(1)2(1)-14(1)C(25)65(2)62(2)51(2)-22(1)-9(1)-8(1)C(26)55(1)37(1)37(1)-8(1)1(1)-2(1)C(27)72(2)41(1)39(1)-9(1)-2(1)-6(1)C(28)79(2)39(1)43(1)-10(1)11(1)1(1)C(29)62(2)45(2)48(2)-2(1)7(1)8(1)C(30)58(2)45(2)42(1)-1(1)-1(1)1(1)C(31)54(1)34(1)34(1)-4(1)2(1)-4(1)C(32)50(1)30(1)33(1)-4(1)-6(1)0(1)C(33)63(2)45(1)54(2)-9(1)17(1)-28(1)C(34)59(2)38(1)58(2)-9(1)-1(1)-22(1)C(35)46(1)46(1)56(2)-17(1)16(1)-11(1)C(36)39(1)36(1)53(1)-15(1)12(1)-13(1) Step 4. Synthesis of methyl 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C50 ).

[0333] A solution of C48 (500 mg of the foamy white solid from above, corrected for p-toluenesulfonic acid: 1.25 mmol) in acetonitrile (6 mL) was treated with N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and allowed to stir for 5 minutes at 45 °C. After addition of P15 (319 mg, 1.08 mmol), stirring at 45 °C was continued for 7.25 hours, whereupon the reaction mixture was diluted with water (6 mL) and acetonitrile (2 mL) at 45 °C. The resulting heterogeneous mixture was allowed to cool to room temperature and stir for 72 hours. More water (5 mL) was added, and after a further 30 minutes of stirring, the solid was collected via filtration and washed with a mixture of acetonitrile and water (15:85, 3 x 5 mL), to afford C50 as a white solid with a slight pink cast. Yield: 605 mg, 1.02 mmol, 82%. LCMS m / z 592.0+ [M+H] +< . 1< H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 8.0, 8.0 Hz, 1H), 7.19 (br s, 1H), 7.18 - 7.14 (m, 2H), 6.85 - 6.79 (m, 1H), 6.76 - 6.71 (m, 2H), 5.26 - 5.18 (m, 1H), 4.73 (dd, component of ABX pattern, J = 15.3, 5.9 Hz, 1H), 4.67 (dd, component of ABX pattern, J = 15.3, 3.5 Hz, 1H), 4.63 - 4.55 (m, 1H), 4.38 (ddd, J = 9.1, 6.0, 5.9 Hz, 1H), 3.94 (s, 5H), 3.03 - 2.89 (m, 2H), 2.77 - 2.65 (m, 2H), 2.51 - 2.39 (m, 1H), 2.34 - 2.20 (m, 2H), 1.91 - 1.76 (m, 4H).Step 5. Synthesis of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid (5, free acid ).

[0334] A suspension of C50 (595 mg, 1.00 mmol) in methanol (10 mL) was heated to 45 °C and treated with aqueous sodium hydroxide solution (1 M; 2.01 mL, 2.01 mmol). After 21 hours at 45 °C, the reaction mixture was allowed to cool to room temperature; it was then treated with aqueous citric acid solution (1 M, 1 mL), which brought the pH to 5 to 6. Water (10 mL) was added, and the mixture was stirred for 1 hour, whereupon the solid was collected by filtration. It was washed with a mixture of methanol and water (1:10, 3 x 5 mL), to afford a solid (433 mg). A portion of this material (300 mg) was stirred with a mixture of heptane and ethyl acetate (1:3, 5 mL) at 40 °C for 1 hour; after cooling to room temperature with continued stirring, the solid was collected via filtration, and washed with a mixture of heptane and ethyl acetate (3:1, 3 x 3 mL) to afford 5, free acid, as a white solid. Yield: 260 mg, 0.450 mmol, corresponding to 65% for the entire reaction. LCMS m / z 578.0+ [M+H] +< . 1< H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (v br s, 1H), 8.26 (br s, 1H), 7.79 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 - 7.56 (m, 3H), 7.40 (dd, J = 8.3, 2.0 Hz, 1H), 7.35 (s, 1H), 6.87 - 6.75 (m, 3H), 5.13 - 5.03 (m, 1H), 4.76 (dd, component of ABX pattern, J = 15.3, 7.2 Hz, 1H), 4.62 (dd, component of ABX pattern, J = 15.2, 2.8 Hz, 1H), 4.46 - 4.38 (m, 1H), 4.34 (ddd, J = 9.0, 5.9, 5.8 Hz, 1H), 3.84 (AB quartet, J AB = 13.5 Hz, Δν AB = 67.7 Hz, 2H), 3.00 (br d, J = 11.2 Hz, 1H), 2.84 br (d, J = 11.3 Hz, 1H), 2.71 - 2.56 (m, 2H), 2.45 - 2.34 (m, 1H), 2.28 - 2.08 (m, 2H), 1.84 - 1.65 (m, 4H).

[0335] This material was determined to be of the same absolute configuration as Example 5 above by comparison of its biological activity with that of both 4 and 5: in Assay 2, this sample of 5, free acid exhibited an EC 50 of 25 nM (geometric mean of 3 replicates). The activity in Assay 2 for the ammonium salts of Example 4 and Example 5 were >20000 nM (2 replicates) and 20 nM (geometric mean of 3 replicates), respectively.Synthesis of Example 5, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (5, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt ).

[0336]

[0337] A mixture of 5, free acid (0.50 g, 0.86 mmol) in tetrahydrofuran (4 mL) was treated with an aqueous solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris, 1.0 M; 0.5 mL, 1.0 mmol). After 20 hours, the mixture was concentrated in vacuo with ethanol (2 x 6 mL). The mixture was treated with ethanol (4 mL). After stirring for 48 hours, the solid was collected via filtration, washed with ethanol (2 x 10 mL) and dried under vacuum to afford 5, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt, as a white solid. Yield: 410 mg, 0.586 mmol, 68%. 1< H NMR (600 MHz, DMSO-d 6 ), characteristic peaks: δ 8.19 (s, 1H), 7.78 (br d, J = 8.4 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (s, 1H), 6.85 - 6.80 (m, 2H), 6.79 (dd, J = 6.9, 2.4 Hz, 1H), 5.11 - 5.05 (m, 1H), 4.73 (dd, J = 15.2, 7.2 Hz, 1H), 4.60 (dd, J = 15.3, 2.9 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.34 (ddd, J = 9.0, 6.0, 5.8 Hz, 1H), 3.91 (d, J = 13.5 Hz, 1H), 3.74 (d, J = 13.5 Hz, 1H), 2.99 (br d, J = 11.1 Hz, 1H), 2.85 (br d, J = 11.3 Hz, 1H), 2.68 - 2.59 (m, 2H), 2.44 - 2.37 (m, 1H), 2.25 - 2.18 (m, 1H), 2.17 - 2.10 (m, 1H), 1.80 - 1.69 (m, 4H). mp = 168 °C to 178 °C.Examples 6 and 7 Ammonium 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (6 ) and Ammonium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (7 )

[0338] Step 1. Synthesis of 4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidine, p-toluenesulfonate salt (C13 ).

[0339] A solution of P2 (150 mg, 0.335 mmol) and p-toluenesulfonic acid monohydrate (159 mg, 0.836 mmol) in ethyl acetate (2.0 mL) was stirred at 60 °C for 3.5 hours. The reaction mixture was concentrated in vacuo to afford C13 as a brown oil, which was used directly in the following step. LCMS m / z 348.1 [M+H] +< .Step 2. Synthesis of methyl 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C51 ).

[0340] To a suspension of C13 (from the previous step; ≤0.335 mmol) and potassium carbonate (232 mg, 1.68 mmol) in acetonitrile (5.0 mL) was added P15 (99.1 mg, 0.336 mmol). The reaction mixture was stirred at 60 °C for 10 hours, whereupon it was filtered, and the filtrate was concentrated in vacuo. After the residue (390 mg) had been combined with the material from a similar reaction carried out using C13 (≤0.11 mmol), it was diluted with water (20 mL) and extracted with a mixture of dichloromethane and methanol (10:1, 3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo, and subjected to preparative thin-layer chromatography (Eluent: 1:1 dichloromethane / methanol), providing C51, a mixture of diastereomers, as a colorless oil. Combined yield: 80.6 mg, 0.133 mmol, 30% over 2 steps. LCMS m / z 606.2 [M+H] +< .Step 3. Isolation of methyl 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C52 ) and methyl 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C53 ).

[0341] Separation of C51 (180 mg, 0.297 mmol) into its component diastereomers was carried out via repeated SFC [Column: Chiral Technologies Chiralpak AD, 10 µm; Mobile phase: 65:35 carbon dioxide / (ethanol containing 0.1% ammonium hydroxide)]. The first-eluting diastereomer was designated as C52. Yield: 61.2 mg, 0.101 mmol, 34%. LCMS m / z 627.9 [M+Na +< ]. Retention time: 5.03 minutes (Column: Chiral Technologies Chiralpak AD-3, 4.6 x 150 mm, 3 µm; Mobile phase A: carbon dioxide; Mobile phase B: ethanol containing 0.05% diethylamine; Gradient: 5% to 40% B over 5.5 minutes, then held at 40% B for 3.0 minutes; Flow rate: 2.5 mL / minute).

[0342] The second-eluting diastereomer was designated as C53. Upon analysis, this material proved to be contaminated with the corresponding ethyl ester; it was taken into the hydrolysis step (to generate 7 ) as this mixture. Yield: 40.0 mg, 66.0 µmol, 22%. LCMS m / z 606.0 [M+H] +< . Retention time: 5.19 minutes (Analytical conditions identical to those used for C52 ).

[0343] The indicated absolute stereochemistries at the dioxolane were assigned via potency correlation of 7 with a sample of 7, free acid synthesized from intermediate P3 (see below, Alternate Synthesis of Example 7, free acid ); the absolute stereochemistry of P3 was established via single-crystal X-ray structure determination of C8 (see above).Step 4. Synthesis of ammonium 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (6 ).

[0344] Aqueous lithium hydroxide solution (2 M; 0.990 mL, 1.98 mmol) was added to a solution of C52 (60 mg, 99 µmol) in a mixture of methanol (1.0 mL) and tetrahydrofuran (1.0 mL), and the reaction mixture was stirred at 20 °C for 16 hours. Trifluoroacetic acid was added until the pH of the reaction mixture reached 7, whereupon it was concentrated in vacuo, and the residue was purified using reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile; Gradient: 29% to 49% B), affording 6 as a white solid. Yield: 14.4 mg. 23.6 µmol, 24%. LCMS m / z 592.0+ [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ), characteristic peaks: δ 8.35 (d, J = 1.3 Hz, 1H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.3, 8.3 Hz, 1H), 7.28 (dd, J = 10.9, 2.0 Hz, 1H), 7.21 (br dd, J = 8.4, 1.9 Hz, 1H), 6.81 - 6.75 (m, 1H), 6.74 - 6.68 (m, 2H), 5.33 - 5.25 (m, 1H), 4.72 (dd, J = 15.4, 2.7 Hz, 1H), 4.49 (dt, J = 9.1, 6.0 Hz, 1H), 4.03 (AB quartet, J AB = 13.9 Hz, Δν AB = 47.8 Hz, 2H), 3.14 (br d, J = 11 Hz, 1H), 3.02 (br d, J = 11.5 Hz, 1H), 2.88 - 2.78 (m, 1H), 2.77 - 2.68 (m, 1H), 2.60 - 2.50 (m, 1H), 2.47 - 2.32 (m, 2H), 2.03 (d, J = 1.1 Hz, 3H), 2.01 - 1.87 (m, 2H), 1.87 - 1.78 (br m, 2H).Step 5. Synthesis of ammonium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (7 ).

[0345] Aqueous lithium hydroxide solution (2 M; 0.642 mL, 1.28 mmol) was added to a solution of C53 (38.9 mg, 64.2 µmol) in a mixture of methanol (1.0 mL) and tetrahydrofuran (1.0 mL). After the reaction mixture had been stirred at 20 °C for 16 hours, it was adjusted to pH 7 by addition of trifluoroacetic acid, concentrated in vacuo, and purified using reversed-phase HPLC (Column: Agela Durashell C18, 5 µm; Mobile phase A: 0.05% ammonium hydroxide in water; Mobile phase B: acetonitrile; Gradient: 0% to 80% B), affording 7 as a white solid. Yield: 25.1 mg, 41.2 µmol, 64%. LCMS m / z 591.9 [M+H] +< . 1< H NMR (400 MHz, methanol-d 4 ), characteristic peaks: δ 8.34 (d, J = 1.5 Hz, 1H), 7.98 (dd, J = 8.5, 1.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.3, 8.3 Hz, 1H), 7.28 (dd, J = 10.9, 2.0 Hz, 1H), 7.20 (br dd, J = 8.4, 1.9 Hz, 1H), 6.81 - 6.74 (m, 1H), 6.74 - 6.67 (m, 2H), 5.33 - 5.23 (m, 1H), 4.73 (dd, J = 15.4, 2.7 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.48 (dt, J = 9.1, 5.9 Hz, 1H), 4.05 (AB quartet, J AB = 13.9 Hz, Δν AB = 44.1 Hz, 2H), 3.15 (br d, J = 11.7 Hz, 1H), 3.03 (br d, J = 11.6 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.60 - 2.49 (m, 1H), 2.48 - 2.33 (m, 2H), 2.03 (br s, 3H), 2.01 - 1.77 (m, 4H).Alternate Synthesis of Example 7, free acid 2-({4-[(2S)-2-(4-Chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid (7, free acid )

[0346] Step 1. Synthesis of methyl 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (C53 ).

[0347] N,N-Diisopropylethylamine (15.1 mL, 86.9 mmol) was added to a mixture of P3 (8.22 g, 15.8 mmol) in acetonitrile (185 mL); after stirring for 5 minutes, P15 (4.57 g, 15.5 mmol) was added, and the reaction mixture was heated at 45 °C. After 4 hours, the reaction mixture was concentrated in vacuo to half of its original volume, and the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane) afforded C53 as a white solid. Yield: 8.4 g, 13.9 mmol, 88%. LCMS m / z 606.1 [M+H] +< . 1< H NMR (600 MHz, DMSO-d 6 ) δ 8.30 (s, 1H), 7.82 (br d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 6.80 - 6.76 (m, 2H), 6.76 - 6.72 (m, 1H), 5.14 - 5.07 (m, 1H), 4.81 (dd, J = 15.2, 7.2 Hz, 1H), 4.67 (dd, J = 15.3, 2.8 Hz, 1H), 4.51 - 4.44 (m, 1H), 4.37 (ddd, J = 8.9, 5.9, 5.9 Hz, 1H), 3.97 (d, J = 13.6 Hz, 1H), 3.87 (s, 3H), 3.78 (d, J = 13.5 Hz, 1H), 3.02 (br d, J = 11.1 Hz, 1H), 2.86 (br d, J = 11.3 Hz, 1H), 2.74 - 2.60 (m, 2H), 2.48 - 2.41 (m, 1H), 2.29 - 2.22 (m, 1H), 2.21 - 2.14 (m, 1H), 2.02 (s, 3H), 1.83 - 1.73 (m, 2H), 1.73 - 1.64 (m, 2H).Step 2. Synthesis of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid (7, free acid ).

[0348] A mixture of C53 (8.40 g, 14.0 mmol) in methanol (135 mL) was heated to 45 °C, and treated with aqueous sodium hydroxide solution (1 M; 27.7 mL, 27.7 mmol). After 20 hours, the reaction mixture was concentrated in vacuo to half its original volume. The resulting mixture was diluted with water (100 mL), and aqueous citric acid solution (1 M, 15 mL) was used to adjust the pH to 5 to 6. The resultant solid was filtered, washed with water (2 x 15 mL), and transferred to a separatory funnel as a solution in ethyl acetate (50 mL); residual water was removed in this way. The organic layer was dried over magnesium sulfate, filtered, combined with four previously prepared batches from a similar procedure (amount of C53 used in these reactions was 987 mg, 1.63 mmol; 1.15 g, 1.90 mmol; 8.57 g, 14.1 mmol; and 12.6 g, 20.8 mmol) and concentrated in vacuo. The resulting sticky solid was treated with 10% ethyl acetate in heptane (500 mL). After 4 hours, the solid was collected via filtration and washed with 10% ethyl acetate in heptane (2 x 25 mL) to afford 7, free acid, as a white solid. Yield 29.4 g, 0.527 mmol, 74% for combined reactions. LCMS 592.2 [M+H]+. 1< H NMR (600 MHz, DMSO-d 6 ): δ 12.74 (br s, 1H), 8.28 (s, 1H), 7.80 (br d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 6.81 - 6.76 (m, 2H), 6.76 - 6.72 (m, 1H), 5.14 - 5.07 (m, 1H), 4.79 (dd, J = 15.3, 7.3 Hz, 1H), 4.65 (dd, J = 15.2, 2.8 Hz, 1H), 4.51 - 4.45 (m, 1H), 4.38 (ddd, J = 9.0, 5.9, 5.9 Hz, 1H), 3.96 (br d, J = 13.6 Hz, 1H), 3.78 (br d, J = 13.5 Hz, 1H), 3.02 (br d, J = 11.1 Hz, 1H), 2.86 (br d, J = 11.1 Hz, 1H), 2.74 - 2.60 (m, 2H), 2.48 - 2.41 (m, 1H), 2.29 - 2.21 (m, 1H), 2.21 - 2.14 (m, 1H), 2.02 (s, 3H), 1.83 - 1.74 (m, 2H), 1.74 - 1.64 (m, 2H). This material was determined to be of the same absolute configuration as Example 7 above by comparison of its biological activity with that of both 6 and 7: in Assay 2, this sample of 7, free acid exhibited an EC 50 of 4.3 nM (geometric mean of 3 replicates). The activity in Assay 2 for the ammonium salts of Example 6 and Example 7 were 2400 nM (geometric mean of 5 replicates) and 2.9 nM (geometric mean of 8 replicates), respectively.Synthesis of Example 7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt 1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate (7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt ).

[0349]

[0350] A mixture of 7, free acid (2.00 g, 3.38 mmol) in tetrahydrofuran (16 mL) was treated with an aqueous solution of 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris,1.0 M; 3.55 mL, 3.55 mmol). After 18 hours, the reaction mixture was concentrated in vacuo and treated with ethanol (30 mL). After this mixture had been stirred for 23 hours, the solid was collected via filtration and washed with ethyl acetate (2 x 10 mL) to afford 7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt as a white solid. Yield: 1.41 g, 1.98 mmol, 59%. LCMS m / z 592.3 [M+H] +< . 1< H NMR (600 MHz, DMSO-d 6 ), characteristic peaks: δ 8.20 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.59 - 7.52 (m, 3H), 7.33 (br d, J = 8.5 Hz, 1H), 6.81 - 6.72 (m, 3H), 5.14 - 5.07 (m, 1H), 4.76 (dd, J = 15.2, 7.2 Hz, 1H), 4.63 (br d, J = 15.4 Hz, 1H), 4.50 - 4.44 (m, 1H), 4.37 (ddd, J = 8.9, 5.9, 5.9 Hz, 1H), 3.94 (d, J = 13.4 Hz, 1H), 3.76 (d, J = 13.4 Hz, 1H), 3.01 (br d, J = 11.1 Hz, 1H), 2.86 (br d, J = 11.2 Hz, 1H), 2.73 - 2.60 (m, 2H), 2.5 - 2.41 (m, 1H), 2.27 - 2.20 (m, 1H), 2.20 - 2.13 (m, 1H), 2.02 (s, 3H), 1.83 - 1.64 (m, 4H). mp = 175 °C to 180 °C.Acquisition of Powder X-ray Diffraction (PXRD) Data for Form I of Example 7, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium salt

[0351] The white solid of the tris salt of Example 7 was submitted for PXRD analysis and found to be a crystalline material (which is designated as Form I of this anhydrous crystal form). Powder X-ray diffraction analysis was conducted using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set at 15 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector, with the detector PSD opening set at 2.99 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA respectively. Data was collected at the Cu wavelength (CuK α = 1.5418 λ) in the Theta-Theta goniometer from 3.0 to 40.0 degrees 2-Theta using a step size of 0.01 degrees and a step time of 1.0 second. The antiscatter screen was set to a fixed distance of 1.5 mm. Samples were rotated during data collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data were collected using Bruker DIFFRAC Plus software and analysis was performed by EVA diffract plus software. The PXRD data file was not processed prior to peak searching. Using the peak search algorithm in the EVA software, peaks selected with a threshold value of 1 were used to make preliminary peak assignments. To ensure validity, adjustments were manually made; the output of automated assignments was visually checked, and peak positions were adjusted to the peak maximum. Peaks with relative intensity of ≥ 3% were generally chosen. Typically, the peaks which were not resolved or were consistent with noise were not selected. A typical error associated with the peak position from PXRD stated in USP up to + / - 0.2° 2-Theta (USP-941). One diffraction pattern was consistently observed and is provided in Figure 24. A list of diffraction peaks expressed in terms of the degree 2θ and relative intensities with a relative intensity of ≥ 3.0% is provided above in Table X1. Table X1Angle (2theta)Relative Intensity (%)3.774.37.383.38.112.58.56.510.16.613.63.514.749.815.27.915.528.715.918.316.960.817.426.317.711.417.913.518.975.419.718.720.2100.020.924.821.514.822.231.722.910.123.534.623.78.224.46.524.98.725.26.425.914.726.448.626.712.527.515.827.96.128.310.529.515.529.812.630.212.130.93.431.716.433.317.234.014.935.84.837.53.238.65.3

[0352] One embodiment provides a crystal form of anhydrous tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid. In some further embodiments, the crystal form of anhydrous (anhydrate) tris salt of 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid is designated as "Form I" that is characterized according to its unique solid state signatures with respect to, for example, powder X-ray diffraction (PXRD), described herein (such as substantially as depicted in Figure 24). In some embodiments, Form I exhibits a powder X-ray diffraction pattern comprising at least two characteristic peaks, in terms of 2θ, selected from at 3.7 ± 0.2°; 7.3 ± 0.2°; 8.5 ± 0.2°; 10.1± 0.2°; 14.7± 0.2°; and 16.9± 0.2°. In some embodiments, Form I exhibits a ...

Claims

1. A combination comprising (1) a GLP-1R agonist and (2) 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist is selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

2. A combination for use in a method of treating, as claimed in claim 1, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or a pharmaceutically acceptable salt thereof.

3. A combination for use in a method of treating, as claimed in claim 2, wherein the GLP-1R agonist is 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof.

4. A combination for use in a method of treating, as claimed in claim 2, wherein the GLP-1R agonist is 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

5. A combination for use in a method of treating, as claimed in any one of claims 1 to 4, wherein the 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or pharmaceutically acceptable salt thereof is the 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid.

6. A combination comprising (1) GLP-1R agonist and (2) [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist is selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

7. A combination for use in a method of treating, as claimed in claim 6, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or a pharmaceutically acceptable salt thereof.

8. A combination for use in a method of treating, as claimed in claim 7, wherein the GLP-1R agonist is 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof.

9. A combination for use in a method of treating, as claimed in claim 7, wherein the GLP-1R agonist is 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

10. A combination for use in a method of treating, as claimed in any one of claims 6 to 9, wherein the [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or salt thereof is a crystal form of [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

11. A combination comprising (1) a GLP-1R agonist and (2) (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition is selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist is selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1 H-imidazol-5-yl)methyl]-1 H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

12. A combination for use in a method of treating, as claimed in claim 11, wherein the disease or condition is nonalcoholic steatohepatitis with liver fibrosis.

13. A combination for use in a method of treating, as claimed in claim 11, wherein the disease or condition is nonalcoholic steatohepatitis with cirrhosis.

14. A combination for use in a method of treating, as claimed in any one of claims 11 to 13, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1 ,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or a pharmaceutically acceptable salt thereof.

15. A combination for use in a method of treating, as claimed in claim 14, wherein the GLP-1R agonist is 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof.

16. A combination for use in a method of treating, as claimed in claim 14 wherein the GLP-1R agonist is 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

17. A combination for use in a method of treating, as claimed in claim 15 or claim 16, wherein the pharmaceutically acceptable salt is a tris salt.

18. A combination for use in a method of treating, as claimed in any one of claims 11 to 17, wherein the (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or salt thereof is a crystal form of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide.

19. A combination comprising (1) GLP-1R agonist and (2) 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, for use in a method for treating a disease or condition in a patient in need thereof, wherein: the disease or condition selected from nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease; and the GLP-1R agonist is selected from: 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6- carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-4-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(pyridin-3-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-5-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-1,2,3-triazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-7-fluoro-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-(1,3-oxazol-2-ylmethyl)-1H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-7-fluoro-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1H-imidazol-5-yl)methyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or pharmaceutically acceptable salt thereof.

20. A combination for use in a method of treating, as claimed in claim 19, wherein the GLP-1R agonist is selected from: 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-3-(1,3-oxazol-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-({4-[2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(1-ethyl-1 H-imidazol-5-yl)methyl]-1 H-benzimidazole-6- carboxylic acid; 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(4-cyano-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid; 2-({4-[(2S)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; 2-({4-[(2R)-2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; and 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, DIAST-X2; or a pharmaceutically acceptable salt thereof.

21. A combination for use in a method of treating, as claimed in claim 20, wherein the GLP-1R agonist is 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1 H-benzimidazole-6-carboxylic acid, DIAST-X2, or a pharmaceutically acceptable salt thereof.

22. A combination for use in a method of treating, as claimed in claim 20, wherein the GLP-1R agonist is 2-({4-[(2S)-2-(4-chloro-2-fluorophenyl)-2-methyl-1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof.

23. A combination for use in a method of treating, as claimed in any one of claims 19 to 22, wherein the 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid or salt thereof is 2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid.