2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[D][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole derivatives as GLP1 receptor activators 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, preparations thereof, pharmaceutical compositions comprising 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 G protein-coupled receptor (GPCR) family B1 and is expressed in many tissues, including the pancreas, heart, intestine, and brain (Kieffer T.J and Habener, JFEndocrin. Rev. 20: 876-913 (1999); Drucker, D.J, Endocrinology 142: 521-7 (2001); Hoist, J.J, Diabetes Metab. Res. Rev. 18: 430-41 (2002); Regard JB, Cell 135: 561-71 (2008)). The native agonist ligands for GLP1R are GLP-1 (7-36, 30aa) and oxytomodulin (OXM, 37aa), both derived from pro-glucagon. Upon activation, GLP1R is G αs - It binds to proteins, subsequently activating adenylyl cyclase and increasing 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, 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 generally accompanied by hyperinsulinemia, hyperglycemia, or both. In addition, T2DM is associated with a 2-4 times increased risk of coronary artery disease. Currently, the most effective treatment for obesity is bariatric surgery, but this is costly and dangerous 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 have more side effects than bariatric surgery. Among the GLP1R agonist peptides on the market, 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 the remission of type 2 diabetes in adults who cannot maintain normal glycemic control with antidiabetic drugs and / or insulin due to insulin resistance, nor are there any approved drug therapies for heart failure with preserved ejection fraction (HFpEF). Alternatively, GLP1R agonists may be an effective therapy for the remission of type 2 diabetes mellitus. GLP1R receptor agonists may reduce the risk of cardiovascular death and hospitalization in patients with chronic HFpEF.

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

[0005] This disclosure, in particular, relates to compounds of formula (I): [ka] The following are provided: and pharmaceutically acceptable salts thereof, the components of which are defined herein.

[0006] Compounds of formula (I) as defined herein, and their pharmaceutically acceptable salts, are GLP1R agonists. Therefore, these compounds may be useful in the treatment of metabolic 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. The compounds may also be useful in the treatment of progressive liver disease and neuropathy.

[0007] Furthermore, this specification provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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

[0009] This specification provides a method for treating, preventing or relieving a therapeutic condition, disease, or disorder in a patient by activating or stimulating GLP1R, the method comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., in a therapeutically effective dose).

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

[0011] Furthermore, this specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in any of the methods described herein.

[0012] Furthermore, this specification provides 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, for example, reach the maximum concentration (C) in plasma. max ) and / or may exhibit favorable ADME (absorption, distribution, metabolism, and elimination) characteristics, such as in vivo exposure (especially when administered orally), as demonstrated by the measurement of certain pharmacokinetic parameters, including total exposure (area under the curve (AUC)) values. [Modes for carrying out the invention]

[0014] Various aspects and embodiments of the present invention are described herein. Certain features are specified in the context of separate embodiments for clarity (and / or brevity), but it will be recognized that such embodiments may be combined with other specified features (e.g., in any preferred subcombinations) to provide further embodiments of the present invention.

[0015] The definition of substituent applies to any of the formulas provided herein, for example, compounds of formulas (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va) as appropriate. The definition of substituent applies as appropriate to the final product and the corresponding intermediate.

[0016] In one embodiment, the compound of formula (I) is used herein: [ka] or a pharmaceutically acceptable salt thereof (in the formula, [ka] It is either a single bond or a double bond; [ka] is selected from [Chem.] and is such that, in the formula, where [Chem.] represents a point of attachment to the remainder of the molecule; W is O or CH2; X is O or CH2; R 1 and R 2 are each independently selected from H, C 1~3 alkyl, and halo; R 3 is selected from H and C 1~3 -alkyl; R 4 is selected from 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, 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, 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 OR4a , 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 )), O(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 ) is selected from, R 4 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 each, 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)R4B 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 ) is optionally replaced by one, two, or three bases independently selected from ); R 5 H, C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, halo, CN, NO2, OR 5a , 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 Ure 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 )), O(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 ) is selected from, R 5 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively.5A 、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 ) is optionally replaced by one, two, or three bases independently selected from ); R 5’ H, C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member 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)2NR 5c’ R 5d’ ) is selected from, R 5’ C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, and 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A’ , SR 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’ ) is optionally replaced by one, two, or three bases independently selected from ); R 6 and R 6’ Each of these is independently (4-10 member heterocycloalkyl)-C 1~3 -alkyl- and (5-10 member heteroaryl)-C 1~3 Selected from -alkyl-, R 6 and R 6’ (4-10 member heterocycloalkyl)-C 1~3 -alkyl- and (5-10 member heteroaryl)-C 1~3 -alkyl- represents C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 4a , R 4b , R 4c , and R 4d These are H and C, respectively, independently. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 4a , R 4b , R 4c , and R 4d C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 4e , R 4f, and R 4g These are H and C, respectively, independently. 1~6 -Selected from alkyl groups; R 4A , R 4B , R 4C , and R 4D These are H and C, respectively, independently. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 4A , R 4B , R 4C , and R 4D C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 4E , R 4F , and R 4G These are H and C, respectively, independently. 1~6 -Selected from alkyl groups; R 5a , R 5b , R 5c , and R 5d These are H and C, respectively, independently. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 5a , R 5b , R 5c , and R 5d C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 5e , R 5f , and R 5g These are H and C, respectively, independently. 1~6 -Selected from alkyl groups; R 5A , R 5B , R 5C , and R 5D These are H and C, respectively, independently. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 5A , R 5B , R 5C , and R 5D C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 5E , R5F , and R 5G These are H and C, respectively, independently. 1~6 -Selected from alkyl groups; R 5a’ , R 5b’ , R 5c’ , and R 5d’ These are H and C, respectively, independently. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 5a’ , R 5b’ , R 5c’ , and R 5d’ C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; R 5A’ , R 5B’ , R 5C’ , and R 5D’ H and C are independent of each other. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R 5A’ , R 5B’ , R 5C’ , and R 5D’ C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C 1~6 -Optionally substituted with one, two, or three groups independently selected from alkyl, -OH, and halo; and R 5E’ , R 5F’ , and R 5G’ These are H and C, respectively, independently. 1~6 -Selected from alkyl is provided.

[0017] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is a halo.

[0018] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 It is a halo.

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

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

[0021] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 3 This is either H or -CH3.

[0022] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 3 It is -CH3.

[0023] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] That is the case.

[0024] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, 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 Ure 4a , NR 4c R 4d , NR 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)2NR 4c R 4d ), NR 4c (C(O)NR 4c (S(O)2R 4b )), O(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 ) is selected from, R 4 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 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 replaced by one, two, or three elements selected independently of ).

[0025] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~3 -alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from, R 4 C 1~3 -alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each a halo, C 1~3 -alkyl and C(O)OR 4A Replaced by any choice of one, two, or three elements independently selected from; R 4a , R 4c , R 4d and R 4A H and C are independent of each other. 1~3 - Selected from alkyl groups.

[0026] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~3 -alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from, R 4 C 1~3-alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl and phenyl are each substituted with at least one group that is C(O)OH, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each halo, C 1~3 -alkyl and C(O)OR 4A Replaced by any choice of one, two, or three elements independently selected from; R 4a , R 4c , R 4d and R 4A H and C are independent of each other. 1~3 - Selected from alkyl groups.

[0027] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~3 -C substituted with alkyl or 1, 2, or 3 halos 1~3 -It is alkyl.

[0028] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 H, C 1~3 -alkyl, C 2~4 Alkenil, 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 -Cycloalkyls are respectively halo and C(O)OR 4A It is optionally replaced by one, two, or three elements independently selected from the above; R 4a H and C 1~3 -Selected from alkyl groups; and R 4A H and C 1~3 - Selected from alkyl groups.

[0029] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 H, C1~3 -alkyl, C 2~4 Alkenil, C 3~6 -Selected from cycloalkyl and C(O)OH, R 4 C 1~3 -alkyl, C 2~4 Alkenyl and C 3~6 Each cycloalkyl group is optionally substituted with one, two, or three groups independently selected from the halo and C(O)OH groups.

[0030] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] Selected from.

[0031] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] Selected from.

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

[0033] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C(O)OR 4A or a 5-10 member heteroaryl substituted with a carboxylic acid isoster.

[0034] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 The structure of formula H1 or H2 is: [ka] (In the formula, X1 is either C or N, and each of X2, X3, X4, X5, and X6 independently has C=O and CR. 4h , NR 4i It is O, or S; W is C(O)OR 4A or a carboxylic acid isoster; each [ka] It is either a single bond or a double bond; Each R 4h H and C are independent of each other. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, 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 Ure 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 4cR 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 )), O(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 ) is selected from C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 4A , SR 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 ) is optionally substituted with one, two or three groups independently selected from; each R 4i is independently absent, 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, 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-, 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)2NR 4c R 4d ), and is selected from 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, 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- are each 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 NR 4D 、P(O)(OR 4E )(OR 4F )、and P(O)(OR 4E )(R 4F) is optionally replaced by one, two, or three bases independently selected from ); R 4h and R 4i Combined, C 3~6 -Cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl can be formed, and these can further form C 1~6 (It may be substituted with a group independently selected from -alkyl, -OH, and halo.)

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

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

[0037] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 This is a C1-C3 alkyl group, for example, methyl or trifluoromethyl, which is optionally substituted with one, two, or three halos.

[0038] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, halo, CN, NO2, OR 5a , 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 Ure 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 )), O(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)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 ) is selected from, R 5 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A , 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 Ure 5A , NR 5C R 5D , NR 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)2NR 5C R 5D ), NR 5C (C(O)NR 5C (S(O)2R 5B )), O(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 ) is optionally replaced by one, two, or three elements selected independently of ).

[0039] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 C 1~3 -alkyl, C 2~4 Alkenil, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, halo, C(O)OR 5a Selected from, C 1~3 -alkyl, C2~4 Alkenil, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are respectively halo and C(O)OR 5A Replaced by any choice of one, two, or three elements independently selected from; R 5a H and C 1~3 -Selected from alkyl; and R 5A H and C 1~3 - Selected from alkyl groups.

[0040] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 C 1~3 -alkyl, C 2~4 Alkenyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR 5a Selected from, C 1~3 -alkyl, C 2~4 Alkenyls, 4-10 membered heterocycloalkyls, 5-10 membered heteroaryls, and phenyls are each optionally substituted with at least one C(O)OH group.

[0041] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 Hello, C 1~3 - Selected from alkyl and phenyl, C 1~3 - Alkyl and phenyl are each optionally substituted with 1, 2, or 3 halos.

[0042] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 H, C 1~3 -alkyl, C 2~4 Alkenil, 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 -Cycloalkyls are respectively halo and C(O)OR 5AIt is optionally replaced by one, two, or three elements independently selected from the above; R 5a H and C 1~3 -Selected from alkyl groups; and R 5A H and C 1~3 - Selected from alkyl groups.

[0043] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 H, C 1~3 -alkyl, C 2~4 Alkenil, C 3~6 -Selected from cycloalkyl and C(O)OH, R 5 C 1~3 -alkyl, C 2~4 Alkenyl and C 3~6 Each cycloalkyl group is optionally substituted with one, two, or three groups independently selected from the halo and C(O)OH groups.

[0044] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 teeth, [ka] Selected from.

[0045] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 teeth, [ka] Selected from.

[0046] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 These are -CH3, CF3, F, -CH2CH3, and [ka] Selected from.

[0047] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~3 -alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR 4a , and C(O)NR 4c R 4d Selected from, R 4 C 1~3 -alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~6 -Cycloalkyl and phenyl are each substituted with at least one group that is C(O)OH, and 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each halo, C 1~3 -alkyl and C(O)OR 4A Replaced by any choice of one, two, or three elements independently selected from; R 4a , R 4c , R 4d and R 4A H and C are independent of each other. 1~3 -Selected from alkyl; and R 5 Hello, C 1~3 - Selected from alkyl and phenyl, C 1~3 - Alkyl and phenyl are each optionally substituted with 1, 2, or 3 halos.

[0048] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 C 1~3 -C substituted with alkyl or 1, 2, or 3 halos 1~3 -It is alkyl; and R 5 C 1~3 -alkyl, C 2~4 Alkenyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR 5a Selected from, C1~3 -alkyl, C 2~4 Alkenyls, 4-10 membered heterocycloalkyls, 5-10 membered heteroaryls, and phenyls are each optionally substituted with at least one C(O)OH group.

[0049] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth, [ka] Selected from; and R 5 These are -CH3, CF3, F, -CH2CH3, and [ka] Selected from.

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

[0051] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 C(O)OR 5A or a 5-10 member heteroaryl substituted with a carboxylic acid isoster.

[0052] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5 The structure of formula H11 or H12 is: [ka] (In the formula, X1 is either C or N, and each of X2, X3, X4, X5, and X6 independently has C=O and CR. 5h , NR 5i It is O, or S; W is C(O)OR 5A or a carboxylic acid isoster; each [ka] It is either a single bond or a double bond; Each R 5h H and C are independent of each other. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, halo, CN, NO2, OR 5a , 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 Ure 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 5cR 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 )), O(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 ) is selected from C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A , SR 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 ) is optionally replaced by one, two, or three bases independently selected from ); Each R 5i H and C are independent and do not exist. 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member 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)2NR 5c R 5d ) is selected from C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A , 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)NR 5C NR 5D 、P(O)(OR 5E )(OR 5F )、and P(O)(OR 5E )(R 5F) is optionally replaced by one, two, or three bases independently selected from ); R 5h and R 5i Combined, C 3~6 -Cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl can be formed, and these can further form C 1~6 (It may be substituted with a group independently selected from -alkyl, -OH, and halo.)

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

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

[0055] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 This is a C1-C3 alkyl group, for example, methyl or trifluoromethyl, which is optionally substituted with one, two, or three halos.

[0056] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5’ C 1~6 -alkyl, C 2~6Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member 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)2NR 5c’ R 5d’ ) is selected from, R 5’ C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, and 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A’ , 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’ Ure5A’ , 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’ )), O(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’ ) is optionally replaced by one, two, or three elements selected independently of ).

[0057] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5’ H, C 1~3 -alkyl, C2~4 Alkenil, 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 -Cycloalkyls are respectively halo and C(O)OR 5A’ It is optionally replaced by one, two, or three elements independently selected from the above; R 5a’ H and C 1~3 -Selected from alkyl groups; and R 5A’ H and C 1~3 - Selected from alkyl groups.

[0058] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 5’ H, C 1~3 -alkyl, C 2~4 Alkenil, C 3~6 -Selected from cycloalkyl and C(O)OH, R 5’ C 1~3 -alkyl, C 2~4 Alkenyl and C 3~6 Each cycloalkyl group is optionally substituted with one, two, or three groups independently selected from the halo and C(O)OH groups.

[0059] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ Each is independently selected from (4-6 member heterocycloalkyl)-CH2- and (5-6 member heteroaryl)-CH2-, R 6 and R 6’ The (4-6 member heterocycloalkyl)-CH2- and (5-6 member heteroaryl)-CH2- are, respectively, C 1~6 It is optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo.

[0060] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ Each of them operates independently. [ka] Selected from, [ka] This indicates the bonding site to the rest of the molecule.

[0061] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ teeth, [ka] And, [ka] This indicates the bonding site to the rest of the molecule.

[0062] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 6 and R 6’ teeth, [ka] And, [ka] This indicates the bonding site to the rest of the molecule.

[0063] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X is O.

[0064] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, W is O.

[0065] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] It is a single bond.

[0066] In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0067] In some 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 some 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 some 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 some 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 some 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 some 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 some 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 some 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 some embodiments, any of the compounds of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 4 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, 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 Ure 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 )), O(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 ) is selected from, R 4 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 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 4CR 4D ), NR 4C Ure 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 )), O(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 ) is optionally replaced by one, two, or three elements selected independently of ).

[0076] In some embodiments, any of the compounds of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 4 H, C 1~3 -alkyl, C 2~4 Alkenil, 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 -Cycloalkyls are respectively halo and C(O)OR 4A It is optionally replaced by one, two, or three elements independently selected from the above; R 4a H and C 1~3 -Selected from alkyl groups; and R 4A H and C 1~3 - Selected from alkyl groups.

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

[0078] In some embodiments, any of the compounds of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 5 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-,phenyl-C 1~3 -alkyl-, halo, CN, NO2, OR 5a , 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 Ure 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 )), O(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 ) is selected from, R 5 C 1~6 -alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~6 -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl-, (4-10 member heterocycloalkyl)-C 1~3 -alkyl-, (5-10 member heteroaryl)-C 1~3 -alkyl-, and phenyl-C 1~3 -Alkyl- represents Halo, CN, NO2, and OR respectively. 5A , 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 Ure 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 )), O(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 ) is optionally replaced by one, two, or three elements selected independently of ).

[0079] In some embodiments, any of the compounds of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof, R 5 H, C 1~3 -alkyl, C 2~4 Alkenil, C 3~6 -Cycloalkyl and C(O)OR 5a Selected from, R5 C 1~3 -alkyl, C 2~4 Alkenyl and C 3~6 -Cycloalkyls are respectively halo and C(O)OR 5A It is optionally replaced by one, two, or three elements independently selected from the above; R 5a H and C 1~3 -Selected from alkyl groups; and R 5A H and C 1~3 - Selected from alkyl groups.

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

[0081] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] or selected from pharmaceutically acceptable salts thereof.

[0082] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)acrylic acid; and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylic acid Alternatively, a selection is made from its pharmaceutically acceptable salts.

[0083] In one embodiment, 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 any embodiment of any of the formulas provided herein, or any pharmaceutically acceptable salt thereof, the variable element R is optionally substituted. 4 and R 5 (or R 5’ One or both of ) include a carboxylic acid or a carboxylic acid isosterone (see, for example, 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’ Only one of these contains a carboxylic acid or a carboxylic acid isoster.

[0093] The following is an unrestricted list of the acyclic carboxylic acid isosteres:

[0094] [Table 9]

[0095] [Table 10]

[0096] An unrestricted list of cyclic carboxylic acid isosteres is as follows:

[0097] [Table 11]

[0098] [Table 12]

[0099] Unless otherwise specified, the terms “the compound(s) of the present invention,” “the compound of the present invention,” “the compound of the invention,” or “the compound(s) of the invention” refer to the compounds of formula (I) or its subformulas (e.g., (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va)) and the exemplified compounds, as well as their salts, and all stereoisomers (including diastereoisomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and essentially formed moieties.

[0100] Depending on the selection of starting materials and procedures, compounds may exist in one form of any possible stereoisomer or as a mixture thereof, for example, as a pure optical isomer depending on the number of chiral carbon atoms, or as a mixture of stereoisomers such as a racemate and a mixture of diastereoisomers. The present invention shall encompass all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or they may be divided using the prior art. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomer forms are also intended to be included.

[0101] The phrase "substituted by arbitrary choice" means either not substituted or substituted. Substituents are selected independently, and substitutions can occur at any chemically accessible position. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It should be understood that substitutions at a given atom are limited by the bond valence.

[0102] As used herein, "C" is used alone or in combination with other terms. n~m "Alkyl" refers to a saturated hydrocarbon group that may be a straight or branched chain 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] When used in this specification, "C n~m "Alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and 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] When used in this specification, "C n~m "Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and n to m carbon atoms. 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 may be monocyclic or polycyclic (for example, having two, three, or four 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 non-aromatic cyclic hydrocarbons comprising cyclized alkyl and alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having two fused rings) groups, spiro rings, and bridging rings. The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted with oxo or sulfide (e.g., C(O) or C(S)). In some embodiments, the cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C 3~10 (Cycloalkyl). 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, the ring-forming N in the heteroaryl group may be an N-oxide. In some embodiments, the heteroaryl is a 5- to 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, the heteroaryl is a 5- to 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 ring), wherein one or more ring-forming carbon atoms of the heterocycloalkyl are replaced by heteroatoms selected from N, O, S, and B, and the ring-forming carbons or heteroatoms of the heterocycloalkyl can be optionally replaced by one or more oxo or sulfide atoms (e.g., C(O), S(O), C(S), S(O)2, etc.). In some embodiments, the heterocycloalkyl contains 4 to 10 ring-forming atoms (i.e., 4 to 10 members), and 1 to 4 atoms are heteroatoms independently selected from N, O, and S.

[0109] When used in this specification, "C o~p -Cycloalkyl-C n~m- "Alkyl" refers to the group of the formula cycloalkyl-alkylene, where the cycloalkyl group has 0 to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0110] When used in this specification, "heterocycloalkyl-C n~m The "-alkyl" designation refers to the group of the heterocycloalkyl-alkylene formula, where the alkylene linking group has n to m carbon atoms.

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

[0112] When used in this specification, "aryl-C" n~m- Alkyl (for example, "phenyl-C") n~m The "-alkyl" designation refers to the aryl-alkylene group, where the alkylene linkage group has n to m carbon atoms.

[0113] As used herein, the terms “salt” or “salts” refer to acid-addition salts or base-addition salts of the compounds provided herein. “Salt” includes, in particular, “pharmaceutically acceptable salts.” “pharmaceutically acceptable salts” refers to salts that retain the biological efficacy and properties of the compounds provided herein and are not typically biologically or otherwise undesirable. In many cases, the compounds provided herein can form acid salts and / or base salts by the presence of basic nitrogen atoms, as found, for example, in amino and pyridine groups or other similar groups, and / or acidic protons, as found, for example, in carboxylic acids or other similar groups.

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

[0115] Examples of inorganic acids from which salts can be induced include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0116] Examples of organic acids from which salts can be derived include 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, and sulfosalicylic acid.

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

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

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

[0120] In another embodiment, the compounds provided herein exist in the form of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or trometamine salts.

[0121] In another embodiment, the compounds provided herein include acetates, ascorbic acid, adipine acid, aspartate acid, benzoate acid, besilate acid, bromide / hydrobromide acid, bicarbonate / carbonate acid, bisulfate / sulfate acid, camphor sulfonate acid, caprine acid acid, chloride / hydrochloride acid acid, chlorotheophylline acid acid, citrate acid, ethane disulfonate acid, fumarate acid acid, gluceptate acid acid, gluconate acid acid, glucuronate acid acid, glutamate acid acid, glutarate acid acid, glycolate acid acid acid, hippurate acid acid acid acid acid, hydroiodide / iodide acid acid, isethionate acid acid acid acid, lactobionic acid acid It exists in the form of salts, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalactulose, propionate, sebacinate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate.

[0122] Any formula given herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. The isotopically labeled compound has the structure depicted by the formulas given herein, except in which one or more atoms are substituted by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen.

[0123] Furthermore, certain isotopes, particularly deuterium (i.e., 2 The incorporation of H or D may result in certain therapeutic benefits derived from higher metabolic stability, e.g., increased in vivo half-life, or reduced required dose, or improved therapeutic index or tolerability. In this context, deuterium is understood to be a substituent of the compound of the present invention. The concentration of deuterium may be defined by the isotopic enrichment factor. As used herein, the term “isotopic enrichment factor” means the ratio between the isotopic abundance and the endemic abundance of a particular isotope. When a substituent in a compound of the present invention is indicated as deuterium, such a compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation into 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) for each designated deuterium atom. It should be understood that the term “isotopic enrichment factor” can be applied to any of the isotopes in the same manner as that described for deuterium.

[0124] Other examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, fluorine, and sulfur isotopes, for example, 3 H, 11 C, 13 C, 14C, 15 N, 18 F, 35 S is one example. Therefore, the present invention is, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13 It should be understood that this includes compounds that incorporate one or more of the aforementioned isotopes, including those that have non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic tests. 14 (by C), reaction rate test (for example) 2 H or 3 It is useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays (by H), or in radiotherapy for patients. In particular, 18 F or the labeled compound may be particularly desirable for PET or SPECT testing. The isotope-labeled compounds of the present invention can generally be prepared by the prior art known to those skilled in the art, or by using a suitable isotope-labeling reagent instead of previously used unlabeled reagents, by a process similar to that described in the accompanying examples and preparations.

[0125] As used herein, the term “pharmaceutical composition” means 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” means a substance useful in the preparation or use of a pharmaceutical composition, and as known to those skilled in the art, includes, for example, suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, colorants, and combinations thereof (e.g., Remington, The Science and Practice of Pharmacy, 22 ndSee Ed. Pharmaceutical Press, 2013, pp. 1049-1070.

[0127] The term "therapeutic dose" of the compound of the present invention refers to an amount of the compound that would induce a biological or medical response in a subject, for example, by stimulating GLP1R activity, alleviating symptoms, reducing a condition, slowing or delaying the progression of a disease, disorder, or condition, or preventing a disease, disorder, or condition. In one embodiment, the term "therapeutic dose" refers to an amount of the compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, preventing, and / or relieving a condition, disorder, or disease that responds to increased or stimulating GLP1R activity. In another embodiment, the term "therapeutic dose" refers to an amount of the compound of the present invention that, when administered to a subject, cell, or tissue, or a non-cellular biological material, or culture medium, is effective in partially or completely stimulating GLP1R activity. In another embodiment, the term “therapeutic dose” refers to the amount of the compound of the present invention that, when administered to a subject, is effective in causing an observable level of one or more desired biological or medical response, 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 fat and / or visceral fat).

[0128] As used herein, the term “subject” refers to primates (e.g., humans, males or females), 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 “stimulate” refer to an increase in GLP1R signaling and / or activity, as measured, for example, by an increase in intracellular cyclic adenosine monophosphate (cAMP).

[0130] As used herein, the terms “to treat,” “to treat,” or “to cure” any disease, disorder, or condition mean reducing or relieving the disease, disorder, or condition (i.e., delaying or stopping the onset or progression of the disease, disorder, or condition, or at least one of its clinical symptoms); or reducing or relieving at least one physical parameter or biomarker associated with the disease, disorder, or condition, including those that may not be identifiable to the patient.

[0131] As used herein, the terms “prevent,” “prevent,” or “prevention” in reference to any disease, disorder, or condition mean the preventive treatment of a disease, disorder, or condition; or delaying the onset or progression of a disease, disorder, or condition.

[0132] As used herein, an object "needs" treatment if such object would benefit from such treatment biologically, medically, or in terms of quality of life.

[0133] As used herein, the terms “one (a),” “one (an),” and “it,” as well as similar terms used in connection with the present invention (particularly in connection with the claims), should be construed to encompass both singular and plural forms unless otherwise indicated herein or unless clearly inconsistent with the context.

[0134] Unless otherwise indicated herein or unless explicitly stated otherwise, all methods described herein may be carried out in any preferred order. Any examples or illustrative terms provided herein (e.g., "etc.") are intended solely to further illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0135] Any chiral atom (e.g., carbon) of the compounds of the present invention can be enriched in a racemic or enantiomer manner and exist in, for example, (R)-, (S)-, or (R,S)- configurations. In certain embodiments, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R)- or (S)- configuration.

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

[0137] Any mixture from which stereoisomers are obtained can be separated, for example, by chromatography and / or fractional recrystallization, based on the physicochemical differences of the constituent components, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates.

[0138] Any racemic mixture from which the compounds or intermediates of the present invention are obtained can be divided into optical counterparts by known methods, for example, by separating their diastereomer salts obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the compounds of the present invention may be divided into their optical counterparts by fractional recrystallization of salts formed using an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using the basic moiety. The racemic compounds or racemic intermediates of the present invention can also be divided by chiral chromatography using a chiral adsorbent, for example, by high-pressure liquid chromatography (HPLC).

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

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

[0141] Those skilled in the art will recognize whether stereocenters are present 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 ELEliel, SHWilen, and LNMander (Wiley-Interscience, 1994).

[0142] In another embodiment, this specification provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0143] In another embodiment, the Specified herein provides 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. The pharmaceutical composition may 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 may also relate to inhalation or intranasal application. The pharmaceutical composition of the present invention may be 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 may be either film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing an 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, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

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

[0146] The compounds of the present invention (e.g., compounds of formulas (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), and their pharmaceutically acceptable salts) 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 syndromes, progressive liver disease, cardiovascular disease, and neuropathy (especially, for example, peripheral neuropathy associated with diabetes).

[0147] Progressive liver diseases may include, for example, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0148] Cardiovascular diseases may be selected from, for example, hypertension, atherosclerosis, peripheral artery 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 present invention may be useful in treating several coexisting diseases, disorders, or conditions (referred to as "comorbidities") in a subject.

[0150] Comorbidities may include, for example, those in subjects who have type 2 diabetes and are also obese and / or show heart failure and / or NASH. For example, an obese subject may also show type 2 diabetes and / or cardiovascular disease (e.g., heart failure). Such a subject may also show progressive liver disease (e.g., NASH). For example, an obese subject may also show type 2 diabetes and / or cardiovascular disease (e.g., heart failure) and / or progressive liver disease (e.g., NASH). The subject may also have hypertension and / or high blood cholesterol levels. The subject may also have peripheral neuropathy.

[0151] Accordingly, the compounds provided herein may be useful in the treatment of diseases, disorders, or 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, peripheral artery disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral artery disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (especially 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 (especially atrial and ventricular arrhythmias), and neuropathy (especially peripheral artery disease).

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

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

[0154] Accordingly, in a further embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) in a therapy is provided herein. In a further embodiment, the therapy is the treatment of a disease, disorder, or condition that can be treated by agonism of GLP1R. In another embodiment, the therapy is the treatment of a disease, disorder, or condition selected from the aforementioned list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (in particular heart failure with preserved ejection fraction), including, for example, when present as comorbidities in a subject having type 2 diabetes that is also obese, and / or having type 2 diabetes that also has heart failure, and / or having type 2 diabetes that also has NASH.

[0155] Accordingly, in a further embodiment, the Specified Provisions provide compounds of formula (I) or pharmaceutically acceptable salts thereof for use in therapy (e.g., compounds of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or pharmaceutically acceptable salts thereof). In a further embodiment, the therapy is the treatment of a disease, disorder, or condition that can be treated by agonism of GLP1R. In another embodiment, the therapy is the treatment of a disease, disorder, or condition selected from the aforementioned list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (in particular heart failure with preserved ejection fraction), including those present as comorbidities in subjects having type 2 diabetes who are also obese, and / or having type 2 diabetes who also have heart failure, and / or having type 2 diabetes who also have NASH.

[0156] In another embodiment, the Specified Provision provides a method for treating a disease, disorder or condition treatable by GLP1R agonism, comprising administering a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (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 for treating a disease, disorder or condition in a subject of interest, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, wherein the disease, disorder or condition is selected from the aforementioned list, preferably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), and which 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 embodiment, the use of compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., compounds of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or pharmaceutically acceptable salts thereof) for the manufacture of pharmaceuticals is provided herein. In a further embodiment, the pharmaceutical is for the treatment of a disease that can be treated by agonism of GLP1R. In another embodiment, the disease is selected from the aforementioned list, preferably obesity, type 2 diabetes, atherosclerosis, and heart failure (in particular heart failure with preserved ejection fraction), and includes cases where these are present as comorbidities in subjects having type 2 diabetes who are also obese, and / or having type 2 diabetes who also have heart failure, and / or having type 2 diabetes who also have NASH.

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

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

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

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

[0162] The term "glucose intolerance" encompasses any disorder characterized by clinical symptoms or combinations of clinical symptoms associated with elevated basal or postprandial glucose levels in a subject compared to a healthy individual, and / or elevated insulin levels or abnormal glucose-stimulated insulin release or HOMA-IR (Hostasis Model Assessment of Insulin Resistance). Elevated glucose and / or insulin levels may manifest in the following diseases, disorders, and conditions: obesity, metabolic syndromes, impaired glucose tolerance, type II diabetes, gestational diabetes, type I diabetes, insulin resistance, hyperinsulinemia, lipodystrophy, lipodystrophy, and various MODY (young-onset adult-onset diabetes) variants. Using the GLP1R agonists and compositions provided herein, it is possible, for example, to achieve and / or maintain glucose homeostasis, thereby reducing blood glucose levels and / or insulin levels to, for example, the range found in a healthy subject.

[0163] As used herein, the term "hyperglycemia" refers to a condition in which an elevated amount of glucose circulates in the plasma of a subject compared to that of a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including the measurement of 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 as well as 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 resulting in damage to blood vessels and other cells in the kidneys that reduces kidney function.

[0166] The term "obesity" in adult humans refers to a Body Mass Index (BMI) of 30 or higher (Centers for Disease Control and Prevention). Such individuals are sometimes also referred to as obese. This is called Class I obesity. Class II obesity includes individuals with a BMI of 35-39.9, and Class III obesity refers to individuals with a BMI greater than 40. The 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 That is the case.

[0167] In one embodiment, 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. A BMI <40 could be, for example, 39.9. In some embodiments, 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, including overproduction or abnormal metabolism of lipoproteins. Dyslipidemia can manifest as elevated blood levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, as well as decreased levels of high-density lipoprotein (HDL) cholesterol.

[0169] The term "atherosclerosis" refers to a vascular disease characterized by irregularly distributed lipid deposits in the intima of the aorta and medium-sized arteries, leading to narrowing of the lumen of the ductus arteriosus and ultimately progression to fibrosis and calcification. The lesions are usually localized and progress slowly and intermittently. Restriction of blood flow explains the cause of most clinical symptoms, which varies 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, as evidenced by fibrosis and cirrhosis, which are predisposing factors for hepatocellular carcinoma. The progression of obesity-associated non-alcoholic fatty liver (NAFL) to NASH, fibrosis, and cirrhosis is well documented.

[0171] The term "non-alcoholic fatty liver disease (FLD)," also known as NAFLD, is a condition characterized by the accumulation of excess lipids in hepatocytes, which may result from either excessive de novo lipid biosynthesis or abnormal clearance and oxidation of fatty acids in the liver. NAFLD is excluded from other causes of liver disease, including alcoholic liver disease and viral liver disease. NAFLD encompasses three histological manifestations that reflect the progression of the disease: fatty liver, hepatic steatosis, and fibrosis or cirrhosis. While obesity is the most common cause of NAFLD, it can also occur in lean individuals. The accumulation of lipids can lead to inflammation accompanied by macrophage infiltration and changes in hepatocyte histological examination, including steatohepatitis and ballooning degeneration, referred to as non-alcoholic steatohepatitis (NASH). NASH can progress to interlobular bridging fibrosis or fibrosis with cirrhosis. As used herein, the term NASH may encompass steatohepatitis, hepatocyte ballooning degeneration, and lobular inflammation.

[0172] The term "metabolic syndrome" refers to a cluster of risk factors that increase the risk of 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, post-fasting hyperglycemia (at least 110 mg / dl per deciliter); high triglycerides in the bloodstream (at least 150 mg / dL); low HDL (less than 40 mg / dl); and blood pressure ≥ 130 / 85 mmHg (World Health Organization).

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

[0174] The term "peripheral artery disease" refers to a condition in which blood supply to the leg muscles is restricted due to the accumulation of fatty deposits in the arteries.

[0175] The term "stroke" refers to a condition in which the blood supply to a part of the brain is cut off.

[0176] The term "heart failure" refers to a condition in which the heart's ability to pump blood is reduced, and may 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 artery disease," also known as coronary artery disease, refers to the narrowing of the arteries that supply blood to the heart.

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

[0179] The term "neuropathy" refers to any damage to nerves. This term includes peripheral neuropathy, which occurs when nerves in the limbs, 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 myocardium of the atria or ventricles that may affect cardiac function, or physiological function, and conduction.

[0181] The pharmaceutical compositions or combinations provided herein may have a unit dose of approximately 1 to 1000 mg of the active ingredient for a subject weighing approximately 50 to 70 kg. The therapeutically effective dose of a 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] The compounds of the present invention (e.g., any of the compounds of formulas (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or their pharmaceutically acceptable salts) may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately, by the same or different routes of administration, or together in the same pharmaceutical composition as the other agents. The therapeutic agents are, for example, chemical compounds, peptides, peptide conjugates and fusions, antibodies, antibody fragments, or nucleic acids that are therapeutically active or enhance therapeutic activity when administered to a subject in combination with the compounds of the present invention.

[0183] Accordingly, in another embodiment, the Specified provides combinations, in particular combination pharmaceuticals, of a compound of formula (I) (for example, in a therapeutically effective amount) or a pharmaceutically acceptable salt thereof (for example, any compound of formula (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, the Specified Provisions provide a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) as a combined preparation for simultaneous, separate, or sequential use in therapy, and at least one other therapeutic agent. In one embodiment, the therapy is the treatment of a disease, disorder, or condition selected from the aforementioned list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including, for example, when present as comorbidities 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., any compound of formulas (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof), and other therapeutic agents combined in the same pharmaceutical composition, or a composition comprising the compound of the present invention and other therapeutic agents in separate forms, for example, 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., any compound 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 comprise a pharmaceutically acceptable carrier as described herein.

[0187] In one embodiment, this specification provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains the compound of the present invention. In one embodiment, the kit includes means for holding the compositions separately, such as a container, a divided bottle, or a divided metal foil bag. An example of such a kit is a blister pack, as is commonly used for packaging tablets, capsules, and the like.

[0188] The kit may be used to administer different dosage forms, for example, orally and parenterally, to administer separate compositions at different dosing intervals, or to escalate separate compositions relative to each other. To aid in medication adherence, the kits provided herein typically include instructions for administration.

[0189] In the combination therapies provided herein, the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof), and other therapeutic agents 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 other therapeutic agents may be incorporated into the combination therapy (i) before the combination product is delivered to the physician (e.g., in the case of a kit containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and other therapeutic agents); (ii) immediately before administration by the physician himself (or under the guidance of the physician); or (iii) by the patient himself, for example, between the sequential administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and other therapeutic agents.

[0190] Accordingly, this specification provides for the use of compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., any of the compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or pharmaceutically acceptable salts thereof) in the preparation of a medicament for treating a disease, disorder, or condition, preferably selected from the aforementioned list, most preferably from type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including cases where these are present as comorbidities 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 medicament is prepared for administration with another therapeutic agent.

[0191] This specification provides for the use of another therapeutic agent for treating a disease, disorder or condition, selected from the above-mentioned list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including, for example, when present as a comorbidity in a subject having type 2 diabetes that is also obese, or in a subject having type 2 diabetes that also has heart failure, wherein the pharmacopoeia is administered together with the compound of the present invention.

[0192] This specification provides for use in methods of treating diseases, disorders or conditions selected from the aforementioned list, preferably from type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including, for example, a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, including any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or any pharmaceutically acceptable salt thereof, the compound of formula (I) or any pharmaceutically acceptable salt thereof is prepared for administration with another therapeutic agent.

[0193] Furthermore, this specification provides other therapeutic agents for use in methods of treating diseases, disorders or conditions, selected from the aforementioned list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including, for example, when present as comorbidities in a subject with type 2 diabetes who is also obese, or in a subject with type 2 diabetes who also has heart failure, and the other therapeutic agents are prepared for administration with a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof).

[0194] Furthermore, this specification provides for use in methods of treating diseases, disorders, or conditions selected from the aforementioned list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including, for example, a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, where these conditions are present as comorbidities, and the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof) is administered together with another therapeutic agent.

[0195] Furthermore, the aforementioned list, preferably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), is provided for use in methods of treating diseases, disorders or conditions, including, for example, when present as comorbidities in a subject with type 2 diabetes who is also obese, or in a subject with type 2 diabetes who also has heart failure, the other therapeutic agents are administered together with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0196] Furthermore, this specification provides for the use of compounds of formula (I) or pharmaceutically acceptable salts thereof (e.g., any of the compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or pharmaceutically acceptable salts thereof) for treating diseases, disorders, or conditions selected from the aforementioned list, preferably type 2 diabetes, obesity, atherosclerosis, and heart failure (particularly heart failure with preserved ejection fraction), including, for example, when these are present as comorbidities in a subject having type 2 diabetes who is also obese, or in a subject having type 2 diabetes who also has heart failure, wherein the patient has previously been treated with another therapeutic agent (e.g., within 24 hours).

[0197] Furthermore, this specification provides for the use of another therapeutic agent for treating a disease, disorder or condition selected from the aforementioned list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including, for example, when present as a comorbidity in a subject having type 2 diabetes that is also obese, or in a subject having type 2 diabetes that is also heart failure, wherein the patient has previously (for example, within 24 hours) been treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof (for example, any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), and (Va), or a pharmaceutically acceptable salt thereof).

[0198] In one embodiment, other therapeutic agents are selected from the following: 1. Antidiabetic agents such as insulin, insulin derivatives and mimics; insulin secretagogues such as sulfonylureas (e.g., chlorpropamide, trazamide, acetohexamide, tolbutamide, glibride, glimepiride, glipizide); glibride and Amaryl; insulin-secreting sulfonylurea receptor ligands such as meglitinide, e.g., nateglinide and repaglinide; thiazolidinediones that enhance insulin action (e.g., by insulin sensitization) and thereby promote glucose utilization in peripheral tissues (e.g., rosiglitazone (AVANDIA), troglitazone (REZULIN), pioglitazone (ACTOS), paraglitazone, riboglitazone, netoglitazone, troglitazone, englitazone, siglita Protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as adaglitazone, dalglitazone; PTP-112 and other similar inhibitors; 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, erzgliflozin, ipragliflozin, luseogliflozin, remogliflozin etavonate, sotagliflozin, 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 excretion; alpha-glucosidase inhibitors such as acarbose and miguitoy, and other drugs that slow carbohydrate digestion and consequently absorption from the intestines, thereby reducing postprandial hyperglycemia; GIPR modifiers such as trizepatide, CT-868, CT-388, AMG133, HM15211, NN9423, TAK-094, LBT-6030, ZP-I-98, NN9709, RG7685, RG7697, and SAR438335;Also, DPPIV (dipeptidyl peptidase IV) inhibitors such as vildagliptin; 2.3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, such as lipid-lowering agents like lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, berostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; bile acid sequenstrants such as cholestyramine and coleseveram; fibrates; nicotinic acid and aspirin; 3. Anti-obesity agents such as orlistat, limonabant, phentermine, topiramate, quinexa, and locaserin; GDF15 (including its variants, conjugates, fusions, analogues, variants and fragments, including other GFRAL modifiers such as NGM386 and NGM395); PCT publications International Publication No. 2013 / 148117, International Publication No. 2014 / 120619 and related patent family members (including, but not limited to, U.S. Patent No. 9,161,966B1), International Publication No. 2012 / 138919, International Publication No. 2013 / 113008, International Publication No. 2015 / 017710, International Publication No. 2015 / 200078, and International Publication No. 2015 / 197446 This includes molecules described in International Publication No. 2015 / 198199 and International Publication No. 2017 / 109706, in particular GDF15 conjugates with fatty acids (such as those described in PCT International Publication No. 2015 / 200078 and International Publication No. 2017 / 109706) and GDF15 fusions described in PCT International Publication No. 2015 / 197446, International Publication No. 2015 / 198199 and International Publication No. 2017 / 109706 (e.g., GDF15 fusions with human serum albumin (HSA)); FGF21 mimics such as PEG-FGF21 and pegberfermin; ActRII antagonists such as ramatercept; and Alk7 antagonists. 4. Antihypertensive drugs, such as loop diuretics including ethacrine, furosemide, and torsemide; angiotensin-converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, hosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril, and trandolapril; Na-K-ATPase membrane pump inhibitors such as digoxin; neutral endopeptidase (NEP) inhibitors; ACE / NEP inhibitors such as omapatrilat, sanpatrilat, and facidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan, especially valsartan; angiotensin receptor-neprilysin inhibitors (ARNi) such as sacubitril / valsartan (Entresto); ditexerene, zanquilen, tellacirene, aliskilen, RO Renin inhibitors such as 66-1132 and RO-66-1168; β-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. Compounds specifically described in Brochure International Publication No. 2004 / 103995, i.e., compounds of Examples 1 to 35 or compounds specifically enumerated in Claim 21, or compounds specifically described in Brochure International Publication No. 03 / 043985, i.e., compounds of Examples 1 to 7 or compounds specifically enumerated in Claim 19, and in particular, peroxisome proliferator-activator receptor agonists such as (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxy or salts thereof; 6. Specific antidiabetic compounds listed in Expert Opin Investig Drugs 2003, 12(4):623-633, Figures 1-7. 7. Compounds that bind to corticotropin-releasing hormone receptors such as Urocortin 2.

[0199] Furthermore, this disclosure provides combination therapies of drugs that stimulate metabolism or suppress appetite, as well as drugs and methods for promoting weight loss, such as dietary changes and / or exercise programs to promote weight loss. [Examples]

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

[0201] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art. Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art, as shown in the following examples.

[0202] The following abbreviations used in the following examples and elsewhere in this specification are as follows: Hill curve plateau value at low A0 concentrations AC 50 Concentration of the maximum half-size compound effect A inf Hill curve plateau value at high concentrations BSA (Bovine Serum Albumin) BOC (Tertiary Butyl Carboxylate) 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 Medium DMF (N,N-dimethylformamide) DMI (Dimethylimidazolidinone) DMPU N,N-dimethylpropylene urea DMSO (Dimethyl Sulfoxide) EC effective concentration Effective concentration of compounds that do not produce an EC0 response EC 50 Effective concentration of the compound that yields the maximum half-size response (AC in μM units) 50 ) EC 100 Effective concentration of the compound that yields the maximum (100%) response EDTA (Ethylenediaminetetraacetic acid) E max Efficacy: The maximum response achievable from the administered drug. ESI Electrospray Ionization HCl ethyl acetate EtOH Ethanol FA Formic Acid FBS Fetal Bovine Serum G418 Genethecin, a selective antibiotic. GLP1 Glucagon-like Peptide 1 GLP1R (Glucagon-like peptide 1 receptor) GPCRs (G Protein-Coupled Receptors) 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 milligrams min ml (milliliter) mM millimolar concentration mmol millimol 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)-CH2Cl21,1'-bis(diphenylphosphin)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 racemi R t retention time rt room temperature s Single line SFC Superfluid Carbon Dioxide SM Starting material / Starting material(s) SEM-Cl 2-(trimethylsilyl)ethoxymethylchloride t triple line TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TMS (trimethylsilyl) TMSCl (Trimethylsilyl Chloride) Tol Turbogrignard Isopropylmagnesium Chloride Lithium Chloride Complex Solution v / v volume / volume μL (microliter) μM micromolar concentration

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

[0204] NMR-01 Unless otherwise specified, reagents and solvents were obtained from commercially available suppliers. Proton nuclear magnetic resonance (1H 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 at 293K–298K unless otherwise specified and referenced to solvent resonance. 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 specified, reagents and solvents were obtained from commercially available suppliers. Proton nuclear magnetic resonance (1H 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 at 293K–298K unless otherwise specified and referenced to solvent resonance. 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 acquired using an Agilent 1100 HPLC system equipped with an Agilent 6110 mass spectrometer. [M+H] + This refers to the protonated molecular ion of a chemical species. The column temperature was 50°C. The flow rate was 1.0 ml / min.

[0207] LCMS method 1: (acidic) Equipment: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; analysis time 2 min; 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 uL; UV detection array 210~400, mass detection 120~1250 (electrospray ionization); column 50℃; flow rate 1.0 mL / min.

[0208] LCMS method 2: (basic) Equipment: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 50 mm; Analysis time: 2 min, 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) Equipment: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 181.7 μm, 21 × 30 mm; 5.2 min analysis 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) Equipment: Waters Acquity UPLC, photodiode array detector; column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; 5.2 min analysis 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 uL; UV detection array 210 ~ 400, mass detection 120 ~ 1600; column 50°C, flow rate 1.0 mL / min.

[0211] HRMS method 5: Equipment: Agilent 1200 LC / G1956A, diode array detector; Column: Chromolith Flash C 18 1.6 micron 2×25 mm; analysis time 1.5 min; 5 → 95% solvent B: solvent A 0 → 1.2 min, followed by 95% solvent B 1.2 → 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 uL; UV detection 220 and 254 nM, mass detection 100~1000 (electrospray ionization); column 50℃; 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: Flow rate: 0.550 ml / min at 95:5 at 0.01 min, flow rate: 0.600 ml / min at 30:70 at 0.60 min, flow rate: 0.650 ml / min at 10:90 at 0.80 min, flow rate: 0.650 ml / min at 0:100 from 1.10 min to 1.70 min, flow rate: 0.550 ml / min at 95:5 from 1.71 min to 2.0 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. The UV spectrum was recorded at 276.0 nm lambdamax. The uniform concentration ratios were as follows:

[0215] [Table 13]

[0216] HPLC method MC-1: Equipment: Waters AutoPurification HPLC; Column: Waters XBridge BEH C 18OBD preparative column (130 Å, 5 μm, 10 mm × 150 mm); analysis time 4.7 mins, 98% solvent A 0-0.2 mins, 98% to 2% solvent A 0.2-2.8 mins, 2% solvent A 2.8-3.8 mins, 2% to 98% solvent A 3.8-3.85 mins, 98% solvent A 3.85-4.7 mins. 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 Equipment: Waters AutoPurification HPLC; Column: Waters XBridge BEH C 18 OBD preparative column (130 Å, 5 μm, 10 mm × 150 mm); analysis time 4.7 mins, 98% solvent A 0~0.2 mins, 98→55% solvent A 0.2~1.09 mins, 55→45% solvent A 1.09~1.91 mins, 45→2% solvent A 1.91~2.8 mins, 2% solvent A 2.8~3.8 mins, 2→98% solvent A 3.8~3.85 mins, 98% solvent A 3.85~4.7 mins. 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 Equipment: 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→50% solvent A 0.2~1.09 min, 50→40% solvent A 1.09~1.91 min, 40→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.

[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); Analysis time 3 min, 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; 50°C column, 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); Analysis time 3 min, 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; 55°C column, flow rate 1.0 mL / min.

[0221] Example 1A: Preparation of intermediate 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]dioxol (II.3) [ka] To a solution of 1-(4-chloro-2-fluorophenyl)ethane-1-one (150 g, 793.61 mmol) in Tol (1500 mL), 3-bromobenzene-1,2-diol (123.27 g, 714.25 mmol) and p-TsOH (27.33 g, 158.72 mmol) were added at 25°C. The mixture was stirred at 140°C for 48 hours. TLC (petroleum ether:ethyl acetate = 30:1) showed that 1-(4-chloro-2-fluorophenyl)ethane-1-one was completely consumed and a new spot (Rf = 0.4) was detected. The mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether) to obtain II.3 (175 g, crude product) as black oil. This 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 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl(II.4) [ka] To a solution of II.3 (150 g, 436.58 mmol) in dioxane (1500 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (162.00 g, 523.90 mmol), Na2CO3 (254.50 g, 2401.19 mmol), and Pd(dppf)Cl2 (31.99 g, 43.66 mmol) were added at 25°C. The mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to obtain II.4 (50 g, 112.11 mmol, purity 96%, yield 44%) 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 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate tert-butyl (II.5) [ka] To a solution of II.4 (50 g, 112.13 mmol) in MeOH (200 mL), ((C6H5)3P)3RhCl (5.19 g, 5.61 mmol) was added at 25 °C. The mixture was stirred under H2 at 50 °C for 16 hours. The reaction mixture was filtered and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (SiO2, PE:EA = 10:1) to obtain II.5 (37.5 g, 83.71 mmol, purity 98%, yield 75%) 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 (170g, 379.52 mmol, 96% purity) was purified by SFC (CAS-WH-ANA-SFC-A (Agilent-1260), column: Chiralpak AD-3 50×4.6mm ID, 3um; mobile phase: phase A for CO2 and phase B for IPA (0.05% DEA); gradient elution: 5%~40% of B in A; flow rate: 3 mL / min; detector: DAD; column temperature: 35℃; back pressure: 100 Bar) to obtain II.6a (77g, 171.90 mmol, 100% ee) and II.6b (75g, 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 siRNA (200 mL), TsOH.H2O (9.88 g, 51.9 mmol, 1.20 eq) was added. After the addition, the pale yellow suspension was stirred at 45°C for 12 hours. The reaction mixture was poured into petroleum ether (400 mL), filtered, recovered, and dried. No purification was performed. II.1 (20.0 g, 36.9 mmol, yield 85.2%, purity 96.0%) 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), HCl (670 mL, 1 M in dioxane) was added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to obtain the crude product. The crude product was triturated with MTBE:MeOH = 10:1 (700 mL) to obtain II.2 (71 g, 204.13 mmol, purity 98%, 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: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.3a); and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl(III.3b) [ka] Step 1: Synthesis of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl (I.2a and I.2b, respectively) [ka] In a 3 L four-necked 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), 55-60% NaH in mineral oil (18.56 g, 0.464 mol) was added in small amounts under nitrogen at 0°C. After 30 minutes, SEM-Cl (43.1 ml, 235 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored on a TLC. After the reaction was complete, 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 on sodium sulfate, and concentrated. Chromatographic purification on SiO2 (0-40% SiO2 / heptane) yielded 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl (I.2a) (50 g, yield: 51.8%) and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl (I.2b) (21 g, yield: 21.8%). 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl(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). 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(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 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.3) [ka] In a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl (I.2b) (6 g, 0.022 mol) in CCl4 (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 hours. The progress of the reaction was monitored on TLC. After the completion of the reaction, the reaction mixture was diluted with water (250 mL), extracted with DCM (2 × 200 mL), and the organic layer was dried over sodium sulfate and concentrated. Chromatographic purification on SiO2 (0-12% Depositphotos) yielded 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl (I.3) (4.5 g, yield 58.1%). 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 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.4) [ka] To a solution of 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.3) (4.5 g, 0.0129 mol) in dry THF (148 mL), i-PrMgCl 2.0 M (13.39 mL, 0.0387 mol) in THF was added dropwise over 20 minutes at -40°C. The reaction mixture was further cooled to -78°C and stirred for 15 minutes. 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 hour. The progress of the reaction was monitored on a TLC. After the completion of the reaction, the reaction mixture was quenched with 3N 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 obtain the crude product 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.4) (3.5 g, yield 91.0%), which was used for the next step without further purification. LC-MS method C2: Rt = 1.32 mins; 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 2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.5) [ka] To a solution of 2-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.4) (3.5 g, 0.011 mol) in ethanol (53 mL), NaBH4 (0.830 g, 0.022 mol) was added under nitrogen, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extract was dried over sodium sulfate and concentrated to obtain crude 2-(hydroxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl(I.5) (3.5 g, yield 99.3%). This was used in the next step without further purification. LC-MS method C2: Rt = 1.22 min; MS m / z 301.4 [M+1]+.

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

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

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

[0234] Step 8: Synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.3a) and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl (III.3b) [ka] To a solution of (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.2) (0.5 g, 0.001 mol) in DMF (5 mL), 4-methylbenzenesulfonic acid (S)-oxetane-2-ylmethyl (IV.1) (0.315 g, 0.0013 mol), K2CO3 (0.415 g, 0.003 mol), and KI (0.166 g, 0.001 mol) were added under nitrogen, and the mixture was stirred at 80°C for 6 hours. The reaction was monitored on a TLC. After the reaction was complete, 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 with sodium sulfate, and concentrated. Chromatographic purification using a neutral alumina column (SiO2 / heptane 60-80%) yielded 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.3a) (0.09 g, yield: 15.8%) and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl (III.3b) (0.140 g, yield: 24.6%). 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.3a). LCMS method C2: Rt=1.40 min; MS m / z 570.5[M+1]+. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl(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: 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl, 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate ethyl (I.8) [ka] Ethyl 4-methyl-1H-imidazole-5-carboxylate (I.7) (10.47 g, 67.9 mmol) was dissolved in DMF (170 mL), then cooled to 0°C, and 60% NaH (3.53 g, 88 mmol) from the oil was added. The solution was immediately bubbling and stirred for 10 minutes, after which SEMCl (13.25 mL, 74.7 mmol) was added. Next, the solution was stirred at 0°C for 1 hour, then quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic matter was then washed multiple times with saturated ammonium chloride solution, and the organic matter was dried over sodium sulfate. The organic phase was filtered and concentrated to an orange oil. The oil was injected directly onto a normal-phase column and purified over 40 minutes via 0-70% siRNA:heptane. The product (I.8) eluted with 45% siRNA. The identified fraction was collected and concentrated to obtain a yellow oil, which was dried under high vacuum and then proceeded with the analysis (12.32 g, yield 60.1%). LC-MS method 3: Rt = 1.98 min; MS m / z 285.1[M+1]+.

[0236] Step 2: 2-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl(I.9) [ka] 4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl (I.8) (12.32 g, 40.8 mmol) was dissolved in DCM (204 mL), and then NBS (7.84 g, 44.1 mmol) and AIBN (0.670 g, 4.08 mmol) were added. Next, the solution was refluxed at 70°C for 1 hour, and then concentrated to an orange recovery solution, which was placed directly on a normal-phase column and purified over 40 minutes via 0-40% siRNA:heptane. Product (I.9) eluted with 25% siRNA. The identified fraction was collected and concentrated to obtain a yellow oil, which was dried under high vacuum and used as is (14.169 g, yield 88%). LCMS method 3: Rt=2.61 min; MS m / z 365.0[M+1]+.

[0237] Step 3: 2-Formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl(I.10) [ka] 2-Bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl(I.9) (500 mg, 1.274 mmol) was dissolved in THF (6.3 mL), and then DMF (691 μL) was added. Next, the solution was cooled to -78°C, and then 1.3N turbogrignard (2940 μL, 3.82 mmol) was added. Next, the solution was stirred at -78°C for 1 hour, followed by the addition of 1.3N turbogrignard (1960 μL, 2.55 mmol) to the solution. After warming to room temperature, the solution was then quenched with saturated ammonium chloride to concentrate the organic matter. Next, the solution was extracted with ethyl acetate and washed with saturated ammonium chloride. Next, the organic matter was dried over sodium sulfate, followed by filtration and concentrated to a yellowish oil, which was purified via a normal-phase column over 20 minutes under a 0–100% siRNA:heptane gradient. Product (I.10) eluted with 40% siRNA. The identified fraction was recovered and concentrated to obtain a yellowish oil (275.5 mg, yield 59.5%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl(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 then washed with saturated sodium bicarbonate. Next, the organic matter was dried over sodium sulfate, filtered, and concentrated to a colorless oil. Then, 2-formyl-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl (I.10) (275.5 mg, 0.758 mmol), sodium triacetoxyborohydride (321 mg, 1.515 mmol), and acetic acid (87 μL, 1.515 mmol) were mixed in solution with DCM (3.8 mL). Next, the solution was heated to 40°C for 13 hours, then quenched with saturated ammonium chloride solution and extracted by DCM. The organic matter was dried over sodium sulfate, followed by filtration and concentrated to an orange oil, which was purified over 25 minutes via normal-phase 0-100% siRNA:heptane. Product (III.7) eluted with 70% siRNA. The identified fraction was collected and concentrated to obtain a yellowish oil, which was then continued (243.9 mg, yield 46.7%). LCMS method 3: Rt = 2.55 min; MS m / z 644.4[M+1]+.

[0239] Step 5: (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate ethyl(III.8) [ka] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate ethyl (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 hours, followed by the addition of 1 M TBAF (1768 μL, 1.768 mmol) in THF. The solution was stirred at 50°C for a further 12 hours, and then directly injected onto a reversed-phase basic column over 25 minutes under a 0.01% NH4OH gradient in 0-50% ACN:H2O. The product (III.8) eluted with 100% ACN. A void volume of 5 columns (0.01% NH4OH in 100% H2O) was set at the start of washing away excess TBAF. The identified fraction was collected and concentrated to obtain a yellowish-white solid, which was dried under high vacuum and the process continued. (218.8 mg) LCMS method 4: Rt=2.97 min; MS m / z 514.2[M+1]+.

[0240] Step 6: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.9a) and 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl (III.9b) [ka] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1H-imidazole-5-carboxylate ethyl (218.8 mg, 0.414 mmol) III.8 was dissolved in THF (2 mL), and then IV.1 (201 mg, 0.829 mmol) and DBU (125 μL, 0.829 mmol) were added. The solution was stirred at 80°C for 32 hours, then the temperature was raised to 100°C and stirred for 48 hours, after which a further amount of IV.1 (301 mg, 1.243 mmol) and DBU (125 μL, 0.829 mmol) were added. Next, the solution was stirred at 100°C for a further 48 hours, then concentrated and subsequently injected directly onto a normal-phase column for purification over 25 minutes via 0-100% RINKAN:heptane.

[0241] The product (mixture of III.9a and III.9) elutes with 100% ethyl acetate. The identified fraction was collected and concentrated to obtain a white, crushed solid, which was dried under high vacuum and then continued. (110.9 mg, yield 43.51%). III.9a: LC-MS method 4: Rt = 3.25 min; MS m / z 584.2[M+1]+. III.9b: LC-MS 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)methanol(III.4a) [ka] To a solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (III.3a) (0.09 g, 0.1578 mmol) in anhydrous THF (2 mL), LAH (1 M in THF, 0.23 mL, 0.237 mmol) was added dropwise at 0°C. The reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (5 mL) and quenched with sodium sulfate decahydrate. The mixture was filtered through a Celite bed, and the filtrate was concentrated to obtain the crude product, (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)methanol (III.4a) (0.08 g, 96.0%). This 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)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)methanol (III.4a) (0.08 g, 0.151 mmol) in DCM (4 mL), Dess-Martin periodinane (0.1 g, 0.235 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours, while the progress of the reaction was monitored on TLC. After the 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 obtain the crude product 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbaldehyde (III.5a) (0.08 g, yield 100%). This 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (III.6a) [ka] To a solution of 2-(diethoxyphosphoryl)ethyl acetate (0.044 g, 0.198 mmol) in THF (1 mL), NaH (55-60% of mineral oil, 0.009 g, 0.225 mmol) was added at 0°C, and the mixture was then stirred at room temperature for 30 minutes. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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 hours. After the reaction was complete, 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 obtain the crude product, (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (III.6a) (0.05 g, yield 55.2%). This 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (compound 1) [ka] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (III.6a) (0.05 g, 0.083 mmol) in ethanol (3 mL), NaOH (0.010 g, 0.250 mmol) in water (1.5 mL) was added, and the mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored on a TLC. After the completion of the reaction, the reaction solution was concentrated, the pH was adjusted to 4 with citric acid solution, and this was extracted with DCM (2 × 15 mL) and concentrated. The crude substance was purified by HPLC (MeCN / H2O + 0.1% NH4OH, X-bridge C18) to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (compound 1) (0.007 g, yield 14.7%). LC-MS 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)methanol(III.4b) [ka] A solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylate ethyl (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 allowed to proceed at room temperature for 1 hour. The progress of the reaction was monitored on a TLC. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (5 mL) and quenched with sodium sulfate decahydrate. The mixture was filtered through a Celite bed and concentrated to obtain the crude product, (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)methanol (III.4b) (0.128 g, yield 98.71%), 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)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)methanol(III.4b) (0.128 g, 0.242 mmol) in DCM (6.5 mL), Dess-Martin periodinane (0.154 g, 0.363 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, 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 obtain the crude product, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carbaldehyde (III.5b) (0.120 g, yield 94.1%), 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.6b) [ka] To a solution of 2-(diethoxyphosphoryl)ethyl acetate (0.066 g, 0.294 mmol) in THF (1 mL), 55-60% NaH (0.014 g, 0.350 mmol) from mineral oil was added at 0°C and the mixture was stirred at room temperature for 30 minutes. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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 mixture was stirred at 60°C for 2 hours. After the reaction was complete, 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 obtain the crude product, (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.6b) (0.1 g, yield 73.5%), 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid (compound 2) [ka] To a solution of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.6b) (0.1 g, 0.083 mmol) in ethanol (6 mL), NaOH (0.02 g, 0.500 mmol) in water (3 mL) was added, and the reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored on a TLC. After the reaction was complete, the solvent was evaporated, the pH was adjusted to 4 with a citric acid solution, and the mixture was further extracted with DCM (2 × 15 mL) and concentrated. The crude substance was purified by HPLC (MeCN / H2O + 0.1% NH4OH, X-bridge C18) to obtain product (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid (compound 2) (0.020 g, yield 21.0%). LCMS method C2: Rt = 1.24 min; MS m / z 568[M+1]+. 1 1H NMR (400 MHz, 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid (C-3) and synthesis of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-carboxylic acid (C-4) [ka] Step 1: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (110.3 mg, 0.179 mmol) was dissolved in THF (897 μL), and then lithium hydroxide (42.9 mg, 1.793 mmol) and 1 mL of water were added. Next, the solution was stirred at 70°C for 30 minutes, and then the temperature was raised to 80°C for 24 hours. Next, lithium hydroxide (21.47 mg, 0.897 mmol) was added, and the solution was stirred at 80°C for a further 24 hours. It was then concentrated until only water remained, and this was directly injected onto a reversed-phase basic column over 25 minutes under 0.01% NH4OH in 0-50% ACN:H2O. The product was eluted with 40% ACN.

[0251] Compound 3: The identified fraction was collected and concentrated to obtain a yellow to white solid, which was then separated for purification. (23.1 mg, yield 22.08%). 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 fraction was collected and concentrated to obtain a yellow to white solid, which was then separated for purification. (15.4 mg, 0.027 mmol, yield 15.17%). 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (C-5) [ka] Step 1: (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl(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)-oxetane-2-ylmethanol (IV.2) (2162 mg, 24.54 mmol) in THF (120 mL), diisopropyl azodicarboxylate (4.77 mL, 24.54 mmol) was added dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated and purified by chromatography (siRNA / heptane 0-100%). The fractions containing the product were combined, concentrated, and re-purified using the same conditions as above to obtain the title compound (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (I.12). LCMS method 1: Rt = 0.72 min; MS m / z 303.0 [M+1]+. 1 ¹H NMR (400MHz, chloroform-d) δ 5.06 (dtd, J=7.7, 6.5, 4.3Hz, 1H), 4.76-4.58 (m, 3H), 4.52 (dt, J=9.0, 6.2Hz, 1H), 4.34 (q, J=7.1Hz, 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-imidazole-5-yl)methanol(I.13) [ka] To a solution of (S)-2-bromo-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (I.12) (1.331 g, 4.39 mmol) and MeOH (0.888 ml, 21.95 mmol) in THF (20 mL), 2N LiBH4THF solution (8.78 ml, 17.56 mmol) was added. The reaction mixture was heated to 50°C for 16 hours. LC-MS indicated that 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 minutes, then diluted with THF (50 mL), quenched with saturated NH4Cl aqueous solution (2 mL), and very slowly added to the reaction mixture. The reaction mixture was stirred for 30 minutes, followed by the addition of Na2SO4. 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-imidazole-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-imidazole-5-yl)methanol (I.13) (1.146 g, 4.39 mmol) in ACN (22 mL), MnO2 (5.72 g, 65.9 mmol) was added. The reaction mixture was heated to 50°C for 16 hours. 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-imidazole-5-yl)ethyl acrylate (I.15) [ka] To a solution of triethyl phosphonoacetate (3813 μL, 19.05 mmol) in DMF (60 mL), 60% NaH (863 mg, 21.59 mmol) from oil was added at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, followed by the addition of (S)-2-bromo-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carbaldehyde (I.14) (3.29 g, 12.7 mmol) in DMF (5 mL). The reaction mixture was stirred at 0°C for 15 minutes, followed by 15 minutes at room temperature. The reaction mixture was cooled to 0°C, quenched with saturated NH4Cl aqueous solution, and then extracted 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 (Â100%). The fractions containing the product were combined, concentrated, and re-purified using the same conditions as above to obtain (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (I.15). LCMS method 2: Rt = 1.34 min; MS m / z 329.2 [M+1]+. 1¹H NMR (400MHz, chloroform-d)δ: 7.70 (d, J=16.0Hz, 1H), 6.12 (dd, J=16.1, 0.5Hz, 1H), 5.06 (dtd, J=7.7, 6.6, 3.9Hz, 1H), 4.66 (ddd, J=8.5, 7.3, 6.0Hz, 1H), 4.51 (dt, J=9.1, 6.1Hz, 1H), 4.38-4.22 (m, 4H), 2.77 (dddd, J=11.5, 8.4, 7.6, 6.1Hz, 1H), 2.55-2.44 (m, 1H), 2.42 (s, 3H), 1.35 (t, J=7.1Hz, 3H).

[0257] Step 5: (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (I.16) [ka] To a solution of (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (I.15) (0.48 g, 1.458 mmol) and DMF (1.129 ml, 14.58 mmol) in THF (15 mL), 1.3N turbogrignard (3.36 mL, 4.37 mmol) in THF was slowly added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution 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)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (III.10a) [ka] To a solution of (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-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)piperidine-1-ium,4-methylbenzenesulfonic acid HCl salt (II.2) (107 mg, 0.278 mmol) in DCM (2 mL), pyridine (22.49 μL, 0.278 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (77 mg, 0.362 mmol). The reaction mixture 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 by DCM. The combined organic layer was concentrated, and the residue was purified by chromatography (Â100%) to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (III.10a) (50 mg 0.082 mmol) in THF (0.6 mL)-MeOH (0.2 mL)-water (0.1 mL), LiOH.H2O (17.19 mg 0.410 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The mixture was quenched with 2 drops of formic acid and directly purified by preparative HPLC (conditions: basic 15-40% acetonitrile-3.ACN / H2O + 5 mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30×50 mm) to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (compound 5) (1.6 mg, 3.25%). HRMS method 5: 582.2191[M+H]+, calculated value for C31H34ClFN3O5: 582.2207[M+H]+. 1 ¹H NMR (400MHz, methylene chloride-d2) δ 7.61 (d, J=15.9Hz, 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=16.0Hz, 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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid (C-6) [ka] Step 1: (E)-3-(4-methyl-1H-imidazole-5-yl) ethyl acrylate (I.19) [ka] To a mixture of 1,4-dioxane (30 mL) and 4-bromo-5-methyl-1H-imidazole (I.18) (3.0 g, 18.63 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl acrylate (I.17) (5.05 g, 22.36 mmol), K3PO4 (2 M in water, 7.9 g, 18.63 mL, 2 molar concentration, 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 hours. The reaction mixture was filtered through Celite. 50 mL of water was added to the reaction mixture and extracted with SiO2 (50 mL x 3). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated to dryness. The crude material was purified by chromatography (methanol / DCM 0-15%) to obtain the title compound (E)-3-(4-methyl-1H-imidazole-5-yl)acrylate ethyl (I.19) as a brown powder (2.52 g, yield 75%). 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-imidazole-4-yl)ethyl acrylate (I.20) [ka] Ethyl (E)-3-(4-methyl-1H-imidazole-5-yl)acrylate (I.19) (600 mg, 2.99 mmol) in CH3CN (14 mL) was mixed with cesium carbonate (1.46 g, 4.49 mmol) and 4-methylbenzenesulfonic acid ((S)-oxetane-2-ylmethyl (IV.1)) (798 mg, 3.29 mmol) at room temperature. The mixture was stirred at 120 °C for 1 hour under microwave irradiation. The reaction mixture was partitioned between ethyl phosphate and saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl phosphate (40 mL). The organic phase was dried over magnesium sulfate and concentrated. The crude substance was purified by chromatography (methanol / DCM 0-15%) to obtain the title compound (S,E)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)ethyl acrylate (I.20) as a light brown liquid (370 mg, yield 49%). 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-imidazole-4-yl)ethyl acrylate (I.21) [ka] To 180 mg (647.22 μmol) of (S,E)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)ethyl acrylate (I.20) in 4 mL of THF, 97.072 mg (906.11 μL, 1 molar concentration, 906 μmol) was added at -78°C, and the mixture was stirred at -78°C for 30 minutes. Next, 283.9 mg (301 μL, 3.88 mmol) of DMF was added, and the mixture was stirred at -78°C for 30 minutes, then warmed to room temperature and stirred for another 30 minutes. A saturated solution of NH4Cl (10 mL) and HCl (10 mL) were added. The reaction mixture was partitioned between the HCl. The aqueous layer was extracted with HCl (10 mL). The organic phase was dried over magnesium sulfate and concentrated. The crude substance was purified by chromatography (siRNA / heptane 0-70%) to obtain the title compound (S,E)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)acrylate ethyl (I.21) as a colorless oil (83 mg, yield 46%). LCMS method 2: Rt = 0.78 min; MS m / z 279.1 [M + H]+. 1¹H NMR (400MHz, methylene chloride-d6) δ 9.57 (s, 1H), 7.45 (d, J=15.6Hz, 1H), 6.48 (d, J=15.6Hz, 1H), 4.94-4.82 (m, 1H), 4.54-4.35 (m, 3H), 4.22 (dt, J=9.1, 6.2Hz, 1H), 4.07 (q, J=7.2Hz, 2H), 2.58 (dtd, J=11.7, 8.1, 6.1Hz, 1H), 2.30 (s, 3H), 2.22 (ddt, J=11.7, 9.2, 7.0Hz, 1H), 1.16 (t, J=7.1Hz, 3H).

[0263] Step 4: (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.10b) [ka] A mixture of (S,E)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)ethyl 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 mixed with sodium triacetoxyhydroborate (77 mg, 366.5 μmol) and acetic acid (14.67 mg, 13.99 μL, 244.3 μmol). The reaction mixture was stirred overnight at room temperature. 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 substance was purified by chromatography (SiO2 / heptane 0-100%) to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.10b) as a colorless oil (97 mg, yield 65%). 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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid (compound 6) [ka] A mixture of (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)ethyl acrylate (III.10b) (97.00 mg, 1 equivalent, 159 μmol) in THF (1.5 mL) and methanol (1.5 mL) was to which lithium hydroxide hydrate (1 M solution, 20.01 mg, 477.0 μL, 477.0 μmol) was added at room temperature. The reaction mixture was stirred at 65 °C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was acidified to pH 2-3 with 2N HCl solution. The crude substance was purified by preparative HPLC (conditions: basic 15-40% acetonitrile-3.ACN / H2O + 5 mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30×50 mm) to obtain the title compound (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid (compound 6) as a white solid (89 mg, yield 75%). 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]+. 1¹H NMR (400MHz, methylene chloride-d2) δ 7.52 (s, 1H), 7.44 (t, J=8.3Hz, 1H), 7.04 (t, J=8.7Hz, 2H), 6.70-6.56 (m, 3H), 6.38 (d, J=15.4Hz, 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7) [ka] Step 1: 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl(I.23) [ka] 4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (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 hours. The reaction mixture was concentrated and partitioned between ethyl and saturated sodium bicarbonate solution. The aqueous phase was extracted once with ethyl. The combined organic phase was dried over magnesium sulfate and concentrated. The crude reaction mixture was purified by chromatography (ethyl / heptane 0-50%). The fractions containing the product were combined and concentrated to obtain 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (I.23) (240 mg, yield 52.3%). LCMS method 1: Rt = 0.81 min; MS m / z 287.2 [M + H]+.

[0266] Step 2: (S)-2-bromo-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl(I.24) [ka] Triphenylphosphine (274 mg, 1.045 mmol), (S)-oxetane-2-ylmethanol (IV.2) (92 mg, 1.045 mmol), and 2-bromo-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (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 mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated and purified by chromatography (Â100%) to obtain (S)-2-bromo-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (I.24) (200 mg, yield 74.7%). LCMS method 1: Rt=0.97 min; MS m / z 357.0[M+H]+.

[0267] Step 3: (S)-2-formyl-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl(I.25) [ka] (S)-2-bromo-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (I.24) (62 mg, 0.174 mmol) and DMF (0.134 mL, 1.736 mmol) were combined in THF, and the reaction mixture was cooled to -20°C under nitrogen. Turbogrignard (0.267 mL, 0.347 mmol) was added dropwise, and the reaction mixture was stirred under nitrogen for 2 hours, during which time it was warmed to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with ethyl ethyl (S)-2-formyl-1-(oxetane-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: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl(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 obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (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 hour. The mixture was partially concentrated, diluted with water and acetonitrile, and purified by reverse-phase HPLC eluting with MeCN / H2O + 0.1% NH4OH to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid (C-7, 16.2 mg, yield 26%). 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)methanol(III.12) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate ethyl (III.11) (42 mg, 0.066 mmol) was combined with tetrahydrofuran (1 mL) and methanol (0.017 mL), and lithium borohydride (1 M in THF, 0.066 mL, 0.132 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was extracted again with ethyl acetate. The combined organic matter was dried over magnesium sulfate and concentrated to obtain (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-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)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)methanol (III.12) (39.2 mg, 0.066 mmol) was dissolved in DCM (1 mL). Des-Martin periodinane (41.8 mg, 0.099 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. 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 obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)ethyl acrylate (III.14) [ka] A vial was filled 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 minutes. 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed again with water and brine. The organic phase was dried over magnesium sulfate and concentrated to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)acrylic acid (C-8) [ka] (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)ethyl 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 hour. The reaction mixture was partially concentrated and purified by reverse-phase HPLC eluting with MeCN / H2O + 0.1% NH4OH to obtain (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)acrylic acid (C-8, 5.8 mg, yield 21%). 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylic acid (C-9) [ka] Step 1: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylate ethyl(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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl phosphate and brine. The organic phase was dried over magnesium sulfate and concentrated to obtain 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylate ethyl (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)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylic acid (C-9) [ka] 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylate ethyl(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 / H2O + 0.1% NH4OH to obtain 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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), 4-methylbenzenesulfonic acid (S)-oxetane-2-ylmethyl (3.33 g, 13.0 mmol) and cesium carbonate (10.1 g, 31.1 mmol) were added at room temperature. The mixture was stirred using a findenser at 80°C for 16 hours, and then cooled to room temperature. Water was added, 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% siRNA / heptane, 0-5% MeOH / siRNA), and the isomers were separated to obtain (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2a) (1.2g, 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) (0.35g, 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), LDA (2.51 mL, 2 molar concentration, 5.02 mmol) in THF / heptane / ethylbenzene was slowly added at -78°C. The reaction mixture was stirred at -78°C for 40 minutes, followed by the addition of N,N-dimethylformamide (972 μL, 12.5 mmol). The reaction mixture was stirred from -78°C to room temperature for 2 hours. The reaction mixture 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 obtain (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (3) (588.9 mg, yield 90.6%) as a brownish solid. The crude product was used for the next step without further purification. LC-MS 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-imidazole-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), (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-ium chloride (II2) (1.9 g, 4.94 mmol) and TEA (1.72 mL, 12.4 mmol) were added. The reaction mixture was stirred at room temperature for 15-25 minutes, followed by the addition of sodium triacetoxyborohydride (1.36 g, 6.43 mmol). The reaction mixture was stirred at room temperature for a further 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 Na2SO4, filtered, and concentrated to obtain a grayish-white foamy solid. This crude product was further purified by normal-phase chromatography (0-100% siRNA / heptane) to obtain 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (4) as a white foamy solid (1.7 g, yield 58.2%). 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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)benzoic acid (6) [ka] To a solution of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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), 3-voronobenzoic acid (5) (13 mg, 79 μmol), K3PO4 (0.30 mL, 1 molar concentration, 0.30 mmol) and Pd 118 (4.3 mg, 6.6 μmol) were added. The mixture was degassed under N2 and subsequently microwaved at 120°C for 20 minutes. The reaction mixture was diluted with water, filtered through a plug, and purified on a basic HPLC to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)benzoic acid (6) as a grayish-white solid (8 mg, yield 20%). 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (C-13) Stage 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 mixture was then stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The TLC showed consumption of SM and formation of new polar spots. The reaction mixture 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 obtain the crude product. The crude products from both batches were mixed and purified by flash chromatography using a flash silica 40-60 μm (60 Å) and 0-50% ethyl acetate in hexane in a stepwise gradient manner to obtain 2-(3-bromo-2-fluorophenyl)acetonitrile (15.00 g, 93.88%) as a colorless liquid. LC-MS: 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% NaOH aqueous solution (200 mL) and stirred at 100 °C for 5 hours. The progress of the reaction was monitored on a TLC. The TLC showed that SM was consumed and polar spots were formed. Upon completion of the reaction, the reaction mixture was cooled to room temperature and acidified to pH 3 by the dropwise addition of concentrated HCl. The resulting precipitate was filtered and thoroughly washed with water. Next, the solid was transferred to a round-bottom flask and dried under vacuum to obtain 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 the mixture was stirred at 0°C for 15 minutes. After 15 minutes, N,O-dimethylhydroxylamine HCl (10.17 g, 104.27 mmol) was added at 0°C, and stirring was continued at 0°C for 15 minutes. The reaction mixture was then slowly brought to room temperature, stirred at room temperature for 16 hours, and monitored on a TLC. The TLC showed consumption of SM and formation of nonpolar spots. The reaction mixture was quenched with water (500 mL), and the DCM was evaporated under vacuum. Next, the aqueous layer was extracted with siRNA (3 × 250 mL). The siRNA layer was recovered, dried over Na₂SO₄, and evaporated to obtain a crude oily product, which was purified by a flash chromatography system using flash silica 40–60 μm (60 Å) and 0–60% ethyl acetate in hexane in a stepwise gradient manner to obtain 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 each 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, 3M methylmagnesium bromide (2.7 mL, 7.97 mmol) in diethyl ether was added at 0°C, and the mixture was stirred for 1 hour, followed by a slow RM (methyl methyl acetamide) reaction to reach room temperature over 2 hours. The progress of the reaction was monitored on a TLC plane. The TLC showed that SM (methyl methyl acetamide) was consumed and nonpolar spots were formed. Upon completion of the reaction, all three reactants were quenched with water (100 mL) and combined. The combined aqueous layer was extracted with siRNA (3 × 250 mL). The siRNA layer was recovered, dried over Na2SO4, and evaporated to obtain a crude oily product, which was purified by flash chromatography using a flash silica 40-60 μm (60 Å) and 0-50% ethyl acetate in hexane in a stepwise gradient manner to obtain 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 a 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 hexane) was added at -78°C and the mixture was 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 the mixture was stirred at -78°C for 1 hour. The reaction mixture was then slowly allowed to reach room temperature over 1 hour, and the progress of the reaction was monitored on a TLC. The TLC showed consumption of SM and formation of nonpolar spots. All four reaction mixtures were quenched with water (10 mL) and combined. The combined aqueous layers were extracted with siRNA (3 × 50 mL). The siRNA layers were combined and washed with water and brine. After drying with Na₂SO₄, the solvent was evaporated to obtain the crude product, which was purified by a flash chromatography system using 40–60 μm (60 Å) flash silica and 0–20% ethyl acetate in hexane in a stepwise gradient manner to obtain 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 hours. The progress of the reaction was monitored on TLC. The TLC showed consumption of SM and formation of nonpolar spots. The reaction mixture was quenched with water (10 mL) and extracted with ₹ (3 × 25 mL). The organic layers were combined and washed with water and brine. After drying with Na2SO4, the solvent was evaporated to obtain the crude product, which was purified by flash chromatography using a flash silica 40-60 μm (60 Å) and 0-10% ethyl acetate in hexane in a stepwise gradient manner to obtain 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 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl 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 the mixture was purged with nitrogen for 5 minutes. Next, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (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 mixture was then stirred at 90°C for 16 hours. The progress of the reaction was monitored on a TLC. TLC showed that SM was consumed and polar spots were formed. The reaction mixture was cooled to room temperature and filtered on Celite. The Celite bed was washed with siRNA (150 mL). The filtrate was collected, dried over Na₂SO₄, and evaporated to obtain the crude product, which was purified by flash chromatography using a flash silica 40-60 μm (60 Å) flash and 0-50% ethyl acetate in hexane in a stepwise gradient manner to obtain 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (1.05 g, 96.18%) as a colorless gummous 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 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate tert-butyl In a 100 mL round-bottom flask, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (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. Next, the nitrogen atmosphere was replaced with hydrogen, and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere with balloon pressure. The progress of the reaction was monitored on a TLC. The TLC showed consumption of SM and formation of nonpolar spots. The reaction mixture was filtered on Celite and washed with MeOH (100 mL). The filtrate was collected and evaporated to obtain 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 stepwise gradient manner to obtain a mixture with racemic 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate tert-butyl (0.80 g, 75.85%) and 0.130 g of the dechloroform product. LCMS: Purity: 100%, RT: 2.679 min. (Method-C2), MS(ES+) m / z: 390.4[M-56]+. Chiral HPLC: 2 peaks; 5.11 min (50.01%): 9.31 min (49.80%).

[0290] A 0.8 g racemic mixture was further purified by chiral preparative HPLC, and the resulting fraction was concentrated. Fraction 1: Pale yellow sticky rubber (35.08%). Fraction 2: Pale yellow sticky rubber (33.18%).

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

[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] Stage 2 [ka] Step 1: 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine [ka] To a solution of 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate tert-butyl (400 mg, 0.897 mmol) in AcOEt (9 mL), 4 M HCl (330 μL) in dioxane was added. The mixture was stirred at room temperature for 5 hours. After LC / MS indicated completion of the reaction, the mixture was diluted in AcOEt, washed with saturated Na2CO3 and brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound (279 mg, 95% yield). LC / MS method 1: Rt = 0.89 min; MS m / z 346.3 [M + H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 7.60 (t, J=8.5Hz, 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)piperidine-1-yl)methyl)-4-methyl-1-((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate [ka] To a solution of 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine (145 mg, 0.270 mmol) and (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (85 mg, 0.246 mmol) in DCM (1.3 mL), TEA (34.3 μL, 0.246 mmol) was added. The mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyhydroborate (67.7 mg, 0.320 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 0°C, quenched with saturated NaHCO3 aqueous solution, and extracted twice in DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase LC-MS using a C18 column under 0.01% NH4OH in 0-70% ACN (0.01% NH4OH) / H2O to obtain the title compound (96 mg, yield 64%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-((oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (95.5 mg, 1 Eq, 157 μmol) in THF (0.90 mL) / MeOH (0.30 mL), 1 M LiOH aqueous solution (471 μL, 471 μmol) was added, and the mixture was stirred overnight at room temperature. LC / MS indicated completion of the reaction. The reaction product was quenched with 1M KH2PO4, extracted three times with AcOEt, concentrated, and the residue was purified by reverse-phase C18 column under 0.01% NH4OH in 0-50% ACN (0.01% NH4OH) / H2O to obtain the title compound (73 mg, yield 79%). 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoic acid (C-14) [ka] Synthesis scheme: [ka] Note: The synthesis of Int-6 is common and is described in Example 19.

[0298] Step 5: Synthesis of ethyl (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)acrylate [ka] To a solution of 2-(diethoxyphosphoryl)ethyl acetate (7) (1.43 g, 0.0063 mol) in DMF (20.7 mL), 55-60% NaH (0.301 g, 7.5 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 20 minutes. After 20 minutes, (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 mixture was stirred at room temperature for 30 minutes. The reaction mixture was monitored by TLC and LC-MS. After completion of the reaction, confirmation was made by TLC. The reaction mixture was quenched with saturated NH4Cl, extracted with ethyl acetate (3 × 50 mL), the combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated to obtain the crude product. Chromatographic purification using a neutral alumina column (Â10-28%) yielded ethyl (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)acrylate (0.74 g, yield 53%). LC-MS 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 ethyl (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)acrylate [ka] To a solution of (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (0.740 g, 2.2 mmol) and DMF (1.15 g, 15.4 mmol) in THF (7.4 mL), isopropylmagnesium lithium chloride complex (1.3 M in THF) (1.29 g, 8.9 mmol) was added at -20°C, and the reaction mixture was stirred at the same temperature for 15 minutes. The progress of the reaction was monitored on a TLC. After the completion of the reaction, the reaction mixture was quenched with saturated NH4Cl, extracted with diethyl ether (3 × 30 mL), and concentrated to obtain the crude product. Chromatographic purification using a neutral alumina column (0-18% Â1 / Heptane) yielded ethyl (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)acrylate (0.35 g, yield 56%). 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-imidazole-5-yl)propanoate [ka] To a stirred solution of (S,E)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (0.350 g, 1.26 mmol) in ethanol (3.5 mL), (150 mg, 10% Pd / C 50% water) was added in small increments, and the reaction mixture was stirred at room temperature for 24 hours under a 10 kg H2 pressure. The reaction was monitored by TLC and LCMS. After the reaction was complete, the mixture was filtered through a Celite bed, and the filtrate was evaporated to obtain the crude product, (S)-3-(2-(hydroxymethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl propanoate (0.30 g, crude yield 84.5%). This 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 ethyl (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)propanoate [ka] To a solution of (S)-3-(2-(hydroxymethyl)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)propanoate ethyl (0.3 g, 1.124 mmol) in DCM (3 mL), Desmartin periodinane (0.715 g, 1.686 mmol) was added in small amounts at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NaHCO3, extracted with DCM (3 × 25 mL), and concentrated to obtain the crude product, (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)propanoate ethyl (0.25 g, crude yield 83.9%). This was carried over directly to the next step of the reaction without purification.

[0302] Step 9: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propyl ethyl [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 minutes. After adding (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl propanoate (0.25 g, 0.892 mmol), 0.5 M ZnCl2 solution (7.5 mL, 2.678 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours, then the solution was cooled to °C, and NaCNBH4 (0.168 g, 2.678 mmol) was added in small amounts. The reaction mixture was stirred at 60°C for 12 hours and monitored by LC-MS. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 and extracted with DCM (3 × 30 mL) to obtain the crude product. Chromatographic purification by neutral alumina column (siRNA / heptane 0-70%) yielded ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate (0.06 g, yield 11%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate (0.195 g, 0.318 mmol) in ethanol (5.85 mL), 2.9 mL aq. NaOH (0.038 g, 0.95 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and monitored by LC-MS. After the reaction was complete, the ethanol was evaporated and the pH of the reaction mixture was adjusted to 3-4 with an aqueous citric acid solution. The mixture 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 / H2O + 0.1% NH4OH, X-bridge C18] to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoic acid (0.015 g, crude yield 5.4%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoropropanoic acid (C-15) [ka] Synthesis scheme: [ka] For steps 1-6, please refer to Example 14.

[0305] Step 7: Synthesis of 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl [ka] To a stirred solution of (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (0.7 g, 2.3 mmol) in humid ethanol (7 mL), 10% Pd / C 50% (300 mg) was added in small increments, and the reaction mixture was stirred at room temperature for 24 hours under a 10 kg H2 pressure. The reaction mixture was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was filtered through a Celite bed, and the filtrate was evaporated to obtain the crude product, 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl propanoate (0.550 g, crude yield 77.5%). This 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 2-fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl [ka] To a solution of ethyl 2-fluoro-3-(2-(hydroxymethyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate (0.410 g, 1.367 mmol) in DCM (4.1 mL), desmartin periodinane (0.870 g, 2.05 mmol) was added in small amounts at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was quenched with saturated NaHCO3 solution, extracted with DCM (3 × 30 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the crude product, ethyl 2-fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoropropanoate ethyl [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 the mixture was stirred at room temperature for 20 minutes. 2-Fluoro-3-(2-formyl-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl (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 increments at 0°C. The reaction mixture was stirred at room temperature for 16 hours and monitored by LC-MS. After the reaction was complete, the product was quenched with saturated NaHCO3 and extracted with DCM (3 × 30 mL) to obtain the crude product. Chromatographic purification (RINKAN 0-70%) yielded 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-ethyl fluoropropanoate (0.150 g, crude yield 11.8%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoropropanoic acid [ka] To a solution of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoropropanoate ethyl (0.150 g, 0.238 mmol) in ethanol (4.5 mL), 2.25 mL aq. NaOH (0.028 g, 0.71 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and monitored by LC-MS. After the reaction was complete, the ethanol was evaporated and the pH of the reaction solution was adjusted to 3-4 using an aqueous citric acid solution. The mixture was extracted with ethyl acetate (3 × 15 mL), the organic layer was dried over sodium sulfate, concentrated, and the crude product was purified by reverse-phase preparative HPLC [MeCN / H2O + 0.1% NH4OH, X-bridge C18] to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoropropanoic acid (0.026 g, crude yield 18.1%). LC-MS 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)piperidine-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonyl)methyl glycinate [ka] To a solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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), DIPEA (0.11 mL, 0.65 mmol) and HATU (49 mg, 0.13 mmol) were added. After stirring for 5 minutes, methyl glycinate, AA-hydrochloride (16 mg, 0.13 mmol) was added, and the reaction mixture was stirred overnight at room temperature. LC-MS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was diluted with H2O and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was carried over to the next step without purification (87 mg, yield 88%). LC-MS 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)piperidine-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)piperidine-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), lithium hydroxide (s) (8.8 mg, 0.37 mmol) and 1 M LiOH (aq) (0.12 mL, 0.12 mmol) were added. When LC-MS showed consumption of the starting material and formation of the desired product, the reaction was stirred overnight at room temperature. The reaction mixture was diluted with DMSO and purified by preparative HPLC (conditions: basic 15-40% acetonitrile-3.ACN / H2O + 5mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30×50 mm) to obtain the title compound (28 mg, yield 37%). 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid (C-17b) [ka] Synthesis scheme: [ka] [ka] Step 1: Synthesis of (S)-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (3) [ka] A solution of ethyl 1H-imidazole-5-carboxylate (15 g, 107.04 mmol) and methyl 4-methylbenzenesulfonic acid (S)-oxetane-2-ylmethyl (28.52 g, 117.74 mmol) in DMF (150 mL) was mixed with potassium carbonate (44.38 g, 321.13 mmol) under a nitrogen atmosphere, followed by the addition of potassium iodide (17.76 g, 107.04 mmol), and the mixture was heated at 80°C for 9 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted in ethyl acetate (3 × 250 mL). The combined organic layers were washed with cold water (150 mL) and brine (100 mL), dried over sodium sulfate, and concentrated. Chromatographic purification using a neutral alumina column yielded the upper spot eluted in 19–21% HCl / hexane and the lower spot eluted in 100% HCl–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-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (3.5 g, yield 15.6%). The lower spot contained (S)-1-(oxetane-2-ylmethyl)-1H-imidazole-4-carboxylate ethyl (3A) (1.78 g, yield 7.9%). Upper isomer (3), (S)-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl: LCMS method C3: Rt = 1.33 min; MS m / z 211.1 [M + H]+. 1 ¹H NMR (400MHz, DMSO-d6) δ 7.94 (s, 1H), 7.66 (s, 1H), 4.91 (qd, J=6.5, 3.8Hz, 1H), 4.61 (dd, J=14.2, 6.4Hz, 1H), 4.42-4.56 (m, 2H), 4.26 (dq, J=14.4, 7.1, 6.5Hz, 3H), 2.57-2.70 (m, 1H), 2.22-2.35 (m, 1H), 1.28 (t, J=7.1Hz, 3H). The isomer below (3A), (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-4-carboxylate ethyl: 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-imidazole-5-yl)methanol [ka] To a solution of (S)-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (3) (3.5 g, 16.666 mmol) in THF (35 mL), lithium aluminum hydride (2 M in THF) (0.949 g, 24.999 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 1 hour. The progress of the reaction was monitored by LC-MS. The reaction mixture was quenched by the dropwise addition of ethyl acetate (15 mL) at 0°C. Sodium sulfate decahydrate was added to this reaction mixture, and the mixture was stirred for 5 minutes. Subsequently, the mixture was filtered through a Celite bed, the Celite bed was washed with ethyl acetate (150 mL), and the filtrate was concentrated under vacuum to obtain (S)-(1-(oxetane-2-ylmethyl)-1H-imidazole-5-yl)methanol (2.7 g, yield 96.4%). 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-(oxetane-2-ylmethyl)-1H-imidazole-5-carbaldehyde [ka] To a solution of (S)-(1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)methanol (2.7 g, 16.071 mmol) in acetonitrile (40.5 mL), MnO2 (20.97 g, 241.07 mmol) was added, and the mixture was heated at 50 °C for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was complete, the mixture was cooled to room temperature, filtered on a Celite bed, and concentrated under vacuum to obtain (S)-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde (2.5 g, crude product). LC-MS 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-imidazole-5-yl)acrylate [ka] To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (5.38 g, 22.590 mmol) in THF (10 mL), 60% sodium hydride (1.2 g, 30.12 mmol) was added in small increments at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, and then (S)-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carbaldehyde (2.5 g, 15.06 mmol) in THF (15 mL) was added dropwise to the above solution at 0°C. Next, the reaction mixture was 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, quenched with ice water, and then extracted with ethyl acetate (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by combiflash (Â1-28%) using neutral alumina to obtain ethyl (S,E)-2-methyl-3-(1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)acrylate (1.4 g, yield 37.18%). LC-MS 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 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl [ka] To a solution of (S,E)-2-methyl-3-(1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (1.4 g, 5.592 mmol) in methanol (21 mL), 10% Pd / C, 50% water (0.750 g, 0.5 w / w) was added under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours under hydrogen pressure (1 atm) using a hydrogen balloon. The progress of the reaction was monitored on a TLC. After the completion of the reaction, the reaction mixture was filtered through a Celite bed and subsequently washed with methanol (50 mL). The filtrate was concentrated under vacuum to obtain 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl (1.2 g, yield 85.03%). 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 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate ethyl [ka] To a solution of ethyl 2-methyl-3-(1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate (1.2 g, 4.761 mmol) in DMF (12 mL), DIPEA (3.077 g, 23.809 mmol) and 37% HCHO (2.85 g, 95.238 mmol) were added, and the mixture was heated in a microwave at 135°C for 3 hours. The reaction was monitored by LC-MS, which showed that some SM still remained after 3 hours, so DIPEA (1.53 g, 11.904 mmol) and 37% HCHO (1.42 g, 47.619 mmol) were added again, and the reaction mixture was heated in a microwave at 135°C for 1.5 hours. The reaction mixture was cooled and concentrated under vacuum to completely remove the DMF, followed by stripping with toluene to remove trace amounts of water. The crude product was purified by column chromatography using neutral alumina with 0-10% MeOH / DCM to obtain ethyl 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate (0.515 g, yield 38.35%). LC-MS method H3: Rt = 2.12 mins; 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 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl [ka] To a solution of ethyl 3-(2-(hydroxymethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate (0.515 g, 1.826 mmol) in DCM (6 mL), TEA (0.554 g, 5.478 mmol) was added. The mixture was cooled to 0°C, and then mesyl chloride (0.313 g, 2.739 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours. The progress of the reaction was monitored on a TLC. After the reaction was complete, the reaction mixture 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 with sodium sulfate and concentrated under vacuum to obtain crude 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoate ethyl (0.375 g). This crude product was used in the next reaction without further purification.

[0318] Step 8: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate ethyl [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), DIPEA (0.672 g, 5.202 mmol) was added. After stirring the reaction mixture for 10 minutes, 2-methyl-3-(2-(((methylsulfonyl)oxy)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propyl ethyl (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 mixture was heated at 60 °C for 16 hours and monitored by TLC. The reaction mixture was cooled to room temperature, the acetonitrile was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate (3 × 15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (MeCN / H2O + 0.1% NH4OH, YMC ACTUS TRIART C18) to obtain ethyl 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate (0.040 g, yield 6.3%). LC-MS 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid and 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid [ka] Step 9-1: Chiral separation of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate ethyl Column: Chiralpak IC 21×250mm 5um Flow rate: 80g per minute Cosolvent: 10 mM NH3 in 30% IPA w / CO2 Detection: 220nm BPR Setpoint: 125 bar injection Size: 3mg (3.0mg / mL of MeOH) System: CA_GDCSEPS_PrepSFC02 Acronyms: MeOH = methanol, IPA = isopropanol, NH3 = ammonia

[0320] Process-9-2: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid [ka] To a solution of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate ethyl (fraction 1 from chiral separation) (17.5 mg, 28.6 μmol) in THF (100 μL), 1 M LiOH (85.8 μL, 85.8 μmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was purified by preparative HPLC (conditions: basic 25-50% acetonitrile-3.ACN / H2O + 5 mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30 × 100 mm) to obtain 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] Process-9-3: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid [ka] To a solution of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoate ethyl (fraction 2 from chiral separation) (13.5 mg, 22.1 μmol) in THF (100 μL), 1 M LiOH (66.2 μL, 66.2 μmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was purified by preparative HPLC (conditions: basic 25-50% acetonitrile-3.ACN / H2O + 5 mM NH4OH 75 ml / min; column: Waters XBridge C18 OBD 30 × 100 mm) to obtain 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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid (C-18) Synthesis scheme: [ka] Step 1: 4-fluoro-1H-imidazole-5-carboxylate ethyl [ka] 4-amino-1H-imidazole-5-carboxylate ethyl (2 g, 12.89 mmol) was dissolved in 48% HBF4 (68.5 mL) in H2O. The solution was cooled to -10°C, and NaNO2 (4.11 g, 59.6 mmol) was dissolved in H2O (5.15 mL) and added dropwise to the above solution. The solution turned blue-green, and the solution was then transferred to a quartz flask and stirred in a box (pre-cooled with dry ice). The reactants were irradiated overnight at 28-30°C with a 302 nm UV 16x12 W lamp, and LC / MS showed that the reaction was complete. The solution was stirred on ice, neutralized with cooled concentrated NaOH, extracted three times with AcOEt, and dried over MgSO4. The solvent was removed. The residue was purified by chromatography (ÃO / heptane 0-70%) to obtain the title compound (760 mg, yield 37%). 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), NBS (754 mg, 4.24 mmol) was added, and the mixture was stirred at 50°C for 1 hour. After completion, the solution was concentrated, and the residue was purified by chromatography (siRNA / heptane 0-50%) to obtain the title compound (221 mg, 146 mg of starting material recovered, yield 29%). LCMS method 2: Rt = 0.42 min; MS m / z 239.2 [M + H]+. 1 ¹H 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-(oxetane-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)-oxetane-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 the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated, and the residue was purified by chromatography (Â100-60%) to obtain the title compound (194 mg, yield 62%). LCMS method 2: Rt = 0.83 min; MS m / z 306.9 [M + H]+. 1 ¹H NMR (400MHz, chloroform-d) δ: 5.11-5.00 (m, 1H), 4.74-4.57 (m, 3H), 4.53 (dt, J=9.2, 6.3Hz, 1H), 4.32 (q, J=7.3Hz, 2H), 2.84-2.71 (m, 1H), 2.50-2.39 (m, 1H), 1.35 (d, J=14.2Hz, 3H).

[0325] Step 4: (S)-4-fluoro-2-formyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of (S)-2-bromo-4-fluoro-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (373 mg, 1.215 mmol) and DMF (658 μL, 8.50 mmol) in THF (6 mL), the Turbogrignard reagent, 1.3 M in THF (2.3 mL, 3.04 mmol), was added at -15°C and stirred for 20 minutes at -15°C. The reaction mixture was then warmed to 0°C and stirred for 1 hour. LC / MS indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl, extracted three times by DCM, and concentrated to obtain the crude product, which was carried over to the next step without purification. LC / MS 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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (351 mg, 1 Eq, 1.370 mmol) and (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), triethylamine (416 mg, 4.11 mmol) was added, the reaction mixture was stirred for 15 minutes, then sodium triacetoxyhydroborate (377 mg, 1.781 mmol) was added, and the mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 0°C, quenched with saturated NaHCO3 aqueous solution, and extracted three times by DCM. The combined organic layer was washed with brine and concentrated under reduced pressure to obtain the crude product. The residue was purified by chromatography (Â100%) to obtain 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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)methanol [ka] To a solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl (328 mg, 0.558 mmol) in THF (6 mL), 2 M LAH (418 μL, 0.837 mmol) in THF was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was complete, it was quenched by adding Na2SO4.10H2O and extracted with DCM. Crude product (238 mg, yield 93%) was obtained by filtration and concentration, and the crude product was carried over to the next step 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)piperidine-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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)methanol (270.8 mg, 0.496 mmol) in ACN (3 mL), MnO2 (647 mg, 7.44 mmol) was added. The mixture was stirred overnight at 50°C, and LC / MS indicated that the reaction was complete. The mixture was filtered through Celite, rinsed with ACN, and concentrated to obtain the crude title product (263 mg, 97% yield). The crude was carried over to the next step without purification. LC / MS 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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate [ka] To a solution of ethyl 2-(diethoxyphosphoryl)(144 μl, 0.725 mmol) in DMF (2 mL), 60% NaH (32.9 mg, 0.822 mmol) from oil was added at 0°C. The reaction mixture 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)piperidine-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 mixture was stirred at 0°C for 15 minutes, then warmed to room temperature and stirred at the same temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to 0°C, quenched with saturated NH4Cl aqueous solution, 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 C18 column under 0.01% NH4OH in 0-80% ACN (0.01% NH4OH) / H2O to obtain the title compound (195 mg, yield 66%). LCMS method 2: Rt = 0.46 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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)ethyl acrylate (98.6 mg, 0.161 mmol) in THF (0.9 mL) / MeOH (0.3 mL) (ratio: 3:1), 1 M LiOH aqueous solution (482 μL, 0.482 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DMSO and purified by reverse-phase filtration using a C18 column under 0.01% NH4OH in 0-80% ACN (0.01% NH4OH) / H2O to obtain the title compound (75 mg, yield 78%). 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)-oxetane-2-ylmethanol (1.5 eq), TPP (1.5 eq), DIAD (1.5 eq), THF (22 vol), room temperature, 24 hours. Step 3: NaBH4 (10 eq), ethanol (10 vol), 0°C to 50°C, 30 hours. Step 4: MnO2 (15 eq), acetonitrile (20 vol), 50°C, 16 hours. Step 5: 2-(diethoxyphosphoryl)-2-ethyl fluoroethyl acetate (1.5 eq), 2.5M 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 2-bromo-4-methyl-1H-imidazole-5-carboxylate ethyl [ka] 4-methyl-1H-imidazole-5-carboxylate ethyl (5 g, 32 mmol) was stirred in acetonitrile (160 mL), and NBS (7.46 g, 42 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete when the reaction solution became clear, 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 × 150 mL). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, and concentrated. Chromatographic purification (Â100 mL + . 1 ¹H 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 (S)-2-bromo-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl [ka] To a solution of ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate (4 g, 17 mmol) in THF (88 mL), (S)-oxetane-2-ylmethanol (2.26 g, 25 mmol) was added, followed by the addition of triphenylphosphine (6.747 g, 25 mmol). DIAD (5.202 g, 25 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was monitored by LC-MS, and after completion of the reaction, the solvent was removed to obtain the crude product. Chromatographic purification using a neutral alumina column (siRNA / heptane 0-20%) yielded ethyl (S)-2-bromo-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate (3.3 g, yield 63.4%). LCMS method C2: Rt=1.133 min, MS m / z 303[M+1] + . 1 ¹H NMR (400MHz, chloroform-d)δ 5.07 (s, 1H), 4.68-4.77 (m, 2H), 4.64 (q, J=6.9Hz, 1H), 4.53 (q, J=7.0, 6.3Hz, 1H), 4.38 (dq, J=14.1, 7.1Hz, 2H), 2.78 (s, 1H), 2.55 (S, 3H), 2.44 (s, 1H), 1.40 (t, J=7.0Hz, 3H).

[0334] Step 3: Synthesis of (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)methanol [ka] A solution of (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (3.3 g, 10 mmol) in ethanol (33 mL) was cooled to 0°C, and NaBH4 (1.64 g, 43 mmol) was added in small increments. The reaction mixture was stirred at 50°C for 6 hours. The reaction mixture was monitored by TLC and LC-MS. After 6 hours, SM remained on the TLC with product formation, so further NaBH4 (1.64 g, 43 mmol) was added at 0°C, and the mixture was heated again at 50°C for 12 hours. LC / MS still showed that 15% SM remained, so NaBH4 (0.823 g, 21 mmol) was added again at 0°C, and the reaction mixture was heated for another 6 hours at 50°C until the SM was consumed on the TLC and LC-MS. After the reaction was complete, 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 × 100 mL) to obtain the crude product, which was used directly in the next step without purification. (S)-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-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-imidazole-5-yl)methanol (2.3 g, 8.8 mmol) in acetonitrile (46 mL), MnO2 (11.5 g, 132 mmol) was added, and the mixture was stirred at 50°C for 16 hours. The reaction was monitored by LC-MS and TLC. After the completion of the reaction, the reaction mixture was filtered through Celite, washed with acetonitrile, and the filtrate was concentrated to obtain the crude product (1.7 g, crude yield 74.5%). Chromatographic purification (Â100-30% Â100%) yielded (S)-2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbaldehyde. LC-MS 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-imidazole-5-yl)-2-ethyl fluoroacrylate (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)-2-ethyl fluoroacrylate (8A) [ka] To a solution of 2-(diethoxyphosphoryl)-2-ethyl fluoroethyl acetate (2.25 g, 9 mmol) in THF (32 mL), n-Buli (2.5 M in hexane) (4.5 mL, 11 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. After 1 hour, 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 mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC and LCMS. After completion, the reaction product was quenched with saturated NH4Cl, extracted with ethyl acetate (3 × 75 mL), washed with brine, and dried over sodium sulfate to obtain the crude product. Chromatographic purification by neutral alumina column (Â100-60%) yielded a mixture of both isomers, (S,Z)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)-2-fluoroacrylate (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)-2-fluoroacrylate (8A) (1.1 g, yield of isomer mixture 51.31%) (cis and trans). LC-MS 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-imidazole-5-yl)ethyl acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (9A) [ka] A solution of (S,Z)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)-2-fluoroacrylate (8) and (S,E)-3-(2-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)-2-fluoroacrylate (8A) (1 g, 2.9 mmol) and DMF (1.47 g, 20 mmol) in THF (10 mL) was cooled to -20°C, and isopropylmagnesium lithium chloride complex (1.3 M in THF) (1.68 g, 11 mmol) was added dropwise to the above solution. The reaction mixture was stirred at the same temperature for 30 minutes. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated NH4Cl and extracted with (3 × 50 mL) diethyl ether to obtain the crude product. Chromatographic purification by neutral alumina column (Â10-30%) yielded a mixture of both isomers, (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (9A) (0.3 g, yield of both isomers 35.2%) (cis and trans). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-ethyl fluoroacrylate (11) and (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-ethyl 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), DIPEA (0.261 g, 2.0 mmol) was added. The mixture was stirred at room temperature for 20 minutes, then acetic acid (0.061 g, 1.01 mmol) was added to the solution, followed by the addition of the mixture, (S,Z)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)ethyl acrylate (9) and (S,E)-2-fluoro-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-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 increments. The reaction solution was stirred at room temperature for 16 hours and monitored by LC-MS. After completion, the reaction mixture was quenched with saturated NaHCO3 and extracted three times with DCM to obtain the crude product. By chromatographic purification (0-80% SiO2 / heptane), both isomers (Z)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoroacrylate ethyl(11) and (E)- 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-ethyl fluoroacrylate (11A) (0.22 g, yield of both isomers 34.6%) was obtained. LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoroacrylic acid and (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoroacrylate ethyl (11A) (0.18 g, 0.287 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was monitored by LC-MS, and after the completion of the reaction, the ethanol was evaporated, and the pH of the reaction mixture was adjusted to 3-4 using an aqueous citric acid solution. It was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and concentrated. The crude product 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoroacrylic acid (0.032 g). LCMS method H3: Rt = 2.83 mins; 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one (C-20) [ka] Step 1: (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) [ka] 4-methyl-1H-imidazole-5-carbonitride (1) (2.0 g, 19 mmol) was added dropwise to tetrahydrofuran (60 mL) with (S)-oxetane-2-ylmethanol (1) (1.8 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), and then (E)-diazene-1,2-dicarboxylic acid diisopropyl (4.2 g, 4.0 mL, 21 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated and purified by silica gel chromatography (0-100% AcOEt / heptane). Both isomers appeared and were purified again by SFC (column: (S,S)Whelk-O1 21×250mm 5um; flow rate: 80g / min; cosolvent: 15% MeOH in CO2; detection: 230nm; BPR setpoint: 125bar) to obtain (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) (1.1g, 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) (0.89g, 27%). LCMS method 2: Rt=0.48 min; MS m / z 178.1[M+1]+.

[0343] Step 2: (S)-2-formyl-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carbonitrili (3) [ka] (S)-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (2a) (155 mg, 875 µl) was added dropwise to tetrahydrofuran (4 mL), and lithium diisopropylamide (103 mg, 481 μL, 2 molar concentration, 962 μmol) was added, and the mixture was stirred at -78°C for 30 minutes. Next, N,N-dimethylformamide (639 mg, 677 μL, 8.75 mmol) was added, and the mixture was stirred at -78°C for 10 minutes, then warmed to room temperature and stirred for another 30 minutes. Water was added, the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. Next, the crude product (S)-2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-carbonitrile (3) was placed on a high vacuum pump for 16 hours and used as is 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonitrile(4) [ka] (S)-2-formyl-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carbonitrile (3) (143 mg, 0.697 mmol) in DCM (3.5 mL) was mixed with (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (268 mg, 0.697 mmol), Et3N (388 μl, 2.79 mmol), and NaBH(OAc)3 (222 mg, 1.05 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction product was further diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuum to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carbonitrile (4) (80 mg, 0.15 mmol) was added to 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 (approximately 5 mL) was added, 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 under vacuum, 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, and the mixture was stirred at room temperature for 2 hours. Water was added, followed by two extractions with ethyl acetate, drying over magnesium sulfate, filtration, and concentration under vacuum. The residue was purified by preparative HPLC under basic conditions to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one (C-20) as a white solid (24 mg, 27%). 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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)-1,2,4-oxadiazole-5(2H)-one [ka] The same procedure as in Example 20 was used, but 2b was used after step 1 for synthesis. 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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 4-methylbenzenesulfonic acid (S)-oxetane-2-ylmethyl (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), Cs2CO3 (2.92 g, 8.96 mmol) was added. The reaction mixture was heated under reflux for 16 hours. 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 obtain compound 1. LC-MS (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), 1N LDA (1.600 ml, 1.600 mmol) was slowly added at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, followed by the addition of DMF (0.310 ml, 4.00 mmol). The reaction mixture was stirred at -78°C to room temperature for 2 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted three times with ether. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the compound 2 residue 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-imidazole-2-yl)methyl)piperidine(3) [ka] To a solution of compound 2 (245 mg, 0.800 mmol) and (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), pyridine (64.7 μl, 0.800 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of sodium triacetoxyborohydride (170 mg, 0.800 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was cooled to 0°C, quenched with saturated aqueous NaHCO3 solution, and extracted twice with DCM. The combined organic layer was concentrated, and the residue was purified by FCC (EA / Hep = 0-100%) to obtain 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propylate ethyl(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), Pd(PPh3)4 (83 mg, 0.072 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of 1N TBAF (1082 μl, 1.082 mmol). The reaction mixture 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 obtain 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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), LiOH-H2O (62.1 mg, 1.480 mmol) was added. The reaction mixture was stirred overnight, followed by quenching with 1N NaH2PO4 aqueous solution and extraction twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (MeOH / DCM = 0-10%) to obtain compound (C-22). 1H 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)bicyclo[1.1.1]pentan-1-carboxylic acid (C-23) Step 1: 3-Propionylbicyclo[1.1.1]pentane-1-carboxylate methyl [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), 2N (COCl)2 (4.56 ml, 9.11 mmol) in DCM was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C, and then PdCl2(dppf).CH2Cl2 adduct (154 mg, 0.188 mmol) in THF (15 mL) and 1N ZnEt2 (4517 μl, 4.52 mmol) in hexane were added. The reaction mixture was stirred at 0°C for 5 minutes, followed by 16 hours at room temperature. The reaction mixture was slowly quenched with 1N HCl aqueous solution, followed by three extractions with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified using ISCO (EA / Hep = 0-60%) to obtain 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: 3-(2-bromopropanoyl)bicyclo[1.1.1]pentane-1-carboxylate methyl [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), bromine (553 mg, 178 μL, 1.05 Eq, 3.46 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water (200 mL), and unreacted bromine was reduced by adding Na2S2O3 solid. The crude product was extracted three times with ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution and dried over Na2SO4. After filtration and concentration, the residue was purified by FCC (EA / Hep = 0-100%) to obtain 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: 3-(4-methyl-1H-imidazole-5-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl [ka] To a solution of methyl 3-(2-bromopropanoyl)bicyclo[1.1.1]pentane-1-carboxylate in MeOH (5 mL), formimidoacetic acid (1.03 g, 10 eq, 9.88 mmol) was added. 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 under reflux for 12 hours, then cooled to room temperature. The reaction mixture was concentrated, 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 obtain methyl 3-(4-methyl-1H-imidazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylate. LC-MS (basic) R t =0.61, M=207.1[M+1] +

[0355] Step 4: (S)-3-(4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (2a) and (S)-3-(5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (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), Cs2CO3 (246 mg, 1.5 Eq, 756 μmol) was added. The reaction mixture was heated to 120 °C for 4 hours, 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 obtain positional isomers, products 2a and 2b. LC-MS (basic) R t =1.30, mass = 277.1 and R t =1.33, mass=277.1[M+1] +

[0356] Step 5: (S)-3-(2-formyl-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-5-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (3a) and (S)-3-(2-formyl-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-4-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (3b) [ka] A solution of compounds 2a and 2b (39 mg, 1 Eq, 0.14 mmol) in THF (0.5 mL) was mixed with 1N LDA (0.28 mL, 1 molar concentration, 2 Eq, 0.28 mmol) in THF at -78°C. The reaction mixture 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 mixture was stirred at -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: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (4a) and 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)bicyclo[1.1.1]pentan-1-carboxylate methyl (4b) [ka] To a solution of a mixture of compounds 25a and 25b (43 mg, 1 Eq, 0.14 mmol) in DCM (1 mL), intermediate 3.1 (54 mg, 1 Eq, 0.14 mmol) and pyridine (11 mg, 11 μL, 1 Eq, 0.14 mmol) were added. 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, followed by quenching with saturated aqueous solution of NaHCO3 and extraction twice with DCM. The combined organic layer was concentrated, and the residue was purified by FCC (ethyl acetate / DCM = 0-100%) to obtain 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (23b) [ka] A solution of compounds 4a and 4b (17.0 mg, 1 Eq, 26.7 μmol) in a mixed solvent THF / MeOH (1.2 mL / 0.4 mL) was mixed with 2N LiOH aqueous solution (66.8 μL, 2 molar concentration, 5 Eq, 134 μmol). 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. I obtained it.

[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-tetrazole-5-yl)-4-(trifluoromethyl)-1H-imidazole-2-yl)methyl)piperidine(C-24) [ka] Step 1: (S)-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) [ka] 4-(trifluoromethyl)-1H-imidazole-5-carbonitride (1 g, 6 mmol) was added dropwise to tetrahydrofuran (30 mL) with (S)-oxetane-2-ylmethanol (656 mg, 7.45 mmol), triphenylphosphan (1.95 g, 7.45 mmol), and then (E)-diazene-1,2-dicarboxylic acid diisopropyl (1.51 g, 1.47 mL, 7.45 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated and purified by silica gel chromatography (0-100% AcOEt / heptane). Both isomers appeared and were purified again by SFC (column: (S,S)Whelk-O1 21×250mm 5um; flow rate: 80g / min; cosolvent: 15% MeOH in CO2; detection: 230nm; BPR setpoint: 125bar) to obtain (S)-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) (617mg, 43%) LCMS method 2: Rt=0.72 min; MS m / z 232.1[M+1]+ and (S)-1-(oxetane-2-ylmethyl)-5-(trifluoromethyl)-1H-imidazole-4-carbonitrile (2b) (209mg, 15%) LCMS method 2: Rt=0.74 min; MS m / z 232.1[M+1]+ I obtained it.

[0361] Step 2: (S)-2-formyl-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) [ka] To 3 mL of THF, (S)-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (2a) (177 mg, 766 μmol) was added, followed by the addition of LDA (98.4 mg, 459 μL, 2 molar concentration, 919 μmol) at -78°C. The mixture was then stirred at -78°C for 30 minutes. Next, DMF (560 mg, 593 μL, 7.66 mmol) was added, and the mixture was stirred at -78°C for 10 minutes. The mixture was then warmed to room temperature and stirred for a further 2 hours. Water was added, the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. Next, the crude product (S)-2-formyl-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) was placed on a high vacuum pump for 16 hours and used as is 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile(4) [ka] (S)-2-formyl-1-(oxetane-2-ylmethyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (3) (176 mg, 0.679 mmol) in DCM (3 mL) was mixed with (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (261 mg, 0.679 mmol), Et3N (379 μl, 2.72 mmol), and NaBH(OAc)3 (216 mg, 1.02 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction product was further diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuum to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)-oxetane-2-yl)methyl)-5-(1H-tetrazole-5-yl)-4-(trifluoromethyl)-1H-imidazole-2-yl)methyl)piperidine(24) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile (4) (71 mg, 0.12 mmol)) was added dropwise to toluene (0.6 mL) with 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 under basic conditions to obtain 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((1-(((S)-oxetan-2-yl)methyl)-5-(1H-tetrazole-5-yl)-4-(trifluoromethyl)-1H-imidazole-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-tetrazole-5-yl)-5-(trifluoromethyl)-1H-imidazole-2-yl)methyl)piperidine(C-25) [ka] C-25 was synthesized using the same procedure as compound 24, but with 2b added after step 1. LC-MS 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one(C-26) [ka] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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) was added to EtOH (2 mL) with 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 (approximately 5 mL) was added, 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 under vacuum, 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 ethyl acetate, drying over magnesium sulfate, filtration, and concentration under vacuum. The residue was purified by preparative HPLC under basic conditions to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one (C-26) as a white solid (15 mg, 15%). 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)piperidine-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 tetrahydrofuran (16 mL), methyl 4-ethyl-1H-imidazole-5-carboxylate (0.365 g, 2.37 mmol) was added dropwise to (S)-oxetane-2-ylmethanol (250 mg, 2.84 mmol), triphenylphosphan (745 mg, 2.84 mmol), and then (E)-diazene-1,2-dicarboxylate diisopropyl (547 mg, 0.55 mL, 2.84 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated and purified by silica gel chromatography (0-100% AcOEt / heptane) to obtain (S)-4-ethyl-1-(oxetane-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-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate methyl(10) [ka] To 5 mL of THF, 200 mg, 892 μmol of (S)-4-ethyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate methyl (9) was added, followed by the addition of LDA (105 mg, 491 μL, 2 molar concentration, 981 μmol) at -78°C. The mixture was then stirred at -78°C for 30 minutes. Next, 652 mg, 691 μL, 8.92 mmol of DMF was added, and the mixture was stirred at -78°C for 10 minutes. The mixture was then warmed to room temperature and stirred for 2 hours. Water was added, the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product (S)-4-ethyl-2-formyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate methyl (10) was then placed on a high vacuum pump for 16 hours and used as is 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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carbonitrile(11) [ka] (S)-4-ethyl-2-formyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate methyl (10) (37 mg, 0.15 mmol) in DCM (2 mL) was mixed with (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.2) (56 mg, 0.15 mmol), Et3N (82 μl, 0.59 mmol), and NaBH(OAc)3 (46 mg, 0.22 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction product was further diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% AcOEt / heptane). The desired fractions were combined and concentrated in vacuum to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate methyl(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)piperidine-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylic acid(12) [ka] A solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate methyl (14 mg, 23.97 μmol) in THF (0.6 mL)-MeOH (0.3 mL) was mixed with 240 μl of 2N LiOH aqueous solution at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with AcOEt, acidified to approximately pH 5 with aq.KH2PO4, extracted twice with AcOEt, washed with brine, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC under basic conditions to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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%). LC-MS 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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoic acid (C-28) [ka] Step 1: (S)-2-formyl-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl(2) [ka] To a solution of (S)-2-bromo-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (1) (353.0 mg, 1.164 mmol) and DMF (902 μL, 11.64 mmol) in THF (3 mL), 2.687 mL, 3.493 mmol of turbogrignard (1.3 M in THF) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. LC-MS indicated that the reaction was nearly complete. The reaction mixture was quenched with saturated NH4Cl solution and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotovap to obtain (S)-2-formyl-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (294 mg). It was used in the next process without further purification. LCMS method 2: Rt = 0.71 min; MS m / z 251.3[M+1]+.

[0371] Step 2: 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl(4) [ka] To a solution of (S)-2-formyl-4-methyl-1-(oxetane-2-ylmethyl)-1H-imidazole-5-carboxylate ethyl (2) (293.0 mg, 1.161 mmol) and (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), pyridine (103 μL, 1.278 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of NaBH(OAc)3 (393.9 mg, 1.858 mmol). The reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. Further NaBH(OAc)3 (150 mg) was added. LC-MS did not show further progress. The reaction mixture was cooled to 0°C, quenched with saturated NaHCO3 solution, and extracted twice by DCM. The combined organic layer was concentrated, and the residue was purified by ISCO (Âi / heptane = 10-100%, the desired product appeared after 100% ethyl acetate, peak 3) to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl(4) (305.0 mg, 45%) as a white foaming solid. LCMS method 2: Rt = 1.40 min; MS m / z 584.3 [M+1]+.

[0372] Step 3: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-oxopropanoate ethyl(5) [ka] To 151 μL, 1.541 mmol of ELISA in 2.5 mL of THF at -78°C in the presence of nitrogen, 1.541 mL, 1.541 mmol of LiHMDS in hexane was added. The reaction mixture was stirred at -78°C for 30 minutes, then warmed to 0°C. A solution of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-carboxylate ethyl(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. Subsequently, LC-MS showed a major peak as the desired product. The reaction product was quenched with saturated NaHCO3 and extracted by DCM (2×). The combined organic layer was concentrated and purified by ISCO (12g silica gel column, 0-10% MeOH in DCM) to obtain 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-oxopropanoate ethyl (5) (150.0 mg, 93%) as a yellow oil. Trace amounts of SM (approximately 5%) were present. LCMS method 2: Rt = 1.34 min; MS m / z 626.2 [M+1]+.

[0373] Step 4: 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoate ethyl(6) [ka] To a solution of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-oxopropanoate ethyl (5) (150.0 mg, 239.6 μmol) in MeOH (1,000 mL), NaBH4 (18 mg, 1 μmol) was added at 0°C. The reaction mixture was stirred at 0°C for 15 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl and extracted with ELISA (2×). The combined organic layers were washed with brine, filtered (to remove trace amounts of water), concentrated, and purified by ISCO (0-10% MeOH in DCM, 12g 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 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoate ethyl (6) (26mg, 17%) and 1 -(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propan-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoic acid (C-28) [ka] To a solution of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoate ethyl (6) (26 mg, 41.4 μmol) in THF (0.600 mL) and MeOH (0.200 mL), 1N LiOH (165 μL, 165.6 μmol) was added. The resulting mixture was stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The crude product was directly loaded onto a 15.5 g C18 column and purified by ISCO (buffered with 10-100% ACN in water and 0.1% concentrated NH4OH). After lyophilization, a diastereoisomer mixture of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoate lithium salt (12.0 mg, 47.8%) was obtained. C-28a is 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-(4-fluorophenyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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 hours. Step 2: Int.2 (1.00 eq), Int-3 (1.5 eq), cesium carbonate (3 eq), acetonitrile (10V), 100℃, 3 hours. Step 3: Int.4 (1.00 eq), THF (10V), LDA (2 eq), -78℃, 40 minutes, DMF (5 eq), -78℃, 0℃ to room temperature, 2 hours. Step 4: Int-6 (1.00 eq), Int-7 (0.40 eq), pyridine (1.00 eq), STAB (1.3 eq), DCM, RT, 16 hours. Step 05: Int...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, 【Chemistry 2】 It is either a single bond or a double bond; 【Transformation 3】 teeth, 【Chemistry 4】 And, 【Transformation 5】 This indicates a bond point to the rest of the molecule; W is O or CH ２ And; X is O; R １ and R ２ These are H and C, respectively, independently. １～３ - Selected from alkyl and halo; R ３ H and C １～３ - Selected from alkyl groups; R ４ is 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, 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 , 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) 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<s 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 ), selected from R ４ of the 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, 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- are each, C １～３ alkyl, halo, CN, NO ２ , 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) 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 ) (Caution ４Ｆ ) is optionally replaced by one, two, or three elements independently selected from the above; R ５ H, C １～６ - Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4-10 member heterocycloalkyl)-C １～３ -Alkyl-, (5-10 member heteroaryl)-C １～３ -alkyl-,phenyl-C １～３ -Alkyl-, Halo, CN, NO ２ , OR ５ａ , 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) 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 ) (Caution ５ｆ ) is selected from, R ５ C １～６ - Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4-10 member heterocycloalkyl)-C １～３ -Alkyl-, (5-10 member heteroaryl)-C １～３ -Alkyl- and phenyl-C １～３ -Alkyl- represents C １～３ Alkyl, Halo, CN, NO ２ , OR ５Ａ , 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) 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 ) (Caution ５Ｆ ) is optionally replaced by one, two, or three elements independently selected from the above; R ６ teeth, 【Transformation 6】 And, 【Transformation 7】 This indicates the bonding site to the rest of the molecule. R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ These are H and C, respectively, independently. １～６ - Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl, R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ C １～６ - Alkyl, C ２～６ Alkenyl and C ２～６ Alkinyl is C(O)OR ４Ａ , -OH and halo are optionally substituted with one, two, or three groups independently selected, and R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C １～６ Optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo; R ４ｅ , R ４ｆ , and R ４ｇ These are H and C, respectively, independently. １～６ - Selected from alkyl groups; R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ These are H and C, respectively, independently. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C １～６ Optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo; R ４Ｅ , R ４Ｆ , and R ４Ｇ These are H and C, respectively, independently. １～６ - Selected from alkyl groups; R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ These are H and C, respectively, independently. １～６ - Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C １～６ Optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo; R ５ｅ , R ５ｆ , and R ５ｇ These are H and C, respectively, independently. １～６ - Selected from alkyl groups; R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ These are H and C, respectively, independently. １～６ - Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ - Selected from cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member 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 one, two, or three groups independently selected from -OH and halo, and R ５Ａ , R ４Ｂ , R ５Ｃ , and R ５Ｄ C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each C １～６ Optionally substituted with one, two, or three groups independently selected from -alkyl, -OH, and halo; R ５Ｅ , R ５Ｆ , and R ５Ｇ These are H and C, respectively, independently. １～６ - Selected from alkyl groups).

2. R １ However, it is chloro or fluoro; and R ２ However, it is chloro or fluoro, and R ３ However, -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ４ However, C １～３ - Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, C(O)OR ４ａ , and C(O)NR ４ｃ R ４ｄ Selected from, R ４ C １～３ - Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each halo, C １～３ - Alkyl and C(O)OR ４Ａ Replaced by any choice of one, two, or three groups independently selected from; R ４ａ , R ４ｃ , R ４ｄ and R ４Ａ However, independently, H and C １～３ - A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

4. R ４ However, H, C １～３ - Alkyl, C ２～４ Alkenil, C ３～６ - Selected from cycloalkyl, 5-10 member heteroaryl, and C(O)OH, R ４ C １～３ - Alkyl, C ２～４ Alkenil, C ３～６ - The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl and 5-10 membered heteroaryl groups are optionally substituted with one, two, or three groups independently selected from the halo and C(O)OH groups.

5. R ４ but, 【Transformation 8】 Select from, or R ４ but, 【Chemistry 9】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt thereof.

6. R ５ However, C １～３ - Alkyl, C ２～４ Alkenil, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, phenyl, halo, C(O)OR ５ａ Selected from, Said C １～３ - Alkyl, C ２～４ Alkenil, C ３～６ -Cycloalkyl, 4-10 member heterocycloalkyl, 5-10 member heteroaryl, and phenyl are each halo and C(O)OR ５Ａ It is optionally replaced by one, two, or three elements independently selected from; R ５ａ However, H and C １～３ - Selected from alkyl groups; and R ５Ａ However, H and C １～３ - A compound according to claim 1, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

7. R ５ However, H, C １～３ - Alkyl, C ２～４ Alkenil, C ３～６ - Selected from cycloalkyl and C(O)OH, R ５ C １～３ - Alkyl, C ２～４ Alkenyl and C ３～６ -Each cycloalkyl group is optionally substituted with one, two, or three groups independently selected from the halo and C(O)OH groups, or R ５ but, 【Chemistry 10】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

8. R ５ but, 【Chemistry 11】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

9. Compound of formula (IIa): 【Chemistry 16】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. Compound of formula (IIIa): 【Chemistry 17】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. Compound of formula (Va): [Chemistry 18] The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 12】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from among the pharmaceutically acceptable salts thereof.

13. (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)acrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)acrylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)cyclopropane-1-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)-1,2,4-oxadiazole-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-tetrazole-5-yl)-4-(trifluoromethyl)-1H-imidazole-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-tetrazole-5-yl)-5-(trifluoromethyl)-1H-imidazole-2-yl)methyl)piperidine; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazole-5-yl)-1,2,4-oxadiazole-5(2H)-one; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propiolic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)benzoic acid; 4-(2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)benzoic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)nicotinic acid; (E)-3-(2-((4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2,3-dihydrobenzofuran-7-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propanoic acid; (2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-methylpropanoic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)acrylic acid; (E)-3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-2-fluoroacrylic acid; 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)-3-hydroxypropanoic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-(4-fluorophenyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)propiolic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)-5-fluorobenzoic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)furan-2-carboxylic acid; 2-(2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)oxazole-5-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)oxazole-2-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)-1,3,4-oxadiazole-2-carboxylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)oxazole-4-carboxylic acid; 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)isoxazole-3-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)isoxazole-5-carboxylic acid; 4-(2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4-yl)oxazole-2-carboxylic acid; 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-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)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)nicotinic acid; 4-(2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)thiazole-2-carboxylic acid; 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)oxazole-4-carboxylic acid; and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5-yl)oxazole-5-carboxylic acid The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

15. A combination comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more therapeutically effective agents.

16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

17. A compound according to any one of claims 1 to 13, or a pharmaceutically 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 artery disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy.

18. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product 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 artery disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy.

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