2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[D][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole derivatives as activators of the GLP1 receptor for the treatment of obesity

Abstract

The present invention relates to compounds of formula (I) as activators of glucagon-like peptide 1 (GLP1) receptor for the treatment of obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications, diabetic nephropathy, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy.Preferred compounds are, for example, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole derivatives and similar compounds, such as C-1, C-2, C-3, C-4 and other compounds. [Formula 1] TIFF2024514826000258.tif26170 [chemical 2] TIFF2024514826000259.tif58170

Description

[Technical Field]

[0001] The present invention relates to benzo[d][1,3]dioxole derivatives, their preparation, pharmaceutical compositions containing them, and their use in the treatment of conditions, diseases and disorders treatable by activating the glucagon-like peptide 1 receptor (GLP1R). [Background technology]

[0002] The glucagon-like peptide 1 receptor (GLP1R) belongs to the family B1 of G protein-coupled receptors (GPCRs) and is expressed in many tissues, including the pancreas, heart, intestine, and brain (Kieffer TJ and Habener, JF Endocrin. Rev. 20:876-913 (1999); Drucker, DJ, Endocrinology 142:521-7 (2001); Hoist, JJ, Diabetes Metab. Res. Rev. 18:430-41 (2002); Regard JB, Cell 135:561-71 (2008)). The natural agonist ligands of GLP1R are GLP-1 (7-36, 30 aa) and oxyntomodulin (OXM, 37 aa), both derived from proglucagon. Upon activation, GLP1R translocates the G αs GLP1R binds to the GLP1R-protein, which then activates adenylate cyclase and increases intracellular cAMP levels, thereby enhancing glucose-stimulated insulin secretion acting on pancreatic beta cells. Therefore, GLP1R is an attractive therapeutic target for lowering blood glucose in diabetic patients. Several GLP1R agonist peptides (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide) have been developed for the treatment of patients with diabetes, NASH, and / or obesity.

[0003] Obesity is a highly prevalent chronic disease in modern society and is associated with several comorbidities, including hypertension, hypercholesterolemia, and coronary heart disease. It is also highly associated with type 2 diabetes mellitus (T2DM) and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia, hyperglycemia, or both. Additionally, T2DM is associated with a two- to four-fold increased risk of coronary artery disease. Currently, the most effective obesity treatment is bariatric surgery, which is costly and risky for patients. Therefore, pharmacological replacement of bariatric surgery is an attractive alternative. Nevertheless, pharmacological interventions for the treatment of obesity have been shown to be less effective and associated with side effects than bariatric surgery. Among the commercially available GLP1R agonist peptides, liraglutide is approved as a once-daily treatment for obesity. Semaglutide is currently in phase 3 clinical trials as a once-weekly treatment for obesity. Currently, there are no approved drug therapies for remission of type 2 diabetes in adults who are unable to maintain normal glycemic control with antidiabetic drugs and / or insulin due to insulin resistance, and there are no approved drug therapies for heart failure with preserved ejection fraction (HFpEF). Alternatively, GLP1R agonists may be an effective therapy for remission of T2DM. GLP1R receptor agonists may reduce the risk of cardiovascular death and hospitalization for patients with chronic HFpEF.

[0004] Therefore, metabolic disorders are potentially treatable with small molecule agonists of GLP1R. Summary of the Invention

[0005] The present disclosure relates, inter alia, to compounds of formula (I): [ka] and pharmaceutically acceptable salts thereof, wherein the components are defined herein.

[0006] The compound of formula (I) as defined herein and its pharmaceutically acceptable salt are GLP1R agonists.Therefore, these compounds can be useful in treating metabolic diseases, disorders and conditions such as obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including but not limited to chronic kidney disease), diabetic nephropathy, dyslipidemia and cardiovascular disease.Compounds can also be useful in treating progressive liver disease and neuropathy.

[0007] Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0008] Provided herein is a method of stimulating or activating the glucagon-like peptide 1 receptor (GLP1R), comprising contacting the GLP1R with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0009] Provided herein are methods for treating, preventing, or ameliorating a condition, disease, or disorder treatable by activating or stimulating GLP1R in a patient, the methods comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., in a therapeutically effective amount).

[0010] Provided herein are methods for treating, preventing, or ameliorating a disease, disorder, or condition selected from metabolic and related disorders, including obesity and type 2 diabetes, cardiovascular disease such as heart failure (e.g., heart failure with preserved ejection fraction (HFpEF)), and non-alcoholic steatohepatitis (NASH) in a patient, the methods comprising administering to the patient (e.g., a therapeutically effective amount) a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0011] Also provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0012] Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein.

[0013] The compounds of the present invention may be used, for example, to achieve a maximum plasma concentration (C max The compound may exhibit favorable ADME (absorption, distribution, metabolism and excretion) properties, e.g., in vivo exposure (particularly when administered orally), as demonstrated by measurements of certain pharmacokinetic parameters such as pharmacokinetic (AUC)) and / or total exposure (area under the curve (AUC)) values. DETAILED DESCRIPTION OF THE INVENTION

[0014] Various aspects and embodiments of the invention are described herein. Although certain features are specified in the context of separate embodiments for clarity (and / or brevity), it will be appreciated that such embodiments may be combined with other specified features (e.g., in any suitable subcombination) to provide further embodiments of the invention.

[0015] The substituent definitions apply to compounds of any formula provided herein, for example, Formulas (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), as appropriate. The substituent definitions apply to the final products and corresponding intermediates, as appropriate.

[0016] In some embodiments, provided herein are compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof (wherein [ka] is a single or double bond; [ka] teeth, [ka] is selected from During the ceremony, [ka] indicates the point of attachment to the rest of the molecule; W is O or CH; X is O or CH; R 1 and R 2 are independently H, C 1~3 selected from alkyl, and halo; R 3 is H and C 1~3 - selected from alkyl; R 4 is H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), C(O)NR 4c (S(O)NR 4c R 4d ), NR 4c OR4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), NR 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), NR 4c (C(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), NR 4c (S(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (S(O)2R 4b )), OC(O)R 4b , OC(O)NR 4c R 4d , ONR 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6-Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)OR 4A , C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O)2R 4B ), C(O)NR 4C (S(O)NR 4C R 4D ), NR 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), NR 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), NR 4C (C(O)NR 4C R 4D ), NR 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), NR 4C (S(O)NR 4C R 4D ), NR 4C (C(O)NR 4C (S(O)2R 4B )), OC(O)R 4B , OC(O)NR 4C R 4D , ONR 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 5 is H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)NR 5c R 5d ), NR 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), NR 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b), NR 5c (C(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), NR 5c (S(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (S(O)2R 5b )), OC(O)R 5b , OC(O)NR 5c R 5d , ONR 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR5A 、SR 5A 、C(O)OR 5A 、C(O)R 5B 、C(O)NR 5C R 5D 、C(O)NR 5C (OR 5A )、C(O)NR 5C (S(O)2R 5B )、C(O)NR 5C (S(O)2NR 5C R 5D )、NR 5C OR 5A 、NR 5C R 5D 、NR 5C (C(O)R 5B )、NR 5C (C(O)OR 5A )、N(OR 5A )(C(O)R 5B )、NR 5C (C(O)NR 5C R 5D )、NR 5C (C(O)NR 5C (C(O)R 5B ))、NR 5C (S(O)2R 5B )、NR 5C (S(O)2NR 5C R 5D )、NR 5C (C(O)NR 5C (S(O)2R 5B ))、OC(O)R 5B 、OC(O)NR 5C R 5D 、ONR 5C (C(O)R 5B )、OS(O)2R 5B 、OP(O)(OR 5E )(OR 5F )、S(O)OR 5A 、S(O)R 5B 、S(O)2R 5B 、S(O)2NR 5C R 5D 、S(O)2OR 5A 、S(=NR 5G )(O)R 5B 、S(=NR 5G )(O)NR5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5’ is H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, C(O)OR 5a’ , C(O)R 5b’ , C(O)NR 5c’ R 5d’ , C(O)NR 5c’ (OR 5a’ ), C(O)NR 5c’ (S(O)2R 5b’ ), and C(O)NR 5c’ (S(O)NR 5c’ R 5d’ ) and R 5’ C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, and 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A’ , S.R. 5A’ , C(O)OR 5A’ , C(O)R5B’ 、C(O)NR 5C’ R 5D’ 、C(O)NR 5C’ (OR 5A’ )、C(O)NR 5C’ (S(O)2R 5B’ )、C(O)NR 5C’ (S(O)2NR 5C’ R 5D’ )、NR 5C’ OR 5A’ 、NR 5C’ R 5D’ 、NR 5C’ (C(O)R 5B’ )、NR 5C’ (C(O)OR 5A’ )、N(OR 5A’ )(C(O)R 5B’ )、NR 5C’ (C(O)NR 5C’ R 5D’ )、NR 5C’ (C(O)NR 5C’ (C(O)R 5B’ ))、NR 5C’ (S(O)2R 5B’ )、NR 5C’ (S(O)2NR 5C’ R 5D’ )、NR 5C’ (C(O)NR 5C’ (S(O)2R 5B’ ))、OC(O)R 5B’ 、OC(O)NR 5C’ R 5D’ 、ONR 5C’ (C(O)R 5B’ )、OS(O)2R 5B’ 、OP(O)(OR 5E’ )(OR 5F’ )、S(O)OR 5A’ 、S(O)R 5B’ 、S(O)2R 5B’ 、S(O)2NR 5C’ R 5D’ 、S(O)2OR 5A’ 、S(=NR 5G’ )(O)R 5B’ 、S(=NR 5G’ )(O)NR 5C’ NR 5D’ 、P(O)(OR 5E’ )(OR 5F’), and P(O)(OR 5E’ )(R 5F’ Optionally substituted with 1, 2, or 3 groups independently selected from R 6 and R 6’ are each independently (4 to 10-membered heterocycloalkyl)-C 1~3 -Alkyl- and (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, and R 6 and R 6’ (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and (5- to 10-membered heteroaryl)-C 1~3 -alkyl- are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4a , R 4b , R 4c , and R 4d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 4a , R 4b , R 4c , and R 4d C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 4a , R 4b , R 4c , and R 4d C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4e , R 4f, and R 4g are each independently H and C 1~6 - selected from alkyl; R 4A , R 4B , R 4C , and R 4D are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 4A , R 4B , R 4C , and R 4D C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 4A , R 4B , R 4C , and R 4D C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4E , R 4F , and R 4G are each independently H and C 1~6 - selected from alkyl; R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 5a , R 5b , R 5c , and R 5dC 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 5a , R 5b , R 5c , and R 5d C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 5e , R 5f , and R 5g are each independently H and C 1~6 - selected from alkyl; R 5A , R 5B , R 5C , and R 5D are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 5A , R 5B , R 5C , and R 5D C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 5A , R 5B , R 5C , and R 5D C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 5E , R5F , and R 5G are each independently H and C 1~6 - selected from alkyl; R 5a’ , R 5b’ , R 5c’ , and R 5d’ are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 5a’ , R 5b’ , R 5c’ , and R 5d’ C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 5a’ , R 5b’ , R 5c’ , and R 5d’ C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 5A’ , R 5B’ , R 5C’ , and R 5D’ are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R 5A’ , R 5B’ , R 5C’ , and R 5D’ C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R 5A’ , R 5B’ , R 5C’ , and R 5D’ C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; and R 5E’ , R 5F’ , and R 5G’ are each independently H and C 1~6 -alkyl).

[0017] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is a halo.

[0018] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 2 is a halo.

[0019] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is chloro or fluoro, and R 2 is chloro or fluoro.

[0020] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 1 is chloro; and R 2 is fluoro.

[0021] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3 is H or -CH3.

[0022] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 3 is -CH3.

[0023] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] is.

[0024] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), C(O)NR 4c (S(O)NR 4c R 4d ), NR 4c OR 4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), NR 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), NR4c (C(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), NR 4c (S(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (S(O)2R 4b )), OC(O)R 4b , OC(O)NR 4c R 4d , ONR 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A、SR 4A 、C(O)OR 4A 、C(O)R 4B 、C(O)NR 4C R 4D 、C(O)NR 4C (OR 4A )、C(O)NR 4C (S(O)2R 4B )、C(O)NR 4C (S(O)2NR 4C R 4D )、NR 4C OR 4A 、NR 4C R 4D 、NR 4C (C(O)R 4B )、NR 4C (C(O)OR 4A )、N(OR 4A )(C(O)R 4B )、NR 4C (C(O)NR 4C R 4D )、NR 4C (C(O)NR 4C (C(O)R 4B ))、NR 4C (S(O)2R 4B )、NR 4C (S(O)2NR 4C R 4D )、NR 4C (C(O)NR 4C (S(O)2R 4B ))、OC(O)R 4B 、OC(O)NR 4C R 4D 、ONR 4C (C(O)R 4B )、OS(O)2R 4B 、OP(O)(OR 4E )(OR 4F )、S(O)OR 4A 、S(O)R 4B 、S(O)2R 4B 、S(O)2NR 4C R 4D 、S(O)2OR 4A 、S(=NR 4G )(O)R 4B 、S(=NR 4G )(O)NR 4C NR4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F ) is optionally substituted with 1, 2, or 3 groups independently selected from

[0025] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each independently selected from halo, C 1~3 -alkyl, and C(O)OR 4A optionally substituted with 1, 2, or 3 groups independently selected from 4a , R 4c , R 4d and R 4A are independently H and C 1~3 -alkyl.

[0026] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from R 4 C 1~3-Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl and phenyl are each substituted with at least one group that is C(O)OH, and 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each substituted with at least one group that is halo, C 1~3 -alkyl, and C(O)OR 4A optionally substituted with 1, 2, or 3 groups independently selected from 4a , R 4c , R 4d and R 4A are independently H and C 1~3 -alkyl.

[0027] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 - alkyl.

[0028] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OR 4a Selected from R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl is halo and C(O)OR 4A optionally substituted with 1, 2, or 3 groups independently selected from R 4a is H and C 1~3 -alkyl; and R 4A is H and C 1~3 -alkyl.

[0029] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is H, C1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OH; R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 Each -cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

[0030] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] is selected from.

[0031] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] is selected from.

[0032] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is selected from CH3 and CF3.

[0033] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C(O)OR 4A or a 5-10 membered heteroaryl substituted with a carboxylic acid isostere.

[0034] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 has a structure of formula H1 or H2: [ka] (In the formula, X1 is C or N, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 4h , N.R. 4i , O, or S; W is C(O)OR 4A or a carboxylic acid isostere; each [ka] is a single or double bond; Each R 4h are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), C(O)NR 4c (S(O)NR 4c R 4d ), NR 4c OR 4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), NR 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), NR 4c (C(O)NR 4cR 4d ), NR 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), NR 4c (S(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (S(O)2R 4b )), OC(O)R 4b , OC(O)NR 4c R 4d , ONR 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)OR 4A , C(O)R4B 、C(O)NR 4C R 4D 、C(O)NR 4C (OR 4A )、C(O)NR 4C (S(O)2R 4B )、C(O)NR 4C (S(O)2NR 4C R 4D )、NR 4C OR 4A 、NR 4C R 4D 、NR 4C (C(O)R 4B )、NR 4C (C(O)OR 4A )、N(OR 4A )(C(O)R 4B )、NR 4C (C(O)NR 4C R 4D )、NR 4C (C(O)NR 4C (C(O)R 4B ))、NR 4C (S(O)2R 4B )、NR 4C (S(O)2NR 4C R 4D )、NR 4C (C(O)NR 4C (S(O)2R 4B ))、OC(O)R 4B 、OC(O)NR 4C R 4D 、ONR 4C (C(O)R 4B )、OS(O)2R 4B 、OP(O)(OR 4E )(OR 4F )、S(O)OR 4A 、S(O)R 4B 、S(O)2R 4B 、S(O)2NR 4C R 4D 、S(O)2OR 4A 、S(=NR 4G )(O)R 4B 、S(=NR 4G )(O)NR 4C NR 4D 、P(O)(OR 4E )(OR 4F), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from Each R 4i are independent and do not exist, H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, CN, C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), and C(O)NR 4c (S(O)NR 4c R 4d ) and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)OR 4A , C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C(OR 4A )、C(O)NR 4C (S(O)2R 4B )、C(O)NR 4C (S(O)2NR 4C R 4D )、NR 4C OR 4A 、NR 4C R 4D 、NR 4C (C(O)R 4B )、NR 4C (C(O)OR 4A )、N(OR 4A )(C(O)R 4B )、NR 4C (C(O)NR 4C R 4D )、NR 4C (C(O)NR 4C (C(O)R 4B ))、NR 4C (S(O)2R 4B )、NR 4C (S(O)2NR \ 4C R 4D )、NR 4C (C(O)NR 4C (S(O)2R 4B ))、OC(O)R 4B 、OC(O)NR 4C R 4D 、ONR 4C (C(O)R 4B )、OS(O)2R 4B 、OP(O)(OR 4E )(OR 4F )、S(O)OR 4A 、S(O)R 4B 、S(O)2R 4B 、S(O)2NR 4C R 4D 、S(O)2OR 4A 、S(=NR 4G )(O)R 4B 、S(=NR 4G )(O)NR 4C NR 4D 、P(O)(OR 4E )(OR 4F )、及びP(O)(OR 4E )(R 4FOptionally substituted with 1, 2, or 3 groups independently selected from R 4h and R 4i Combined, C 3~6 -cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which can further be 1~6 -substituted with groups independently selected from -alkyl, -OH, and halo.

[0035] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 has a structure of formula H1a or H2a: [ka] (wherein the ring is aromatic; at least one of X1 to X6 is N, O, or S; Optionally, R 4h is C1-C3 alkyl or halo and R 4i is a C1-C3 alkyl).

[0036] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] It has the following structure.

[0037] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C1-C3 alkyl optionally substituted with 1, 2 or 3 halo, for example, methyl or trifluoromethyl.

[0038] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)NR 5c R 5d ), NR 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), NR 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), NR 5c (C(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), NR 5c (S(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (S(O)2R 5b )), OC(O)R 5b , OC(O)NR 5c R 5d , ONR 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C(O)OR 5A , C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O)2R 5B ), C(O)NR 5C (S(O)NR 5C R 5D ), NR 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), NR 5C (C(O)OR 5A ), N(OR5A )(C(O)R 5B ), NR 5C (C(O)NR 5C R 5D ), NR 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), NR 5C (S(O)NR 5C R 5D ), NR 5C (C(O)NR 5C (S(O)2R 5B )), OC(O)R 5B , OC(O)NR 5C R 5D , ONR 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F ) is optionally substituted with 1, 2, or 3 groups independently selected from

[0039] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, halo, C(O)OR 5a Selected from C 1~3 -Alkyl, C2~4 Alkenyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each independently selected from halo and C(O)OR 5A optionally substituted with 1, 2, or 3 groups independently selected from 5a is H and C 1~3 -alkyl; and R 5A is H and C 1~3 -alkyl.

[0040] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C 1~3 -Alkyl, C 2~4 Alkenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR 5a Selected from C 1~3 -Alkyl, C 2~4 The alkenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each optionally substituted with at least one group that is C(O)OH.

[0041] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 Ha, Halo, C 1~3 -alkyl, and phenyl; C 1~3 - alkyl and phenyl are each optionally substituted with 1, 2, or 3 halo.

[0042] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OR 5a Selected from R 5 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl is halo and C(O)OR 5Aoptionally substituted with 1, 2, or 3 groups independently selected from R 5a is H and C 1~3 -alkyl; and R 5A is H and C 1~3 -alkyl.

[0043] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OH; R 5 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 Each -cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

[0044] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 teeth, [ka] is selected from.

[0045] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 teeth, [ka] is selected from.

[0046] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 -CH3, CF3, F, -CH2CH3, and [ka] is selected from.

[0047] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl and phenyl are each substituted with at least one group that is C(O)OH, and 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each substituted with at least one group that is halo, C 1~3 -alkyl, and C(O)OR 4A optionally substituted with 1, 2, or 3 groups independently selected from 4a , R 4c , R 4d and R 4A are independently H and C 1~3 -alkyl; and R 5 Ha, Halo, C 1~3 -alkyl, and phenyl; C 1~3 - alkyl and phenyl are each optionally substituted with 1, 2, or 3 halo.

[0048] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl; and R 5 is C 1~3 -Alkyl, C 2~4 Alkenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR 5a Selected from C1~3 -Alkyl, C 2~4 The alkenyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each optionally substituted with at least one group that is C(O)OH.

[0049] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] and R 5 -CH3, CF3, F, -CH2CH3, and [ka] is selected from.

[0050] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is selected from CH3 and CF3; and R 5 teeth, [ka] is selected from.

[0051] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 is C(O)OR 5A or a 5-10 membered heteroaryl substituted with a carboxylic acid isostere.

[0052] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 has a structure of formula H11 or H12: [ka] (In the formula, X1 is C or N, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 5h , N.R. 5i , O, or S; W is C(O)OR 5A or a carboxylic acid isostere; each [ka] is a single or double bond; Each R 5h are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)NR 5c R 5d ), NR 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), NR 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), NR 5c (C(O)NR 5cR 5d ), NR 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), NR 5c (S(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (S(O)2R 5b )), OC(O)R 5b , OC(O)NR 5c R 5d , ONR 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C(O)OR 5A , C(O)R5B 、C(O)NR 5C R 5D 、C(O)NR 5C (OR 5A )、C(O)NR 5C (S(O)2R 5B )、C(O)NR 5C (S(O)2NR 5C R 5D )、NR 5C OR 5A 、NR 5C R 5D 、NR 5C (C(O)R 5B )、NR 5C (C(O)OR 5A )、N(OR 5A )(C(O)R 5B )、NR 5C (C(O)NR 5C R 5D )、NR 5C (C(O)NR 5C (C(O)R 5B ))、NR 5C (S(O)2R 5B )、NR 5C (S(O)2NR 5C R 5D )、NR 5C (C(O)NR 5C (S(O)2R 5B ))、OC(O)R 5B 、OC(O)NR 5C R 5D 、ONR 5C (C(O)R 5B )、OS(O)2R 5B 、OP(O)(OR 5E )(OR 5F )、S(O)OR 5A 、S(O)R 5B 、S(O)2R 5B 、S(O)2NR 5C R 5D 、S(O)2OR 5A 、S(=NR 5G )(O)R 5B 、S(=NR 5G )(O)NR 5C NR 5D 、P(O)(OR 5E )(OR 5F), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from Each R 5i are independent and do not exist, H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, CN, C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)NR 5c R 5d ) and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C(O)OR 5A , C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C(OR 5A )、C(O)NR 5C (S(O)2R 5B )、C(O)NR 5C (S(O)2NR 5C R 5D )、NR 5C OR 5A 、NR 5C R 5D 、NR 5C (C(O)R 5B )、NR 5C (C(O)OR 5A )、N(OR 5A )(C(O)R 5B )、NR 5C (C(O)NR 5C R 5D )、NR 5C (C(O)NR 5C (C(O)R 5B ))、NR 5C (S(O)2R 5B )、NR 5C (S(O)2NR 5C R<00014​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Optionally substituted with 1, 2, or 3 groups independently selected from R 5h and R 5i Combined, C 3~6 -cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which can further be 1~6 -substituted with groups independently selected from -alkyl, -OH, and halo.

[0053] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 has a structure of formula H11a or H12a: [ka] (wherein the ring is aromatic; at least one of X1 to X6 is N, O, or S; Optionally, R 5h is C1-C3 alkyl or halo and R 5i is a C1-C3 alkyl).

[0054] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5 has the structure of formula H11a, for example, R 5 teeth, [ka] is.

[0055] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 4 is C1-C3 alkyl optionally substituted with 1, 2 or 3 halo, for example, methyl or trifluoromethyl.

[0056] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5’ is C 1~6 -Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, C(O)OR 5a’ , C(O)R 5b’ , C(O)NR 5c’ R 5d’ , C(O)NR 5c’ (OR 5a’ ), C(O)NR 5c’ (S(O)2R 5b’ ), and C(O)NR 5c’ (S(O)NR 5c’ R 5d’ ) and R 5’ C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, and 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A’ , S.R. 5A’ , C(O)OR 5A’ , C(O)R 5B’ , C(O)NR 5C’ R 5D’ , C(O)NR 5C’ (OR 5A’ ), C(O)NR 5C’ (S(O)2R 5B’ ), C(O)NR 5C’ (S(O)NR 5C’ R 5D’ ), NR 5C’ OR5A’ , N.R. 5C’ R 5D’ , N.R. 5C’ (C(O)R 5B’ ), NR 5C’ (C(O)OR 5A’ ), N(OR 5A’ )(C(O)R 5B’ ), NR 5C’ (C(O)NR 5C’ R 5D’ ), NR 5C’ (C(O)NR 5C’ (C(O)R 5B’ )), NR 5C’ (S(O)2R 5B’ ), NR 5C’ (S(O)NR 5C’ R 5D’ ), NR 5C’ (C(O)NR 5C’ (S(O)2R 5B’ )), OC(O)R 5B’ , OC(O)NR 5C’ R 5D’ , ONR 5C’ (C(O)R 5B’ ), OS(O)2R 5B’ , OP(O)(OR 5E’ )(OR 5F’ ), S(O)OR 5A’ , S(O)R 5B’ , S(O)2R 5B’ , S(O)NR 5C’ R 5D’ , S(O)2OR 5A’ , S(=NR 5G’ )(O)R 5B’ , S(=NR 5G’ )(O)NR 5C’ NR 5D’ , P(O)(OR 5E’ )(OR 5F’ ), and P(O)(OR 5E’ )(R 5F’ ) is optionally substituted with 1, 2, or 3 groups independently selected from

[0057] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5’ is H, C 1~3 -Alkyl, C2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OR 5a’ Selected from R 5’ C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl is halo and C(O)OR 5A’ optionally substituted with 1, 2, or 3 groups independently selected from R 5a’ is H and C 1~3 -alkyl; and R 5A’ is H and C 1~3 -alkyl.

[0058] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 5’ is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OH; R 5’ C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 Each -cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

[0059] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ are each independently selected from (4- to 6-membered heterocycloalkyl)-CH- and (5- to 6-membered heteroaryl)-CH-; R 6 and R 6’ (4- to 6-membered heterocycloalkyl)-CH2- and (5- to 6-membered heteroaryl)-CH2- are each C 1~6 -Optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo.

[0060] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ are each independently [ka] is selected from [ka] indicates the point of attachment to the rest of the molecule.

[0061] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ teeth, [ka] and [ka] indicates the point of attachment to the rest of the molecule.

[0062] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ teeth, [ka] and [ka] indicates the point of attachment to the rest of the molecule.

[0063] In certain embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, X is O.

[0064] In certain embodiments of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, W is O.

[0065] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, [ka] is a single bond.

[0066] In certain embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, Compounds of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0067] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (II): [ka] , or a pharmaceutically acceptable salt thereof.

[0068] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0069] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (III): [ka] , or a pharmaceutically acceptable salt thereof.

[0070] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0071] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0072] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (IVa): [ka] or a pharmaceutically acceptable salt thereof.

[0073] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (V): [ka] , or a pharmaceutically acceptable salt thereof.

[0074] In certain embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (Va): [ka] or a pharmaceutically acceptable salt thereof.

[0075] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 4 is C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), C(O)NR 4c (S(O)NR 4c R 4d ), NR 4c OR 4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), NR 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), NR 4c (C(O)NR 4c R 4d ), NR 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), NR 4c (S(O)NR 4c R 4d ), NR 4c(C(O)NR 4c (S(O)2R 4b )), OC(O)R 4b , OC(O)NR 4c R 4d , ONR 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)OR 4A , C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O)2R 4B ), C(O)NR 4C (S(O)NR 4CR 4D ), NR 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), NR 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), NR 4C (C(O)NR 4C R 4D ), NR 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), NR 4C (S(O)NR 4C R 4D ), NR 4C (C(O)NR 4C (S(O)2R 4B )), OC(O)R 4B , OC(O)NR 4C R 4D , ONR 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F ) is optionally substituted with 1, 2, or 3 groups independently selected from

[0076] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 4 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OR 4a Selected from R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl is halo and C(O)OR 4A optionally substituted with 1, 2, or 3 groups independently selected from R 4a is H and C 1~3 -alkyl; and R 4A is H and C 1~3 -alkyl.

[0077] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 4 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OH; R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 Each -cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

[0078] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 5 is C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)NR 5c R 5d ), NR 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), NR 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), NR 5c (C(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), NR 5c (S(O)NR 5c R 5d ), NR 5c (C(O)NR 5c (S(O)2R 5b )), OC(O)R 5b , OC(O)NR 5c R 5d , ONR 5c (C(O)R 5b ), OS(O)2R 5b, OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C(O)OR 5A , C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR 5A ), C(O)NR 5C (S(O)2R 5B ), C(O)NR 5C (S(O)NR 5C R 5D ), NR 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), NR 5C (C(O)OR 5A), N(OR 5A )(C(O)R 5B ), NR 5C (C(O)NR 5C R 5D ), NR 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), NR 5C (S(O)NR 5C R 5D ), NR 5C (C(O)NR 5C (S(O)2R 5B )), OC(O)R 5B , OC(O)NR 5C R 5D , ONR 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F ) is optionally substituted with 1, 2, or 3 groups independently selected from

[0079] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 5 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OR 5a Selected from R5 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl is halo and C(O)OR 5A optionally substituted with 1, 2, or 3 groups independently selected from R 5a is H and C 1~3 -alkyl; and R 5A is H and C 1~3 -alkyl.

[0080] In certain embodiments of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 5 is H, C 1~3 -Alkyl, C 2~4 Alkenyl, C 3~6 -cycloalkyl, and C(O)OH; R 5 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 Each -cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

[0081] In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is [ka] or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxy; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylic acid; and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0083] In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from Table A.

[0084] [Table 1]

[0085] [Table 2]

[0086] [Table 3]

[0087] [Table 4]

[0088] [Table 5]

[0089] [Table 6]

[0090] [Table 7]

[0091] [Table 8]

[0092] In certain embodiments of any of the formulae provided herein, or a pharmaceutically acceptable salt thereof, the optionally substituted variable R 4 and R 5 (or R 5’ ) comprises a carboxylic acid or a carboxylic acid isostere (see, e.g., J. Med. Chem. 2016, 59, 3183-3203). In a preferred embodiment, R 4 and R 5 (or R 5’ ) are not the same. For example, in a preferred embodiment, R 4 and R 5 (or R 5’ ) contains a carboxylic acid or a carboxylic acid isostere.

[0093] A non-limiting list of example acyclic carboxylic acid isosteres is as follows:

[0094] [Table 9]

[0095] [Table 10]

[0096] A non-limiting list of cyclic carboxylic acid isosteres is as follows:

[0097] [Table 11]

[0098] [Table 12]

[0099] Unless otherwise specified, the terms "compounds of the invention," "compound of the invention," "compound of the invention," or "compounds of the invention" refer to compounds of Formula (I), or subformulas thereof (e.g., (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va)), and exemplified compounds, and salts thereof, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), and inherently formed moieties.

[0100] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, for example, as pure optical isomers or as stereoisomeric mixtures, such as racemic and diastereoisomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to encompass all such possible stereoisomers, including racemic mixtures, diastereoisomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain double bonds, the substituents may be in the E- or Z-configuration. When the compounds contain disubstituted cycloalkyls, the cycloalkyl substituents may have cis- or trans-configurations. All tautomeric forms are also intended to be included.

[0101] The phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and substitution can occur at any chemically accessible position. The term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valency.

[0102] As used herein, "C" used alone or in combination with other terms n~m "Alkyl" refers to a saturated hydrocarbon group that may be straight or branched, having n to m carbon atoms. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0103] As used herein, "C n~m "Alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbon atoms. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0104] As used herein, "C n~m "Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0105] As used herein, "aryl" refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). n~m The term aryl refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0106] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having two fused rings) groups, spirocyclic, and bridged rings. The ring-forming carbon atoms of a cycloalkyl can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). In some embodiments, a cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C 3~10 In some embodiments, the cycloalkyl group has 3, 4, 5, or 6 ring-forming carbon atoms (i.e., C 3~6 cycloalkyl).

[0107] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, and S. In some embodiments, a ring-forming N in a heteroaryl group can be an N-oxide. In some embodiments, a heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, a heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S.

[0108] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, S, and B, and wherein the ring-forming carbons or heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), S(O), etc.). In some embodiments, a heterocycloalkyl group contains 4 to 10 ring-forming atoms (i.e., 4 to 10 members), wherein 1 to 4 atoms are heteroatoms independently selected from N, O, and S.

[0109] As used herein, "C o~p -Cycloalkyl-C n~m- "Alkyl" refers to a group of the formula cycloalkyl-alkylene where the cycloalkyl has from o to p carbon atoms and the alkylene linking group has from n to m carbon atoms.

[0110] As used herein, "heterocycloalkyl-C n~m "-alkyl" refers to a group of formula heterocycloalkyl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0111] As used herein, "heteroaryl-C n~m- "Alkyl" refers to a group of formula heteroaryl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0112] As used herein, "aryl-C n~m- alkyl" (e.g., "phenyl-C n~m "-alkyl") refers to a group of formula aryl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0113] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds provided herein. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and are not typically biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and / or base salts by virtue of the presence of basic nitrogen atoms, such as those found in amino and pyridine groups or other similar groups, and / or acidic protons, such as those found in carboxylic acids or other similar groups.

[0114] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0115] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0116] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0117] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0118] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0119] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0120] In another aspect, the compounds provided herein are present in a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt form.

[0121] In another aspect, the compounds provided herein are acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate and the like. The compounds may be present in the form of salts of the following: lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate.

[0122] Any formula given herein is intended to represent the unlabeled form of the compound as well as the isotopically labeled form.Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.Isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen isotopes.

[0123] Additionally, certain isotopes, particularly deuterium (i.e. 2 Incorporation of H or D) may result in certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements, or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound has, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to either isotope in the same manner as described for deuterium.

[0124] Other examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and sulfur, for example, 3 H, 11 C. 13 C. 14C. 15 N, 18 F, 35 Therefore, the present invention provides, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 It should be understood to include compounds incorporating one or more of any of the foregoing isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction rate tests (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of previously utilized non-labeled reagents.

[0125] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, combined with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0126] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, as known to those skilled in the art, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof (see, e.g., Remington: The Science and Practice of Pharmacy, 22 nd(See Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0127] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject, for example, stimulate GLP1R activity, ameliorate symptoms, reduce a condition, slow or delay the progression of a disease, disorder, or condition, or prevent a disease, disorder, or condition. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to at least partially reduce, prevent, and / or ameliorate a condition, or disorder or disease responsive to increasing or stimulating the activity of GLP1R. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, cell, or tissue, or non-cellular biological material, or culture medium, is effective to partially or fully stimulate the activity of GLP1R. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to elicit an observable level of one or more desired biological or medical responses selected from, for example, lowering glucose levels (or improving glucose homeostasis), increasing insulin sensitivity, lowering triglyceride or cholesterol levels, reducing body weight, reducing food intake, and reducing body fat mass (such as peripheral and / or visceral fat).

[0128] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0129] As used herein, the terms "stimulate," "agonism," and "stimulating" refer to an increase in GLP1R signaling and / or activity, for example, as measured by an increase in intracellular cyclic adenosine monophosphate (cAMP).

[0130] As used herein, the terms "treat," "treating," or "treatment" of any disease, disorder, or condition refers to reducing or ameliorating the disease, disorder, or condition (i.e., slowing or halting the onset or progression of the disease, disorder, or condition, or at least one clinical symptom thereof); or reducing or ameliorating at least one physical parameter or biomarker associated with the disease, disorder, or condition, including those that may not be discernible to the patient.

[0131] As used herein, the terms "prevent," "preventing," or "prevention" of any disease, disorder, or condition refers to the prophylactic treatment of the disease, disorder, or condition; or to delaying the onset or progression of the disease, disorder, or condition.

[0132] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0133] As used herein, the terms "a," "an," and "the," and similar terms used in connection with the present invention (particularly in connection with the claims), are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0134] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to further clarify the invention and do not limit the scope of the invention as otherwise claimed.

[0135] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the invention can be racemic or enantiomerically enriched, e.g., in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

[0136] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as substantially pure diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0137] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization on the basis of the physical chemical differences of the constituent components.

[0138] Any resulting racemic forms of the compounds or intermediates of the present invention can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. Thus, in particular, compounds of the present invention can be resolved into their optical antipodes by fractional recrystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using basic moieties. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0139] The compounds provided herein (e.g., compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), and pharmaceutically acceptable salts thereof) can be prepared in several ways well known to those skilled in the art of organic synthesis. By way of example, the compounds provided herein can be synthesized using synthetic methods known in the art of synthetic organic chemistry, or the methods described in the Examples, together with variations thereof as will be appreciated by those skilled in the art.

[0140] It is well understood that protecting groups for sensitive or reactive groups are utilized where necessary in accordance with general principles of chemistry. Protecting groups are manipulated in accordance with standard methods of organic synthesis, for example, as described in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. The protecting groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0141] Those skilled in the art will recognize whether a stereocenter exists in the compounds disclosed herein. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0142] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0143] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0144] In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration can also involve inhalation or intranasal application. Pharmaceutical compositions of the present invention can be configured in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets can be either film-coated or enteric-coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient in combination with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; (also for tablets) c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavors and sweeteners.

[0145] The compounds of the invention (e.g., compounds of Formulas (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), and pharmaceutically acceptable salts thereof), in free form or in pharmaceutically acceptable salt form, exhibit useful pharmacological properties, e.g., as agonists of GLP1R, as shown, e.g., in in vitro and in vivo tests as provided in the following section, and are therefore suitable for use as tool compounds, for therapy or as research chemicals.

[0146] The compounds of the present invention (e.g., compounds of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), and pharmaceutically acceptable salts thereof) may be useful in the treatment of metabolic and related diseases, disorders, and conditions. In particular, the compounds of the present invention may be useful in the treatment of metabolic and related diseases, disorders, and conditions selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including, but not limited to, chronic kidney disease), diabetic nephropathy, dyslipidemia, metabolic syndrome, progressive liver disease, cardiovascular disease, and neuropathy (particularly, for example, peripheral neuropathy associated with diabetes).

[0147] The progressive liver disease can be, for example, non-alcoholic fatty liver disease (NAFLD), or, for example, non-alcoholic steatohepatitis (NASH).

[0148] The cardiovascular disease may be selected from, for example, hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (e.g., heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF)) and heart failure with preserved ejection fraction (HFpEF), coronary heart disease and arrhythmias (e.g., atrial arrhythmias and ventricular arrhythmias).

[0149] The compounds of the invention may be useful in treating several diseases, disorders or conditions (called "comorbidities") that co-exist in a subject.

[0150] The comorbidity may be, for example, in a subject who has type 2 diabetes and is also obese and / or who also exhibits heart failure and / or NASH. For example, an obese subject may also exhibit type 2 diabetes and / or cardiovascular disease (e.g., heart failure). Such a subject may also exhibit progressive liver disease (e.g., NASH). For example, an obese subject may also exhibit type 2 diabetes and / or cardiovascular disease (e.g., heart failure) and / or progressive liver disease (e.g., NASH). The subject may also have high blood pressure and / or high blood cholesterol levels. The subject may also suffer from peripheral neuropathy.

[0151] Accordingly, the compounds provided herein may be useful in the treatment of a disease, disorder, or condition selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including, but not limited to, chronic kidney disease), diabetic nephropathy, peripheral arterial disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (particularly heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF)), coronary heart disease, arrhythmias (particularly atrial arrhythmias and ventricular arrhythmias), and neuropathy (particularly peripheral arterial disease).

[0152] In certain embodiments, the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis, heart failure (particularly HFpEF) and NASH.

[0153] In certain embodiments, the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis and heart failure (particularly HFpEF).

[0154] Thus, in a further aspect, there is provided herein the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) in therapy. In a further embodiment, the therapy is treatment of a disease, disorder, or condition that can be treated by agonism of GLP1R. In another embodiment, the therapy is treatment of a disease, disorder, or condition selected from the foregoing list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example, in subjects with type 2 diabetes who are also obese, and / or in subjects with type 2 diabetes who also have heart failure, and / or in subjects with type 2 diabetes who also have NASH.

[0155] Thus, in a further aspect, there is provided herein a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) for use in therapy. In a further embodiment, the therapy is treatment of a disease, disorder, or condition that can be treated by agonism of GLP1R. In another embodiment, the therapy is treatment of a disease, disorder, or condition selected from the foregoing list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example, in subjects with type 2 diabetes who are also obese, and / or in subjects with type 2 diabetes who also have heart failure, and / or in subjects with type 2 diabetes who also have NASH.

[0156] In another aspect, provided herein is a method for treating a disease, disorder, or condition treatable by agonism of GLP1R, comprising administering a therapeutically acceptable amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., including a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof). In another embodiment, the present invention provides a method of treating a disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from the foregoing list, preferably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as comorbidities in, for example, a subject with type 2 diabetes who is also obese, and / or a subject with type 2 diabetes who also has heart failure, and / or a subject with type 2 diabetes who also has NASH.

[0157] In a further aspect, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease that can be treated by agonism of GLP1R. In another embodiment, the disease is selected from the foregoing list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as comorbidities in subjects with type 2 diabetes who are also obese, and / or subjects with type 2 diabetes who also have heart failure, and / or subjects with type 2 diabetes who also have NASH.

[0158] The term "metabolic disorder or disease" refers to a cluster of related conditions, including, but not limited to, glucose intolerance, insulin resistance, hyperinsulinemia, obesity, excessive visceral adiposity, hypertension, dyslipidemia characterized by elevated triglycerides, low high-density lipoprotein (HDL) cholesterol, and elevated low-density lipoprotein (LDL) cholesterol. Subjects with metabolic diseases or disorders are at risk of developing type 2 diabetes and, for example, atherosclerosis.

[0159] The term "type 2 diabetes" refers to a condition characterized by persistently high glucose levels in both fasting and fed states, resulting from a combination of impaired glucose utilization and excessive glucose production, which can result from either insufficient production of insulin from the pancreas or peripheral insulin resistance.

[0160] The term "insulin resistance," as used herein, refers to a condition in which normal amounts of insulin fail to induce the expected physiological response and to activate downstream pathways. In many instances, insulin produced endogenously or administered exogenously above the physiological range is sufficient to induce a complete or partial biological response that induces the expected physiological response.

[0161] The term "hyperinsulinemia" refers to a condition in which excess insulin can be detected in the blood.

[0162] The term "glucose intolerance" encompasses any disorder characterized by a clinical symptom or combination of clinical symptoms associated with elevated basal or postprandial glucose levels in a subject, and / or elevated insulin levels or abnormal glucose-stimulated insulin release or HOMA-IR (homeostatic model assessment of insulin resistance) compared to a healthy individual. Elevated glucose and / or insulin levels can be manifested in the following diseases, disorders, and conditions: obesity, metabolic syndrome, impaired glucose tolerance, type II diabetes, gestational diabetes, type I diabetes, insulin resistance, hyperinsulinemia, lipodystrophy, lipodystrophy, and various MODY (maturity-onset diabetes of the young) mutations. The GLP1R agonists provided herein, and compositions thereof, can be used, for example, to achieve and / or maintain glucose homeostasis, for example, to reduce glucose levels and / or reduce insulin levels in the bloodstream to the range found in healthy subjects.

[0163] The term "hyperglycemia," as used herein, refers to a condition in which elevated amounts of glucose circulate in the plasma of a subject compared to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measuring fasting blood glucose levels as described herein.

[0164] The term "diabetic complications" refers to problems caused by persistently high blood glucose levels that damage other organs, including the kidneys, peripheral limbs, and eyes (e.g., retinopathy), or induce vascular disease and neuropathy. Impaired vascular function can contribute to erectile dysfunction and lead to an increased risk of skin infections. Diabetes also increases the risk of heart disease and bone and joint disorders. Other long-term complications of diabetes include an increased risk of cancer, including hepatocellular carcinoma, endometrial cancer, breast cancer, and pancreatic cancer.

[0165] The term "diabetic nephropathy" refers to a condition caused by diabetes and caused by damage to blood vessels and other cells in the kidney that reduces kidney function.

[0166] The term "obesity" refers to a body mass index (BMI) of 30 or greater in human adults (Centers for Disease Control and Prevention). Such subjects may also be referred to as obese. This is referred to as Class I obesity. Class II obesity includes individuals with a BMI between 35 and 39.9, and Class III obesity refers to individuals with a BMI greater than 40. Body mass index (BMI) is a measure of body fat based on height and weight. The formula for calculation is BMI = weight in kilograms / height in meters. 2 is.

[0167] In certain embodiments, a human subject suffering from obesity has a BMI of ≧30 or ≧35, or a BMI in the range ≧35 to <40, or ≧30 to <40. An amount <40 can be, for example, 39.9. In some embodiments, the obesity is severe obesity or morbid obesity, and the human subject has a BMI of ≧40.

[0168] The term "dyslipidemia" refers to a complex disorder of lipoprotein metabolism involving overproduction or abnormal metabolism of lipoproteins. Dyslipidemia can be manifested by elevated blood levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and reduced high-density lipoprotein (HDL) cholesterol.

[0169] The term "atherosclerosis" refers to a vascular disease characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, which cause narrowing of the arterial lumen and ultimately progress to fibrosis and calcification. Lesions are usually focal and progress slowly and intermittently. Blood flow restriction accounts for most clinical symptoms, which vary depending on the distribution and severity of the lesions.

[0170] The term "progressive liver disease" refers to the progression from a benign state of hepatic steatosis evidenced by fibrosis and cirrhosis that predisposes to hepatocellular carcinoma. The progression of obesity-associated nonalcoholic fatty liver disease (NAFL) to NASH, fibrosis, and cirrhosis is well documented.

[0171] The term "nonalcoholic fatty liver disease (FLD)," also known as NAFLD, refers to a condition in which excess lipids accumulate in hepatocytes. This condition can result from either excessive de novo lipid synthesis in the liver or abnormal clearance and oxidation of fatty acids. NAFLD is excluded from other causes of liver disease, including alcoholic liver disease and viral liver disease. NAFLD includes three histological entities that reflect the progression of the disease: fatty liver, hepatic steatosis, and fibrosis or cirrhosis. The most common cause of NAFLD is obesity, but NAFLD can also be seen in lean individuals. Fat accumulation can lead to inflammation accompanied by macrophage infiltration and changes in hepatocyte histology, including steatohepatitis and ballooning, termed nonalcoholic steatohepatitis (NASH). NASH can progress to fibrosis accompanied by interlobular bridging fibrosis or cirrhosis. As used herein, the term NASH can encompass steatohepatitis, hepatocyte ballooning, and lobular inflammation.

[0172] The term "metabolic syndrome" refers to a cluster of risk factors that increase the risk for cardiovascular disease, including coronary artery disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, cerebrovascular disease, and peripheral vascular disease. These risk factors include abdominal fat, high blood sugar after fasting (at least 110 milligrams per deciliter (mg / dL)), high triglycerides in the bloodstream (at least 150 mg / dL), low HDL (less than 40 mg / dL), and blood pressure of 130 / 85 mmHg or higher (World Health Organization).

[0173] The term "cardiovascular disease" refers to diseases related to the heart or blood vessels.

[0174] The term "peripheral arterial disease" refers to when the buildup of fatty deposits in the arteries restricts the blood supply to the leg muscles.

[0175] The term "stroke" refers to when the blood supply to part of the brain is cut off.

[0176] The term "heart failure" refers to when the heart has a reduced ability to pump blood and can include heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with mildly reduced ejection fraction (HFmrEF).

[0177] The term "coronary heart disease," also known as coronary artery disease, is the narrowing of the arteries that supply blood to the heart.

[0178] The term "arrhythmia" refers to an abnormal heart rhythm and can include atrial arrhythmias, atrial fibrillation, and ventricular arrhythmias.

[0179] The term "neuropathy" refers to when nerves are damaged. This term includes peripheral neuropathy, which occurs when nerves in the extremities, such as the hands, feet, and arms, are damaged. Diabetes is a common cause of peripheral neuropathy.

[0180] The term "cardiomyopathy" is defined as an acquired or congenital structural abnormality of the atrial or ventricular myocardium that can affect cardiac function, or physiology, and conduction.

[0181] The pharmaceutical compositions or combinations provided herein may be administered in a unit dosage of about 1 to 1000 mg of active ingredient for a subject weighing about 50 to 70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity.

[0182] A compound of the present invention (e.g., comprising any compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) can be administered simultaneously with, prior to, or after one or more other therapeutic agents. A compound of the present invention can be administered separately, by the same or different route of administration, or in combination with other agents in the same pharmaceutical composition. A therapeutic agent is, for example, a chemical compound, peptide, peptide conjugate and fusion, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a subject in combination with a compound of the present invention.

[0183] Thus, in another aspect, provided herein are combinations, particularly pharmaceutical combinations, comprising (e.g., a therapeutically effective amount of) a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof), and one or more other therapeutically effective agents.

[0184] In one embodiment, provided herein is a product comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof), and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a disease, disorder, or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including when these exist as comorbidities, for example, in a subject with type 2 diabetes who is also obese, or in a subject with type 2 diabetes who also has heart failure.

[0185] Products provided as combined preparations include a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) and another therapeutic agent combined in the same pharmaceutical composition, or a composition comprising a compound of the invention and another therapeutic agent in separate forms, e.g., in the form of a kit.

[0186] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described herein.

[0187] In one embodiment, provided herein is a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises a means for retaining the compositions separately, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0188] Kits may be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to each other. To aid in compliance, kits provided herein typically include directions for administration.

[0189] In the combination therapies provided herein, the compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the other therapeutic agent may be incorporated into the combination therapy (i) prior to delivery of the combination product to a physician (e.g., in the case of a kit containing the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the other therapeutic agent); (ii) by the physician (or under the guidance of a physician) immediately prior to administration; or (iii) in the patient themselves, for example, during sequential administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and the other therapeutic agent.

[0190] Accordingly, provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for treating a disease, disorder, or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the medicament is prepared for administration with another therapeutic agent.

[0191] Provided herein is the use of another therapeutic agent to treat a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the medicament is administered together with a compound of the invention.

[0192] Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) for use in a method of treating a disease, disorder, or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity in, for example, a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated for administration with another therapeutic agent.

[0193] Also provided herein is another therapeutic agent for use in a method of treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these exist as comorbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the other therapeutic agent is formulated for administration with a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including, for example, a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof).

[0194] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., including a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) for use in a method of treating a disease, disorder, or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity in, for example, a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent.

[0195] Also provided is another therapeutic agent for use in a method of treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the other therapeutic agent is administered together with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0196] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) for treating a disease, disorder, or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including when these exist as comorbidities, for example, in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent.

[0197] Also provided herein is the use of another therapeutic agent for treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these exist as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof).

[0198] In one embodiment, the other therapeutic agent is selected from: 1. Antidiabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as sulfonylureas (e.g., chlorpropamide, tolazamide, acetohexamide, tolbutamide, glyburide, glimepiride, glipizide); glyburide and amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; thiazolidinediones (e.g., rosiglitazone (AVANDIA), troglitazone (REZULIN), pioglitazone (ACTOS), balaglitazone, rivoglitazone, netoglitazone, troglitazone, englitazone, ciglitazone), which enhance insulin action (e.g., by insulin sensitization), thereby promoting glucose utilization in peripheral tissues; protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; cholesteryl ester transfer protein (CETP) inhibitors such as torcetrapib; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose cotransporter inhibitors such as canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sotagliflozin, and tofogliflozin; BAY glycogen phosphorylase A inhibitors such as R3401; biguanides such as metformin and other drugs that act by promoting glucose utilization, reducing hepatic glucose production and / or reducing intestinal glucose output; alpha-glucosidase inhibitors such as acarbose and migiitoi and other drugs that slow carbohydrate digestion and consequent absorption from the intestine, reducing postprandial hyperglycemia; GIPR modulators such as trizepatide, CT-868, CT-388, AMG133, HM15211, NN9423, TAK-094, LBT-6030, ZP-I-98, NN9709, RG7685, RG7697, SAR438335;as well as DPPIV (dipeptidyl peptidase IV) inhibitors such as vildagliptin; 2. Lipid-lowering agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, for example, lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, belostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; bile acid sequestrants such as cholestyramine and colesevelam; fibrates; nicotinic acid and aspirin; 3. Anti-obesity agents such as orlistat, rimonabant, phentermine, topiramate, qunexa, and lorcaserin; GDF15 (including variants, conjugates, fusions, analogs, mutants, and fragments thereof, including other GFRAL modulators such as NGM386 and NGM395); PCT publications WO 2013 / 148117, WO 2014 / 120619, and related patent family members (including, but not limited to, U.S. Pat. No. 9,161,966 B1), WO 2012 / 138919, WO 2013 / 113008, WO 2015 / 017710, WO 2015 / 200078, WO 2015 / 197446 GDF15 fusions (including, for example, GDF15 fusions with human serum albumin (HSA)), such as GDF15 conjugates with fatty acids (such as those described in PCT Publication Nos. WO 2015 / 200078 and WO 2017 / 109706) and fusions described in PCT Publication Nos. WO 2015 / 197446, WO 2015 / 198199, and WO 2017 / 109706; FGF21 mimetics such as PEG-FGF21, pegbelfermin; ActRII antagonists such as ramatercept; and Alk7 antagonists; 4. Antihypertensive drugs, for example, loop diuretics such as ethacrynic acid, furosemide and torsemide; angiotensin-converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutral endopeptidase (NEP) inhibitors; ACE / NEP inhibitors such as omapatrilat, sampatrilat, and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan, especially valsartan; angiotensin receptor-neprilysin inhibitors (ARNi) such as sacubitril / valsartan (Entresto); ditekiren, zankiren, terlaskiren, aliskiren, RO beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol; inotropes such as digoxin, dobutamine, and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors. 5. Agonists of peroxisome proliferator-activated receptors, such as fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585, L-796449, the compounds specifically described in patent application WO 2004 / 103995, i.e. the compounds of Examples 1 to 35 or the compounds specifically listed in claim 21, or the compounds specifically described in patent application WO 03 / 043985, i.e. the compounds of Examples 1 to 7 or the compounds specifically listed in claim 19, and in particular (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxy or a salt thereof; 6. Certain antidiabetic compounds described in Expert Opin Investig Drugs 2003, 12(4):623-633, Figures 1-7. 7. Compounds that bind to the corticotropin-releasing hormone receptor, such as Urocortin 2.

[0199] Additionally, the present disclosure provides combination therapies with agents that stimulate metabolism or reduce appetite, as well as agents and methods for promoting weight loss, such as dietary modifications and / or exercise regimens to promote weight loss. [Example]

[0200] The following examples are intended to illustrate the present invention and should not be construed as limiting thereto. Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0201] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0202] Abbreviations used in the following examples and elsewhere in this specification are as follows: Plateau value of the Hill curve at low A0 concentrations AC 50 Half-maximal compound effect concentration A inf Hill curve plateau value at high concentrations BSA Bovine serum albumin BOC Tertiary butyl carboxy br Broad BSA Bovine serum albumin cAMP cyclic adenosine monophosphate CDI Carbonyldiimidazole CO2 Carbon dioxide d double line dd double line double line DBU Diazabicycloundecene DCM dichloromethane DIEA / DIPEA Diethylisopropylamine DMA Dimethylacetamide DMEM Dulbecco's Modified Eagle's Medium DMF N,N-dimethylformamide DMI Dimethylimidazolidinone DMPU N,N-dimethylpropylene urea DMSO dimethyl sulfoxide EC Effective Concentration Effective concentration of compound that does not produce an EC0 response EC 50 The effective concentration of compound that produces a half-maximal response (AC in μM) 50 ) EC 100 Effective concentration of compound that produces a maximal (100%) response EDTA Ethylenediaminetetraacetic acid E max Efficacy: The maximum response achievable from an administered drug ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol FA formic acid FBS Fetal Bovine Serum G418 Geneticin, a selective antibiotic GLP1 glucagon-like peptide 1 GLP1R Glucagon-like peptide 1 receptor GPCR G protein-coupled receptor h time HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) hGLP1R human glucagon-like peptide 1 receptor HPLC High Pressure Liquid Chromatography HTRF homogeneous time-resolved fluorescence IBMX 3-isobutyl-1-methylxanthine KHMDS Potassium bis(trimethylsilyl)amide LCMS Liquid Chromatography and Mass Spectrometry MeCN acetonitrile MeOH Methanol MS mass spectrometry m multiplet mg milligram min ml milliliter mM millimolar concentration mmol millimole nM nanomolar concentration m / z mass-to-charge ratio NMR nuclear magnetic resonance ND Not decided PBS Phosphate Buffered Saline Pd(OAc)2 Palladium(II) Acetate PdCl2(dppf)-CH2Cl2 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex Pd(OAc)2 Palladium(II) Acetate ppm parts per million PyBOP Benzotriazole-1-oxytripyrrolidinophosphonium hexafluorophosphate PyBroP Bromotripyrrolidinophosphonium hexafluorophosphate rac racemic R t retention time rt room temperature s single line SFC Superfluid Carbon Dioxide SM Starting material / starting materials(s) SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride t triple line TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilyl TMSCl Trimethylsilyl chloride Tol Toluene Turbo Grignard Isopropylmagnesium Chloride Lithium Chloride Complex Solution v / v volume / volume μL microliter μM micromolar

[0203] General conditions: NMR Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. 1H NMR spectra were recorded on (a) a Bruker AVANCE 400 MHz or 500 MHz NMR spectrometer using ICON-NMR under TopSpin program control; (b) a Bruker ASCEND 400 MHz NMR spectrometer using Console-Avance III 400 under TopSpin 3.2 program control; or (c) a Bruker ASCEND 400 MHz NMR spectrometer using Console-Avance III HD under TopSpin 3.2 program control. Spectra were measured at 293-298 K and referenced to the solvent resonance unless otherwise specified. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0204] NMR-01 Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (H NMR) spectra were recorded on a Bruker ASCEND 400 MHz NMR spectrometer using a Console-Avance III 400 under TopSpin 3.2 program control. Spectra were measured between 293 and 298 K and referenced to solvent resonances unless otherwise specified. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0205] NMR-02 Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (H NMR) spectra were recorded on a Bruker ASCEND 400 MHz NMR spectrometer using Console-Avance III HD under TopSpin 3.2 program control. Spectra were measured between 293 and 298 K and referenced to solvent resonances unless otherwise specified. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0206] LCMS equipment Mass spectra were obtained using an Agilent 1100 HPLC system equipped with an Agilent 6110 mass spectrometer. [M+H] + refers to the protonated molecular ion of the species. The column temperature was 50° C. The flow rate was 1.0 ml / min.

[0207] LCMS method 1: (acidic) Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; 2 min analysis time: 2% Solvent B 0–0.1 min, 2 → 98% Solvent B: Solvent A 0.1–1.8 min, 98% Solvent B 0.2 min. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = 0.1% formic acid (v / v) in acetonitrile. Injection volume: 2–5 μL; UV detection array: 210–400, mass detection: 120–1250 (electrospray ionization); column temperature: 50 °C; flow rate: 1.0 mL / min.

[0208] LCMS method 2: (basic) Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 50 mm; 2 min run time: 2% Solvent B 0–0.1 min, 2 → 98% Solvent B: Solvent A 0.1–1.8 min, 98% Solvent B 0.2 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1250 (electrospray ionization); column 50 °C; flow rate 1.0 mL / min.

[0209] LCMS method 3: (Product analysis - acidic) Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 181.7 μm, 21 × 30 mm; 5.2 min run time, 2 → 98% Solvent B: Solvent A 0–5.15 min, 98% Solvent B 5.15–5.20 min. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = 0.1% formic acid (v / v) in acetonitrile. Injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1600; column 50°C, flow rate 1.0 mL / min.

[0210] LCMS method 4: (Product analysis - basic) Instrument: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 18 1.7 μm, 21 x 30 mm; 5.2 min run time, 2 → 98% Solvent B: Solvent A = 0–5.15 min, 98% Solvent B = 5.15–5.20 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume: 2–5 μL; UV detection array: 210–400, mass detection: 120–1600; column temperature: 50°C, flow rate: 1.0 mL / min.

[0211] HRMS method 5: Instrument: Agilent 1200 LC / G1956A, diode array detector; Column: Chromolith Flash C 18 1.6 micron 2 x 25 mm; 1.5 min run time, 5 → 95% Solvent B: Solvent A 0 → 1.2 min, followed by 95% Solvent B 1.21 → 1.5 min. Solvents: Solvent A = 0.0375% TFA (v / v) in water, Solvent B = 0.01875% TFA (v / v) in acetonitrile. Injection volume 2-5 μL; UV detection 220 and 254 nM, mass detection 100-1000 (electrospray ionization); column 50 °C; flow rate 1.5 mL / min.

[0212] LCMS-Method-C2: Instrument: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; Eluent A: 2 mM ammonium acetate followed by 0.1% formic acid in water; Eluent B: 0.1% formic acid in acetonitrile; Gradient: 95:5 at 0.01 min at 0.550 ml / min, 30:70 at 0.60 min at 0.600 ml / min, 10:90 at 0.80 min at 0.650 ml / min, 0:100 from 1.10 to 1.70 min at 0.650 ml / min, 95:5 from 1.71 to 2.0 min at 0.550 ml / min; Column temperature: room temperature

[0213] LCMS-Method-H3: Equipment: Waters, X-Bridge C18(50*4.6mm), 3.5um; Eluent A: 5 mM ammonium bicarbonate in water; Eluent B: acetonitrile; Gradient: Flow rate: 95:05 at 0.01 min at 1.0 ml / min, 15:85 at 2.80 min at 1.0 ml / min, 05:95 from 3.50 min to 5.0 min, 95:05 from 5.01 min to 6.0 min; Column temperature: room temperature

[0214] Chiral Preparative HPLC Method Equipment: Shimadzu LC-20AP and UV detector. Column: CHIRALPAK IG, (250*21.0) mm, 5 microns, Column flow rate: 16.0 ml / min. Mobile phase: (A) 0.1% DEA in methanol. UV spectra were recorded at 276.0 nm lambda max. The uniform concentration ratio was:

[0215] [Table 13]

[0216] HPLC method MC-1: Instrument: Waters AutoPurification HPLC; Column: Waters XBridge BEH C 18OBD preparative column (130 Å, 5 μm, 10 mm × 150 mm); 4.7 min run time: 98% solvent A 0–0.2 min, 98 → 2% solvent A 0.2–2.8 min, 2% solvent A 2.8–3.8 min, 2 → 98% solvent A 3.8–3.85 min, 98% solvent A 3.85–4.7 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume: 300 μL; Waters 2998 Photodiode Array Detector 210-400, Waters Acquity QDa Mass Spectrometer (150–200 amu); flow rate: 10 mL / min.

[0217] HPLC method MC-2 Instrument: Waters AutoPurification HPLC; Column: Waters XBridge BEH C 18 OBD preparative column (130 Å, 5 μm, 10 mm × 150 mm); 4.7 min analysis time: 98% solvent A 0–0.2 min, 98 → 55% solvent A 0.2–1.09 min, 55 → 45% solvent A 1.09–1.91 min, 45 → 2% solvent A 1.91–2.8 min, 2% solvent A 2.8–3.8 min, 2 → 98% solvent A 3.8–3.85 min, 98% solvent A 3.85–4.7 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume: 300 μL; Waters 2998 Photodiode Array Detector 210-400, Waters Acquity QDa Mass Spectrometer (150–200 amu); flow rate: 10 mL / min.

[0218] HPLC method MC-3 Instrument: Waters AutoPurification HPLC; Column: Waters XBridge BEH C 18OBD preparative column (130 Å, 5 μm, 10 mm × 150 mm); 4.7 min analysis time: 98% solvent A 0–0.2 min, 98% to 50% solvent A 0.2–1.09 min, 50% to 40% solvent A 1.09–1.91 min, 40% to 2% solvent A 1.91–2.8 min, 2% solvent A 2.8–3.8 min, 2% to 98% solvent A 3.8–3.85 min, 98% solvent A 3.85–4.7 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume: 300 μL; Waters 2998 Photodiode Array Detector 210-400, Waters Acquity QDa Mass Spectrometer (150–200 amu); flow rate: 10 mL / min.

[0219] LCMS method MC-1: (Product analysis - acidic) Equipment: Waters Acquity Classic; Column: Waters Acquity UPLC BEH C 18 (2.1 × 50 mm, 1.7 μm); 3 min run time: 98% solvent A 0–0.1 min, 98 → 2% solvent A 0.1–2.10 min, 2% solvent A 2.1–2.6 min, 2 → 98% solvent A 2.6–2.7 min, 98% solvent A 2.7–3 min. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = 0.1% formic acid (v / v) in acetonitrile. Injection volume: 1 μL; Acquity UPLC photodiode array detector 200–400, Waters SQ Detector 2 mass spectrometer (mass detection 150–1500 amu), Thermo Corona Veo RS charged aerosol detector; column temperature: 50 °C, flow rate: 1.0 mL / min.

[0220] LCMS Method MC-2: (Product Analysis - Acidic) Equipment: Waters Acquity Classic; Column: Waters Acquity UPLC BEH C 18(2.1 × 50 mm, 1.7 μm); 3 min run time: 98% solvent A 0–0.1 min, 98 → 2% solvent A 0.1–2.10 min, 2% solvent A 2.1–2.6 min, 2 → 98% solvent A 2.6–2.7 min, 98% solvent A 2.7–3 min. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = 0.1% formic acid (v / v) in acetonitrile. Injection volume: 1 μL; Acquity UPLC photodiode array detector 200–300, Waters SQ detector mass spectrometer (mass detection 150–1500 amu), Thermo Corona Veo RS charged aerosol detector; column temperature: 55 °C, flow rate: 1.0 mL / min.

[0221] Example 1A: Preparation of intermediates Intermediates II.1 and II.2: 4-Methylbenzenesulfonic acid (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (II.1); and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) [ka] Step 1: Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (II.3) [ka] To a solution of 1-(4-chloro-2-fluorophenyl)ethan-1-one (150 g, 793.61 mmol) in Tol (1500 mL) were added 3-bromobenzene-1,2-diol (123.27 g, 714.25 mmol) and p-TsOH (27.33 g, 158.72 mmol) at 25 °C. The mixture was stirred at 140 °C for 48 h. TLC (petroleum ether:ethyl acetate = 30:1) showed that 1-(4-chloro-2-fluorophenyl)ethan-1-one was completely consumed and a new spot (Rf = 0.4) was detected. The mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO, petroleum ether) to give II.3 (175 g, crude) as a black oil, which was used for the next step without further purification. 1 H-NMR(400MHz,CDCl3)δ 2.04(s,3H),)7.47(t,J=8.38Hz,1H),7.05-7.09(m,2H),6.88(dd,J=7.88,1.13Hz,1H),6.57-6.71(m,2H),2.04(s,3H).

[0222] Step 2: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (II.4) [ka] To a solution of II.3 (150 g, 436.58 mmol) in dioxane (1500 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (162.00 g, 523.90 mmol), NaCO (254.50 g, 2401.19 mmol), and Pd(dppf)Cl (31.99 g, 43.66 mmol) at 25 °C. The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO, petroleum ether:ethyl acetate = 10:1) to give II.4 (50 g, 112.11 mmol, 96% purity, 44% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.52(t,J=8.3Hz,1H),7.19-7.10(m,2H),6.85-6.73(m,3H),6.37(br s,1H),4.22-4.03(m,2H),3.79-3.55(m,2H),2.56(br d,J=14.3Hz,2H),2.08(d,J=0.6Hz,3H),1.51(s,9H).

[0223] Step 3: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (II.5) [ka] To a solution of II.4 (50 g, 112.13 mmol) in MeOH (200 mL) was added ((CH)P)RhCl (5.19 g, 5.61 mmol) at 25 °C. The mixture was stirred under H at 50 °C for 16 h. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO, PE:EA = 10:1) to give II.5 (37.5 g, 83.71 mmol, 98% purity, 75% yield) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 7.52(t,J=8.3Hz,1H),7.19-7.08(m,2H),6.81-6.75(m,1H),6.74-6.70(m,1H),6.67(dd,J=0.9,7.8Hz,1H),4.25(br s,2H),2.83(tt,J=3.7,11.9Hz,3H),2.06(d,J=0.7Hz,3H),1.86-1.64(m,4H),1.50(s,9H).

[0224] Step 4: SFC Separation II.6a and II.6b [ka] II.5 (170 g, 379.52 mmol, 96% purity) was purified by SFC (CAS-WH-ANA-SFC-A (Agilent-1260), column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; mobile phase: phase A with CO and phase B with IPA (0.05% DEA); gradient elution: 5% to 40% B in A; flow rate: 3 mL / min; detector: DAD; column temperature: 35 °C; back pressure: 100 Bar) to give II.6a (77 g, 171.90 mmol, 100% ee) and II.6b (75 g, 167.44 mmol, 100% ee). SFC: Rt = 0.884 min, II.6a peak 1. SFC: Rt = 1.118 min, II.6b peak 2.

[0225] Step 5a: Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonic acid II.1 [ka] To a solution of compound II.6b (19.4 g, 43.3 mmol, 1.0 eq) in EtOAc (200 mL) was added TsOH.HO (9.88 g, 51.9 mmol, 1.20 eq). After the addition, the pale yellow suspension was stirred at 45 °C for 12 h. The reaction mixture was poured into petroleum ether (400 mL), filtered, collected, and dried without further purification. II.1 (20.0 g, 36.9 mmol, 85.2% yield, 96.0% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ)8.58(br d,J=8.63Hz,1H),8.31(br d,J=8.25Hz,1H),7.49(d,J=8.00Hz,2H),7.56-7.65(m,2H),7.34(dd,J=8.38,1. 75Hz,1H),7.12(d,J=7.88Hz,2H),6.82-6.87(m,2H),6.68-6.74(m,1H),3.37(br d,J=12.51Hz,2H),2.94-3.07(m,3H),2.03(s,3H),2.29(s,3H),1.84-1.94(m,4H).

[0226] Step 5b: Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) [ka] To a solution of II.6b (67 g, 149.58 mmol) in dioxane (670 mL) was added HCl (670 mL, 1 M in dioxane) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give the crude product. The crude product was triturated with MTBE:MeOH = 10:1 (700 mL) to give II.2 (71 g, 204.13 mmol, 98% purity, 99.27% ​​ee quantitative) as a white solid. 1H NMR(400MHz,CDCl3)δ 9.98-9.43(m,2H),7.57(t,J=8.3Hz,1H),7.19-7.09(m,2H),6.87-6.65(m,3H),3.96(s,1H),3.64(br d,J=10.9Hz,2H),3.50(s,2H),3.22(s,1H),3.12-2.90(m,3H),2.39-2.19(m,2H),2.15-1.98(m,5H),1.20(s,1H).

[0227] Intermediates III.3a and III.3b: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.3a); and Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.3b) [ka] Step 1: Synthesis of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate and ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.2a and I.2b, respectively) [ka] In a 3 L four-neck flask, to a solution of ethyl imidazole-4-carboxylate 1-((2-(trimethylsilyl)ethoxy)methyl)-1H (I.1) (50 g, 0.356 mol) in DMF (1500 mL) was added NaH 55-60% in mineral oil (18.56 g, 0.464 mol) in small portions under nitrogen at 0 °C. After 30 min, SEM-Cl (43.1 mL, 235 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution (2000 mL), and the aqueous layer was extracted with ethyl acetate (3 × 1000 mL). The combined organic phases were washed with cold water (2 × 500 mL) and brine (250 mL), dried over sodium sulfate, and concentrated. Chromatographic purification on SiO (EtOAc / heptane 0-40%) gave ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.2a) (50 g, 51.8% yield) and ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.2b) (21 g, 21.8% yield). Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.2a): LCMS Method C2: Rt=1.36 min; MS m / z 271.2 [M+H]+; 1 H NMR(400MHz,DMSO-d6)δ 8.15(d,J=1.1Hz,1H),7.69(d,J=1.0Hz,1H),5.64(s,2H),4.27(q,J=7.1Hz,2H) ,3.49(t,J=7.9Hz,2H),1.34-1.15(m,3H),0.83(t,J=7.8Hz,2H),-0.06(s,9H). Ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.2b): LCMS Method C2: Rt=1.31 min; MS m / z 271.2 [M+H]+; 1H NMR(400MHz,DMSO-d6)δ 8.02(d,J=1.4Hz,1H),7.93(d,J=1.3Hz,1H),5.39(s,2H),4.24(q,J=7.0Hz,2H),3.50(d d,J=8.5,7.5Hz,2H),1.28(t,J=7.1Hz,3H),0.86(dd,J=8.6,7.5Hz,2H),-0.024(s,9H).

[0228] Step 2: Synthesis of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.3) [ka] To a solution of ethyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.2b) (6 g, 0.022 mol) in CCl (180 mL), NBS (4.186 g, 0.023 mol) and AIBN (0.193 g, 0.0011 mol) were added under nitrogen, and the reaction mixture was heated to 60 °C for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (250 mL) and extracted with DCM (2 × 200 mL). The organic layer was dried over sodium sulfate and concentrated. Chromatographic purification on SiO (EtOAc / heptane 0–12%) gave ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.3) (4.5 g, 58.1% yield). LCMS method C2: Rt=1.35 min; MS m / z 351.1[M+2]+; 1 H-NMR(400MHz,DMSO-d6)δ 8.24(s,1H),5.34(s,2H),4.23(q,J=7.1Hz,2H),3.54(t,J=7.9Hz,2H),1.27(t,J=7.1Hz,3H),0.85(t,J=7.9Hz,2H),-0.06(s,9H).

[0229] Step 3: Synthesis of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.4) [ka] To a solution of ethyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.3) (4.5 g, 0.0129 mol) in dry THF (148 mL) was added i-PrMgCl 2.0 M in THF (13.39 mL, 0.0387 mol) dropwise over 20 min at −40 °C. The reaction mixture was further cooled to −78 °C and stirred for 15 min. Anhydrous DMF (6.607 g, 0.090 mol) was added at −78 °C, followed by warming to room temperature and stirring at room temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with 3 N HCl to adjust the pH to 6–7, and the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, and concentrated to give the crude product ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.4) (3.5 g, 91.0% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.32 min; MS m / z 299.2 [M+1]+; 1 H NMR(400MHz,DMSO-d6)δ 9.80(s,1H),8.44(s,1H),5.72(s,2H),4.41-4.18(t,2H),3.53(t,J=22.9 ,8.0Hz,2H),1.32(t,J=7.2Hz,3H),1.31-1.17(m,2H),-0.03-0.14(m,9H).

[0230] Step 4: Synthesis of ethyl 2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.5) [ka] To a solution of ethyl 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.4) (3.5 g, 0.011 mol) in ethanol (53 mL) was added NaBH (0.830 g, 0.022 mol) under nitrogen and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were dried over sodium sulfate and concentrated to give crude ethyl 2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.5) (3.5 g, 99.3% yield), which was used in the next step without further purification. LCMS Method C2: Rt = 1.22 min; MS m / z 301.4 [M+1].

[0231] Step 5: Synthesis of ethyl 2-(((methylsulfonyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.6) [ka] To a solution of 2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.5) (4.5 g, 0.01499 mol) in DCM (148 mL) was added TEA (4.88 mL, 0.035 mol) at 0° C., followed by methanesulfonyl chloride (1.47 g, 0.013 mol). The reaction mixture was stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with DCM (150 mL), quenched with saturated sodium bicarbonate, and the pH was adjusted to 8. The organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated to give crude product (I.6) (3 g, 68% yield), ethyl 2-(((methylsulfonyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate, which was used for the next step without further purification.

[0232] Step 6: Synthesis of (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (III.1) [ka] To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-ium, 4-methylbenzenesulfonic acid tosylate (II.1) (1.24 g, 0.0024 mol) in acetonitrile (20 mL), DIPEA (5.12 g, 0.039 mol) was added and stirred at room temperature for 30 min. Ethyl 2-(((methylsulfonyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.6) (3 g, 0.0079 mol) and K2CO3 (3.29 g, 0.0238 mol) were added, followed by KI (1.32 g, 0.0079 mol), and the reaction mixture was stirred at 60 °C for 12 h. After completion of the reaction, the mixture was concentrated, and the residue was dissolved in water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over sodium sulfate, and concentrated. Chromatographic purification on a neutral alumina column (EtOAc / heptane 0-20%) afforded (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (III.1) (1 g, 20% yield). LCMS Method C2: Rt = 1.58 min; MS m / z 631 [M+1]+.

[0233] Step 7: Synthesis of (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1H-imidazole-5-carboxylate (III.2) [ka] To a solution of (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (III.1) (1.3 g, 0.002 mol) in 1,4-dioxane (10 mL) was added dropwise HCl 4M in dioxane (15 mL) at 0° C. and the reaction was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated and the residue was basified to pH 8 with saturated sodium bicarbonate solution and extracted with DCM (3×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Chromatographic purification on a neutral alumina column (EtOAc / heptane 0-80%) gave (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1H-imidazole-5-carboxylate (III.2) (0.5 g, 48.5% yield). LCMS Method C2: Rt = 1.23 min; MS m / z 500.4 [M+1]+.

[0234] Step 8: Synthesis of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.3a) and ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.3b) [ka] To a solution of (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1H-imidazole-5-carboxylate (III.2) (0.5 g, 0.001 mol) in DMF (5 mL) was added (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (IV.1) (0.315 g, 0.0013 mol), K2CO3 (0.415 g, 0.003 mol), KI (0.166 g, 0.001 mol) under nitrogen, and the mixture was stirred at 80 °C for 6 h. The reaction was monitored on TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Chromatographic purification on a neutral alumina column (EtOAc / heptane 60-80%) gave ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.3a) (0.09 g, 15.8% yield) and ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.3b) (0.140 g, 24.6% yield). Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.3a). LCMS Method C2: Rt=1.40 min; MS m / z 570.5 [M+1]+. Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.3b). LCMS Method C2: Rt=1.35 min; MS m / z 570.5 [M+1]+.

[0235] Intermediates III.9a and III.9b: [ka] Step 1: Ethyl 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate, Ethyl 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (I.8) [ka] Ethyl 4-methyl-1H-imidazole-5-carboxylate (I.7) (10.47 g, 67.9 mmol) was dissolved in DMF (170 mL) and cooled to 0 °C. NaH 60% (3.53 g, 88 mmol) in oil was added. The solution was immediately bubbled and stirred for 10 min, after which SEMCl (13.25 mL, 74.7 mmol) was added. The solution was then stirred at 0 °C for 1 h, after which it was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organics were then washed multiple times with saturated ammonium chloride solution and dried over sodium sulfate. The organic phase was filtered and concentrated to an orange oil. The oil was directly loaded onto a normal-phase column and purified via 0–70% EtOAc:heptane over 40 min. The product (I.8) was eluted with 45% EtOAc. The identified fractions were collected and concentrated to give a yellow oil which was dried under high vacuum and carried forward directly (12.32 g, 60.1% yield). LCMS Method 3: Rt=1.98 min; MS m / z 285.1 [M+1]+.

[0236] Step 2: Ethyl 2-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.9) [ka] Ethyl 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.8) (12.32 g, 40.8 mmol) was dissolved in DCM (204 mL), followed by the addition of NBS (7.84 g, 44.1 mmol) and AIBN (0.670 g, 4.08 mmol). The solution was then refluxed at 70 °C for 1 h, after which it was concentrated to an orange solution, which was directly loaded onto a normal-phase column and purified via 0–40% EtOAc:heptane over 40 min. The product (I.9) eluted with 25% EtOAc. The identified fractions were collected and concentrated to give a yellow oil, which was dried under high vacuum and used as is. (14.169 g, 88% yield). LCMS method 3: Rt=2.61 min; MS m / z 365.0[M+1]+.

[0237] Step 3: Ethyl 2-formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.10) [ka] Ethyl 2-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.9) (500 mg, 1.274 mmol) was dissolved in THF (6.3 mL), followed by the addition of DMF (691 μL). The solution was then cooled to −78° C., followed by the addition of 1.3 N Turbo Grignard (2940 μL, 3.82 mmol). The solution was then stirred at −78° C. for 1 h, followed by the addition of 1.3 N Turbo Grignard (1960 μL, 2.55 mmol). The solution was then allowed to warm to room temperature, after which the solution was quenched with saturated ammonium chloride, and the organics were concentrated. The solution was then extracted with ethyl acetate and washed with saturated ammonium chloride. The organics were then dried over sodium sulfate, followed by filtration and concentration to a yellowish oil, which was purified via normal phase column chromatography using a 0-100% EtOAc:heptane gradient over 20 min. The product (I.10) elutes at 40% EtOAc. The identified fractions were collected and concentrated to give a yellowish oil (275.5 mg, 59.5% yield). LCMS Method 4: Rt = 2.61 min; MS m / z 313 [M+1]+.

[0238] Step 4: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (III.7) [ka] (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine tosyl salt (II.1) (433 mg, 0.833 mmol) was dissolved in DCM and washed with saturated sodium bicarbonate. The organics were then dried over sodium sulfate, filtered, and concentrated to a colorless oil. Ethyl 2-formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (I.10) (275.5 mg, 0.758 mmol), sodium triacetoxyborohydride (321 mg, 1.515 mmol), and acetic acid (87 μL, 1.515 mmol) were then mixed in solution with DCM (3.8 mL). The solution was then heated to 40 °C for 13 h, after which the solution was subsequently quenched with saturated ammonium chloride solution and extracted with DCM. The organics were dried over sodium sulfate, filtered, and concentrated to an orange oil, which was purified via normal phase 0-100% EtOAc:heptane over 25 min. The product (III.7) eluted with 70% EtOAc. The identified fractions were collected and concentrated to give a yellowish oil, which was carried forward directly. (243.9 mg, 46.7% yield). LCMS Method 3: Rt = 2.55 min; MS m / z 644.4 [M+1]+.

[0239] Step 5: (S)-ethyl 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate (III.8) [ka] Ethyl (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (III.7) (243.9 mg, 0.354 mmol) was dissolved in THF (1.7 mL). The solution was then stirred at 50 °C for 2 h, after which TBAF 1 M in THF (1768 μL, 1.768 mmol) was added, and the solution was stirred at 50 °C for an additional 12 h before it was directly injected onto a reverse-phase basic column under a 0-50% ACN:HO gradient of 0.01% NHOH over 25 min. The product (III.8) eluted with 100% ACN. A void volume of 5 column volumes (0.01% NHOH in 100% HO) was established to begin washing away excess TBAF. Identified fractions were collected and concentrated to give an off-white solid, which was dried under high vacuum and carried forward as is (218.8 mg). LCMS method 4: Rt=2.97 min; MS m / z 514.2[M+1]+.

[0240] Step 6: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.9a) and ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.9b) [ka] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate (218.8 mg, 0.414 mmol) III.8 was dissolved in THF (2 mL), followed by the addition of IV.1 (201 mg, 0.829 mmol) and DBU (125 μL, 0.829 mmol). The solution was stirred at 80° C. for 32 hours, after which it was heated to 100° C. and stirred for 48 hours, followed by the addition of additional IV.1 (301 mg, 1.243 mmol) and DBU (125 μL, 0.829 mmol). The solution was then stirred at 100° C. for an additional 48 hours before it was concentrated and then loaded directly onto a normal phase column and purified via 0-100% EtOAc:heptane over 25 minutes.

[0241] The product (III.9a and III9 mixture) is eluted with 100% EtOAc. The identified fractions were collected and concentrated to give a white, crumbled solid, which was dried under high vacuum and carried forward. (110.9 mg, 43.51% yield). III.9a: LCMS Method 4: Rt = 3.25 min; MS m / z 584.2 [M+1] +. III.9b: LCMS Method 4: Rt = 3.47 min; MS m / z 584.2 [M+1] +.

[0242] Example 1: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (C-1) [ka] Step 1: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)methanol (III.4a) [ka] To a solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (III.3a) (0.09 g, 0.1578 mmol) in anhydrous THF (2 mL) was added dropwise LAH (1 M in THF, 0.23 mL, 0.237 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5 mL) and quenched with sodium sulfate decahydrate. It was filtered through a celite bed and the filtrate was concentrated to give the crude product, (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)methanol (III.4a) (0.08 g, 96.0%), which was used for the next step without further purification. LCMS Method C2: Rt=1.30 min; MS m / z 528.6 [M+1]+

[0243] Step 2: Synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde (III.5a) [ka] To a solution of (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)methanol (III.4a) (0.08 g, 0.151 mmol) in DCM (4 mL) was added Dess-Martin periodinane (0.1 g, 0.235 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (25 mL) and extracted with DCM (3 × 20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give crude product 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde (III.5a) (0.08 g, 100% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.30 min; MS m / z 526.8 [M+1]+.

[0244] Step 3: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.6a) [ka] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.044 g, 0.198 mmol) in THF (1 mL) was added NaH (55-60% in mineral oil, 0.009 g, 0.225 mmol) at 0 °C, and the mixture was stirred at room temperature for 30 min. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde (III.5a) (0.080 g, 0.152 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product, (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.6a) (0.05 g, 55.2% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.41 min; MS m / z 596.5 [M+1]+

[0245] Step 4: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (Compound 1) [ka]

[0044] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.6a) (0.05 g, 0.083 mmol) in ethanol (3 mL) was added NaOH (0.010 g, 0.250 mmol) in water (1.5 mL), and the mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was concentrated, the pH was adjusted to 4 with citric acid solution, and it was extracted with DCM (2 x 15 mL) and concentrated. The crude material was purified by HPLC (MeCN / HO+0.1% NHOH, X-bridge C18) to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (compound 1) (0.007 g, 14.7% yield). LCMS Method H3: Rt=2.18 min; MS m / z 568.2 [M+1]+. 1 H NMR(400MHz,DMSO- d6)δ 7.61-7.49(m,4H),7.34(dd,J=8.4,2.1Hz,1H),6.81-6.77(m,2H),6.77-6.71(m, 1H),6.28(d,J=15.9Hz,1H),5.01-4.88(m,1H),4.59-4.29(m,4H),3.70(d,J=13.4 Hz,1H),3.52(d,J=13.4Hz,1H),3.02-2.89(m,1H),2.79(d,J=11.4Hz,1H),2.73-2 .57(m,2H),2.44-2.31(m,1H),2.21-2.05(m,2H),2.02(s,3H),1.81-1.59(m,4H).

[0246] Example 2: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (C-2) [ka] Step 1: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)methanol (III.4b) [ka] A solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate (III.3b) (0.140 g, 0.246 mmol) in anhydrous THF (2 mL) was cooled to 0° C. LAH (1 M in THF, 0.36 mL, 0.368 mmol) was added dropwise and the reaction mixture was continued at room temperature for 1 h. The reaction progress was monitored on TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (5 mL) and quenched with sodium sulfate decahydrate. It was filtered through a bed of Celite and concentrated to give the crude product, (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)methanol (III.4b) (0.128 g, 98.71% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.26; MS m / z 528.6 [M+1]+

[0247] Step 2: Synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carbaldehyde (III.5b) [ka] To a solution of (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)methanol (III.4b) (0.128 g, 0.242 mmol) in DCM (6.5 mL) was added Dess-Martin periodinane (0.154 g, 0.363 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (25 mL) and extracted with DCM (3×20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give the crude product, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carbaldehyde (III.5b) (0.120 g, 94.1% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.28 min; MS m / z 526.8, [M+1]+.

[0248] Step 3: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.6b) [ka] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (0.066 g, 0.294 mmol) in THF (1 mL) was added 55-60% NaH in mineral oil (0.014 g, 0.350 mmol) at 0 °C and stirred at room temperature for 30 min. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carbaldehyde (III.5b) (0.120 g, 0.228 mmol) was added and the reaction was stirred at 60 °C for 2 h. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product, (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.6b) (0.1 g, 73.5% yield), which was used for the next step without further purification. LCMS Method C2: Rt=1.31 min; MS m / z 596.8 [M+1]+.

[0249] Step 4: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (Compound 2) [ka]

[0044] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.6b) (0.1 g, 0.083 mmol) in ethanol (6 mL) was added NaOH (0.02 g, 0.500 mmol) in water (3 mL) and the reaction mixture was stirred at room temperature for 12 h. The reaction progress was monitored on TLC. After completion of the reaction, the solvent was evaporated and the pH was adjusted to 4 with citric acid solution, followed by extraction with DCM (2 x 15 mL) and concentration. The crude material was purified by HPLC (MeCN / HO+0.1% NHOH, X-bridge C18) to give the product (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (compound 2) (0.020 g, 21.0% yield). LCMS Method C2: Rt=1.24 min; MS m / z 568 [M+1]+. 1 H NMR (400MHz, methanol-d4) δ 7.65-7.49(m,3H),7.31(dd,J=10.9,2.1Hz,1H),7.24(dd,J=8.4,2.0Hz,1H),6 .86-6.70(m,3H),6.48(d,J=15.8Hz,1H),5.16(s,1H),4.68(t,J=7.1Hz,1H),4 .56-4.37(m,3H),4.00(s,2H),3.73-3.54(m,1H),3.25(s,2H),3.21(d,J=11.6 Hz,2H),2.81(s,2H),2.53(dd,J=22.3,13.0Hz,2H),2.06(s,3H),1.93(s,2H).

[0250] Examples 3 and 4: Synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (C-3) and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylic acid (C-4) [ka] Step 1: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (110.3 mg, 0.179 mmol) was dissolved in THF (897 μL), followed by the addition of lithium hydroxide (42.9 mg, 1.793 mmol) and 1 mL of water. The solution was then stirred at 70° C. for 30 minutes, after which it was heated to 80° C. for 24 hours. Lithium hydroxide (21.47 mg, 0.897 mmol) was then added and the solution was continued stirring at 80 °C for an additional 24 h, after which it was concentrated until only water remained and loaded directly onto a reverse-phase basic column under 0.01% NH OH in 0-50% ACN:HO over 25 min. The product eluted at 40% ACN.

[0251] Compound 3: The identified fractions were collected and concentrated to give a yellow-white solid, which was subsequently subjected to separation for purification (23.1 mg, 22.08% yield). 1H NMR(400MHz,DMSO- d6)δ 7.59-7.55(m,1H),7.55-7.53(m,1H),7.35-7.32(m,1H),6.80-6.72(m,3H),4.92(qd,J=7.1,3.2Hz,1H),4.81(dd,J =14.3,7.1Hz,1H),4.62(dd,J=14.3,3.3Hz,1H),4.45(ddd,J=8.4,7.1,5.7Hz,1H),4.34(dt,J=9.0,6.0Hz,1H),3.75 (d,J=13.4Hz,1H),3.52(d,J=13.4Hz,1H),2.89(dd,J=50.8,11.3Hz,2H),2.70-2.59(m,2H),2.41-2.34(m,1H),2.3 2(s,3H),2.17(q,J=3.1,2.3Hz,1H),2.12-2.04(m,1H),2.04-1.99(m,3H),1.81-1.64(m,4H).LCMS method 3: Rt=1.91 min;MS m / z 556.2[M+1]+.

[0252] Compound 4: The identified fractions were collected and concentrated to give a yellow-white solid, which was subsequently subjected to separation for purification (15.4 mg, 0.027 mmol, 15.17% yield). 1 H NMR(400MHz,DMSO- d6)δ 7.60-7.52(m,2H),7.34(dd,J=8.5,2.2Hz,1H),6.81-6.77(m,2H),6.74(q,J=4.6,4.2Hz,1H),5.01(qd, J=7.5,2.7Hz,1H),4.53-4.36(m,3H),4.26(dd,J=15.2,2.8Hz,1H),3.69(d,J=13.5Hz,1H),3.45(d,J=13 .4Hz,2H),2.95(d,J=11.2Hz,1H),2.79(d,J=11.2Hz,1H),2.73-2.59(m,2H),2.48(s,3H),2.40(ddd,J= MS m / z 556.8[M+1]+.

[0253] Example 5: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (C-5) [ka] Step 1: (S)-ethyl 2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (I.12) [ka] To a solution of ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (I.11) (5200 mg, 22.31 mmol), triphenylphosphine (6437 mg, 24.54 mmol), and (S)-oxetan-2-ylmethanol (IV.2) (2162 mg, 24.54 mmol) in THF (120 mL) was added diisopropyl azodicarboxylate (4.77 mL, 24.54 mmol) dropwise at 0 °C. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated and purified by chromatography (EtOAc / heptane 0-100%). The product-containing fractions were combined, concentrated, and repurified using the same conditions as above to give the title compound (S)-ethyl 2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (I.12). LCMS Method 1: Rt=0.72 min; MS m / z 303.0 [M+1]+. 1 H NMR (400 MHz, chloroform-d) δ 5.06 (dtd, J = 7.7, 6.5, 4.3 Hz, 1H), 4.76-4.58 (m, 3H), 4.52 (dt, J = 9.0, 6.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.82-2.69 (m, 1H), 2.51-2.38 (m, 4H), 1.48-1.25 (m, 3H).

[0254] Step 2: (S)-(2-Bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (I.13) [ka] To a solution of (S)-ethyl 2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (I.12) (1.331 g, 4.39 mmol) and MeOH (0.888 mL, 21.95 mmol) in THF (20 mL) was added 2N LiBH THF solution (8.78 mL, 17.56 mmol). The reaction was heated to 50 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was cooled to 0 °C, followed by the addition of 10 mL of ethyl acetate. The reaction mixture was stirred for 10 min, then diluted with THF (50 mL) and quenched with saturated aqueous NH Cl (2 mL), which was added very slowly to the reaction mixture. The reaction mixture was stirred for 30 min, followed by the addition of Na SO . The reaction mixture was filtered and concentrated. The residue was dissolved in acetone (100 mL), and some white solid precipitated. The mixture was filtered and concentrated, and the resulting residue of (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (I.13) was used in the next step without further purification. LCMS Method 2: Rt=0.64 min; MS m / z 263 [M+1]+.

[0255] Step 3: (S)-2-Bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (I.14) [ka] To a solution of (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (I.13) (1.146 g, 4.39 mmol) in ACN (22 mL) was added MnO (5.72 g, 65.9 mmol). The reaction mixture was heated to 50 °C for 16 h. The reaction mixture was filtered through Celite and concentrated, and the resulting residue of (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (I.14) was used in the next step without further purification. LCMS Method 2: Rt = 0.76 min; MS m / z 259 [M+1] +

[0256] Step 4: (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (I.15) [ka] To a solution of triethyl phosphonoacetate (3813 μL, 19.05 mmol) in DMF (60 mL) was added NaH in oil, 60% (863 mg, 21.59 mmol) at 0 °C. The reaction was stirred at 0 °C for 15 min, followed by the addition of (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (I.14) (3.29 g, 12.7 mmol) in DMF (5 mL). The reaction was stirred at 0 °C for 15 min, followed by 15 min at room temperature. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl, followed by extraction twice with ether. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and concentration, the residue was purified by chromatography (EtOAc / heptane 0 to 100%). The product-containing fractions were combined, concentrated, and repurified using the same conditions as above to give (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (I.15). LCMS Method 2: Rt=1.34 min; MS m / z 329.2 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 16.0 Hz, 1H), 6.12 (dd, J = 16.1, 0.5 Hz, 1H), 5.06 (dtd, J = 7.7, 6.6, 3.9 Hz, 1H), 4.66 (ddd, J = 8.5, 7.3, 6.0 Hz, 1H), 4.51 (dt, J = 9.1, 6.1 Hz, 1H), 4.38-4.22 (m, 4H), 2.77 (dddd, J = 11.5, 8.4, 7.6, 6.1 Hz, 1H), 2.55-2.44 (m, 1H), 2.42 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0257] Step 5: (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (I.16) [ka] To a solution of (S,E)-ethyl 3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (I.15) (0.48 g, 1.458 mmol) and DMF (1.129 mL, 14.58 mmol) in THF (15 mL) was added 1.3 N Turbo Grignard in THF (3.36 mL, 4.37 mmol) slowly at 0 °C. The reaction was stirred at 0 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted three times with ether. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and concentration, the residue of the title compound (S,E)-ethyl 3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (I.16) was used in the next step without further purification. LCMS Method 2: Rt=1.25 min; MS m / z 279.1 [M+1]+.

[0258] Step 6: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.10a) [ka] To a solution of (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (I.16) (77.4 mg, 0.278 mmol) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-ium, 4-methylbenzenesulfonic acid HCl salt (II.2) (107 mg, 0.278 mmol) in DCM (2 mL) was added pyridine (22.49 μL, 0.278 mmol). The reaction was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (77 mg, 0.362 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0 °C, quenched with saturated sodium bicarbonate solution, and extracted twice with DCM. The combined organic layers were concentrated, and the residue was purified by chromatography (EtOAc / heptane 0-100%) to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.10a) (90.5 mg, 53.3%). LCMS Method 2: Rt = 1.39 min; MS m / z 610.3 M+. 1H NMR(400MHz, methylene chloride-d2)δ 7.72(d,J=16.2Hz,1H),7.60(t,J=8.2Hz,1H),7.24-7.15(m,2H),6.86-6.79(m,1H),6.79-6.71(m,2H),6.10( d,J=15.9Hz,1H),5.08(td,J=8.2,5.5Hz,1H),4.64(ddd,J=8.4,7.4,5.8Hz,2H),4.50(dt,J=9.1,5.9Hz,2H),4 .26(q,J=7.1Hz,2H),3.70(d,J=36.9Hz,2H),2.96(d,J=41.3Hz,2H),2.78(dtd,J=11.3,8.1,6.0Hz,2H),2.56 -2.45(m,1H),2.41(s,3H),2.34-2.18(m,1H),2.09(d,J=1.1Hz,4H),2.00-1.74(m,4H),1.35(t,J=7.1Hz,3H).

[0259] Step 7: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (Compound 5) [ka] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.10a) (50 mg 0.082 mmol) in THF (0.6 mL)-MeOH (0.2 mL)-water (0.1 mL) was added LiOH.HO (17.19 mg, 0.410 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was quenched with two drops of formic acid and directly purified by preparative HPLC (conditions: basic 15–40% acetonitrile-3.ACN / HO+5 mM NHOH 75 ml / min; column: Waters XBridge C18 OBD 30 × 50 mm) to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (compound 5) (1.6 mg, 3.25%). HRMS Method 5: 582.2191 [M+H]+, calculated for C31H34ClFN3O5: 582.2207 [M+H]+. 1 H NMR (400 MHz, methylene chloride-d2) δ 7.61 (d, J = 15.9 Hz, 1H), 7.50-7.39 (m, 1H), 7.09-7.01 (m, 2H), 6.70-6.62 (m, 1H), 6.62-6.55 (m, 2H), 6.00 (d, J = 16.0 Hz, 1H), 5.05-4.86 (m, 1H), 4.55-4.39 (m, 2H), 4.31 ( t,J=8.4Hz,2H),3.70-3.44(m,2H),2.86(dd,J=40.7,11.1Hz,2H),2.61(p,J=8.5Hz ,2H),2.28(s,4H),2.22-2.01(m,2H),1.94(d,J=1.1Hz,3H),1.72(d,J=25.9Hz,4H).

[0260] Example 6: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (C-6) [ka] Step 1: (E)-3-(4-methyl-1H-imidazol-5-yl)ethyl acrylate (I.19) [ka] To a mixture of 4-bromo-5-methyl-1H-imidazole (I.18) (3.0 g, 18.63 mmol) in 1,4-dioxane (30 mL), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (I.17) (5.05 g, 22.36 mmol), KPO (2 M in water, 7.9 g, 18.63 mL, 2 molar, 37.27 mmol), and [1,1-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (607.2 mg, 931.7 μmol) were added. The reaction mixture was heated at 100 °C for 20 h. The reaction mixture was filtered through Celite. 50 mL of water was added to the reaction mixture, which was then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude material was purified by chromatography (methanol / DCM 0-15%) to give the title compound (E)-3-(4-methyl-1H-imidazol-5-yl)ethyl acrylate (I.19) as a brown powder (2.52 g, 75% yield). LCMS Method 2: Rt = 0.63 min; MS m / z 181.2 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ 7.66(s,1H),7.50(dd,J=15.5,0.7Hz,1H),6.23(d,J=15.4Hz,1H),4.14(q,J=7.1Hz,2H),2.27(s,3H),1.24(t,J=7.1Hz,3H),1.07(s,1H).

[0261] Step 2: (S,E)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)ethyl acrylate (I.20) [ka] To (E)-ethyl 3-(4-methyl-1H-imidazol-5-yl)acrylate (I.19) (600 mg, 2.99 mmol) in CHCN (14 mL) were added cesium carbonate (1.46 g, 4.49 mmol) and (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (IV.1) (798 mg, 3.29 mmol) at room temperature. The mixture was stirred under microwave irradiation at 120 °C for 1 h. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous layer was extracted twice with EtOAc (40 mL). The organic phase was dried over magnesium sulfate and concentrated. The crude material was purified by chromatography (methanol / DCM 0-15%) to give the title compound (S,E)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)ethyl acrylate (I.20) as a light brown liquid (370 mg, 49% yield). LCMS Method 3: Rt=0.81 min; MS m / z 251.2 [M+H]+. 1H NMR(400MHz, methylene chloride-d2)δ 7.70-7.55(m,2H),6.50(d,J=15.4Hz,1H),5.03(dddd,J=7.7,6.8,5.0,4 .0Hz,1H),4.63(ddd,J=8.5,7.3,5.9Hz,1H),4.37(dt,J=9.2,6.0Hz,1H), 4.23(q,J=7.1Hz,2H),4.08(dd,J=4.5,1.3Hz,2H),2.73(dddd,J=11.4,8. 5,7.7,6.0Hz,1H),2.43-2.28(m,1H),2.34(s,3H),1.33(t,J=7.1Hz,3H).

[0262] Step 3: (S,E)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)ethyl acrylate (I.21) [ka] To (S,E)-ethyl 3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)acrylate (I.20) (180 mg, 647.22 μmol) in THF (4 mL) was added LDA (1 M in THF) (97.072 mg, 906.11 μL, 1 molar, 906 μmol) at −78 °C, and the mixture was subsequently stirred at −78 °C for 30 min. DMF (283.9 mg, 301 μL, 3.88 mmol) was then added, and the mixture was stirred at −78 °C for 30 min, then warmed to room temperature and stirred for an additional 30 min. A saturated solution of NH4Cl (10 mL) and EtOAc (10 mL) were added. The reaction mixture was partitioned between EtOAc. The aqueous layer was extracted with EtOAc (10 mL). The organic phase was dried over magnesium sulfate and concentrated. The crude material was purified by chromatography (EtOAc / heptane 0-70%) to give the title compound (S,E)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)ethyl acrylate (I.21) as a colorless oil (83 mg, 46% yield). LCMS Method 2: Rt=0.78 min; MS m / z 279.1 [M+H]+. 1H NMR (400 MHz, methylene chloride-d6) δ 9.57 (s, 1H), 7.45 (d, J = 15.6 Hz, 1H), 6.48 (d, J = 15.6 Hz, 1H), 4.94-4.82 (m, 1H), 4.54-4.35 (m, 3H), 4.22 (dt, J = 9.1, 6.2 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 2.58 (dtd, J = 11.7, 8.1, 6.1 Hz, 1H), 2.30 (s, 3H), 2.22 (ddt, J = 11.7, 9.2, 7.0 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H).

[0263] Step 4: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.10b) [ka] To a mixture of (S,E)-ethyl 3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)acrylate (I.21) (68 mg, 244.3 μmol), II.1 (127.1 mg, 244.3 μmol), and triethylamine (98.90 mg, 136 μL, 977.3 μmol) in DCM (3 mL) was added sodium triacetoxyborohydride (77 mg, 366.5 μmol) and acetic acid (14.67 mg, 13.99 μL, 244.3 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (15 mL) and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the crude material was purified by chromatography (EtOAc / heptane 0-100%) to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.10b) as a colorless oil (97 mg, 65% yield). LCMS Method 2: Rt=1.37 min; MS m / z 610.3 [M+H]+. 1 H NMR(400MHz, methylene chloride-d2)δ 7.64-7.52(m,2H),7.25-7.12(m,2H),6.80(dd,J=8.0,7.4Hz,1H),6.73(ddd,J=7.3,6.0,1.4Hz,2H),6.44(d,J=15.3Hz, 1H),5.09(qd,J=7.2,2.8Hz,1H),4.64(ddd,J=8.3,7.4,5.9Hz,1H),4.48(dt,J=9.1,5.8Hz,2H),4.35-4.06(m,4H),3.73( d,J=13.5Hz,1H),3.63(d,J=13.5Hz,1H),3.00(d,J=11.1Hz,1H),2.91(d,J=11.1Hz,1H),2.77(dtd,J=11.2,8.0,5.9Hz, 2H),2.46(ddt,J=11.3,9.2,7.3Hz,1H),2.37(s,3H),2.15-2.01(m,5H),1.88-1.82(m,4H),1.30(dt,J=22.0,7.2Hz,3H).

[0264] Step 5: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (Compound 6) [ka] To a mixture of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethyl acrylate (III.10b) (97.00 mg, 1 equiv., 159 μmol) in THF (1.5 mL) and methanol (1.5 mL) was added lithium hydroxide hydrate (1 M solution, 20.01 mg, 477.0 μL, 477.0 μmol) at room temperature. The reaction mixture was stirred at 65° C. for 2 hours. LC-MS showed the reaction was complete. The reaction mixture was acidified to pH 2-3 with 2 N HCl solution. The crude material was purified by preparative HPLC (conditions: basic 15-40% acetonitrile-3.ACN / HO + 5 mM NHOH 75 ml / min; column: Waters XBridge C18 OBD 30 × 50 mm) to give the title compound (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid (compound 6) as a white solid (89 mg, 75% yield). HRMS Method 5: Rt = 1.81 min; MS m / z 582.1 [M+H]. LCMS method 3: Rt=2.1 min; MS m / z 582.1[M+H]+. 1H NMR (400 MHz, methylene chloride-d₂) δ 7.52 (s, 1H), 7.44 (t, J = 8.3 Hz, 1H), 7.04 (t, J = 8.7 Hz, 2H), 6.70-6.56 (m, 3H), 6.38 (d, J = 15.4 Hz, 1H), 4.95 (s, 1H), 4.50 (s, 1H), 4.34 (s, 2H), 4.16 (s, 1H), 3.63 (s, 1H), 3.57 (s, 1H), 2.89 (s, 1H), 2.80 (s, 1H), 2.62 (s, 2H), 2.33 (s, 1H), 2.16-2.04 (m, 5H), 1.93 (s, 3H), 1.75-1.69 (m, 4H).

[0265] Example 7: Synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7) [ka] Step 1: Ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.23) [ka] Ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.22) (0.333 g, 1.600 mmol) and N-bromosuccinimide (0.342 g, 1.920 mmol) were combined in acetonitrile (5 mL) and heated to 50 °C for 2 h. The reaction mixture was concentrated and partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous phase was extracted once with EtOAc. The combined organic phases were dried over magnesium sulfate and concentrated. The crude reaction mixture was purified by chromatography (EtOAc / heptane 0-50%). The product-containing fractions were combined and concentrated to give ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.23) (240 mg, 52.3% yield). LCMS Method 1: Rt = 0.81 min; MS m / z 287.2 [M+H]+.

[0266] Step 2: (S)-ethyl 2-bromo-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.24) [ka] Triphenylphosphine (274 mg, 1.045 mmol), (S)-oxetan-2-ylmethanol (IV.2) (92 mg, 1.045 mmol), and ethyl 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.23) (200 mg, 0.697 mmol) were combined in tetrahydrofuran (2 mL). Diisopropyl azodicarboxylate (0.203 mL, 1.045 mmol) was added dropwise, and the reaction was stirred at 20 °C for 16 h. The reaction mixture was concentrated and purified by chromatography (EtOAc / heptane 0 to 100%) to give ethyl (S)-2-bromo-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.24) (200 mg, 74.7% yield). LCMS method 1: Rt=0.97 min; MS m / z 357.0[M+H]+.

[0267] Step 3: (S)-ethyl 2-formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.25) [ka] (S)-Ethyl 2-bromo-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (I.24) (62 mg, 0.174 mmol) and DMF (0.134 mL, 1.736 mmol) were combined in THF, and the reaction was cooled to −20° C. under nitrogen. Turbo Grignard (0.267 mL, 0.347 mmol) was added dropwise, and the reaction was stirred under nitrogen for 2 hours while warming to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with EtOAc. The combined organics were dried over magnesium sulfate and concentrated to give ethyl (S)-2-formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate. (I.25). LCMS method 1: Rt=0.96 min; MS m / z 307.0[M+H]+.

[0268] Step 4: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (III.11) [ka] (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine tosylate (II.1) (0.071 g, 0.137 mmol) was partitioned between DCM and saturated sodium bicarbonate solution. The organic phase was washed again with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated. The free base was combined with (S)-2-formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (I.25) (0.042 g, 0.137 mmol) and dissolved in DCM (2 mL). Sodium triacetoxyborohydride (0.044 g, 0.206 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (III.11). LCMS Method 2: Rt=1.50 min; MS m / z 638.3 [M+H]+.

[0269] Step 5: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7) [ka] Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (63.8 mg, 0.1 mmol) was combined with lithium hydroxide (III.11) (11.97 mg, 0.500 mmol) in water (0.6 mL), methanol (0.6 mL), and tetrahydrofuran (0.6 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was partially concentrated, diluted with water and acetonitrile, and purified by reverse-phase HPLC eluting with MeCN / HO+0.1% NHOH to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7, 16.2 mg, 26% yield). LCMS Method 4:R t =1.75 min; mass=610.3[M+H]+. 1 H NMR(400MHz,chloroform-d)δ 7.42(d,J=8Hz,1H),7.03(m,2H),6.71-6.57(m,3H),4.99(br s,1H),4.80(m,1H),4.49(m,3H),4.22(br s,1H),3.87(m,2H),2.72(m,2H),2.54(m,3H),2.33(m,3H),2.13(m,2H),1.95(s,3H).

[0270] Example 8: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylic acid (C-8) [ka] Step 1: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)methanol (III.12) [ka] Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (III.11) (42 mg, 0.066 mmol) was combined with tetrahydrofuran (1 mL) and methanol (0.017 mL), lithium borohydride (1 M in THF, 0.066 mL, 0.132 mmol) was added, and the reaction was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and partitioned between EtOAc and saturated sodium bicarbonate solution. The aqueous phase was re-extracted with EtOAc. The combined organics were dried over magnesium sulfate and concentrated to give (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)methanol (III.12). LCMS Method 2: Rt=1.33 min; MS m / z 596.2 [M+H]+.

[0271] Step 2: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbaldehyde (III.13) [ka] (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)methanol (III.12) (39.2 mg, 0.066 mmol) was dissolved in DCM (1 mL). Dess-Martin periodinane (41.8 mg, 0.099 mmol) was added and the reaction was stirred at room temperature for 30 min. The reaction mixture was filtered and partitioned between DCM and 10% sodium thiosulfate solution. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbaldehyde (III.13). LCMS method 2: Rt=1.44 min; MS m / z 594.1[M+H]+.

[0272] Step 3: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)ethyl acrylate (III.14) [ka] A vial was charged with sodium hydride (60%, 3.23 mg, 0.081 mmol) and cooled to 0 °C. A solution of triethyl phosphonoacetate (0.012 mL, 0.061 mmol) in DMF (0.3 mL) was added, and the reaction mixture was stirred for 5 min. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbaldehyde (III.13) (24 mg, 0.040 mmol) in DMF (0.3 mL) was added, and the reaction mixture was stirred at 0 °C for 10 min. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed again with water and brine. The organic phase was dried over magnesium sulfate and concentrated to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)ethyl acrylate (III.14). LCMS Method 2: Rt=1.49 min; MS m / z 664.1 [M+H]+.

[0273] Step 4: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylic acid (C-8) [ka] Ethyl (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylate (III.14) (27 mg, 0.041 mmol) and lithium hydroxide (9.74 mg, 0.407 mmol) were combined in tetrahydrofuran (0.15 mL), methanol (0.15 mL), and water (0.15 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partially concentrated and purified by reverse-phase HPLC eluting with MeCN / HO+0.1% NHOH to give (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylic acid (C-8, 5.8 mg, 21% yield). LCMS Method 4: Rt=1.87 min; MS m / z 636.1 [M+H]. 1 H NMR(400MHz,chloroform-d)δ 7.59(d,J=16Hz,1H),7.42(d,J=8Hz,1H),7.04(m,2H),6.69(m,1H),6.63-6.58(m,2H),6.33(d,J=16Hz,1H),5.03(m,1H) ),4.58(m,2H),4.41(m,2H),3.73(m,2H),2.88(m,1H),2.65(m,2H),2.38(m,1H),2.22(m,2H),1.95(s,3H),1.93(m,1H), 1.86-1.76(m,4H).

[0274] Example 9 Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid (C-9) [ka] Step 1: Ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylate (III.15) [ka] Sodium hydride (3.54 mg, 0.089 mmol) was suspended in DMSO (0.3 mL), and trimethylsulfoxonium iodide (19.48 mg, 0.089 mmol) was added in three portions. The mixture was stirred at room temperature until a clear solution was formed. A solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (III.10a) (18 mg, 0.030 mmol) in DMSO (0.3 mL) was added, and the mixture was heated to 50° C. for 3 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and brine. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylate (III.15). LCMS Method 2: Rt=1.44 min; MS m / z 624.3 [M+H]+.

[0275] Step 2: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid (C-9) [ka] Ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylate (III.15) (18.72 mg, 0.03 mmol) and lithium hydroxide (3.59 mg, 0.150 mmol) were combined in tetrahydrofuran (0.2 mL), methanol (0.2 mL), and water (0.2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partially concentrated and purified by reverse-phase HPLC eluting with MeCN / HO+0.1% NHOH to give 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid (C-9). LCMS Method 4: Rt=1.69 min; MS m / z 596.3 [M+H]. 1 H NMR(400MHz,chloroform-d)δ 7.41(d,J=8Hz,1H),7.02(m,2H),6.66(m,1H),6.63-6.55(m,2H),5.06(m,1H),4.55(m,2H),4.38(m,2H),3.63(m,1H),2.94 (m,1H),2.62(m,2H),2.46-2.20(m,4H),2.09(s,3H),1.97(m,1H)1.94(s,3H),1.80-1.64(m,5H),1.40(m,2H),1.04(m,1H).

[0276] Example 10: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)benzoic acid (C-10) [ka] Step 1: Synthesis of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2a) and (S)-5-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2b) [ka] To a solution of 4-bromo-5-methyl-1H-imidazole (1) (2.000 g, 12.4 mmol) in acetonitrile (50 mL) was added (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (3.33 g, 13.0 mmol) and cesium carbonate (10.1 g, 31.1 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h using a fincondenser and then cooled to room temperature. Water was added, and the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (0-100% EtOAc / heptane, 0-5% MeOH / EtOAc) and the isomers separated to give (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2a) (1.2 g, 42%) LCMS Method 2: Rt = 0.67 min; MS m / z 233.0 [M+1] and (S)-5-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2b) (0.35 g, 12%) LCMS Method 2: Rt = 0.68 min; MS m / z 231.3 [M+1].

[0277] Step 2: Synthesis of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (3) [ka] To a solution of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2a) (580 mg, 2.51 mmol) in THF (12 mL) was slowly added LDA (2.51 mL, 2 molar, 5.02 mmol) in THF / heptane / ethylbenzene at −78° C. The reaction was stirred at −78° C. for 40 minutes, followed by the addition of N,N-dimethylformamide (972 μL, 12.5 mmol). The reaction was stirred from −78° C. to room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted three times with ethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (3) (588.9 mg, 90.6% yield) as a brownish solid. The crude was used for the next step without further purification. LCMS method (rxnmon-basic-polar): Rt = 1.02 min; MS m / z 259.1 [M+H] +

[0278] Step 3: Synthesis of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (4) [ka] To a solution of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (1.6 g, 6.18 mmol) (3) in DCM (40 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-ium chloride (II2) (1.9 g, 4.94 mmol) and TEA (1.72 mL, 12.4 mmol). The reaction was stirred at room temperature for 15-25 minutes, followed by the addition of sodium triacetoxyborohydride (1.36 g, 6.43 mmol). The reaction was stirred at room temperature for an additional 2 hours. The reaction mixture was cooled to 0 °C and quenched with a saturated aqueous solution of NaHCO3. The reaction mixture was extracted twice with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated to give an off-white foam solid. The crude material was further purified by normal phase chromatography (0-100% EtOAc / heptane) to give 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (4) as a white foam solid (1.7 g, 58.2% yield). LCMS Method 4: Rt = 3.42 min; MS m / z 592.3 [M+H] + . 1 H NMR(400MHz,CD2Cl2)δ 7.58(t,J=8.4Hz,1H),7.24-7.13(m,2H),6.85-6.77(m,1H),6.74(s,2H),5.07(qd,J=7.3,2.9Hz ,1H),4.64(td,J=8.0,5.8Hz,1H),4.53-4.37(m,2H),4.29(d,J=15.0Hz,1H),3.67(d,J=13.5Hz,1 H),3.56(d,J=13.7Hz,1H),3.07-2.84(m,2H),2.76(dtd,J=11.4,8.0,5.9Hz,2H),2.46(ddt,J=1 1.3,9.3,7.2Hz,1H),2.23(s,3H),2.21(br,s,2H),2.08(d,J=1.2Hz,3H),1.84(d,J=23.4Hz,4H).

[0279] Step 4: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)benzoic acid (6) [ka] To a solution of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4 (39 mg, 66 μmol) in 1,4-dioxane (0.7 mL) was added 3-boronobenzoic acid 5 (13 mg, 79 μmol), KPO (0.30 mL, 1 molar, 0.30 mmol), and Pd 118 (4.3 mg, 6.6 μmol). The mixture was degassed under N and then microwaved at 120 °C for 20 min. The reaction mixture was diluted with water, filtered through a plug, and purified on basic HPLC to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)benzoic acid (6) as an off-white solid (8 mg, 20% yield). LCMS Method 4: Rt=1.95 min; MS m / z 632.3 [M+H] + . 1H NMR(400MHz,DMSO)δ 8.13(d,J=1.9Hz,1H),7.70-7.58(m,2H),7.54-7.45(m,2H),7.32(t,J=7.6Hz,1H),7.27(dd,J=8.3,2.1Hz,1H), 6.74-6.65(m,3H),4.97(qd,J=7.4,2.9Hz,1H),4.50-4.29(m,3H),4.21(dd,J=15.2,2.9Hz,1H),3.67(d,J=13.3H) z,1H),3.43(d,J=13.4Hz,1H),2.93(dd,J=11.3,4.1Hz,1H),2.82(dd,J=8.8,5.8Hz,1H),2.69-2.51(m,2H),2.34 (m,4H),2.09(ddd,J=14.7,7.1,4.2Hz,1H),2.05-1.98(m,1H),1.96(s,3H),1.66(dqd,J=28.1,11.3,3.5Hz,4H).

[0280] Example 11 Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)benzoic acid (C-11). The title compound was synthesized according to the protocol described in Example 10, using intermediate 2b instead of 2a in step 2.

[0281] Example 12 Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid (C-12). The title compound was synthesized according to the protocol described in Example 10, using 5-carboxypyridine-3-boronic acid instead of 3-bromobenzoic acid.

[0282] Example 13: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (C-13) Phase 1 [ka] Step 1: Synthesis of 2-(3-bromo-2-fluorophenyl)acetonitrile In a 500 mL round-bottom flask, 1-bromo-3-(bromomethyl)-2-fluorobenzene (10 g, 37.33 mmol) was dissolved in acetonitrile (200 mL). To this solution, TMSCN (7 mL, 55.99 mmol) and 1 M TBAF in THF (56 mL, 55.99 mmol) were added sequentially. The reaction was then stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. TLC indicated that SM was consumed and a new polar spot was formed. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3 × 250 mL). The ethyl acetate layers were combined and washed with water and brine. After drying over Na2SO4, the solvent was evaporated to give the crude product. The crude products from both batches were combined and purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-50% ethyl acetate in hexane in a step gradient to give 2-(3-bromo-2-fluorophenyl)acetonitrile (15.00 g, 93.88%) as a colorless liquid. LCMS: Purity: 99.44%, RT: 1.244 min. (Method-C2), mass not supported. 1H NMR (400 MHz, chloroform-d): δ 3.83 (s, 2H), 7.11 (t, J = 7.9 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.3 Hz, 1H).

[0283] Step-2: Synthesis of 2-(3-bromo-2-fluorophenyl)acetic acid (3) In a 500 mL round-bottom flask, 2-(3-bromo-2-fluorophenyl)acetonitrile (15.00 g, 70.08 mmol) was dissolved in 20% aqueous NaOH (200 mL) and stirred at 100° C. for 5 hours. The progress of the reaction was monitored by TLC. TLC showed that SM was consumed and a polar spot was formed. Upon completion of the reaction, the reaction mixture was cooled to room temperature and acidified to pH 3 by dropwise addition of concentrated HCl. The resulting precipitate was filtered and washed thoroughly with water. The solid was then transferred to a round-bottom flask and dried under vacuum to give 2-(3-bromo-2-fluorophenyl)acetic acid (16.20 g, 99.19%) as a colorless solid. LCMS: Purity: 99.39%, RT: 1.193 min. (Method-C2), MS(ES+) m / z: 187.0 [M-COOH]+ and 189.0 [M+2-COOH]+. 1H NMR (400MHz, DMSO-d6): δ 3.70(s,2H),7.12(t,J=7.8Hz,1H),7.36(t,J=7.2Hz,1H),7.61(t,J=7.2Hz,1H),12.60(s,1H).

[0284] Step 3: Synthesis of 2-(3-bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide In a 1000 mL round-bottom flask, 2-(3-bromo-2-fluorophenyl)acetic acid (16.20 g, 69.52 mmol) was dissolved in DCM (320 mL) under nitrogen and cooled to 0 °C. Next, TEA (29 mL, 208.55 mmol), EDC HCl (19.99 g, 104.27 mmol), and HOBT (14.09 g, 104.27 mmol) were added sequentially at 0 °C and stirred at 0 °C for 15 min. After 15 min, N,O-dimethylhydroxylamine HCl (10.17 g, 104.27 mmol) was added at 0 °C and stirring was continued at 0 °C for 15 min. The reaction was then slowly brought to room temperature and stirred at room temperature for 16 h and monitored by TLC. TLC showed the consumption of SM and the formation of a nonpolar spot. The reaction was quenched with water (500 mL) and the DCM was evaporated under vacuum. The aqueous layer was then extracted with EtOAc (3 × 250 mL). The EtOAc layers were collected, dried over NaSO, and evaporated to give a crude oily product, which was purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-60% ethyl acetate in hexane in a step gradient mode to give 2-(3-bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide (14.00 g, 72.94%) as a colorless liquid. LCMS: Purity: 92.11%, RT: 1.230 min. (Method-C2), MS(ES+)m / z:276.0[M]+ and 278.0[M+2]+. 1H NMR (400MHz, chloroform-d): δ 3.23(s,3H),3.73(s,3H),3.85(s,2H),7.01(dt,J=8.1,4.1Hz,1H),7.21-7.28(m,1H),7.42-7.51(m,1H).

[0285] Step 4: Synthesis of 1-(3-bromo-2-fluorophenyl)propan-2-one The reaction was carried out in three batches of 2 g of 2-(3-bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide (5). In a 100 mL round-bottom flask, 2-(3-bromo-2-fluorophenyl)-N-methoxy-N-methylacetamide (2 g, 7.24 mmol) was dissolved in THF (40 mL) and cooled to 0 °C. Next, 3 M methylmagnesium bromide (2.7 mL, 7.97 mmol) in diethyl ether was added at 0 °C and stirred for 1 h, followed by allowing the RM to slowly reach room temperature over 2 h. The progress of the reaction was monitored by TLC. TLC indicated the consumption of SM and the formation of a nonpolar spot. Upon completion of the reaction, all three reactions were quenched with water (100 mL) and combined. The combined aqueous layers were extracted with EtOAc (3 × 250 mL). The EtOAc layer was collected, dried over Na2SO4, and evaporated to give a crude oily product, which was purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-50% ethyl acetate in hexane in a step gradient mode to give 1-(3-bromo-2-fluorophenyl)propan-2-one (3.50 g, 69.70%) as a colorless liquid. LCMS: Purity: 100%, RT: 1.305 min. (Method-C2), mass not supported. 1H NMR (400 MHz, chloroform-d): δ 2.25 (s, 3H), 3.80 (s, 2H), 7.02 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 6.8 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H).

[0286] Step 5: Synthesis of 1-(3-bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)propan-2-ol The reaction was carried out in four batches of 0.25 g of 1-(3-bromo-2-fluorophenyl)propan-2-one (6). In a 25 mL three-necked round-bottom flask equipped with a thermometer pocket and nitrogen bubbler, 1-bromo-4-chloro-2-fluorobenzene (0.25 g, 1.19 mmol) was dissolved in dry THF (10 mL) under nitrogen and cooled to −78°C. Next, n-BuLi (0.53 mL, 1.31 mmol, 2.5 M in hexanes) was added at −78°C and stirred at −78°C for 45 minutes. Next, 1-(3-bromo-2-fluorophenyl)propan-2-one (0.25 g, 1.07 mmol) was added as a solution in THF (2 mL) at −78°C and stirred at −78°C for 1 hour. The reaction was then allowed to slowly reach room temperature over 1 hour, and the progress of the reaction was monitored by TLC. TLC indicated the consumption of SM and the formation of a nonpolar spot. All four reactions were quenched with water (10 mL) and combined. The combined aqueous layers were extracted with EtOAc (3 × 50 mL). The combined EtOAc layers were washed with water and brine. After drying over NaSO, the solvent was evaporated to give the crude product, which was purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-20% ethyl acetate in hexane in a step gradient mode to give 1-(3-bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)propan-2-ol (0.41 g, 26.41%) as a colorless liquid. LCMS: Purity: 93.82%, RT: 1.531 min. (Method-C2), mass not supported. 1H NMR(400MHz,DMSO-d6):δ 1.54(s,3H),3.12(s,2H),5.56(s,1H),7.00(t,J=7.8Hz,1H),7.08-7.22(m,2H),7.33-7.45(m,2H),7.45-7.52(m,1H).

[0287] Step 6: Synthesis of 7-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran In a 50 mL sealed tube, 1-(3-bromo-2-fluorophenyl)-2-(4-chloro-2-fluorophenyl)propan-2-ol (0.93 g, 2.57 mmol) was dissolved in dry THF (20 mL) under nitrogen, and KOtBu (0.38 g, 3.34 mmol) was added at room temperature. The reaction vial was sealed with a PTFE screw cap and stirred at 40 °C for 16 h. The progress of the reaction was monitored by TLC. TLC indicated the consumption of SM and the formation of a nonpolar spot. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with water and brine. After drying over Na2SO4, the solvent was evaporated to give the crude product, which was purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-10% ethyl acetate in hexane in a step gradient mode to give 7-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran (0.50 g, 56.91%) as a colorless liquid. LCMS: Purity: 97.17%, RT: 1.674 min. (Method-C2), mass not supported. 1H NMR (400 MHz, chloroform-d): δ 1.87 (s, 3H), 3.51-3.66 (m, 2H), 6.78 (t, J = 7.7 Hz, 1H), 7.05-7.21 (m, 3H), 7.32-7.38 (m, 1H), 7.65 (t, J = 8.7 Hz, 1H).

[0288] Step-7: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate In a 100 mL sealed tube, 7-bromo-2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran (0.84 g, 2.46 mmol) and K2CO3 (1.02 g, 7.38 mmol) were dissolved in dioxane:water (35 mL, 6:1) under nitrogen and purged with nitrogen for 5 minutes. Next, tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.91 g, 2.95 mmol) and Pd(PPh3)4 (0.14 g, 0.12 mmol) were added at room temperature, and the tube was sealed with a PTFE screw cap. The reaction was then stirred at 90 °C for 16 hours. The reaction progress was monitored by TLC. TLC showed that SM was consumed and a polar spot was formed. The reaction mixture was cooled to room temperature and filtered over Celite. The Celite bed was washed with EtOAc (150 mL). The filtrate was collected, dried over Na2SO4, and evaporated to give the crude product, which was purified by flash chromatography using flash silica 40-60 μm (60 Å) and 0-50% ethyl acetate in hexane in a step gradient mode to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.05 g, 96.18%) as a colorless gummy solid. LCMS: Purity: 100%, RT: 1.865 min. (Method-C2), MS (ES+) m / z: 388.3 [M-56]+. 1H NMR (400MHz, chloroform-d):δ 1.56(s,9H),1.80(s,3H),2.69(s,2H),3.44(d,J=16.0Hz,1H),3.52(d,J=16.0Hz,1H),3.65-3.78(m,2H),4.1 8(s,2H),6.42(s,1H),6.89(t,J=7.6Hz,1H),7.07(d,J=7.3Hz,1H),7.12-7.19(m,3H),7.56(t,J=8.6Hz,1H).

[0289] Step 8: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate In a 100 mL round-bottom flask, tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.05 g, 2.37 mmol) was dissolved in MeOH (25 mL) and Raney Ni (1 g) was added at room temperature under a nitrogen atmosphere. The nitrogen atmosphere was then replaced with hydrogen and the reaction was stirred at room temperature under a balloon pressure hydrogen atmosphere for 16 hours. The progress of the reaction was monitored by TLC. TLC showed the consumption of SM and the formation of a nonpolar spot. The reaction was filtered over Celite and washed with MeOH (100 mL). The filtrate was collected and evaporated to give a crude oily product, which was purified by silica gel column chromatography using #100-200 mesh size silica gel and 0-20% ethyl acetate in hexane in a step gradient mode to give racemic tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.80 g, 75.85%) and a mixture with 0.130 g of the dechloro product. LCMS: Purity: 100%, RT: 2.679 min. (Method-C2), MS (ES+) m / z: 390.4 [M-56]+. Chiral HPLC: two peaks; 5.11 min (50.01%): 9.31 min (49.80%).

[0290] 0.8 g of the racemic mixture was further purified by chiral preparative HPLC purification and the resulting fractions were concentrated. Fraction-1: Light yellow sticky gum (35.08%). Fraction-2: Light yellow sticky gum (33.18%).

[0291] Racemic mixture tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate: 44 mg as a pale yellow sticky gum.

[0292] Fraction 1: LCMS: Purity: 100%, RT: 2.649 min. (Method-C3), MS(ES+)m / z:346.0[M-Boc]+. Chiral HPLC: 5.07 min (100%). 1H NMR (400MHz, chloroform-d):δ 1.54(s,9H),1.70-1.87(m,5H),1.93(t,J=13.0Hz,2H),2.85-3.06(m,3H),3.40-3.56(m,2H),4.2 7-4.38(m,2H),6.88(t,J=7.5Hz,1H),7.01-7.09(m,2H),7.11-7.20(m,2H),7.58(t,J=8.6Hz,1H).

[0293] Fraction 2: Purity: 100%, RT: 2.648 min. (Method-C3), MS(ES+) m / z:446.0[M]+ and 448.0[M+2]+. Chiral HPLC: 9.25 min (99.82%). 1H NMR (400MHz, chloroform-d):δ 1.54(s,9H),1.70-1.85(m,5H),1.93(t,J=12.8Hz,2H),2.83-3.06(m,3H),3.40-3.57(m,2H),4 .32(s,2H),6.88(t,J=7.5Hz,1H),7.00-7.09(m,2H),7.11-7.20(m,2H),7.58(t,J=8.5Hz,1H).

[0294] Phase 2 [ka] Step-1: 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine [ka] To a solution of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (400 mg, 0.897 mmol) in AcOEt (9 mL) was added 4 M HCl in dioxane (330 μL). The mixture was stirred at room temperature for 5 hours. After LC / MS showed the reaction was complete, the mixture was diluted with AcOEt, washed with saturated Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated to give the title compound (279 mg, 95% yield). LCMS Method 1: Rt=0.89 min; MS m / z 346.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.60 (t, J = 8.5 Hz, 1H), 7.16-7.07 (m, 2H), 7.07-6.96 (m, 2H), 6.89-6.76 (m, 1H), 3.52-3.34 (m, 4H), 3.05-2.83 (m, 3H), 2.10-1.86 (m, 4H), 1.74 (s, 3H).

[0295] Step-2: (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-4-methyl-1-((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylate ethyl ester [ka] To a solution of 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine (145 mg, 0.270 mmol), (S,E)-ethyl 3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (85 mg, 0.246 mmol) in DCM (1.3 mL) was added TEA (34.3 μL, 0.246 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (67.7 mg, 0.320 mmol). The reaction was stirred at room temperature for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NaHCO3, and extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase on a C18 column under 0-70% ACN (0.01% NH4OH) / 0.01% NH4OH in HO to give the title compound (96 mg, 64% yield). LCMS Method 2: Rt = 1.49 min; MS m / z 608.3 [M+H]+.

[0296] Step-3: (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid [ka] To a solution of (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-4-methyl-1-((oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (95.5 mg, 1 Eq, 157 μmol) in THF (0.90 mL) / MeOH (0.30 mL) was added 1 M aqueous LiOH (471 μL, 471 μmol) and the mixture was stirred at room temperature overnight. LC / MS showed the reaction was complete. The reaction was quenched with 1M KH2PO4, extracted three times with AcOEt, concentrated, and the residue purified by reverse phase on a C18 column under 0-50% ACN (0.01% NH4OH) / 0.01% NH4OH in HO to give the title compound (73 mg, 79% yield). LCMS Method 2: Rt = 0.94 min; MS m / z 580.2 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.54(t,J=8.5Hz,1H),7.49(dd,J=11.4,2.1Hz,1H),7.32(dd,J=8.5,2.1Hz,1H),7.02(d,J=7.5Hz,2H),6.8 0(t,J=7.4Hz,1H),5.93(d,J=16.1Hz,1H),5.02-4.84(m,1H),4.55-4.41(m,2H),4.41-4.30(m,2H),3.69(d, J=13.4Hz,1H),3.53-3.41(m,2H),3.37(s,1H),2.97(d,J=11.0Hz,1H),2.85(d,J=11.5Hz,1H),2.80-2.68(m ,1H),2.69-2.53(m,2H),2.45-2.35(m,1H),2.22(s,3H),2.20-2.03(m,2H),1.83-1.73(m,3H),1.70(s,4H).

[0297] Example 14 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoic acid (C-14) [ka] Synthesis scheme: [ka] Note: The synthesis of Int-6 is common and described in Example 19.

[0298] Step 5: Synthesis of (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate [ka] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (7) (1.43 g, 0.0063 mol) in DMF (20.7 mL) was added 55-60% NaH (0.301 g, 7.5 mmol) at 0 °C, and the reaction was stirred at the same temperature for 20 min. After 20 min, (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (1.1 g, 4.2 mmol) in DMF (1.7 mL) was added, and the reaction was stirred at room temperature for 30 min. The reaction was monitored by TLC and LCMS. Completion of the reaction was confirmed by TLC. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated to give the crude product. Chromatographic purification on a neutral alumina column (EtOAc / heptane 0-28%) gave (S,E)-ethyl 3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (0.74 g, 53% yield). LCMS Method H: Rt = 2.64 min; MS m / z 329 [M+1]+. 1H NMR(400MHz,chloroform-d)δ 1.38(td,J=7.3,3.9Hz,3H),2.42-2.58(m,4H),2.80(dq,J=14.5,7.7Hz,1H),4.22-4.43(m,4H),4.53(dt,J=9.1 ,5.9Hz,1H),4.68(q,J=7.4Hz,1H),5.09(tt,J=10.3,5.2Hz,1H),6.15(d,J=16.0Hz,1H),7.72(d,J=16.0Hz,1H).

[0299] Step 6: Synthesis of (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate ethyl [ka] To a solution of (S,E)-ethyl 3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (0.740 g, 2.2 mmol) and DMF (1.15 g, 15.4 mmol) in THF (7.4 mL), isopropylmagnesium chloride lithium chloride complex (1.3 M in THF) (1.29 g, 8.9 mmol) was added at −20° C., and the reaction was stirred at the same temperature for 15 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with saturated NH4Cl, extracted with diethyl ether (3×30 mL), and concentrated to give the crude product. Chromatographic purification on a neutral alumina column (EtOAc / heptane 0-18%) gave (S,E)-ethyl 3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (0.35 g, 56% yield). 1H NMR(400MHz,DMSO-d6)δ 9.71(s,1H),7.79(d,J=16.3Hz,1H),6.37(d,J=16.1Hz,1H),4.79-4.95(m,1H),4.90(s,1H),4.69(d,J=14.5Hz,1H) ,4.24(dd,J=16.3,9.5Hz,1H),4.13(s,2H),4.01-4.22(m,1H),3.40(s,3H),3.19(s,3H),2.57(s,1H),2.43(s,1H).

[0300] Step 7: Synthesis of ethyl (S)-3-(2-(hydroxymethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate [ka] To a stirred solution of (S,E)-ethyl 3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (0.350 g, 1.26 mmol) in ethanol (3.5 mL), (150 mg, 10% Pd / C 50% water) was added in small portions, and the reaction was stirred at room temperature under 10 kg H pressure for 24 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was filtered through a celite bed, and the filtrate was evaporated to give the crude product, ethyl (S)-3-(2-(hydroxymethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate (0.30 g, crude yield 84.5%), which was used for the next step without purification. LCMS method H3: Rt=2.06 min, MS m / z 282[M+1]+.

[0301] Step 8: Synthesis of (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate [ka] To a solution of (S)-ethyl 3-(2-(hydroxymethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate (0.3 g, 1.124 mmol) in DCM (3 mL) was added Dess-Martin periodinane (0.715 g, 1.686 mmol) in small portions at 0 °C. The reaction was slowly warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC. After completion, the reaction was quenched with saturated NaHCO, extracted with DCM (3 × 25 mL), and concentrated to give the crude product, ethyl (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate (0.25 g, crude yield 83.9%), which was carried directly to the next step reaction without purification.

[0302] Step 9: Synthesis of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate [ka] To a stirred solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.137 g, 0.357 mmol) in EtOH (3 mL), TEA (0.054 g, 5.35 mmol) was added at room temperature, and the mixture was stirred for 15 min. (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)propanoate (0.25 g, 0.892 mmol) was added, followed by 0.5 M solution of ZnCl (7.5 mL, 2.678 mmol). The reaction mixture was stirred at 60 °C for 4 h, after which the solution was cooled to °C, and NaCNBH (0.168 g, 2.678 mmol) was added in small portions. The reaction was stirred at 60° C. for 12 hours and monitored by LCMS. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO and extracted with DCM (3×30 mL) to give the crude product, which was purified by chromatography on a neutral alumina column (EtOAc / heptane 0-70%) to give ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.06 g, 11% yield). LCMS Method H: Rt=4.08 min; MS m / z 612 [M+1] + .

[0303] Step 10: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoic acid [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.195 g, 0.318 mmol) in ethanol (5.85 mL) was added 2.9 mL aq. NaOH (0.038 g, 0.95 mmol). The reaction was stirred at room temperature for 16 hours and monitored by LCMS. After completion of the reaction, ethanol was evaporated and the pH of the reaction was adjusted to 3-4 with aqueous citric acid. It was extracted with ethyl acetate (3×15 mL) and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by reverse phase preparative HPLC [MeCN / HO+0.1% NHOH, X-bridge C18] to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoic acid (0.015 g, crude yield 5.4%). LCMS Method H: Rt=2.74 min; MS m / z 584 [M+1] + . 1 H NMR(400MHz, methanol-d4)δ 7.60(t,J=8.3Hz,1H),7.20-7.35(m,2H),6.70-6.84(m,3H),5.13(d,J=7.5Hz,1H) ,4.68(s,2H),4.55(dt,J=11.2,5.9Hz,1H),4.45(d,J=15.5Hz,1H),3.99(d,J=14. 5Hz,1H),3.88(d,J=14.5Hz,1H),3.12-3.16(m,2H),2.98(h,J=8.0Hz,2H),2.75-2 .84(m,2H),2.40-2.54(m,6H),2.24(s,3H),1.89-2.08(m,3H),1.88-1.91(s,3H).

[0304] Example 15: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoic acid (C-15) [ka] Synthesis scheme: [ka] For steps 1 to 6, see Example 14.

[0305] Step 7: Synthesis of ethyl 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate [ka] To a stirred solution of ethyl (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (0.7 g, 2.3 mmol) in moist ethanol (7 mL), 10% Pd / C 50% (300 mg) was added in small portions, and the reaction was stirred at room temperature under 10 kg H pressure for 24 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite bed, and the filtrate was evaporated to give the crude product, ethyl 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.550 g, crude yield 77.5%), which was used for the next step without purification. LCMS method H3: Rt=2.08 min, MS m / z 301[M+1] + .

[0306] Step 8: Synthesis of ethyl 2-fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate [ka] To a solution of ethyl 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.410 g, 1.367 mmol) in DCM (4.1 mL) was added Dess-Martin periodinane (0.870 g, 2.05 mmol) in small portions at 0° C. The reaction was allowed to warm slowly to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After completion of the reaction, it was quenched with saturated NaHCO3 solution and extracted with DCM (3 x 30 mL), the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, ethyl 2-fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate, (0.6 g), which was used in the next step without further purification. LCMS Method C2: Rt = 1.06 min, MS m / z 299 [M+1] + .

[0307] Step 9: Synthesis of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoate [ka] To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.308 g, 0.805 mmol) in 1,2-EDC (10 vol), DIPEA (0.520 g, 4.02 mmol) was added and stirred at room temperature for 20 minutes. Ethyl 2-fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (11) (0.6 g, 2.01 mmol) was added and the mixture was stirred at room temperature for 1 hour, followed by the addition of STAB (1.28 g, 6.04 mmol) in small portions at 0° C. The reaction was stirred at room temperature for 16 hours and monitored by LCMS. After completion of the reaction, it was quenched with saturated NaHCO3 and extracted with DCM (3 x 30 mL) to give the crude product, which was chromatographically purified (EtOAc / heptane 0-70%) to give ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoate (0.150 g, crude yield 11.8%). LCMS Method H3: Rt = 3.98 min; MS m / z 631 [M+1] + .

[0308] Step 10: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoic acid [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoate (0.150 g, 0.238 mmol) in ethanol (4.5 mL) was added 2.25 mL aq. NaOH (0.028 g, 0.71 mmol). The reaction was stirred at room temperature for 16 hours and monitored by LCMS. After completion of the reaction, ethanol was evaporated and the pH of the reaction solution was adjusted to 3-4 using aqueous citric acid. It was extracted with ethyl acetate (3 × 15 mL), the organic layer was dried over sodium sulfate, concentrated and the crude was purified by reverse phase preparative HPLC [MeCN / HO + 0.1% NHOH, X-bridge C18] to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoropropanoic acid (0.026 g, crude yield 18.1%). LCMS Method H3: Rt = 2.70 min; MS m / z 603 [M+1] + . 1 H NMR(400MHz, methanol-d4)δ 7.62(t,J=8.3Hz,1H),7.22-7.36(m,2H),6.72-6.88(m,3H),5.13(d,J=7.6Hz,2H),4.85(d,J=14.1Hz,2H),4.72(s,3H),4.55- 4.61(m,3H),4.13(dd,J=7.8,5.4Hz,2H),2.85(s,3H),2.61(s,1H),2.54(d,J=9.5Hz,2H),2.481(s,3H),2.30(d,J=2.3Hz,3H),2.07(s,3H).

[0309] Example 16: Synthesis of (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)glycine (C-16) Synthesis scheme: [ka] Step-1: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)glycinate methyl [ka] To a solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (60 mg, 1 Eq, 0.11 mmol) in DCM (0.6 mL) / DMF (0.6 mL) was added DIPEA (0.11 mL, 0.65 mmol) and HATU (49 mg, 0.13 mmol). After stirring for 5 min, methyl glycinate, AA-hydrochloride (16 mg, 0.13 mmol) was added and the reaction mixture was stirred at room temperature overnight. LCMS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was diluted with HO and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was carried forward to the next step reaction without purification (87 mg, 88% yield). LCMS Method 2: Rt=1.24 min; MS m / z 627.4 [M+H]+.

[0310] Step-2: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)glycine [ka] To a solution of methyl (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)glycinate in THF (0.51 mL) / water (0.17 mL) / methanol (0.17 mL) (ratio: 3:1:1) was added lithium hydroxide(s) (8.8 mg, 0.37 mmol) and 1 M LiOH(aq) (0.12 mL, 0.12 mmol). The reaction was stirred at room temperature overnight when LCMS showed consumption of starting material and formation of desired product. The reaction was diluted with DMSO and purified by preparative HPLC (conditions: basic 15-40% acetonitrile-3.ACN / H2O + 5 mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30 x 50 mm) to give the title compound (28 mg, 37% yield). LCMS Method 2: Rt = 0.84 min; MS m / z 613.3 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ 8.18(t,J=5.9Hz,1H),7.61-7.51(m,2H),7.34(dd,J=8.5,2.2Hz,1H),6.82-6.71(m,3H),4.98- 4.83(m,1H),4.74-4.59(m,1H),4.52-4.39(m,2H),4.39-4.32(m,1H),3.90-3.81(m,2H),3.72( d,J=13.3Hz,1H),3.48(d,J=13.5Hz,1H),2.96(d,J=11.3Hz,1H),2.84(d,J=11.2Hz,1H),2.71- 2.54(m,2H),2.42-2.31(m,1H),2.27(s,3H),2.23-2.05(m,2H),2.02(s,3H),1.84-1.60(m,4H).

[0311] Example 17 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid (C-17a) and 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid (C-17b) [ka] Synthesis scheme: [ka] [ka] Step 1: Synthesis of (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (3) [ka] To a solution of ethyl 1H-imidazole-5-carboxylate (15 g, 107.04 mmol) and (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (28.52 g, 117.74 mmol) in DMF (150 mL) under a nitrogen atmosphere was added potassium carbonate (44.38 g, 321.13 mmol), followed by potassium iodide (17.76 g, 107.04 mmol), and heated at 80 °C for 9 h. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with cold water (150 mL), brine (100 mL), dried over sodium sulfate, and concentrated. Chromatographic purification on a neutral alumina column afforded the top spot eluted in 19–21% EtOAc / hexane and the bottom spot eluted in 100% EtOAc–2% MeOH / DCM. The structures of the upper and lower spots were confirmed by NOE. The upper spot was the desired product, (3) (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (3.5 g, 15.6% yield). The lower spot contained (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-4-carboxylate (3A) (1.78 g, 7.9% yield). The upper isomer (3), (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate: LCMS Method C3: Rt = 1.33 min; MS m / z 211.1 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.66 (s, 1H), 4.91 (qd, J = 6.5, 3.8 Hz, 1H), 4.61 (dd, J = 14.2, 6.4 Hz, 1H), 4.42-4.56 (m, 2H), 4.26 (dq, J = 14.4, 7.1, 6.5 Hz, 3H), 2.57-2.70 (m, 1H), 2.22-2.35 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H). Lower isomer (3A), (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-4-ethyl carboxylate: LCMS Method H3: Rt = 1.84 min; MS m / z 211.0 [M+H]+. 1H NMR(400MHz,DMSO-d6)δ 7.89(s,1H),7.75(s,1H),4.94(td,J=7.3,3.0Hz,1H),4.49(p,J=7.6,6.9Hz,2H),4.13-4.44 (m,4H),2.63(dt,J=14.0,7.3Hz,1H),2.26(q,J=8.5,7.8Hz,1H),1.25-1.28(t,J=6.8Hz,3H).

[0312] Step 2: Synthesis of (S)-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol [ka] To a solution of ethyl (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (3) (3.5 g, 16.666 mmol) in THF (35 mL) was added dropwise lithium aluminum hydride (2 M in THF) (0.949 g, 24.999 mmol) at 0° C. under a nitrogen atmosphere. The reaction was then stirred at room temperature for 1 hour. The reaction progress was monitored by LCMS. The reaction was quenched by the dropwise addition of ethyl acetate (15 mL) at 0° C. Sodium sulfate decahydrate was added to the reaction mixture, which was stirred for 5 minutes. The reaction was then filtered through a Celite bed, the Celite bed was washed with ethyl acetate (150 mL), and the filtrate was concentrated in vacuo to give (S)-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (2.7 g, 96.4% yield). 1 H NMR(400MHz,DMSO-d6)δ 7.59(s,1H),6.81(s,1H),4.86-5.14(m,2H),4.55-4.67(m,3H),4.15-4.41(m,3H),2.54-2.69(m,1H),2.28-2.49(m,1H).

[0313] Step 3: Synthesis of (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde [ka] To a solution of (S)-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (2.7 g, 16.071 mmol) in acetonitrile (40.5 mL) was added MnO (20.97 g, 241.07 mmol) and the mixture was heated at 50 °C for 16 h. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, the mixture was cooled to room temperature, filtered over a bed of Celite, and concentrated in vacuo to give (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (2.5 g, crude). LCMS Method C2: Rt = 0.48 min; MS m / z 167 [M+H]. 1 H NMR(400MHz,DMSO-d6)δ 9.76(s,1H),7.93(s,1H),8.06(s,1H),4.87-4.97(m,1H),4.56-4.69(m,1H),4.51(ddd,J=2 0.9,10.0,5.3Hz,2H),4.27(tq,J=9.5,5.5Hz,1H),2.59-2.69(m,1H),2.30(t,J=9.7Hz,1H).

[0314] Step 4: Synthesis of ethyl (S,E)-2-methyl-3-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate [ka] To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (5.38 g, 22.590 mmol) in THF (10 mL) was added 60% sodium hydride (1.2 g, 30.12 mmol) in small portions at 0 °C. The reaction was stirred at 0 °C for 15 minutes, followed by the dropwise addition of (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (2.5 g, 15.06 mmol) in THF (15 mL) to the above solution at 0 °C. The reaction was then heated at 60 °C for 1.5 hours. The progress of the reaction was monitored by TLC and LCMS. After the reaction was complete, it was cooled to room temperature and quenched with ice-cold water, followed by extraction with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated. The crude was purified by combiflash (EtOAc / heptane 0-28%) using neutral alumina to give (S,E)-ethyl 2-methyl-3-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (1.4 g, 37.18% yield). LCMS Method C2: Rt=0.93 min; MS m / z 251.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.88(s,1H),7.58(s,1H),7.37(s,1H),4.83-4.94(m,1H),4.42-4.52(m,3H),4.22-4.42 (m,3H),2.60-2.74(m,1H),2.24-2.36(m,1H),2.06(s,3H),1.24(dq,J=18.5,7.0Hz,3H).

[0315] Step 5: Synthesis of ethyl 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate [ka] To a solution of ethyl (S,E)-2-methyl-3-(1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (1.4 g, 5.592 mmol) in methanol (21 mL) was added 10% Pd / C, 50% water (0.750 g, 0.5 w / w) under a nitrogen atmosphere. It was stirred at room temperature for 16 hours under hydrogen pressure (1 atm) using a hydrogen balloon. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a celite bed, followed by washing with methanol (50 mL). The filtrate was concentrated under vacuum to give ethyl 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (1.2 g, 85.03% yield). LCMS method C2: Rt=0.91 min; MS m / z 253.2[M+1] + . 1 H NMR(400MHz,chloroform-d)δ 8.79(s,1H),7.11(s,1H),5.10-5.21(m,1H),4.70(p,J=7.0Hz,1H),4.42-4.53(m,1H),4.34-4.41(m,2H),4.07-4. 30(m,2H),3.08(td,J=14.5,7.9Hz,1H),2.81(ddt,J=19.7,15.1,6.8Hz,2H),2.40-2.51(m,2H),1.24-1.43(m,6H).

[0316] Step 6: Synthesis of ethyl 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate [ka] To a solution of ethyl 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (1.2 g, 4.761 mmol) in DMF (12 mL) was added DIPEA (3.077 g, 23.809 mmol) and 37% HCHO (2.85 g, 95.238 mmol) and it was heated in a microwave at 135° C. for 3 h. The reaction was monitored by LCMS and showed that after 3 h there was still some SM remaining, so DIPEA (1.53 g, 11.904 mmol) and 37% HCHO (1.42 g, 47.619 mmol) were added again and the reaction was heated in a microwave at 135° C. for 1.5 h. The reaction mixture was cooled and concentrated in vacuo to completely remove DMF followed by stripping with toluene to remove traces of water. The crude was purified by column chromatography on neutral alumina using 0-10% MeOH / DCM to give ethyl 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate (0.515 g, 38.35% yield). LCMS Method H3: Rt = 2.12 min; MS m / z 283.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 6.52(s,1H),4.93(s,1H),4.61-4.73(m,2H),4.41-4.53(m,2H),4.33(dd,J=15.5,7.9Hz,1H),4.16(d,J=16.0Hz, 1H),3.99-4.10(m,2H),2.90(td,J=17.3,16.4,7.7Hz,1H),2.73(m,1H),2.65(m,3H),1.16(td,J=7.2,2.8Hz,6H).

[0317] Step 7: Synthesis of ethyl 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate [ka] To a solution of ethyl 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate (0.515 g, 1.826 mmol) in DCM (6 mL) was added TEA (0.554 g, 5.478 mmol). It was cooled to 0° C., and then mesyl chloride (0.313 g, 2.739 mmol) was added dropwise to it. The reaction was allowed to warm to room temperature and stirred at room temperature for 5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction was quenched with water and extracted with DCM (3×25 mL). The organic layer was washed with saturated bicarbonate solution (2×15 mL) and brine (25 mL). It was dried over sodium sulfate and concentrated in vacuo to give crude ethyl 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.375 g), which was used in the next step reaction without further purification.

[0318] Step 8: Synthesis of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate [ka] To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.199 g, 0.520 mmol) in acetonitrile (3 mL) was added DIPEA (0.672 g, 5.202 mmol). The reaction was stirred for 10 minutes, after which ethyl 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoate (0.375 g, 1.040 mmol) in acetonitrile (3 mL) was added, followed by potassium carbonate (0.431 g, 3.121 mmol) and potassium iodide (0.172 g, 1.040 mmol). The reaction was heated at 60° C. for 16 hours and monitored by TLC. The reaction was cooled to room temperature, the acetonitrile was concentrated, water was added to the residue and extracted with ethyl acetate (3 x 15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (MeCN / HO + 0.1% NHOH, YMC ACTUS TRIART C18) to give ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate (0.040 g, 6.3% yield). LCMS Method H3: Rt = 4.06 min; MS m / z 612.3 [M+1] + . 1 H NMR(400MHz, methanol-d4)δ 7.60(t,J=8.3Hz,1H),7.19-7.36(m,2H),6.65-6.84(m,4H),5.15(t,J=7 .4Hz,1H),4.33-4.70(m,4H),4.11(qd,J=7.1,4.7Hz,2H),3.76(dd,J=13. 7,1.9Hz,2H),2.94-3.09(m,2H),2.76-2.90(m,5H),2.68(s,1H),2.17(dt ,J=31.0,11.3Hz,2H),2.05(s,3H),1.81-1.95(m,4H),1.16-1.33(m,6H).

[0319] Step 9: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid and 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid [ka] Step 9-1: Chiral separation of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate Column: Chiralpak IC 21 x 250 mm 5 μm Flow rate: 80g per minute Co-solvent: 10 mM NH3 in 30% IPA w / CO2 Detection: 220nm BPR Setpoint: 125bar Injection Size: 3 mg (3.0 mg / mL of MeOH) System:CA_GDCSEPS_PrepSFC02 Acronyms: MeOH = methanol, IPA = isopropanol, NH3 = ammonia

[0320] Step-9-2: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate (fraction-1 from chiral separation) (17.5 mg, 28.6 μmol) in THF (100 μL) was added 1 M LiOH (85.8 μL, 85.8 μmol), and the reaction was stirred at room temperature for 2 days. The reaction mixture was purified by preparative HPLC (conditions: basic 25-50% acetonitrile-3.5 ACN / HO + 5 mM NHOH 75 mL / min; column: Waters XBridge C18 OBD 30 × 100 mm) to give the title compound. LCMS method 2: Rt=0.89 min; MS m / z 584.4[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.62-7.50(m,2H),7.34(dd,J=8.4,2.3Hz,1H),6.83-6.70(m,3H),6.49(s,1H),5. 06-4.88(m,1H),4.54-4.32(m,3H),4.17(dd,J=15.2,2.9Hz,1H),3.64(d,J=13.4Hz ,1H),3.39(d,J=13.3Hz,1H),3.01-2.74(m,3H),2.73-2.57(m,2H),2.46-2.23(m,3 H),2.14-2.05(m,1H),2.05-1.94(m,4H),1.84-1.58(m,4H),0.98(d,J=6.8Hz,3H).

[0321] Step-9-3: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoate (fraction-2 from chiral separation) (13.5 mg, 22.1 μmol) in THF (100 μL) was added 1 M LiOH (66.2 μL, 66.2 μmol), and the reaction was stirred at room temperature for 2 days. The reaction mixture was purified by preparative HPLC (conditions: basic 25-50% acetonitrile-3.5 ACN / HO + 5 mM NHOH 75 mL / min; column: Waters XBridge C18 OBD 30 × 100 mm) to give the title compound. LCMS method 2: Rt=0.85 min; MS m / z 584.5[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 7.61-7.50(m,2H),7.34(dd,J=8.6,2.1Hz,1H),6.79(d,J=4.8Hz,2H),6.77-6.71(m,1H),6. 52(s,1H),5.06-4.89(m,1H),4.53-4.43(m,1H),4.43-4.31(m,2H),4.20(dd,J=15.2,2.9Hz, 1H),3.64(d,J=13.5Hz,1H),3.46-3.36(m,1H),2.98-2.72(m,3H),2.66-2.54(m,4H),2.44- 2.35(m,1H),2.16-2.06(m,1H),2.06-1.95(m,4H),1.78-1.59(m,4H),1.12(d,J=6.4Hz,3H).

[0322] Example 18: Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid (C-18) Synthesis scheme: [ka] Step-1: 4-fluoro-1H-imidazole-5-carboxylate ethyl [ka] Ethyl 4-amino-1H-imidazole-5-carboxylate (2 g, 12.89 mmol) was dissolved in 48% HBF4 (68.5 mL) in HO. The solution was cooled to -10 °C, and NaNO2 (4.11 g, 59.6 mmol) was dissolved in HO (5.15 mL) and added dropwise to the above solution. The solution turned blue-green, and was then transferred to a quartz flask and stirred in a box (pre-cooled with dry ice). The reaction was irradiated with a 302 nm UV 16x12 W lamp at 28-30 °C overnight, and LC / MS showed the reaction was complete. The solution was stirred on ice, neutralized with chilled concentrated NaOH, extracted three times with AcOEt, and dried over MgSO4. The solvent was removed. The residue was purified by chromatography (EtOAc / heptane 0-70%) to give the title compound (760 mg, 37% yield). LCMS Method 2: Rt=0.49 min; MS m / z 159.1 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 13.26(s,1H),7.64(t,J=1.7Hz,1H),4.26(q,J=7.0Hz,2H),1.27(t,J=7.1Hz,3H).

[0323] Step-2: 2-bromo-4-fluoro-1H-imidazole-5-carboxylate ethyl [ka] To a solution of ethyl 4-fluoro-1H-imidazole-5-carboxylate (670 mg, 4.24 mmol) in ACN (21 mL) was added NBS (754 mg, 4.24 mmol) and the mixture was stirred at 50 °C for 1 h. After completion, the solution was concentrated and the residue was purified by chromatography (EtOAc / heptane 0-50%) to give the title compound (221 mg, 146 mg of starting material recovered, 29% yield). LCMS Method 2: Rt = 0.42 min; MS m / z 239.2 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 4.38 (q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0324] Step-3: (S)-2-bromo-4-fluoro-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of ethyl 2-bromo-4-fluoro-1H-imidazole-5-carboxylate (243.2 mg, 1.026 mmol), (S)-oxetan-2-ylmethanol (108 mg, 1.231 mmol), and PPh3 (323 mg, 1.231 mmol) in THF (5 mL), DIAD (213 μL, 1.026 mmol) was added and stirred at room temperature for 2 h. After the reaction was complete, the solution was concentrated, and the residue was purified by chromatography (EtOAc / heptane 0-60%) to give the title compound (194 mg, 62% yield). LCMS Method 2: Rt = 0.83 min; MS m / z 306.9 [M+H]+. 1 H NMR (400 MHz, chloroform-d) δ 5.11-5.00 (m, 1H), 4.74-4.57 (m, 3H), 4.53 (dt, J = 9.2, 6.3 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H), 2.84-2.71 (m, 1H), 2.50-2.39 (m, 1H), 1.35 (d, J = 14.2 Hz, 3H).

[0325] Step-4: (S)-4-fluoro-2-formyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of (S)-ethyl 2-bromo-4-fluoro-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (373 mg, 1.215 mmol) and DMF (658 μL, 8.50 mmol) in THF (6 mL) was added Turbo Grignard reagent, 1.3 M in THF (2.3 mL, 3.04 mmol) at −15° C. and stirred at −15° C. for 20 min. The reaction was then warmed to 0° C. and stirred at 0° C. for 1 h. LC / MS indicated the reaction was complete. The reaction was quenched with saturated NH4Cl, extracted three times with DCM, and concentrated to give the crude product, which was carried on to the next step of the reaction without purification. LCMS Method 2: Rt = 0.79 min; MS m / z 257.3 [M+H]+.

[0326] Step-5: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (351 mg, 1 Eq, 1.370 mmol), (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (526 mg, 1.370 mmol) in DCM (9 mL) was added triethylamine (416 mg, 4.11 mmol) and the reaction mixture was stirred for 15 minutes, followed by the addition of sodium triacetoxyborohydride (377 mg, 1.781 mmol) and stirring at room temperature for 2 hours; LCMS showed the reaction was complete. The reaction mixture was cooled to 0°C, quenched with saturated aqueous NaHCO3, and extracted three times with DCM. The combined organic layers were washed with brine and concentrated under reduced pressure to give the crude product. The residue was purified by chromatography (EtOAc / heptane 0-100%) to give the title compound (400 mg, 50% yield). LCMS Method 2: Rt = 1.46 min; MS m / z 588.3 [M+H]+.

[0327] Step-6: (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)methanol [ka] To a solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (328 mg, 0.558 mmol) in THF (6 mL) was added 2 M LAH in THF (418 μL, 0.837 mmol) at 0° C., and the reaction mixture was stirred at 0° C. for 1 h. After the reaction was complete, it was quenched by adding NaSO.10HO and extracted with DCM. Filtration and concentration gave the crude product (238 mg, 93% yield), which was carried on to the next step of the reaction without purification. LCMS method 1: Rt=1.38 min; MS m / z 546.4[M+H]+.

[0328] Step-7: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde [ka] To a solution of (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)methanol (270.8 mg, 0.496 mmol) in ACN (3 mL) was added MnO (647 mg, 7.44 mmol). The mixture was stirred at 50 °C overnight and LC / MS showed the reaction was complete. The mixture was filtered through Celite, rinsed with ACN and concentrated to give the crude title product (263 mg, 97% yield). The crude was carried forward to the next step without purification. LCMS Method 2: Rt = 1.38 min; MS m / z 544.2 [M+H].

[0329] Step-8: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylate ethyl ester [ka] To a solution of ethyl 2-(diethoxyphosphoryl)acetate (144 μl, 0.725 mmol) in DMF (2 mL) was added NaH in oil, 60% (32.9 mg, 0.822 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, followed by the addition of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde (263 mg, 0.483 mmol) in DMF (200 μL). The reaction was stirred at 0° C. for 15 minutes, then warmed to room temperature and stirred at the same temperature for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl, and extracted twice with AcOEt. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by reverse phase on a C18 column under 0-80% ACN (0.01% NH4OH) / 0.01% NH4OH in HO to give the title compound (195 mg, 66% yield). LCMS Method 2: Rt = 01.46 min; MS m / z 614.3 [M+H]+.

[0330] Step-9: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid [ka] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl acrylate (98.6 mg, 0.161 mmol) in THF (0.9 mL) / MeOH (0.3 mL) (ratio: 3:1) was added 1 M aqueous LiOH (482 μL, 0.482 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DMSO and purified by reverse phase on a C18 column under 0.01% NH4OH in 0-80% ACN (0.01% NH4OH) / HO to give the title compound (75 mg, 78% yield). LCMS method 2: Rt=0.87 min; MS m / z 586.4[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 12.20(s,1H),7.62-7.47(m,3H),7.34(dd,J=8.6,2.1Hz,1H),6.82-6.77(m,2H),6.77-6.71(m,1 H),6.06(d,J=16.0Hz,1H),4.96(qd,J=7.1,2.8Hz,1H),4.55(dd,J=15.6,7.2Hz,1H),4.51-4.32 (m,3H),3.68(d,J=13.8Hz,1H),3.46(d,J=13.7Hz,1H),2.96(d,J=11.2Hz,1H),2.81(d,J=11.2H z,1H),2.74-2.56(m,2H),2.46-2.29(m,1H),2.22-2.04(m,2H),2.02(s,3H),1.81-1.61(m,4H).

[0331] Example 19 Synthesis of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid (C-19a) and (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid (C-19b) [ka] Synthesis scheme: [ka] [ka] reagent: Step 1: NBS (1.3 eq), acetonitrile (0.2 mol), 0°C to room temperature, 1 hour. Step 2: (S)-oxetan-2-ylmethanol (1.5 eq), TPP (1.5 eq), DIAD (1.5 eq), THF (22 vol), room temperature, 24 hours. Step 3: NaBH (10 eq), ethanol (10 vol), 0°C to 50°C, 30 hours. Step 4: MnO (15 eq), acetonitrile (20 vol), 50°C, 16 hours. Step 5: 2-(diethoxyphosphoryl)-2-fluoroethyl acetate (1.5 eq), 2.5 M n-BuLi (1.8 eq), THF (40 vol), 0°C to room temperature, 12 hours. Step 6: Isopropylmagnesium chloride lithium chloride complex (4 eq), DMF (7 eq), THF (10 vol), -20°C, 30 minutes. Step-7: (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.5 eq), DIPEA (2 eq), acetic acid (1 eq), STAB (3 eq), 1,2-dichloroethane (10 vol), 0°C to room temperature, 16 hours. Step-8: NaOH (3 eq), ethanol (30 vol), water (15 vol), 0°C to room temperature, 16 hours.

[0332] Step 1: Synthesis of ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate [ka] Ethyl 4-methyl-1H-imidazole-5-carboxylate (5 g, 32 mmol) was stirred in acetonitrile (160 mL) and NBS (7.46 g, 42 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 hour. The reaction solution became clear, indicating completion, and the progress of the reaction was monitored by TLC. The solution was removed, and the residue was added with saturated NaHCO3 (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, and concentrated. Chromatographic purification (EtOAc / heptane 0-20%) gave ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (4 g, 52.9% yield). LCMS Method C2: Rt = 1.06 min; MS m / z 233 [M+1] + . 1 H NMR (400 MHz, chloroform-d) δ 9.91 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.59 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

[0333] Step 2: Synthesis of ethyl (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate [ka] To a solution of ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (4 g, 17 mmol) in THF (88 mL) was added (S)-oxetan-2-ylmethanol (2.26 g, 25 mmol), followed by triphenylphosphine (6.747 g, 25 mmol). DIAD (5.202 g, 25 mmol) was added at 0 °C. After the addition, the reaction was stirred at room temperature for 24 h. The reaction was monitored by LCMS. Upon completion, the solvent was removed to give the crude product, which was purified by chromatography on a neutral alumina column (EtOAc / heptane 0-20%) to give ethyl (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (3.3 g, 63.4% yield). LCMS method C2: Rt=1.133 min, MS m / z 303[M+1] + . 1 H NMR (400 MHz, chloroform-d) δ 5.07 (s, 1H), 4.68-4.77 (m, 2H), 4.64 (q, J = 6.9 Hz, 1H), 4.53 (q, J = 7.0, 6.3 Hz, 1H), 4.38 (dq, J = 14.1, 7.1 Hz, 2H), 2.78 (s, 1H), 2.55 (S, 3H), 2.44 (s, 1H), 1.40 (t, J = 7.0 Hz, 3H).

[0334] Step 3: Synthesis of (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol [ka] A solution of (S)-ethyl 2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (3.3 g, 10 mmol) in ethanol (33 mL) was cooled to 0 °C, NaBH (1.64 g, 43 mmol) was added portionwise, and the reaction was stirred at 50 °C for 6 h. The reaction was monitored by TLC and LC / MS; after 6 h, SM remained with product formation on TLC, so additional NaBH (1.64 g, 43 mmol) was added at 0 °C and heated again at 50 °C for 12 h. LC / MS still showed 15% SM remaining, so NaBH (0.823 g, 21 mmol) was added again at 0 °C, and the reaction was heated at 50 °C for an additional 6 h until SM was consumed on TLC and LC / MS. After completion of the reaction, the mixture was quenched with water (10 mL) and the solvent was evaporated. The residue was diluted with brine (100 mL) and extracted with 10% methanol in DCM solution (4 x 100 mL) to give the crude product, which was used directly in the next step without purification. (S)-(2-Bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (2.3 g, crude yield 80.9%). LCMS Method C2:R t =0.82 min, MS m / z 261, 263[M+1] + . 1 H NMR(400MHz,DMSO-d6):δ 4.97(ddt,J=18.2,7.1,4.1Hz,2H),4.54-4.35(m,4H),4.39-4.25(m,1H),4.17( d,J=3.2Hz,1H),2.66(d,J=9.8Hz,1H),2.47-2.38(m,1H),2.07(s,J=2.8Hz,3H).

[0335] Step 4: Synthesis of (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde [ka] To a solution of (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)methanol (2.3 g, 8.8 mmol) in acetonitrile (46 mL), MnO (11.5 g, 132 mmol) was added, and the mixture was stirred at 50 °C for 16 h. The reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was filtered through Celite, washed with acetonitrile, and the filtrate was concentrated to give the crude product (1.7 g, crude yield 74.5%). Chromatographic purification (EtOAc / heptane 0-30%) gave (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde. LCMS Method C2: Rt = 0.97 min; MS m / z 259 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 9.72(s,1H),4.87(qd,J=7.0,3.7Hz,1H),4.59(dd,J=14.6,7.1Hz,1H),4.41-4.54(m ,2H),4.36(dt,J=8.9,6.1Hz,1H),2.60-2.76(m,1H),2.41(s,3H),2.29-2.42(m,1H).

[0336] Step 5: Synthesis of (S,Z)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate ethyl (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate ethyl (8A) [ka] To a solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (2.25 g, 9 mmol) in THF (32 mL) was added n-BuLi (2.5 M in hexanes) (4.5 mL, 11 mmol) at 0 °C, and the reaction was stirred at room temperature for 1 h. After 1 h, it was cooled to 0 °C, and (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (1.6 g, 6.2 mmol) in THF (32 mL) was added, and the reaction was stirred at room temperature for 12 h. The reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with saturated NH4Cl and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were washed with brine and dried over sodium sulfate to give the crude product, which was purified by chromatography on a neutral alumina column (EtOAc / heptane 0-60%) to give a (cis and trans) mixture of both isomers, (S,Z)-ethyl 3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate (8A) (1.1 g, 51.31% yield of isomeric mixture). LCMS Method C2: 1.13 min and 1.19 min; MS m / z 347 [M+1] + .

[0337] Step 6: Synthesis of (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (9A) [ka] A solution of a mixture of (S,Z)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)-2-fluoroacrylate (8A) (1 g, 2.9 mmol) in THF (10 mL) and DMF (1.47 g, 20 mmol) was cooled to −20° C., and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF) (1.68 g, 11 mmol) was added dropwise to the above solution. The reaction was stirred at the same temperature for 30 minutes. The progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with saturated NH4Cl and extracted with diethyl ether (3 x 50 mL) to give the crude product. Chromatographic purification on a neutral alumina column (EtOAc / heptane 0-30%) afforded a (cis and trans) mixture of both isomers, (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)acrylate (9A) (0.3 g, 35.2% yield of both isomers). LCMS Method H3: Rt = 2.50 min, 2.62 min; MS m / z 297 [M+1] + .

[0338] Step 7: Synthesis of (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11) and (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11A) [ka] To a solution of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.19 g, 0.494 mmol) in 1,2-EDC (5 mL) was added DIPEA (0.261 g, 2.0 mmol). After the mixture was stirred at room temperature for 20 minutes, acetic acid (0.061 g, 1.01 mmol) was added to the above solution, followed by the mixture, (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)ethyl acrylate (9A) (0.3 g, 1.01 mmol). The reaction mixture was stirred at room temperature for 1 hour, then cooled to 0 °C, and STAB (0.642 g, 3.02 mmol) was added in small portions. The reaction solution was stirred at room temperature for 16 hours, which was monitored by LCMS. After completion, the reaction mixture was quenched with saturated NaHCO and extracted three times with DCM to obtain the crude product. Chromatographic purification (EtOAc / heptane 0–80%) afforded both isomers (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11) and (E)- Ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11A) (0.22 g, 34.6% yield of both isomers) was obtained. LCMS Method H3: Rt = 4.15 min, 4.23 min; MS m / z 628 [M+1] + .

[0339] Step 8: Synthesis of (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid and (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid [ka] Ethyl (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11) in ethanol (5.4 mL) and aq. NaOH (0.034 g, 0.85 mmol). A solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylate (11A) (0.18 g, 0.287 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was monitored by LCMS and after completion of the reaction, ethanol was evaporated and the pH of the reaction was adjusted to 3-4 using aqueous citric acid. It was extracted with ethyl acetate and the organic layer was dried over sodium sulfate and concentrated. The crude was purified by reverse phase preparative HPLC [MeCN / H2O + 5 mmol NH4HCO3 + 0.1% NH4OH, X-bridge C18] to separate both isomers.

[0340] (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid, (0.031 g). LCMS Method H3: Rt=2.77 min; MS m / z 600 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ 7.56-7.60(m,2H),7.37(d,J=8.5Hz,1H),6.89-6.98(dd,J=36Hz,1H),6.75-6.81(m,3H),4.9 2-5.00(m,1H),4.46-4.50(m,1H),4.38-4.42(m,2H),4.27(d,J=15.0Hz,1H),3.70(d,J=13.5H z,1H),3.50(d,J=13.4Hz,1H),3.00(d,J=10.9Hz,1H),2.87(d,J=11.3Hz,1H),2.60-2.69(m,2 H),2.43(s,1H),2.26(s,2H),2.10-2.11(d,J=3.2Hz,3H),2.04(s,3H),1.78(d,J=4.1Hz,4H).

[0341] (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid (0.032 g). LCMS Method H3: Rt=2.83 min; MS m / z 601 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ 7.59(t,J=8.8Hz,2H),7.37(d,J=8.6Hz,1H),6.79(dd,J=20.0,4.6Hz,3H),6.56-6.61(d,J=18.4H z,1H),4.95(d,J=7.7Hz,1H),4.48(q,J=7.2Hz,1H),4.36(dd,J=9.0,5.2Hz,2H),4.20-4.29(m,1H) ,3.75(d,J=13.7Hz,1H),3.58(d,J=13.7Hz,1H),3.03(d,J=11.0Hz,1H),2.92(d,J=11.3Hz,1H),2 .63(t,J=9.2Hz,2H),2.42(m,1H),2.17-2.23(m,2H),2.05(s,3H),1.97(s,3H),1.71-1.82(m,4H).

[0342] Example 20 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one (C-20) [ka] Step 1: (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) [ka] To 4-methyl-1H-imidazole-5-carbonitrile (1) (2.0 g, 19 mmol) in tetrahydrofuran (60 mL) was added dropwise (S)-oxetan-2-ylmethanol (1.8 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), followed by (E)-diazene-1,2-dicarboxylate (4.2 g, 4.0 mL, 21 mmol) at room temperature. The mixture was stirred at room temperature for 16 h, then concentrated and purified by silica gel chromatography (0-100% AcOEt / heptane). Both isomers appeared together and were purified again by SFC (column: (S,S) Whelk-O1 21 x 250 mm 5 μm; flow rate: 80 g per min; cosolvent: 15% MeOH in CO; detection: 230 nm; BPR set point: 125 bar) to give (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) (1.1 g, 33%). LCMS Method 2: Rt = 0.55 min; MS m / z 178.1 [M+1] +, and (S)-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-carbonitrile (2b) (0.89 g, 27%). LCMS Method 2: Rt = 0.48 min; MS m / z 178.1 [M+1] +.

[0343] Step 2: (S)-2-Formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (3) [ka] To (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) (155 mg, 875 μmol) in tetrahydrofuran (4 mL) was added lithium diisopropylamide (103 mg, 481 μL, 2 molar, 962 μmol) dropwise, and the mixture was stirred at −78°C for 30 min. Next, N,N-dimethylformamide (639 mg, 677 μL, 8.75 mmol) was added, and the mixture was stirred at −78°C for 10 min, then warmed to room temperature and stirred for an additional 30 min. Water was added, and the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (3) was then placed on a high vacuum pump for 16 hours and used directly for the next step (143 mg, 80%). LCMS Method 2: Rt = 0.59 min; MS m / z 206.2 [M+1]+.

[0344] Step 3: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonitrile (4) [ka] To (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (3) (143 mg, 0.697 mmol) in DCM (3.5 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (268 mg, 0.697 mmol), EtN (388 μL, 2.79 mmol), and NaBH(OAc) (222 mg, 1.05 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction was diluted with additional dichloromethane and subsequently washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuo to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonitrile (4) (83 mg, 22%). LCMS Method 3: Rt=1.96 min; MS m / z 537.4 [M+1]+.

[0345] Step 4: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one [ka] To 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonitrile (4) (80 mg, 0.15 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (26 mg, 0.37 mmol) and triethylamine (0.15 g, 0.21 mL, 1.5 mmol) at room temperature. The mixture was stirred at 60° C. for 16 hours. Ethyl acetate was added (approximately 5 mL), followed by washing with approximately 2 mL of water and then approximately 2 mL of brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo, and placed on a high vacuum pump for 16 hours. To the residue, DMF (2 mL), CDI (53 mg, 0.33 mmol), and DBU (68 mg, 67 μL, 0.45 mmol) were added, followed by stirring at room temperature for 2 hours. Water was added, followed by extraction twice with EtOAc, drying over magnesium sulfate, filtration, and concentration in vacuo. The residue was purified by preparative HPLC under basic conditions to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one (C-20) (24 mg, 27%) as a white solid. LCMS method 3: Rt=1.91 min; MS m / z 596.6[M+1]+. 1H NMR(400MHz,MeOD)δ 7.49(t,J=8.3Hz,1H),7.19(dd,J=10.8,2.3Hz,1H),7.12(dd,J=8.3,2.2Hz,1H),6 .71(t,J=7.8Hz,1H),6.67-6.59(m,2H),5.09-5.00(m,1H),4.73-4.66(m,1H),4.6 3-4.53(m,2H),4.37(dt,J=9.2,5.9Hz,1H),4.19-3.98(m,2H),3.35-3.25(m,2H), 2.86-2.55(m,4H),2.44-2.30(m,1H),2.27(s,3H),1.94(s,3H),1.91-1.77(m,4H).

[0346] Example 21: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1,2,4-oxadiazol-5(2H)-one [ka] Synthesized using the same procedure as in Example 20 but using 2b after step 1. LCMS method 3: Rt=1.94 min; MS m / z 596.2[M+H] + ,1H NMR(400MHz,MeOD)δ 7.49(t,J=8.3Hz,1H),7.18(dd,J=10.8,2.0Hz,1H),7.11(dd,J=8.3,2.1Hz,1H),6.73-6 .65(m,1H),6.65-6.52(m,2H),5.06(dd,J=7.4,2.5Hz,1H),4.63-4.35(m,3H),4.28(dd, J=15.5,2.5Hz,1H),3.74(d,J=13.8Hz,1H),3.60(d,J=13.7Hz,1H),3.02-2.80(m,2H),2 .76-2.52(m,2H),2.47-2.30(m,4H),2.28-2.08(m,2H),1.93(s,3H),1.90-1.62(m,4H).

[0347] Example 22: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propiolic acid (C-22) [ka] Step 1: (S)-5-iodo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (1) [ka] To a solution of (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (2.17 g, 8.96 mmol) and 5-iodo-4-methyl-1H-imidazole (CAS# 15813-07-72, 2.049 g, 9.85 mmol) in ACN (50 mL) was added CsCO (2.92 g, 8.96 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by FCC (MeOH / ethyl acetate = 0-20%) to give compound 1. LCMS (basic) R t =0.96, mass=278.9[M+1] + ;1H NMR(400MHz, methylene chloride-d2)δ 7.74(s,1H),5.01(dddd,J=7.7,6.6,5.9,3.7Hz,1H),4.61(ddd,J=8.6,7.4,5.9Hz,1H),4.38(dt,J=9.1,6.0Hz,1 H),4.22-4.02(m,2H),2.70(dddd,J=11.4,8.5,7.7,6.1Hz,1H),2.36(ddt,J=11.4,9.2,7.1Hz,1H),2.23(s,3H).

[0348] Step 2: (S)-5-iodo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (2) [ka] To a solution of compound 1 (0.222 g, 0.8 mmol) in THF (4 mL) was added 1N LDA (1.600 ml, 1.600 mmol) slowly at -78 °C. The reaction was stirred at -78 °C for 30 minutes, followed by the addition of DMF (0.310 ml, 4.00 mmol). The reaction was stirred from -78 °C to room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted three times with ether. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue of compound 2 was used in the next step without purification. LCMS (basic) Rt =0.69, mass=306.9[M+1] +

[0349] Step 3: 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((5-iodo-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine (3) [ka] To a solution of compound 2 (245 mg, 0.800 mmol), (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (215 mg, 0.560 mmol) in DCM (5 mL) was added pyridine (64.7 μL, 0.800 mmol). The reaction was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (170 mg, 0.800 mmol). The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NaHCO3, and extracted twice with DCM. The combined organic layers were concentrated, and the residue was purified by FCC (EA / Hep=0-100%) to give compound 3. LCMS (acidic) R t =1.23, mass=638.2[M+1] +

[0350] Step 4: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl propiolate (4) [ka] To a solution of compound 3 (230 mg, 0.361 mmol), silver(I) chloride (20.67 mg, 0.144 mmol), and ethyl 3-(trimethylsilyl)propiolate (205 μL, 1.082 mmol) in DMF (5 mL) was added Pd(PPh3)4 (83 mg, 0.072 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature for 5 minutes, followed by the addition of 1N TBAF (1082 μL, 1.082 mmol). The reaction was stirred at room temperature for 5 minutes, followed by 4.5 hours at 50 °C. The reaction mixture was quenched with brine and extracted three times with ether. The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by FCC (EA / Hep = 0-100%) to give compound 4. LCMS (basic) R t =1.45, M=608.2[M+1] +

[0351] Step 5: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propiolic acid (C-22) [ka] To a solution of compound 4 (180 mg, 0.296 mmol) in a mixed solvent of THF-MeOH-water (0.9 mL / 0.3 mL / 0.1 mL) was added LiOH.HO (62.1 mg, 1.480 mmol). The reaction was stirred overnight, then quenched with 1N aqueous NaHPO and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by FCC (MeOH / DCM = 0-10%) to give compound (C-22). NMR(400MHz,MeOD)δ7.49(t,J=8.3Hz,1H),7.19(dd,J=10.9,2.0Hz,1H),7.12(ddd,J=8.4,2.0,0.8H z,1H),6.68(dd,J=8.0,7.4Hz,1H),6.61(ddd,J=7.3,5.9,1.4Hz,2H),5.13-5.01(m,1H),4.62-4.48( m,2H),4.45-4.33(m,2H),3.74(s,2H),3.10-2.84(m,2H),2.78-2.56(m,2H),2.48(ddt,J=11.5,9.1 ,7.0Hz,1H),2.26(d,J=3.0Hz,2H),2.20(s,3H),1.93(d,J=1.1Hz,3H),1.90-1.68(m,4H).HRMS[M+H] + =580.2054 C 31 H 32 Calculated value for ClFN3O5: 580.2045

[0352] Example 23: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (C-23) Step 1: methyl 3-propionylbicyclo[1.1.1]pentane-1-carboxylate [ka] To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (CAS# 83249-10-9, 1.41 g, 8.29 mmol) and DMF (0.013 mL, 0.166 mmol) in DCM (50 mL) was added 2N (COCl) in DCM (4.56 mL, 9.11 mmol). The reaction was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, followed by the addition of PdCl(dppf).CHCl adduct (154 mg, 0.188 mmol) in THF (15 mL) and 1N ZnEt in hexane (4517 μL, 4.52 mmol). The reaction mixture was stirred at 0 °C for 5 min and then at room temperature for 16 h. The reaction mixture was slowly quenched with 1N aqueous HCl and then extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over NaSO. After filtration and concentration, the residue was purified by isco (EA / Hep=0-60%) to give methyl 3-propionylbicyclo[1.1.1]pentane-1-carboxylate. 1 H NMR(400MHz,CD2Cl2)δ 3.69(d,J=1.1Hz,3H),2.49(q,J=7.2Hz,2H),2.29(s,6H),1.03(t,J=7.3Hz,3H).

[0353] Step 2: methyl 3-(2-bromopropanoyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To a solution of methyl 3-propionylbicyclo[1.1.1]pentane-1-carboxylate (600 mg, 1 Eq, 3.29 mmol) in acetic acid (12 mL) was added bromine (553 mg, 178 μL, 1.05 Eq, 3.46 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water (200 mL), and solid NaSO was added to reduce unreacted bromine. The crude product was extracted three times with ether. The combined organic layers were washed with saturated aqueous NaHCO and dried over NaSO. After filtration and concentration, the residue was purified by FCC (EA / Hep = 0-100%) to give methyl 3-(2-bromopropanoyl)bicyclo[1.1.1]pentane-1-carboxylate. 1H NMR(400MHz,CD2Cl2)δ 4.61(q,J=6.7Hz,1H),3.70(s,3H),2.47-2.37(m,6H),1.73(d,J=6.7Hz,3H).

[0354] Step 3: methyl 3-(4-methyl-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To a solution of methyl 3-(2-bromopropanoyl)bicyclo[1.1.1]pentane-1-carboxylate in MeOH (5 mL) was added acetic acid formimidamide (1.03 g, 10 eq, 9.88 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, followed by the addition of triethylamine (1.10 g, 1.51 mL, 11 eq, 10.9 mmol). The reaction mixture was heated to reflux for 12 hours and then cooled to room temperature. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with brine. After phase separation, the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by FCC (MeOH / DCM = 0-20%) to give methyl 3-(4-methyl-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate. LCMS (basic) R t =0.61, M=207.1[M+1] +

[0355] Step 4: (S)-3-(4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (2a) and (S)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (2b) [ka] To a solution of compound 23 (104 mg, 1 Eq, 504 μmol) and intermediate IV.1 (147 mg, 1.2 Eq, 605 μmol) in DMF (0.5 mL) was added Cs2CO3 (246 mg, 1.5 Eq, 756 μmol). The reaction mixture was heated to 120 °C for 4 h and then cooled to room temperature. The reaction mixture was washed with brine and extracted twice with ether. The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by isco (MeOH / DCM = 0-15%) to give products 2a and 2b as regioisomers. LCMS (basic) R t = 1.30, mass = 277.1 and R t =1.33, mass=277.1[M+1] +

[0356] Step 5: (S)-methyl 3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (3a) and methyl (S)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (3b) [ka] To a solution of a mixture of compounds 2a and 2b (39 mg, 1 Eq, 0.14 mmol) in THF (0.5 mL) was added 1N LDA in THF (0.28 mL, 1 molar, 2 Eq, 0.28 mmol) at −78° C. The reaction was stirred at −78° C. for 30 minutes, followed by the addition of DMF (52 mg, 55 μL, 5 Eq, 0.71 mmol) in THF (0.1 mL). The reaction was stirred from −78° C. to room temperature for 1.5 minutes. The reaction mixture was quenched with brine and extracted three times with ether. The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was used in the next step without further purification. LCMS (basic) R t =0.73, mass=305.3[M+1] +

[0357] Step 6: methyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (4a) and methyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (4b) [ka] To a solution of a mixture of compounds 25a and 25b (43 mg, 1 eq, 0.14 mmol) in DCM (1 mL) was added intermediate 3.1 (54 mg, 1 eq, 0.14 mmol) and pyridine (11 mg, 11 μL, 1 eq, 0.14 mmol). The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (45 mg, 1.5 eq, 0.21 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated aqueous NaHCO3 and extracted twice with DCM. The combined organic layer was concentrated, and the residue was purified by FCC (ethyl acetate / DCM = 0-100%) to give products 4a and 4b as a mixture. LCMS (acidic) R t =1.07, mass=636.3, 638.3[M,M+2] +。

[0358] Step 7: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (23a) and 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (23b) [ka] To a solution of a mixture of compounds 4a and 4b (17.0 mg, 1 Eq, 26.7 μmol) in a mixed solvent of THF / MeOH (1.2 mL / 0.4 mL), 2N aqueous LiOH solution (66.8 μL, 2 molar, 5 Eq, 134 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was complete.

[0359] Obtain the られたreaction mixtureを, HPLC (method: basic_15~40%-アセトニトリル)によりdirect purification, compound C-23a: 1H NMR (400MHz, MeOD)δ 7.60(t,J=8.3Hz,1H),7.30(dd,J=10.9,2.0Hz,1H),7.23(ddd,J=8.4,2.0,0.8Hz,1H),6.83-6.68(m,3H),5.1 8-5.05(m,1H),4.66(qd,J=9.1,6.7Hz,2H),4.46(dt,J=9.2,5.8Hz,1H),4.39(dd,J=15.5,2.2Hz,1H),3.80(d, J=13.6Hz,1H),3.62(d,J=13.6Hz,1H),2.97(dd,J=37.3,11.5Hz,2H),2.82-2.63(m,2H),2.54-2.43(m,1H),2. 38(q,J=1.2Hz,5H),2.31-2.10(m,5H),2.05(d,J=1.0Hz,3H),1.99-1.90(m,1H),1.90-1.73(m,3H).HRMS[M+H] + =622.2599 C 34 H 38 Calculated value of ClFN3O5: 622.2584; and C-23b:1H NMR(400MHz,MeOD)δ 7.60(t,J=8.3Hz,1H),7.30(dd,J=10.9,2.0Hz,1H),7.23(ddd,J=8.4,2.0,0.8Hz,1H),6.78(d,J=7.7Hz,1H),6.71(t d,J=7.5,1.4Hz,2H),5.13(qd,J=7.4,2.6Hz,1H),4.65(ddd,J=8.4,7.5,5.8Hz,1H),4.55-4.41(m,2H),4.29(dd,J=1 5.4,2.7Hz,1H),3.75(d,J=13.7Hz,1H),3.60(d,J=13.6Hz,1H),2.95(dd,J=45.4,11.5Hz,2H),2.81-2.63(m,2H),2. 49(ddt,J=11.3,9.2,7.3Hz,1H),2.29(s,5H),2.27-2.13(m,5H),2.05(d,J=1.1Hz,3H),1.96-1.74(m,4H).HRMS[M+H] + =622.2615 C 34 H38 Calculated value for ClFN3O5: 622.2584. obtained.

[0360] Example 24: 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine (C-24) [ka] Step 1: (S)-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) [ka] To 4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (1 g, 6 mmol) in tetrahydrofuran (30 mL) was added dropwise (S)-oxetan-2-ylmethanol (656 mg, 7.45 mmol), triphenylphosphane (1.95 g, 7.45 mmol), followed by (E)-diazene-1,2-dicarboxylate (1.51 g, 1.47 mL, 7.45 mmol). The mixture was stirred at room temperature for 16 h, then concentrated and purified by silica gel chromatography (0-100% AcOEt / heptane). Both isomers appeared together and were purified again by SFC (column: (S,S) Whelk-O1 21 x 250 mm 5 um; flow rate: 80 g per min; co-solvent: 15% MeOH in CO; detection: 230 nm; BPR set point: 125 bar) to give (S)-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) (617 mg, 43%) LCMS Method 2: Rt = 0.72 min; MS m / z 232.1 [M+1] and (S)-1-(oxetan-2-ylmethyl)-5-(trifluoromethyl)-1H-imidazole-4-carbonitrile (2b) (209 mg, 15%) LCMS Method 2: Rt = 0.74 min; MS m / z 232.1[M+1]+ obtained.

[0361] Step 2: (S)-2-Formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) [ka] To (S)-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) (177 mg, 766 μmol) in THF (3 mL) was added LDA (98.4 mg, 459 μL, 2 molar, 919 μmol) at −78° C., and the mixture was stirred at −78° C. for 30 min. DMF (560 mg, 593 μL, 7.66 mmol) was then added, and the mixture was stirred at −78° C. for 10 min, then warmed to room temperature and stirred for an additional 2 h. Water was added, and the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product (S)-2-formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) was then placed on a high vacuum pump for 16 hours and used directly for the next step (176 mg, 89%). LCMS Method 2: Rt = 0.76 min; MS m / z 260.2 [M+1]+.

[0362] Step 3: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (4) [ka] To (S)-2-formyl-1-(oxetan-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) (176 mg, 0.679 mmol) in DCM (3 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (261 mg, 0.679 mmol), EtN (379 μL, 2.72 mmol), and NaBH(OAc) (216 mg, 1.02 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction was diluted with additional dichloromethane and subsequently washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuo to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (4) (71 mg, 18%). LCMS Method 2: Rt=1.47 min; MS m / z 591.3 [M+1]+.

[0363] Step 4: 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine (24) [ka] To 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (4) (71 mg, 0.12 mmol)) in toluene (0.6 mL) was added dropwise azidotributyltin (166 μL, 0.605 mmol) at room temperature. The mixture was stirred at 110° C. for 16 hours. The mixture was purified by preparative HPLC basic conditions to give 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine (C-24) (16 mg, 21%). LCMS Method 3: Rt=2.26 min; MS m / z 634.5 [M+1]+. 1H NMR(400MHz,MeOD)δ 7.50(t,J=8.4Hz,1H),7.20(dd,J=10.8,2.0Hz,1H),7.13(dd,J=8.3,2.0Hz,1H),6.80-6.51(m,3H),4.96-4.82(m,2H),4.62-4.26( m,4H),4.14(dd,J=15.3,2.6Hz,1H),3.79-3.40(m,2H),3.15-2.78(m,3H),2.54-2.40(m,1H),2.32-2.15(m,1H),2.15-1.78(m,7H).

[0364] Example 25: 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-4-(1H-tetrazol-5-yl)-5-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine (C-25) [ka] C-25 was synthesized using the same procedure as compound 24 but using 2b after step 1. LCMS Method 3 Rt=2.08 min; MS m / z 634.3 [M+H]+. 1H NMR(400MHz,MeOD)δ 7.50(t,J=8.3Hz,1H),7.18(dd,J=11.0,2.1Hz,1H),7.12(dd,J=8.7,2.1Hz,1H),6.80-6.54(m,3H),5.07(q,J=7.5Hz,1H),4.73-4.58(m,2H),4. 57-4.29(m,4H),3.59(d,J=50.6Hz,2H),3.09-2.78(m,3H),2.71(dtd,J =11.3,8.1,5.9Hz,1H),2.47(dq,J=10.8,7.5Hz,1H),2.13-1.85(m,7H).

[0365] Example 26: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one (C-26) [ka] To 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (prepared in Example 24, Step 3) (94 mg, 0.16 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (28 mg, 0.40 mmol) and triethylamine (0.16 g, 0.22 mL, 1.6 mmol) at room temperature. The mixture was stirred at 60° C. for 16 hours. Ethyl acetate was added (approximately 5 mL), followed by washing with approximately 2 mL of water, followed by approximately 2 mL of brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo, and placed on a high vacuum pump for 16 hours. To the residue, DMF (2 mL), CDI (57 mg, 0.35 mmol), and DBU (73 mg, 72 μL, 0.48 mmol) were added, followed by stirring at room temperature for 2 hours. Water was added, followed by extraction twice with EtOAc, drying over magnesium sulfate, filtration, and concentration in vacuo. The residue was purified by preparative HPLC under basic conditions to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one (C-26) (15 mg, 15%) as a white solid. LCMS method 1: Rt=1.04 min; MS m / z 650.2[M+1]+. 1H NMR(400MHz,MeOD)δ 7.49(t,J=8.3Hz,1H),7.19(dd,J=10.9,2.2Hz,1H),7.12(dd,J=8.3,2.1Hz, 1H),6.75-6.59(m,3H),5.05-4.94(m,1H),4.64(dd,J=15.3,7.3Hz,1H),4.5 6(td,J=7.8,5.6Hz,1H),4.43-4.31(m,2H),4.25-4.20(m,1H),3.54-3.27(m ,2H),2.80(s,3H),2.68-2.54(m,1H),2.43-2.30(m,1H),2.05-1.86(m,8H).

[0366] Example 27: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (C-27) [ka] Step 1: (S)-4-ethyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate methyl (9) [ka] To methyl 4-ethyl-1H-imidazole-5-carboxylate (0.365 g, 2.37 mmol) in tetrahydrofuran (16 mL) was added dropwise (S)-oxetan-2-ylmethanol (250 mg, 2.84 mmol), triphenylphosphane (745 mg, 2.84 mmol), followed by (E)-diisopropyl diazene-1,2-dicarboxylate (547 mg, 0.55 mL, 2.84 mmol). The mixture was stirred at room temperature for 16 h, then concentrated and purified by silica gel chromatography (0–100% AcOEt / heptane) to give (S)-4-ethyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (9) (404 mg, 76%). LCMS method 2: Rt=0.67 min; MS m / z 225.1[M+1]+.

[0367] Step 2: (S)-4-ethyl-2-formyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate methyl (10) [ka] To (S)-4-ethyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-methyl carboxylate (9) (200 mg, 892 μmol) in THF (5 mL) was added LDA (105 mg, 491 μL, 2 molar, 981 μmol) at −78°C, followed by stirring the mixture at −78°C for 30 min. Next, DMF (652 mg, 691 μL, 8.92 mmol) was added, and the mixture was stirred at −78°C for 10 min, then warmed to room temperature and stirred for 2 h. Water was added, and the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude (S)-4-ethyl-2-formyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-methyl carboxylate (10) was then placed on a high vacuum pump for 16 h and used directly for the next step. LCMS method 2: Rt=0.74 min; MS m / z 253.1[M+1]+

[0368] Step 3: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (11) [ka] To (S)-4-ethyl-2-formyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-methyl carboxylate (10) (37 mg, 0.15 mmol) in DCM (2 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (56 mg, 0.15 mmol), EtN (82 μL, 0.59 mmol), and NaBH(OAc) (46 mg, 0.22 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction was diluted with additional dichloromethane and subsequently washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuo to give methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (11) (14 mg, 16%). LCMS Method 2: Rt=1.43 min; MS m / z 584.3 [M+1]+.

[0369] Step 4: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (12) [ka] To a solution of methyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (14 mg, 23.97 μmol) in THF (0.6 mL)-MeOH (0.3 mL) was added 2N aqueous LiOH solution (240 μl) at room temperature. The reaction was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt, acidified to pH ∼5 with aq. KH2PO4, extracted twice with AcOEt, washed with brine, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC basic conditions to give 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (C-27) as a white solid (5.6 mg, 41%). LCMS Method 1: Rt=0.99 min; MS m / z 570.1 [M+1]+. 1H NMR (400 MHz, MeOD) δ 7.49(t,J=8.3Hz,1H),7.19(dd,J=10.8,2.0Hz,1H),7.12(dd,J=8.4,2.1Hz,1H),6.7 4-6.53(m,3H),5.08-4.98(m,1H),4.94-4.84(m,2H),4.54(q,J=7.5Hz,1H),4.36(dt, J=9.1,5.9Hz,1H),3.94-3.71(m,2H),3.04(s,2H),2.82(td,J=7.4,2.9Hz,2H),2.66( s,2H),2.46-2.22(m,3H),1.94(s,3H),1.81(d,J=37.5Hz,4H),1.12(t,J=7.5Hz,3H).

[0370] Example 28: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoic acid (C-28) [ka] Step 1: (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (2) [ka] To a solution of (S)-ethyl 2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (1) (353.0 mg, 1.164 mmol) and DMF (902 μL, 11.64 mmol) in THF (3 mL) was slowly added Turbo Grignard (1.3 M in THF) (2.687 mL, 3.493 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min. LCMS showed the reaction was nearly complete. The reaction was quenched with saturated NH Cl solution and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over Na SO , and concentrated by rotovap to give ethyl (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate (294 mg). It was used in the next step without further purification. LCMS Method 2: Rt=0.71 min; MS m / z 251.3 [M+1]+.

[0371] Step 2: Ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (4) [ka] To a solution of (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-ethyl carboxylate (2) (293.0 mg, 1.161 mmol), (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (3) (537.5 mg, 1.278 mmol) in DCM (10 mL) was added pyridine (103 μL, 1.278 mmol). The reaction was stirred at room temperature for 15 minutes, followed by the addition of NaBH(OAc) (393.9 mg, 1.858 mmol). The reaction was stirred at room temperature overnight. LCMS indicated the reaction was complete. Additional NaBH(OAc) (150 mg) was added. LCMS showed no further progress. The reaction mixture was cooled to 0 °C, quenched with saturated NaHCO3 solution, and extracted twice with DCM. The combined organic layers were concentrated, and the residue was purified by ISCO (10 to 100% EtOAc / heptane, the desired product appeared after 100% ethyl acetate, peak 3) to give ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (4) (305.0 mg, 45%) as a white foamy solid. LCMS Method 2: Rt = 1.40 min; MS m / z 584.3 [M+1]+.

[0372] Step 3: Ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-oxopropanoate (5) [ka] To EtOAc (151 μL, 1.541 mmol) in 2.5 mL of THF at −78° C. under nitrogen, 1 M LiHMDS (1.541 mL, 1.541 mmol) in hexanes was added. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to 0° C. A solution of ethyl 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate (4) (150.0 mg, 256.8 μmol) in THF (2.5 mL) was added. The mixture was stirred at the same temperature for 2.5 hours. After that, LCMS showed the major peak as the desired product. The reaction was quenched with saturated NaHCO and extracted with DCM (2x). The combined organic layers were concentrated and purified by ISCO (12 g silica gel column, 0-10% MeOH in DCM) to give ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-oxopropanoate (5) (150.0 mg, 93%) as a yellow oil. Traces of SM (ca. 5%) were present. LCMS Method 2: Rt = 1.34 min; MS m / z 626.2 [M+1]+.

[0373] Step 4: Ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoate (6) [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-oxopropanoate (5) (150.0 mg, 239.6 μmol) in MeOH (1.000 mL) was added NaBH (18 mg, 1 μmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes. LCMS showed the reaction was complete. The reaction was quenched with saturated NH Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, filtered (to remove traces of water), concentrated, and purified by ISCO (0-10% MeOH in DCM, 12 g HP GOLD silica gel column (product 6, peak 1 appeared at approximately 9% MeOH in DCM; product 7, peak 2 appeared at 10% MeOH in DCM) to give ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoate (6) (26 mg, 17%) and 1 -(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propane-1,3-diol (7) (50 mg, 35.6%) was obtained. LCMS Method 2: Rt=1.25 min; MS m / z 628.3 [M+1]+.

[0374] Step 5: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoic acid (C-28) [ka] To a solution of ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoate (6) (26 mg, 41.4 μmol) in THF (0.600 mL) and MeOH (0.200 mL) was added 1N LiOH (165 μL, 165.6 μmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The crude material was loaded directly onto a 15.5 g C18 column and purified by ISCO (10-100% ACN in water, buffered with 0.1% concentrated NH4OH) to give 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoic acid lithium salt (12.0 mg, 47.8%) as a diastereomeric mixture after lyophilization. C-28a is 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-(R)-3-hydroxypropanoic acid, and C-28b is 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-(S)-3-hydroxypropanoic acid. LCMS method 4: Rt=1.63 min; MS m / z 600.2[M+1]+.1H NMR(400MHz,MeOD)δ 7.47(t,J=8.4Hz,1H),7.16(dd,J=11.0,2.1Hz,1H),7.10(dd,J=8.4,2.1Hz,1H), 6.70-6.53(m,3H),5.16-4.97(m,2H),4.72-4.16(m,4H),3.71(dd,J=13.5,7.1Hz, 1H),3.37(dd,J=17.2,13.6Hz,1H),2.90(d,J=11.2Hz,1H),2.82-2.32(m,6H),2. 14(d,J=4.4Hz,3H),2.13-1.92(m,2H),1.92(d,J=1.9Hz,3H),1.86-1.56(m,4H).

[0375] Example 29 Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(4-fluorophenyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propiolic acid (C-29) [ka] Synthesis scheme: [ka] reagent: Step 1: Int. 1 (1.00 eq), N-iodosuccinimide (1.2 eq), dichloromethane (10V), room temperature, 2 h. Step 2: Int. 2 (1.00 eq), Int. 3 (1.5 eq), cesium carbonate (3 eq), acetonitrile (10V), 100 °C, 3 h. Step 3: Int. 4 (1.00 eq), THF (10V), LDA (2 eq), -78 °C, 40 min, DMF (5 eq), -78 °C, 0 °C to room temperature, 2 h. Step 4: Int. 6 (1.00 eq), Int. 7 (0.40 eq), pyridine (1.00 eq), STAB (1.3 eq), DCM, RT, 16 h. Step-05: Int-8 (1 eq), ethyl propiolate (3 eq), PPh3 (0.2 eq), CuI (0.2 eq), PdCl2(PPh3)2 (0.1 eq), TEA (3 eq), DMF, 90°C, 16 hours. Step-06: Int-9 (1 eq), NaOH (2 eq), methanol (10V), water (10V), 0°C to room temperature, 4 hours.

[0376] Step 1: Synthesis of 4-(4-fluorophenyl)-5-iodo-1H-imidazole [ka] To a solution of 4-(4-fluorophenyl)-1H-imidazole (5 g, 30.832 mmol) in dichloromethane (50 mL) was added N-iodosuccinimide (8.3 g, 36.998 mmol) at room temperature. The reaction was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by trituration with dichloromethane to give 4-(4-fluorophenyl)-5-iodo-1H-imidazole (6.3 g, yield: 71%). LCMS Method C3: Rt = 1.391 min; MS m / z 289 [M+1]+. 1H NMR(400MHz,DMSO-d6)δ 7.23(s,1H),7.31(t,J=8.8Hz,1H),7.64-7.73(m,1H),7.78(s,1H),7.89(s,1H),11.05(s,1H).

[0377] Step 2: Synthesis of (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole [ka] To a solution of 4-(4-fluorophenyl)-5-iodo-1H-imidazole (4.0 g, 13.886 mmol, 1.0 eq) in acetonitrile (40 ml, 10 vol) was added cesium carbonate (13.57 g, 41.658 mmol, 3.0 eq) and (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (Int-3) (5.04 g, 20.82 mmol, 1.5 eq) at room temperature under a nitrogen atmosphere, and the reaction was then stirred at 100 °C for 3 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 50 ml), and the organic layer was washed with brine (100 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude material was purified by glass gravity column chromatography using ethyl acetate and hexane (10-50% ethyl acetate in hexane) to give the crude material, which was further purified by chiral preparative HPLC to give (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole, (4) (1.2 g, yield: 24%), LCMS Method C3:R t =1.503 min;MS m / z 359.1=[M+1] +1H NMR(400MHz,DMSO-d6)δ 2.41(ddt,J=15.7,11.6,7.3Hz,1H),2.63-2.76(m,1H),4.18-4.42(m,3H),4.52(q,J=7.7,7.0Hz, 1H),4.97(qd,J=6.8,4.0Hz,1H),7.27(t,J=8.8Hz,2H),7.91(dd,J=8.6,5.5Hz,2H),8.02(s,1H), and (S)-5-(4-fluorophenyl)-4-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole, (5) (0.7 g, yield: 14%) LCMS Method C3:R t =1.502 min;MS m / z 358.8=[M+1] + 1H NMR(400MHz,DMSO-d6)δ 2.11-2.24(m,1H),2.46(m,1H),4.06-4.18(m,2H),4.14-4.32(m,1H),4.34-4.49(m,1H),4 .71(qd,J=6.9,4.1Hz,1H),7.35(t,J=8.7Hz,2H),7.47(dd,J=8.5,5.5Hz,2H),7.84(s,1H). obtained.

[0378] Step 3. Synthesis of (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (6). [ka] To a solution of (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole (4) (0.600 g, 1.675 mmol, 1 eq) in tetrahydrofuran (6 mL, 10 vol), lithium diisopropylamide solution (2.0 M in THF) (1.67 mL, 3.351 mmol, 2.0 eq) was added at −78° C., and the mixture was stirred at −78° C. for 40 minutes. Next, N,N-dimethylformamide (0.612 g, 8.376 mmol, 5.0 eq) was added thereto at −78° C. The reaction was then warmed to 0° C. within 2 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was slowly quenched with saturated ammonium chloride solution (200 ml) at 0° C. and extracted with diethyl ether (3×40 ml). The organic layer was washed with brine (80 ml), dried over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was carried to the next step without any purification to obtain (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (6) (0.573 g, yield: 89%). LCMS Method C3:R t =1.643min;MS m / z 387.5[M+1] + .

[0379] Step 4. Synthesis of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((4-(4-fluorophenyl)-5-iodo-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine (8) [ka] To a solution of tert-butyl (S)-4-(4-fluorophenyl)-5-iodo-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (6) (0.573 g, 1.484 mmol, 1 eq) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (0.228 g, 0.594 mmol, 0.4 eq) in dichloromethane (5.7 ml, 10 vol) was added pyridine (0.117 g, 1.484 mmol, 1.0 eq) at room temperature. The reaction was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mixture was cooled to 0°C, followed by the addition of sodium triacetoxyborohydride (0.409 g, 1.929 mmol, 1.3 eq) to the reaction mixture at 0°C. The reaction mixture was slowly brought to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3 x 30 ml), and the organic layer was washed with saturated bicarbonate solution, brine (30 ml), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude was purified by combiflas...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, 【Chemistry 2】 is a single bond or a double bond; 【Chemistry 3】 teeth, 【Chemistry 4】 is selected from 【Chemistry 5】 indicates the point of attachment to the remainder of the molecule; W is O or CH ２ and X is O or CH ２ and R １ and R ２ are each independently H, C １～３ - selected from alkyl, and halo; R ３ is H and C １～３ - alkyl; R ４ is H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -Alkyl-, Phenyl-C １～３ -Alkyl-, halo, CN, NO ２ , OR ４ａ , S.R. ４ａ , C(O)OR ４ａ , C(O)R ４ｂ , C(O)NR ４ｃ R ４ｄ , C(O)NR ４ｃ (OR ４ａ ), C(O)NR ４ｃ (S(O) ２ R ４ｂ ), C(O)NR ４ｃ (S(O) ２ N.R. ４ｃ R ４ｄ ), N.R. ４ｃ OR ４ａ , N.R. ４ｃ R ４ｄ , N.R. ４ｃ (C(O)R ４ｂ ), N.R. ４ｃ (C(O)OR ４ａ ), N(OR ４ａ ) (C(O)R ４ｂ ), N.R. ４ｃ (C(O)NR ４ｃ R ４ｄ ), N.R. ４ｃ (C(O)NR ４ｃ (C(O)R ４ｂ ) ) NR ４ｃ (S(O) ２ R ４ｂ ), N.R. ４ｃ (S(O) ２ N.R. ４ｃ R ４ｄ ), N.R. ４ｃ (C(O)NR ４ｃ (S(O) ２ R ４ｂ )), O.C.(O)R ４ｂ , O.C.(O)NR ４ｃ R ４ｄ , O.N.R. ４ｃ (C(O)R ４ｂ ), OS(O) ２ R ４ｂ , OP(O)(OR ４ｅ ) (OR ４ｆ ), S(O)OR ４ａ , S(O)R ４ｂ , S(O) ２ R ４ｂ , S(O) ２ N.R. ４ｃ R ４ｄ , S(O) ２ OR ４ａ , S (=NR ４ｇ ) (O) R ４ｂ , S (=NR ４ｇ ) (O) N.R. ４ｃ N.R. ４ｄ , P(O)(OR ４ｅ ) (OR ４ｆ ), and P(O)(OR ４ｅ ) (R ４ｆ ), R ４ The above C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -alkyl- and phenyl-C １～３ -alkyl- is C １～３ Alkyl, halo, CN, NO ２ , OR ４Ａ , S.R. ４Ａ , C(O)OR ４Ａ , C(O)R ４Ｂ , C(O)NR ４Ｃ R ４Ｄ , C(O)NR ４Ｃ (OR ４Ａ ), C(O)NR ４Ｃ (S(O) ２ R ４Ｂ )、C(O)NR ４Ｃ (S(O) ２ NR ４Ｃ R ４Ｄ )、NR ４Ｃ OR ４Ａ 、NR ４Ｃ R ４Ｄ 、NR ４Ｃ (C(O)R ４Ｂ )、NR ４Ｃ (C(O)OR ４Ａ )、N(OR ４Ａ )(C(O)R ４Ｂ )、NR ４Ｃ (C(O)NR ４Ｃ R ４Ｄ )、NR ４Ｃ (C(O)NR ４Ｃ (C(O)R ４Ｂ ))、NR ４Ｃ (S(O) ２ R ４Ｂ )、NR ４Ｃ (S(O) ２ NR ４Ｃ R ４Ｄ )、NR ４Ｃ (C(O)NR ４Ｃ (S(O) ２ R ４Ｂ ))、OC(O)R ４Ｂ 、OC(O)NR ４Ｃ R ４Ｄ 、ONR ４Ｃ (C(O)R ４Ｂ )、OS(O) ２ R ４Ｂ 、OP(O)(OR ４Ｅ )(OR ４Ｆ )、S(O)OR ４Ａ 、S(O)R ４Ｂ 、S(O) ２ R ４Ｂ 、S(O) ２ NR ４Ｃ R ４Ｄ 、S(O) ２ OR ４Ａ 、S(=NR ４Ｇ )(O)R ４Ｂ 、S(=NR ４Ｇ )(O)NR ４Ｃ NR ４Ｄ 、P(O)(OR ４Ｅ ) (OR ４Ｆ ), and P(O)(OR ４Ｅ ) (R ４Ｆ Optionally substituted with 1, 2, or 3 groups independently selected from R ５ is H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -Alkyl-, Phenyl-C １～３ -Alkyl-, halo, CN, NO ２ , OR ５ａ , S.R. ５ａ , C(O)OR ５ａ , C(O)R ５ｂ , C(O)NR ５ｃ R ５ｄ , C(O)NR ５ｃ (OR ５ａ ), C(O)NR ５ｃ (S(O) ２ R ５ｂ ), C(O)NR ５ｃ (S(O) ２ N.R. ５ｃ R ５ｄ ), N.R. ５ｃ OR ５ａ , N.R. ５ｃ R ５ｄ , N.R. ５ｃ (C(O)R ５ｂ ), N.R. ５ｃ (C(O)OR ５ａ ), N(OR ５ａ ) (C(O)R ５ｂ ), N.R. ５ｃ (C(O)NR ５ｃ R ５ｄ ), N.R. ５ｃ (C(O)NR ５ｃ (C(O)R ５ｂ ) ) NR ５ｃ (S(O) ２ R ５ｂ ), N.R. ５ｃ (S(O) ２ N.R. ５ｃ R ５ｄ ), N.R. ５ｃ (C(O)NR ５ｃ (S(O) ２ R ５ｂ )), O.C.(O)R ５ｂ , O.C.(O)NR ５ｃ R ５ｄ , O.N.R. ５ｃ (C(O)R ５ｂ ), OS(O) ２ R ５ｂ , OP(O)(OR ５ｅ ) (OR ５ｆ ), S(O)OR ５ａ , S(O)R ５ｂ , S(O) ２ R ５ｂ , S(O) ２ N.R. ５ｃ R ５ｄ , S(O) ２ OR ５ａ , S (=NR ５ｇ ) (O) R ５ｂ , S (=NR ５ｇ ) (O) N.R. ５ｃ N.R. ５ｄ , P(O)(OR ５ｅ ) (OR ５ｆ ), and P(O)(OR ５ｅ ) (R ５ｆ ), R ５ The above C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -alkyl- and phenyl-C １～３ -alkyl- is C １～３ Alkyl, halo, CN, NO ２ , OR ５Ａ , S.R. ５Ａ , C(O)OR ５Ａ , C(O)R ５Ｂ , C(O)NR ５Ｃ R ５Ｄ , C(O)NR ５Ｃ (OR ５Ａ ), C(O)NR ５Ｃ (S(O) ２ R ５Ｂ )、C(O)NR ５Ｃ (S(O) ２ NR ５Ｃ R ５Ｄ )、NR ５Ｃ OR ５Ａ 、NR ５Ｃ R ５Ｄ 、NR ５Ｃ (C(O)R ５Ｂ )、NR ５Ｃ (C(O)OR ５Ａ )、N(OR ５Ａ )(C(O)R ５Ｂ )、NR ５Ｃ (C(O)NR ５Ｃ R ５Ｄ )、NR ５Ｃ (C(O)NR ５Ｃ (C(O)R ５Ｂ ))、NR ５Ｃ (S(O) ２ R ５Ｂ )、NR ５Ｃ (S(O) ２ NR ５Ｃ R ５Ｄ )、NR ５Ｃ (C(O)NR ５Ｃ (S(O) ２ R ５Ｂ ))、OC(O)R ５Ｂ 、OC(O)NR ５Ｃ R ５Ｄ 、ONR ５Ｃ (C(O)R ５Ｂ )、OS(O) ２ R ５Ｂ 、OP(O)(OR ５Ｅ )(OR ５Ｆ )、S(O)OR ５Ａ 、S(O)R ５Ｂ 、S(O) ２ R ５Ｂ 、S(O) ２ NR ５Ｃ R ５Ｄ 、S(O) ２ OR ５Ａ 、S(=NR ５Ｇ )(O)R ５Ｂ 、S(=NR ５Ｇ )(O)NR ５Ｃ NR ５Ｄ 、P(O)(OR ５Ｅ ) (OR ５Ｆ ), and P(O)(OR ５Ｅ ) (R ５Ｆ Optionally substituted with 1, 2, or 3 groups independently selected from R ５’ is H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -Alkyl-, Phenyl-C １～３ -alkyl-, C(O)OR ５ａ’ , C(O)R ５ｂ’ , C(O)NR ５ｃ’ R ５ｄ’ , C(O)NR ５ｃ’ (OR ５ａ’ ), C(O)NR ５ｃ’ (S(O) ２ R ５ｂ’ ), and C(O)NR ５ｃ’ (S(O) ２ N.R. ５ｃ’ R ５ｄ’ ), R ５’ The above C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, and 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl-, (5- to 10-membered heteroaryl)-C １～３ -alkyl- and phenyl-C １～３ -alkyl- is C １～３ Alkyl, halo, CN, NO ２ , OR ５Ａ’ , S.R. ５Ａ’ , C(O)OR ５Ａ’ , C(O)R ５Ｂ’ , C(O)NR ５Ｃ’ R ５Ｄ’ , C(O)NR ５Ｃ’ (OR ５Ａ’ ), C(O)NR ５Ｃ’ (S(O) ２ R ５Ｂ’ )、C(O)NR ５Ｃ’ (S(O) ２ NR ５Ｃ’ R ５Ｄ’ )、NR ５Ｃ’ OR ５Ａ’ 、NR ５Ｃ’ R ５Ｄ’ 、NR ５Ｃ’ (C(O)R ５Ｂ’ )、NR ５Ｃ’ (C(O)OR ５Ａ’ )、N(OR ５Ａ’ )(C(O)R ５Ｂ’ )、NR ５Ｃ’ (C(O)NR ５Ｃ’ R ５Ｄ’ )、NR ５Ｃ’ (C(O)NR ５Ｃ’ (C(O)R ５Ｂ’ ))、NR ５Ｃ’ (S(O) ２ R ５Ｂ’ )、NR ５Ｃ’ (S(O) ２ NR ５Ｃ’ R ５Ｄ’ )、NR ５Ｃ’ (C(O)NR ５Ｃ’ (S(O) ２ R ５Ｂ’ ))、OC(O)R ５Ｂ’ 、OC(O)NR ５Ｃ’ R ５Ｄ’ 、ONR ５Ｃ’ (C(O)R ５Ｂ’ )、OS(O) ２ R ５Ｂ’ 、OP(O)(OR ５Ｅ’ )(OR ５Ｆ’ )、S(O)OR ５Ａ’ 、S(O)R ５Ｂ’ 、S(O) ２ R ５Ｂ’ 、S(O) ２ NR ５Ｃ’ R ５Ｄ’ 、S(O) ２ OR ５Ａ’ 、S(=NR ５Ｇ’ )(O)R ５Ｂ’ 、S(=NR ５Ｇ’ )(O)NR ５Ｃ’ NR ５Ｄ’ 、P(O)(OR ５Ｅ’ ) (OR ５Ｆ’ ), and P(O)(OR ５Ｅ’ ) (R ５Ｆ’ Optionally substituted with 1, 2, or 3 groups independently selected from R ６ and R ６’ are each independently (4 to 10 membered heterocycloalkyl)-C １～３ -alkyl- and (5- to 10-membered heteroaryl)-C １～３ -alkyl-; R ６ and R ６’ The (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl- and (5- to 10-membered heteroaryl)-C １～３ -alkyl- is C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is C(O)OR ４Ａ , —OH, and halo; and R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４ｅ , R ４ｆ , and R ４ｇ are each independently H and C １～６ - alkyl; R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ are each independently H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４Ｅ , R ４Ｆ , and R ４Ｇ are each independently H and C １～６ - alkyl; R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ５ｅ , R ５ｆ , and R ５ｇ are each independently H and C １～６ - alkyl; R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ５Ａ , R ４Ｂ , R ５Ｃ , and R ５Ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ５Ｅ , R ５Ｆ , and R ５Ｇ are each independently H and C １～６ - alkyl; R ５ａ’ , R ５ｂ’ , R ５ｃ’ , and R ５ｄ’ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ５ａ’ , R ５ｂ’ , R ５ｃ’ , and R ５ｄ’ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ５ａ’ , R ５ｂ’ , R ５ｃ’ , and R ５ｄ’ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ５Ａ’ , R ５Ｂ’ , R ５Ｃ’ , and R ５Ｄ’ are independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ５Ａ’ , R ５Ｂ’ , R ５Ｃ’ , and R ５Ｄ’ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ５Ａ’ , R ５Ｂ’ , R ５Ｃ’ , and R ５Ｄ’ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ optionally substituted with 1, 2, or 3 groups independently selected from -alkyl, -OH, and halo; and R ５Ｅ’ , R ５Ｆ’ , and R ５Ｇ’ are each independently H and C １～６ -alkyl).

2. R １ is chloro or fluoro; and R ２ is chloro or fluoro, and R ３ But -CH ３ 2. The compound of claim 1, wherein: 【Request 3】 【Chemical 6】 but, 【Chemistry 7】 2. The compound of claim 1, wherein:

4. R ４ But, C １～３ -Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C(O)OR ４ａ , and C(O)NR ４ｃ R ４ｄ is selected from R ４ The above C １～３ -Alkyl, C ２～４ Alkenyl, C ２～４ Alkynyl, C ３～６ -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each independently selected from halo, C １～３ -alkyl, and C(O)OR ４Ａ optionally substituted with 1, 2, or 3 groups independently selected from ４ａ , R ４ｃ , R ４ｄ and R ４Ａ independently H and C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

5. R ４ But, H, C １～３ -Alkyl, C ２～４ Alkenyl, C ３～６ - selected from cycloalkyl, 5-10 membered heteroaryl and C(O)OH; R ４ The above C １～３ -Alkyl, C ２～４ Alkenyl, C ３～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH.

6. R ４ but, 【Chemistry 8】 or R ４ but, 【Chemistry 9】 2. The compound of claim 1 having the structure: or a pharma- ceutically acceptable salt thereof.

7. R ５ But, C １～３ -Alkyl, C ２～４ Alkenyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, halo, C(O)OR ５ａ is selected from Said C １～３ -Alkyl, C ２～４ Alkenyl, C ３～６ -cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each independently halo and C(O)OR ５Ａ optionally substituted with 1, 2, or 3 groups independently selected from R ５ａ But H and C １～３ - alkyl; and R ５Ａ But H and C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

8. R ５ But, H, C １～３ -Alkyl, C ２～４ Alkenyl, C ３～６ -cycloalkyl, and C(O)OH; R ５ The above C １～３ -Alkyl, C ２～４ Alkenyl, and C ３～６ each cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from halo and C(O)OH; R ５ but, 【Chemistry 10】 2. The compound of claim 1, selected from:

9. R ５ but, 【Chemistry 11】 2. The compound of claim 1, selected from:

10. R ６ and R ６’ each independently represents (4- to 6-membered heterocycloalkyl)-CH ２ - and (5- to 6-membered heteroaryl)-CH ２ -, R ６ and R ６’ The (4- to 6-membered heterocycloalkyl)-CH ２ - and (5- to 6-membered heteroaryl)-CH ２ - is C １～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo.

11. R ６ and R ６’ However, each independently, 【Chemistry 12】 is selected from 【Chemistry 13】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein indicates the point of attachment to the remainder of the molecule.

12. R ６ and R ６’ but, 【Chemistry 14】 and 【Chemistry 15】 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein indicates the point of attachment to the remainder of the molecule.

13. Compound of formula (IIa): 【Chemistry 16】 2. The compound of claim 1, wherein:

14. Compound of formula (IIIa): 【Chemistry 17】 2. The compound of claim 1, wherein:

15. Compound of formula (Va): 【Chemistry 18】 2. The compound of claim 1, wherein:

16.

19. 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, selected from:

17. (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxy; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)acrylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)cyclopropane-1-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1,2,4-oxadiazol-5(2H)-one; 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine; 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-4-(1H-tetrazol-5-yl)-5-(trifluoromethyl)-1H-imidazol-2-yl)methyl)piperidine; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-1,2,4-oxadiazol-5(2H)-one; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propiolic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)benzoic acid; 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)benzoic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid; (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propanoic acid; (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)glycine; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-methylpropanoic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-2-fluoroacrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-3-hydroxypropanoic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(4-fluorophenyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)propiolic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-fluorobenzoic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-5-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1,3,4-oxazole-2-carboxylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-4-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-3-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-5-carboxylic acid; 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-3-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)nicotinic acid; 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2-carboxylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid; and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid 2. The compound of claim 1, selected from:

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

19. A combination comprising a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, and one or more therapeutically active agents.

20. 18. A compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, for use as a medicine.

21. 18. The compound of any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disorder or disease selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications, diabetic nephropathy, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy.

22. 20. Use of a compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications, diabetic nephropathy, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy.

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