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

Abstract

The present invention relates to compounds of formula (I) as activators of the 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, 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. [Formula 1] JPEG2025505198000134.jpg25170

Description

[Technical field]

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

[0002] The glucagon-like peptide 1 receptor (GLP1R) belongs to family B1 of G protein-coupled receptors (GPCRs) and is expressed in many tissues, including the pancreas, heart, intestine, and brain (Kieffer TJ and Habener, JF Endocrin. Rev. 20:876-913 (1999); Drucker, DJ, Endocrinology 142:521-7 (2001); Hoist, JJ, Diabetes Metab. Res. Rev. 18:430-41 (2002); Regard JB, Cell 135:561-71 (2008)). The natural agonist ligands of GLP1R are GLP-1 (7-36, 30aa) and oxyntomodulin (OXM, 37aa), both derived from pro-glucagon. Upon activation, GLP1R mediates the upregulation of G αs -protein, followed by activation of adenylate cyclase and increase in 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 suffering from diabetes, NASH and / or obesity.

[0003] Obesity is a chronic disease that is highly prevalent in modern societies and associated with several comorbidities, including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly associated with type 2 diabetes mellitus (T2DM) and insulin resistance, the latter generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a 2-4 fold increase in the risk of coronary artery disease. Currently, the most effective obesity treatment is bariatric surgery, which is costly and risky for patients. Therefore, pharmacological replacement of bariatric surgery is an attractive alternative. Nevertheless, pharmacological interventions for the treatment of obesity have been shown to be less effective and associated with side effects than bariatric surgery. Among the marketed GLP1R agonist peptides, liraglutide is approved as a once-daily treatment for obesity. Semaglutide is currently in phase 3 clinical trials as a once-weekly treatment for obesity. Currently, there is no approved drug therapy for remission of type 2 diabetes in adults who cannot maintain normal glycemic control with antidiabetic drugs and / or insulin due to insulin resistance, and there is no approved drug therapy for heart failure with preserved ejection fraction (HFpEF).Alternatively, GLP1R agonists can be an effective therapy for T2DM remission.GLP1R receptor agonists can reduce the risk of cardiovascular death and hospitalization for patients with chronic HFpEF.

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

[0005] The present invention relates in particular to compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein the components are defined herein.

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

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

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

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

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

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

[0012] Also provided herein is the use of a compound of formula (I), or a pharma- ceutically 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 can be used, for example, at a maximum plasma concentration (C max In some embodiments, the compound may exhibit favorable ADME (absorption, distribution, metabolism and excretion) properties, e.g., in vivo exposure (particularly when administered orally), as demonstrated by measurement of certain pharmacokinetic parameters such as total exposure (area under the curve (AUC)) values, and / or total exposure (area under the curve (AUC)) values. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0016] In some embodiments, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, [ka] is a single bond or a double bond; [ka] teeth, [ka] and During the ceremony, [ka] indicates the point of attachment to the rest of the molecule; W is O or CH2; X is O or CH2; R 1 and R 2 are independently H, C 1~3 selected from alkyl, halo, and CN; R 3 H and C 1~3 - alkyl; R 4 (a) H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 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 ), N.R. 4c OR 4a , N.R. 4c R 4d , N.R.4c (C(O)R 4b ), N.R. 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), N.R. 4c (C(O)NR 4c R 4d ), N.R. 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), N.R. 4c (S(O)2NR 4c R 4d ), N.R. 4c (C(O)NR 4c (S(O)2R 4b )), O.C.(O)R 4b , O-C(O)NR 4c R 4d , O.N.R. 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3-Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B, S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4 (b) 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 5 (a) H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 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 5cR 5d ), N.R. 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), N.R. 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), N.R. 5c (C(O)NR 5c R 5d ), N.R. 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), N.R. 5c (S(O)2NR 5c R 5d ), N.R. 5c (C(O)NR 5c (S(O)2R 5b )), O.C.(O)R 5b , O-C(O)NR 5c R 5d , O.N.R. 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6-Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 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)2R5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5 is R 6 is (4-10 membered heterocycloalkyl)-C 1~3 -alkyl- and (5-10 membered heteroaryl)-C 1~3 -alkyl-, R 6 (4-10 membered heterocycloalkyl)-C 1~3 -alkyl- and (5-10 membered heteroaryl)-C 1~3 -alkyl- is C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4a , R 4b , R 4c , and R 4d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl; R 4a , R 4b , R 4c , and R 4d C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH and halo, and R 4a , R 4b , R 4c , and R 4dC 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4e , R 4f , and R 4g are each independently H and C 1~6 - alkyl; R 4A , R 4B , R 4C , and R 4D are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5-10 membered heteroaryl, and phenyl; R 4A , R 4B , R 4C , and R 4D C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is -OH, halo, and -OC(O)-C 1~15 -alkyl; and R 4A , R 4B , R 4C , and R 4D C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5- to 10-membered heteroaryl, and phenyl are each 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4E , R 4F , and R 4G are each independently H and C 1~6 - alkyl; R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl; R 5a , R 5b , R 5c , and R 5d C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH and halo, and R 5a , R 5b , R 5c , and R 5d C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 5e , R 5f , and R 5g are each independently H and C 1~6 - alkyl; R 5A , R 5B , R 5C , and R 5D are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5-10 membered heteroaryl, and phenyl; R 5A , R 5B , R 5C , and R 5D C 1~6 -Alkyl, C2~6 Alkenyl, and C 2~6 Alkynyl is -OH, halo, and -OC(O)-C 1~15 -alkyl; and R 5A , R 5B , R 5C , and R 5D C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5- to 10-membered heteroaryl, and phenyl are each 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; and R 5E , R 5F , and R 5G are each independently H and C 1~6 -alkyl.

[0017] In a preferred embodiment of the present invention, a compound of formula (I) is provided herein: [ka] or a pharma- ceutically acceptable salt thereof, wherein: [ka] is a single bond or a double bond; [ka] teeth, [ka] and During the ceremony, [ka] indicates the point of attachment to the rest of the molecule; W is O or CH2; X is O or CH2; R 1 and R 2 are independently H, C 1~3 - selected from alkyl, halo and CN; R 3 H and C 1~3 - alkyl; R 4 and R 5 is selected from: (aa)R 4 , H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 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 ), N.R. 4c OR 4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), N.R. 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), N.R. 4c (C(O)NR 4c R 4d ), N.R. 4c (C(O)NR 4c (C(O)R4b )), NR 4c (S(O)2R 4b ), N.R. 4c (S(O)2NR 4c R 4d ), N.R. 4c (C(O)NR 4c (S(O)2R 4b )), O.C.(O)R 4b , O-C(O)NR 4c R 4d , O.N.R. 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)R 4B , C(O)NR 4C R 4D , C(O)NR 4C (OR 4A ), C(O)NR 4C (S(O)2R4B ), C(O)NR 4C (S(O)2NR 4C R 4D ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 5is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 5A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E)(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from (bb)R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C(C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 5 , H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 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 )(OR5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 6 is (4-10 membered heterocycloalkyl)-C 1~3 -alkyl- and (5-10 membered heteroaryl)-C 1~3 -alkyl-, R 6 (4-10 membered heterocycloalkyl)-C 1~3 -alkyl- and (5-10 membered heteroaryl)-C 1~3 -alkyl- is C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4a , R 4b , R 4c , and R 4d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl; R 4a , R 4b , R 4c , and R 4d C 1~6 -Alkyl, C2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH and halo; and R 4a , R 4b , R 4c , and R 4d C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4e , R 4f , and R 4g are each independently H and C 1~6 - alkyl; R 4A , R 4B , R 4C , and R 4D are independently H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5-10 membered heteroaryl, and phenyl; R 4A , R 4B , R 4C , and R 4D C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is -OH, halo, and -OC(O)-C 1~15 -alkyl; and R 4A , R 4B , R 4C , and R 4D C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5- to 10-membered heteroaryl, and phenyl are each 1~6- optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 4E , R 4F , and R 4G are each independently H and C 1~6 - alkyl; R 5a , R 5b , R 5c , and R 5d are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl; R 5a , R 5b , R 5c , and R 5d C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH and halo; and R 5a , R 5b , R 5c , and R 5d C 3~6 -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C 1~6 - optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R 5e , R 5f , and R 5g are each independently H and C 1~6 - alkyl; R 5A , R 5B , R 5C , and R 5D are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6-Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5-10 membered heteroaryl, and phenyl; R 5A , R 5B , R 5C , and R 5D C 1~6 -Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is -OH, halo, and -OC(O)-C 1~15 -alkyl; and R 5A , R 5B , R 5C , and R 5D C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C 1~3 -alkyl-, 5- to 10-membered heteroaryl, and phenyl are each 1~6 -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; and R 5E , R 5F , and R 5G are each independently H and C 1~6 -alkyl).

[0018] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 1 is a halo.

[0019] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 1 is CN.

[0020] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 2 is a halo.

[0021] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 1is chloro, fluoro or CN, and R 2 is chloro or fluoro.

[0022] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 1 is chloro; and R 2 is fluoro.

[0023] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 1 is CN; and R 2 is chloro or fluoro.

[0024] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 1 is CN;R 2 is fluoro.

[0025] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 3 is H or -CH3.

[0026] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 3 is -CH3.

[0027] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 (a)C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)R 4b , C(O)NR 4c R4d , 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 )(R4f ) and R 4 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F or R 4 (b) 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein.

[0028] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 (a)C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4 to 10 membered heterocycloalkyl, phenyl, and halo; R 4 C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl are each independently selected from halo and C 1~3 -alkyl, or R 4 (b) 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with a carboxylic acid isostere and halo, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 4A H and C 1~3 -alkyl.

[0029] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0030] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3-alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein.

[0031] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with a carboxylic acid isostere and halo, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 4A H and C 1~3 -alkyl.

[0032] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 4 has the structure of formula H1 or H2: [ka] (In the formula, X1 is C or N, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 4h , N.R. 4i , O, or S; W is C(O)OR 4A or a carboxylic acid isostere; each [ka] is a single bond or a double bond; Each R 4h are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 4a , S.R. 4a , C(O)OR 4a , C(O)R 4b , C(O)NR 4c R 4d , C(O)NR 4c (OR 4a ), C(O)NR 4c (S(O)2R 4b ), C(O)NR 4c (S(O)2NR 4c R 4d ), N.R. 4c OR 4a , N.R. 4c R 4d , N.R. 4c (C(O)R 4b ), N.R. 4c (C(O)OR 4a ), N(OR 4a )(C(O)R 4b ), N.R. 4c (C(O)NR 4cR 4d ), N.R. 4c (C(O)NR 4c (C(O)R 4b )), NR 4c (S(O)2R 4b ), N.R. 4c (S(O)2NR 4c R 4d ), N.R. 4c (C(O)NR 4c (S(O)2R 4b )), O.C.(O)R 4b , O-C(O)NR 4c R 4d , O.N.R. 4c (C(O)R 4b ), OS(O)2R 4b , OP(O)(OR 4e )(OR 4f ), S(O)OR 4a , S(O)R 4b , S(O)2R 4b , S(O)NR 4c R 4d , S(O)2OR 4a , S(=NR 4g )(O)R 4b , S(=NR 4g )(O)NR 4c NR 4d , P(O)(OR 4e )(OR 4f ), and P(O)(OR 4e )(R 4f ), and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C 1~3-alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from Each R 4i are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, 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 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 4A , S.R. 4A , C(O)OR4A 、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)(OR4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4h and R 4i Combined, C 3~6 -cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which can further be 1~6 -alkyl, -OH, and halo; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , R 4g , R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein.

[0033] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 has the structure of formula H1a or H2a: [ka] wherein the ring is aromatic; X1 is C, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 4h , N.R. 4i , O, or S, and at least one of X2 to X6 is N, O, or S; R 4A H and C 1~3 -alkyl; and If present, R 4h Halo, C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3-alkyl, and R 4i is C 1~3 -alkyl).

[0034] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 4 teeth, [ka] (In the formula, Ra, Rb and Rc are H, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 4A H and C 1~3 -alkyl).

[0035] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 (a)C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -alkyl, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 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 ), N.R. 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), N.R.5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), N.R. 5c (C(O)NR 5c R 5d ), N.R. 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), N.R. 5c (S(O)2NR 5c R 5d ), N.R. 5c (C(O)NR 5c (S(O)2R 5b )), O.C.(O)R 5b , O-C(O)NR 5c R 5d , O.N.R. 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ) and R 5 C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -Alkyl- and phenyl-C 1~3-アルキル-はそれぞれ、ハロ、CN、NO2、OR 5A 、SR 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 or R 5 (b) 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 5A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C(S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5a , R 5b , R 5c , R 5d , R 5e , R 5f , R 5g , R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein.

[0036] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 (a)C 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 3~6 -cycloalkyl, 4 to 10 membered heterocycloalkyl, phenyl, and halo; 1~3 -Alkyl, C 2~4 Alkenyl, C 2~4Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl are each independently selected from halo and C 1~3 -alkyl, or R 5 (b) 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 5A or substituted with a carboxylic acid isostere and halo, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 5A H and C 1~3 -alkyl.

[0037] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 Halo, C 1~3 -alkyl, and phenyl; 1~3 -alkyl and phenyl are each optionally substituted with 1, 2, or 3 halo.

[0038] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 is C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -cycloalkyl; R 5 C 1~3 -Alkyl, C 2~4 Alkenyl, and C 3~6 -Each cycloalkyl is optionally substituted with 1, 2 or 3 halo.

[0039] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 -CH3, -CF3, F, -CH2CH3, and [ka] is selected from.

[0040] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0041] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, and R 5 are C(O)OR, respectively. 5A or substituted with carboxylic acid isosteres and halo, CN, NO2, OR 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C(C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F ) and (5-10 membered heteroaryl)-C 1~3 -alkyl, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein.

[0042] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 5 has the structure of formula H11 or H12: [ka] (In the formula, X1 is C or N, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 5h , N.R. 5i , O, or S; W is C(O)OR 5A or a carboxylic acid isostere; each [ka] is a single bond or a double bond; Each R 5h are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, Halo, CN, NO2, OR 5a , S.R. 5a , C(O)OR 5a , C(O)R 5b , C(O)NR 5c R 5d , C(O)NR 5c (OR 5a ), C(O)NR 5c (S(O)2R 5b ), C(O)NR 5c (S(O)2NR 5c R 5d ), N.R. 5c OR 5a , N.R. 5c R 5d , N.R. 5c (C(O)R 5b ), N.R. 5c (C(O)OR 5a ), N(OR 5a )(C(O)R 5b ), N.R. 5c(C(O)NR 5c R 5d ), N.R. 5c (C(O)NR 5c (C(O)R 5b )), NR 5c (S(O)2R 5b ), N.R. 5c (S(O)2NR 5c R 5d ), N.R. 5c (C(O)NR 5c (S(O)2R 5b )), O.C.(O)R 5b , O-C(O)NR 5c R 5d , O.N.R. 5c (C(O)R 5b ), OS(O)2R 5b , OP(O)(OR 5e )(OR 5f ), S(O)OR 5a , S(O)R 5b , S(O)2R 5b , S(O)NR 5c R 5d , S(O)2OR 5a , S(=NR 5g )(O)R 5b , S(=NR 5g )(O)NR 5c NR 5d , P(O)(OR 5e )(OR 5f ), and P(O)(OR 5e )(R 5f ), and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C1~3 -alkyl, C substituted with 1, 2 or 3 halo 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 ), C(O)NR 5C (S(O)2NR 5C R 5D ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B, S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from Each R 5i are independently H, C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl-, Phenyl-C 1~3 -Alkyl-, 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 ), and C 1~6 -Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 -Cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, phenyl, C 3~6 -Cycloalkyl-C 1~3 -Alkyl-, (4-10 membered heterocycloalkyl)-C 1~3 -alkyl-, (5-10 membered heteroaryl)-C 1~3 -Alkyl- and phenyl-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C(O)OR5A 、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)(OR5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5h and R 5i Combined, C 3~6 -cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, which can further be 1~6 -alkyl, -OH, and halo; R 5a , R 5b , R 5c , R 5d , R 5e , R 5f and R 5g , R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein.

[0043] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 has the structure of formula H11a or H12a: [ka] wherein the ring is aromatic; X1 is C, and each of X2, X3, X4, X5, and X6 is independently C=O, CR 5h , N.R. 5i , O, or S, and at least one of X2 to X6 is N, O, or S; R 5A H and C 1~3 -alkyl; and If present, R 5h Halo, C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3-alkyl, R 5i is C 1~3 -alkyl).

[0044] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 5 has the structure of formula H11a, for example, R 5 teeth, [ka] (In the formula, Ra, Rb and Rc are H, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 5A H and C 1~3 -alkyl).

[0045] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 6 is selected from (4- to 6-membered heterocycloalkyl)-CH- and (5- to 6-membered heteroaryl)-CH-; R 6 (4-6 membered heterocycloalkyl)-CH2- and (5-6 membered heteroaryl)-CH2- are each C 1~6 -Optionally substituted with 1, 2, or 3 groups independently selected from -alkyl, -OH, and halo.

[0046] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, R 6 teeth, [ka] is selected from the group consisting of [ka] indicates the point of attachment to the rest of the molecule.

[0047] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 6 is the expression: [ka] (wherein: [ka] indicates the point of attachment to the rest of the molecule).

[0048] In an embodiment of the compound of formula (I), or a pharma- ceutically acceptable salt thereof, R 6 is the expression: [ka] and [ka] indicates the point of attachment to the rest of the molecule.

[0049] In certain embodiments of the compounds of Formula (I), or pharma- ceutically acceptable salts thereof, X is O.

[0050] In certain embodiments of the compounds of Formula (I), or pharma- ceutically acceptable salts thereof, W is O.

[0051] In certain embodiments of a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, [ka] is a single bond.

[0052] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compounds of formula (Ia): [ka] (In the formula, A, W, X, R 1 , R 2 , and R 3 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0053] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compounds of formula (II): [ka] (In the formula, A, R 1 , R 2 , and R 3 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0054] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IIa): [ka] (In the formula, A, R 1 , R 2 , and R 3 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0055] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compounds of formula (III): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0056] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IIIa): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0057] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IIIb): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof).

[0058] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IV): [ka] (In the formula, R 1 is chloro or CN, R 3 , R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0059] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IVa): [ka] (In the formula, R 1is chloro or CN, R 3 , R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0060] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (IVb): [ka] (In the formula, R 1 is chloro or CN, R 3 , R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0061] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (V): [ka] (In the formula, R 1 is chloro or CN, R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0062] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (Va): [ka] (In the formula, R 1 is chloro or CN, R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0063] In one embodiment, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is Compound of formula (Vb): [ka] (In the formula, R 1 is chloro or CN, R 4 and R 5 is as defined herein) or a pharma- ceutically acceptable salt thereof.

[0064] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is as defined herein.

[0065] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 5 is as defined herein.

[0066] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 4A or substituted with a carboxylic acid isostere and halo, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 4A H and C 1~3-alkyl; and R 5 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0067] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 has a structure of formula H1 or H2 as defined herein; and R 5 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0068] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 has the structure of formula H1a or H2a as defined herein; and R 5 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0069] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 teeth, [ka] R, Rb and Rc are selected from the group consisting of H, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 4A H and C 1~3 -alkyl, and R 5 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 -alkyl, for example methyl, ethyl or trifluoromethyl.

[0070] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 - alkyl, for example methyl, ethyl or trifluoromethyl, and R 5 is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is C(O)OR 5A or substituted with a carboxylic acid isostere and halo, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 5A H and C 1~3 -alkyl.

[0071] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 - alkyl, for example methyl, ethyl or trifluoromethyl, and R 5 has the structure of formula H11 or H12, as defined herein.

[0072] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 - alkyl, for example methyl, ethyl or trifluoromethyl, and R 5 has the structure of formula H11a or H12a, as defined herein.

[0073] In an embodiment of any of the compounds of Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof, R 4 is C 1~3 -C substituted with alkyl or 1, 2 or 3 halo 1~3 - alkyl, for example methyl, ethyl or trifluoromethyl, and R 5 teeth, [ka] (In the formula, Ra, Rb and Rc are H, C 1~3 -C substituted with alkyl and 1, 2 or 3 halo 1~3 -alkyl; R 5A H and C 1~3 -alkyl).

[0074] In one embodiment, the compound of formula (I) is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In one embodiment, the compound of formula (I) is 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-ethyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-methyloxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-3-methylfuran-2-carboxylic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1-methyl-1H-pyrazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-3-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)nicotinic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, and 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylate ethyl, or a pharma- ceutically acceptable salt thereof.

[0076] In certain embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is selected from Table A:

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6]

[0083] [Table 7]

[0084] In an embodiment of any of the formulae provided herein, or a pharma- ceutically acceptable salt thereof, the optionally substituted variable R 4 and R 5 One or both of R comprises a carboxylic acid, a carboxylic acid derivative (e.g., a carboxylic acid ester derivative such as a methyl ester or an ethyl ester), or a carboxylic acid isostere (see, e.g., J. Med. Chem. 2016, 59, 3183-3203). 4 and R 5For example, in a preferred embodiment, R 4 and R 5 Only one of the groups includes a carboxylic acid, a carboxylic acid derivative (eg, a carboxylic acid ester derivative such as a carboxylic acid methyl ester or a carboxylic acid ethyl ester), or a carboxylic acid isostere.

[0085] A non-limiting list of example acyclic carboxylic acid isosteres is as follows:

[0086] [Table 8]

[0087] [Table 9]

[0088] A non-limiting list of cyclic carboxylic acid isosteres is as follows:

[0089] [Table 10]

[0090] [Table 11]

[0091] Unless otherwise specified, the terms "compounds of the invention", "compound of the invention", "compound of the invention" or "compounds of the invention" refer to compounds of Formula (I), or subformulas thereof (e.g., Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb)) and exemplified compounds, and salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties.

[0092] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible stereoisomers or as a mixture thereof, for example as a pure optical isomer depending on the number of asymmetric carbon atoms, or as a stereoisomeric mixture, such as racemic and diastereoisomeric mixtures. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereoisomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents may have cis or trans configuration. All tautomeric forms are also intended to be included.

[0093] The phrase "optionally substituted" means unsubstituted or substituted. The substituents are independently selected, and the substitution 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, for example, oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valency.

[0094] As used herein, "C" used alone or in combination with other terms n~m "Alkyl" refers to a saturated hydrocarbon group that may be straight or branched having n to m carbons. In some embodiments, an alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0095] As used herein, "C n~m "Alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons. In some embodiments, the alkenyl group contains 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0096] As used herein, "C n~m "Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons. In some embodiments, the alkynyl group contains 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.

[0097] As used herein, "aryl" refers to an aromatic hydrocarbon group that can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). n~m The term aryl refers to an aryl group having n to m ring carbon atoms. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0098] As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2 fused rings) groups, spirocyclic, and bridged rings. The ring-forming carbon atoms of a cycloalkyl can be optionally substituted with oxo or sulfido (e.g., C(O) or C(S)). In some embodiments, a cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbon atoms (i.e., C 3~10 In some embodiments, the cycloalkyl group has 3, 4, 5, or 6 ring-forming carbon atoms (i.e., C 3~6 cycloalkyl).

[0099] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having two fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, and S. In some embodiments, a ring-forming N in a heteroaryl group can be an N-oxide. In some embodiments, a heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, a heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S.

[0100] 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 of the ring-forming carbon atoms of the heterocycloalkyl are replaced by a heteroatom selected from N, O, S, and B, and wherein the ring-forming carbons or heteroatoms of the heterocycloalkyl group can be optionally substituted by one or more oxo or sulfido (e.g., C(O), S(O), C(S), S(O)2, etc.). In some embodiments, a heterocycloalkyl group contains 4 to 10 ring-forming atoms (i.e., 4 to 10 members), wherein 1 to 4 atoms are heteroatoms independently selected from N, O, and S.

[0101] As used herein, "C o~p -Cycloalkyl-C n~m- "Alkyl" refers to a group of the formula cycloalkyl-alkylene where the cycloalkyl has from op carbon atoms and the alkylene linking group has from n to m carbon atoms.

[0102] As used herein, "heterocycloalkyl-C n~m "-alkyl" refers to a group of the formula heterocycloalkyl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0103] As used herein, "heteroaryl-Cn~m- "Alkyl" refers to a group of the formula heteroaryl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0104] As used herein, "aryl-C n~m- Alkyl (e.g., "phenyl-C n~m "-alkyl") refers to a group of formula aryl-alkylene, where the alkylene linking group has n to m carbon atoms.

[0105] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound provided herein. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds provided herein and are not usually biologically or otherwise undesirable. In many cases, the compounds provided herein can form acid salts and / or base salts due to the presence of basic nitrogen atoms, e.g., as found in amino and pyridine groups or other similar groups, and / or acidic protons, e.g., as found in carboxylic acids or other similar groups.

[0106] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0107] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0108] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0109] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0110] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0111] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0112] In another aspect, the compounds provided herein are present in a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salt form.

[0113] In another aspect, the compounds provided herein may be in the form of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, or the like.

[0033] The oleate salts may be in the form of salts of the following formulas: lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate, or xinafoate.

[0114] Any formula given herein is intended to represent the unlabeled form of the compound as well as the isotopically labeled form.Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.The isotope that can be incorporated in the compound of the present invention includes, for example, hydrogen isotopes.

[0115] Additionally, certain isotopes, particularly deuterium (i.e. 2Incorporation of H or D) may result in certain therapeutic advantages resulting from higher metabolic stability, for example, increased in vivo half-life, or reduced required dosage, or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered as a substituent of the compound of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0116] Other examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and sulfur, e.g., 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 35 Thus, the present invention relates to, for example, 3 H and 14 Radioisotopes such as C, or 2 H and 13 It should be understood to include compounds incorporating one or more of any of the aforementioned isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14C), reaction rate tests (e.g. 2 H or 3 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of previously utilized non-labeled reagents.

[0117] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharma- ceutically acceptable salt thereof, combined with at least one pharma- ceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0118] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, as known to those skilled in the art, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof (see, e.g., Remington The Science and Practice of Pharmacy, 22). nd (See Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0119] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will induce a biological or medical response in a subject, for example, stimulate GLP1R activity, ameliorate symptoms, reduce a pathology, slow or delay the progression of a disease, disorder or condition, or prevent a disease, disorder or condition. In one embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to at least partially reduce, prevent and / or ameliorate a pathology, or a disorder or disease that responds to increasing or stimulating the activity of GLP1R. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, cell, or tissue, or non-cellular biological material, or culture medium, is effective to partially or fully stimulate the activity of GLP1R. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to cause an observable level of one or more desired biological or medical responses selected from, for example, lowering glucose levels (or improving glucose homeostasis), increasing insulin sensitivity, lowering triglyceride or cholesterol levels, reducing body weight, reducing food intake, and reducing body fat mass (such as peripheral and / or visceral fat).

[0120] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0121] As used herein, the terms "stimulate," "agonism," and "stimulating" refer to an increase in GLP1R signaling and / or activity, for example, as measured by an increase in intracellular cyclic adenosine monophosphate (cAMP).

[0122] As used herein, the terms "treat," "treating," or "treatment" of any disease, disorder, or condition refers to reducing or ameliorating the disease, disorder, or condition (i.e., slowing or halting the onset or progression of the disease, disorder, or condition, or at least one clinical symptom thereof); or reducing or ameliorating at least one physical parameter or biomarker associated with the disease, disorder, or condition, including those that may not be discernible to the patient.

[0123] As used herein, the terms "prevent", "preventing" or "prevention" of any disease, disorder or condition refers to the prophylactic treatment of the disease, disorder or condition; or the delay in the onset or progression of the disease, disorder or condition.

[0124] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0125] As used herein, the terms "a," "an," and "the," as well as similar terms used in connection with the present invention (particularly in connection with the claims), are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0126] Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. Any examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to further clarify the invention, and do not limit the scope of the invention as otherwise claimed.

[0127] Any asymmetric atom of the compounds of the invention (e.g., carbon, etc.) can be present in racemic or enantiomerically enriched, e.g., in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

[0128] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example as substantially pure diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0129] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional recrystallization on the basis of the physical chemical differences of the constituent components.

[0130] Any resulting racemic forms of the compounds or intermediates of the present invention can be resolved into their optical antipodes by known methods, for example by separating their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. Thus, in particular, compounds of the present invention can be resolved into their optical antipodes by fractional recrystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, using basic moieties. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example high pressure liquid chromatography (HPLC), using chiral adsorbents.

[0131] The compounds provided herein (e.g., compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), and pharma- ceutically acceptable salts thereof) can be prepared in a number of ways well known to one skilled in the art of organic synthesis. As an example, the compounds provided herein can be synthesized using the methods described in the Examples, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as will be appreciated by one skilled in the art.

[0132] It is well understood that protecting groups for sensitive or reactive groups are utilized where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis, for example as described in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. Protecting groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art.

[0133] Those skilled in the art will recognize whether a stereocenter exists in the compounds disclosed herein. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art. For example, see "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0134] Compounds of formula (I) according to the present invention, as well as any of the compounds of formulae (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), and pharma- ceutically acceptable salts thereof, can be prepared in a number of ways well known to one skilled in the art of organic synthesis. As an example, the compounds provided herein can be synthesized using any of the general synthetic schemes A and B or the methods described in the Examples, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as will be appreciated by those skilled in the art.

[0135] As depicted in Scheme A, intermediate II.A (wherein R 1 , R 2 and R 3 is as defined herein) to intermediate III.A (wherein Y is Br or I and R 4 is as defined herein) to give intermediate IA. 1 , R 2 , R 3 and R 4 is as defined herein) is reacted with the carboxylic acid ester derivative B1 in the presence of a Pd catalyst (e.g., Xphos Pd G2) and a base in a solvent (e.g., toluene) to obtain a compound of formula (I). In the carboxylic acid ester derivative B1 of this embodiment, R is C 1~3 -alkyl, H A is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl- is halo, CN, NO2, OR 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, C(O)R 5B , C(O)NR 5C R 5D , C(O)NR 5C (OR5A )、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 5FOptionally substituted with 1, 2, or 3 groups independently selected from R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein.

[0136] In another embodiment, intermediate IA, where Y is Br or I, and R 1 , R 2 , R 3 and R 4 is as defined herein) with a carboxylic acid ester derivative B1 (wherein R is C 1~3 -alkyl, H A is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -alkyl- is each substituted with a boronic acid or dioxaborolane protecting group (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) and is selected from halo, CN, NO, OR, 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR 5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein.

[0137] In one embodiment, the compound of formula (I) thus obtained is a carboxylic acid ester derivative, where R 1 , R 2 , R 3and R 4 is as defined herein, and H A’ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkylene-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkylene- is halo, CN, NO2, OR 5A , S.R. 5A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 5C OR 5A , N.R. 5C R 5D , N.R. 5C (C(O)R 5B ), N.R. 5C (C(O)OR 5A ), N(OR 5A )(C(O)R 5B ), N.R. 5C (C(O)NR 5C R 5D ), N.R. 5C (C(O)NR 5C (C(O)R 5B )), NR 5C (S(O)2R 5B ), N.R. 5C (S(O)2NR 5C R 5D ), N.R. 5C (C(O)NR 5C (S(O)2R 5B )), O.C.(O)R 5B , O-C(O)NR 5C R 5D , O.N.R. 5C (C(O)R 5B ), OS(O)2R 5B , OP(O)(OR5E )(OR 5F ), S(O)OR 5A , S(O)R 5B , S(O)2R 5B , S(O)NR 5C R 5D , S(O)2OR 5A , S(=NR 5G )(O)R 5B , S(=NR 5G )(O)NR 5C NR 5D , P(O)(OR 5E )(OR 5F ), and P(O)(OR 5E )(R 5F Optionally substituted with 1, 2, or 3 groups independently selected from R 5A , R 5B , R 5C , R 5D , R 5E , R 5F and R 5G is as defined herein), said carboxylic acid ester derivatives can be converted to further compounds of formula (I) by hydrolysis of the carboxylic acid ester moiety to a carboxylic acid moiety in the presence of one or more hydroxide sources (e.g., MeOH and / or LiOH) in water. [ka]

[0138] As depicted in Scheme B, intermediate II.A (wherein R 1 , R 2 and R 3 is as defined herein) to intermediate III.B (wherein Y is Br or I and R 5 is as defined herein) to give intermediate IB. Then, intermediate IB (wherein R 1 , R 2 , R 3 and R 5is as defined herein and Y is Br or I) is reacted with a carboxylic acid ester derivative B2 in the presence of a Pd catalyst (e.g., Xphos Pd G2) and a base in a solvent (e.g., toluene) to obtain a compound of formula (I). In the carboxylic acid ester derivative B2 of this embodiment, R is C 1~3 -alkyl, and HB is a 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkyl is halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein.

[0139] In another embodiment, intermediate IB, where R 1 , R 2 , R 3 and R 5 is as defined herein and Y is Br or I) with a carboxylic acid ester derivative B2 (wherein R is C 1~3 -alkyl, and HB is a 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C 1~3 -alkyl-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -alkyl- is each substituted with a boronic acid or dioxaborolane protecting group (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) and is selected from halo, CN, NO, OR, 4A , S.R. 4A, C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR 4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G)(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein.

[0140] In one embodiment, the compound of formula (I) thus obtained is a carboxylic acid ester derivative, where R 1 , R 2 , R 3 and R 5 is as defined herein, and H B’ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C 1~3 -alkylene-, 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C 1~3 -Alkylene- is halo, CN, NO2, OR 4A , S.R. 4A , C 1~3 -alkyl, C substituted with 1, 2 or 3 halo 1~3 -Alkyl, 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 ), N.R. 4C OR 4A , N.R. 4C R 4D , N.R. 4C (C(O)R 4B ), N.R. 4C (C(O)OR 4A ), N(OR4A )(C(O)R 4B ), N.R. 4C (C(O)NR 4C R 4D ), N.R. 4C (C(O)NR 4C (C(O)R 4B )), NR 4C (S(O)2R 4B ), N.R. 4C (S(O)2NR 4C R 4D ), N.R. 4C (C(O)NR 4C (S(O)2R 4B )), O.C.(O)R 4B , O-C(O)NR 4C R 4D , O.N.R. 4C (C(O)R 4B ), OS(O)2R 4B , OP(O)(OR 4E )(OR 4F ), S(O)OR 4A , S(O)R 4B , S(O)2R 4B , S(O)NR 4C R 4D , S(O)2OR 4A , S(=NR 4G )(O)R 4B , S(=NR 4G )(O)NR 4C NR 4D , P(O)(OR 4E )(OR 4F ), and P(O)(OR 4E )(R 4F Optionally substituted with 1, 2, or 3 groups independently selected from R 4A , R 4B , R 4C , R 4D , R 4E , R 4F and R 4G is as defined herein), said carboxylic acid ester derivatives can be converted to further compounds of formula (I) by hydrolysis of the carboxylic acid ester moiety to a carboxylic acid moiety in the presence of one or more hydroxide sources (e.g., MeOH and / or LiOH) in water. [ka]

[0141] Intermediate II.A is either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. For example, intermediate II.A can be prepared as shown below in Scheme C.

[0142] As shown in Scheme C, intermediate II.1, where R 1 , R 2 and R 3 is as defined herein) is reacted with 3-bromobenzene-1,2-diol in the presence of p-TsOH in a solvent (e.g., toluene) to give intermediate II.2. 1 , R 2 and R 3 is as defined herein) with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate in the presence of a Pd catalyst and a base (e.g., Na2CO3) in a solvent (e.g., dioxane) to give intermediate II.3. 1 , R 2 and R 3 is as defined herein) is converted to intermediate II.4 in the presence of a catalyst (e.g., ((C6H5)3P)3RhCl) under H2. Intermediate II.4 (where R 1 , R 2 and R 3 is as defined herein) is purified by SFC to intermediates II.5a and II.5b. 1 , R 2 and R 3 are as defined herein) can be reacted with intermediates II.Aa and II.Ab, respectively, in the presence of HCl in a solvent (e.g., dioxane) to form 1 , R 2 and R 3is as defined herein. [ka]

[0143] Intermediates III.A and III.B are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. For example, intermediates III.A and III.B can be prepared as shown below in Scheme D. [ka]

[0144] As shown in Scheme D, intermediate III.a (wherein Z is R 4 or R 5 and Y is Br or I) is reacted with oxetan-2-ylmethyl 4-methylbenzenesulfonate in the presence of cesium carbonate in a solvent (e.g., acetonitrile). The residue is purified by chromatography and the isomers are separated to give intermediates III.1a and III.1b (where R 4 or R 5 is as defined herein and Y is Br or I. 4 or R 5 is as defined herein and Y is Br or I) are reacted independently with LDA in a solvent (e.g., THF / heptane / ethylbenzene) to give intermediates III.A and III.B, respectively.

[0145] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0146] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0147] In further embodiments, the composition comprises at least two pharma- ceutically acceptable carriers, such as those described herein. Pharmaceutical compositions 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 involve inhalation or intranasal application. Pharmaceutical compositions of the present invention may be configured in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in 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, pharmaceutical compositions are tablets or gelatin capsules that contain the active ingredient in combination with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; (also for tablets) c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colouring agents, flavouring agents and sweetening agents.

[0148] The compounds of the invention (e.g., compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), and pharma- ceutically acceptable salts thereof), in free form or in pharma- ceutically acceptable salt form, exhibit useful pharmacological properties, e.g., as agonists of GLP1R, as shown, e.g., in in vitro and in vivo tests as provided in the next section, and are therefore suitable for use as tool compounds, e.g., for therapy or as research chemicals.

[0149] The compounds of the present invention (e.g., compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), and pharma- ceutically acceptable salts thereof) may be useful in the treatment of metabolic and related diseases, disorders and conditions. In particular, the compounds of the present invention may be useful in the treatment of metabolic and related diseases, disorders and conditions selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications (including, but not limited to, chronic kidney disease), diabetic nephropathy, dyslipidemia, metabolic syndrome, progressive liver disease, cardiovascular disease and neuropathy (particularly, for example, peripheral neuropathy associated with diabetes).

[0150] The progressive liver disease can be, for example, non-alcoholic fatty liver disease (NAFLD), or, for example, non-alcoholic steatohepatitis (NASH).

[0151] The cardiovascular disease may be selected from, for example, hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (e.g., heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF)) and heart failure with preserved ejection fraction (HFpEF), coronary heart disease and arrhythmias (e.g., atrial arrhythmias and ventricular arrhythmias).

[0152] The compounds of the invention may be useful in the treatment of several co-existing diseases, disorders or conditions (called "comorbidities") in a subject.

[0153] The comorbidity may be, for example, in a subject who has type 2 diabetes and is also obese and / or who also shows heart failure and / or NASH. For example, an obese subject may also show type 2 diabetes and / or show 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 show cardiovascular disease (e.g., heart failure) and / or show progressive liver disease (e.g., NASH). The subject may also have high blood pressure and / or high blood cholesterol levels. The subject may also suffer from peripheral neuropathy.

[0154] Thus, the compounds provided herein may be useful in the treatment of a disease, disorder or condition selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more complications of diabetes (including, but not limited to, chronic kidney disease), diabetic nephropathy, peripheral arterial disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (particularly heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF)), coronary heart disease, arrhythmias (particularly atrial arrhythmias and ventricular arrhythmias) and neuropathy (particularly peripheral arterial disease).

[0155] In certain embodiments, the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis, heart failure (particularly HFpEF) and NASH.

[0156] In certain embodiments, the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis and heart failure (particularly HFpEF).

[0157] Thus, as a further aspect, there is provided herein the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) in therapy. 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 foregoing list, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example, in subjects with type 2 diabetes who are also obese, and / or in subjects with type 2 diabetes who also have heart failure, and / or in subjects with type 2 diabetes who also have NASH.

[0158] Thus, as a further aspect, there is provided herein a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., comprising any of the compounds of formulae (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) for use in therapy. In a further embodiment, the therapy is treatment of a disease, disorder or condition that can be treated by agonism of GLP1R. In another embodiment, the therapy is treatment of a disease, disorder or condition selected from the foregoing list, suitably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example, in subjects with type 2 diabetes who are also obese, and / or in subjects with type 2 diabetes who also have heart failure, and / or in subjects with type 2 diabetes who also have NASH.

[0159] In another aspect, provided herein is a method of treating a disease, disorder, or condition treatable by agonism of GLP1R, comprising administration of a therapeutically acceptable amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), and (Vb), or a pharmaceutically acceptable salt thereof). In another embodiment, the present invention provides a method of treating a disease, disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from the foregoing list, preferably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including where these exist as comorbidities, for example, in 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.

[0160] In a further aspect, there is provided herein the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., including any compound of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease that can be treated by agonism of GLP1R. In another embodiment, the disease is selected from the afore- mentioned list, preferably obesity, type 2 diabetes, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity in 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.

[0161] The term "metabolic disorder or disease" refers to a cluster of related traits, including, but not limited to, glucose intolerance, insulin resistance, hyperinsulinemia, obesity, excess visceral adiposity, hypertension, dyslipidemia characterized by high triglycerides, low high-density lipoprotein (HDL)-cholesterol, and high low-density lipoprotein (LDL)-cholesterol. Subjects with metabolic diseases or disorders are at risk of developing type 2 diabetes and, for example, atherosclerosis.

[0162] The term "type 2 diabetes" refers to a condition characterized by persistently high glucose levels in both fasting and fed states resulting from a combination of impaired glucose utilization and excessive glucose production, which can result from either insufficient production of insulin from the pancreas or peripheral insulin resistance.

[0163] The term "insulin resistance" as used herein refers to a condition in which normal amounts of insulin fail to induce the expected physiological response and fail to activate downstream pathways. In many instances, insulin produced endogenously or administered exogenously above the physiological range is sufficient to induce a complete or partial biological response that induces the expected physiological response.

[0164] The term "hyperinsulinemia" refers to a condition in which excess insulin can be detected in the blood.

[0165] The term "glucose intolerance" encompasses any disorder characterized by a clinical symptom or combination of clinical symptoms associated with elevated basal or postprandial glucose levels in a subject, and / or elevated insulin levels or abnormal glucose-stimulated insulin release or HOMA-IR (homeostatic model assessment of insulin resistance) compared to a healthy individual. Elevated glucose and / or insulin levels may be manifested in the following diseases, disorders and conditions: obesity, metabolic syndrome, impaired glucose tolerance, type II diabetes, gestational diabetes, type I diabetes, insulin resistance, hyperinsulinemia, lipodystrophy, lipodystrophy and various MODY (maturity-onset diabetes of the young) mutations. The GLP1R agonists provided herein, and compositions thereof, can be used, for example, to achieve and / or maintain glucose homeostasis, for example, to reduce glucose levels and / or reduce insulin levels in the bloodstream to the extent found in healthy subjects.

[0166] The term "hyperglycemia" as used herein refers to a condition in which elevated amounts of glucose circulate in the plasma of a subject compared to a healthy individual. Hyperglycemia can be diagnosed using methods known in the art, including measuring fasting blood glucose levels as described herein.

[0167] 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 increased risk of skin infections. Diabetes also increases the risk of heart disease and bone and joint disorders. Other long-term complications of diabetes include excessive risk of cancer, including hepatocellular carcinoma, endometrial cancer, breast cancer, and pancreatic cancer.

[0168] The term "diabetic nephropathy" is a condition caused by damage to blood vessels and other cells in the kidney that results from diabetes and reduces kidney function.

[0169] The term "obesity" refers to a body mass index (BMI) of 30 or greater in human adults (Centers for Disease Control and Prevention). Such subjects may also be referred to as obese. This is referred to as Class I obesity. Class II obesity includes individuals with a BMI between 35 and 39.9, and Class III obesity refers to individuals with a BMI greater than 40. Body Mass Index (BMI) is a measure of body fat based on height and weight. The formula for calculation is BMI=weight in kilograms / height in meters. 2 It is.

[0170] In certain embodiments, the human subject suffering from obesity has a BMI of ≧30 or ≧35, or a BMI in the range ≧35 to <40, or ≧30 to <40. An amount <40 can be, for example, 39.9. In some embodiments, the obesity is severe obesity or morbid obesity, and the human subject has a BMI of ≧40.

[0171] The term "dyslipidemia" refers to a complex disorder of lipoprotein metabolism involving overproduction or abnormal metabolism of lipoproteins. Dyslipidemia can be manifested by elevated total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations in the blood, and reduced high-density lipoprotein (HDL) cholesterol concentrations.

[0172] The term "atherosclerosis" refers to a vascular disease characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, which cause narrowing of the arterial lumen and ultimately progress to fibrosis and calcification. The lesions are usually focal and progress slowly and intermittently. Blood flow restriction accounts for most clinical symptoms, which vary with the distribution and severity of the lesions.

[0173] The term "progressive liver disease" refers to the progression from a benign state of hepatic steatosis evidenced by fibrosis and cirrhosis that predisposes to hepatocellular carcinoma. The progression of obesity-associated nonalcoholic fatty liver (NAFL) to NASH, fibrosis and cirrhosis is well documented.

[0174] The term "non-alcoholic fatty liver disease (FLD)", also known as NAFLD, is a condition in which excess lipids accumulate in hepatocytes, and can result from either excessive de novo lipid synthesis in the liver or abnormal clearance and oxidation of fatty acids. NAFLD excludes other causes of liver disease, including alcoholic liver disease and viral liver disease. NAFLD includes three histological entities that reflect the progression of disease: fatty liver, hepatic steatosis, and fibrosis or cirrhosis. The most common cause of NAFLD is obesity, but NAFLD can also be seen in lean individuals. Fat accumulation can lead to inflammation with macrophage infiltration and changes in hepatocyte histology, including steatohepatitis and ballooning, referred to as non-alcoholic steatohepatitis (NASH). NASH can progress to fibrosis with interlobular bridging fibrosis or cirrhosis. As used herein, the term NASH can encompass steatohepatitis, hepatocyte ballooning, and lobular inflammation.

[0175] The term "metabolic syndrome" refers to a cluster of risk factors that increase the risk for cardiovascular disease, including coronary artery disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, cerebrovascular disease, and peripheral vascular disease. These risk factors include abdominal fat, high blood sugar after fasting (at least 110 milligrams per deciliter (mg / dl)), high triglycerides in the bloodstream (at least 150 mg / dL), low HDL (less than 40 mg / dl), and blood pressure above 130 / 85 mmHg (World Health Organization).

[0176] The term "cardiovascular disease" refers to diseases related to the heart or blood vessels.

[0177] The term "peripheral arterial disease" refers to when the buildup of fatty deposits in the arteries restricts the blood supply to the leg muscles.

[0178] The term "stroke" refers to when the blood supply to part of the brain is cut off.

[0179] The term "heart failure" refers to when the heart has a reduced ability to pump blood, and can include heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with mildly reduced ejection fraction (HFmrEF).

[0180] The term "coronary heart disease", also called coronary artery disease, is the narrowing of the arteries that supply blood to the heart.

[0181] The term "arrhythmia" refers to abnormal heart rhythms and can include atrial arrhythmias, atrial fibrillation, and ventricular arrhythmias.

[0182] The term "neuropathy" refers to when nerves are damaged. This term includes peripheral neuropathy, which occurs when nerves in the extremities, such as the hands, feet, and arms, are damaged. Diabetes is a common cause of peripheral neuropathy.

[0183] The term "cardiomyopathy" is defined as an acquired or congenital structural abnormality of the atrial or ventricular myocardium that can affect cardiac function, or physiology, and conduction.

[0184] The pharmaceutical compositions or combinations provided herein may be in unit dosages of about 1-1000 mg of active ingredient for a subject of about 50-70 kg. The therapeutically effective dose of the compounds, pharmaceutical compositions or combinations thereof depends on the species, weight, age and individual condition of the subject, the disorder or disease being treated, or its severity.

[0185] A compound of the invention (e.g., including any compound of Formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) may be administered simultaneously with, prior to, or after one or more other therapeutic agents. A compound of the invention may be administered separately, by the same or different route of administration, or in combination in the same pharmaceutical composition as other agents. A therapeutic agent is, for example, a chemical compound, peptide, peptide conjugates and fusions, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a subject in combination with a compound of the invention.

[0186] Thus, in another aspect, there is provided herein a combination, particularly a pharmaceutical combination, comprising a compound of Formula (I), or a pharma- ceutical acceptable salt thereof (e.g., a therapeutically effective amount) (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutical acceptable salt thereof), and one or more other therapeutically effective agents.

[0187] In one embodiment, there is provided herein a product comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., comprising any of the compounds of formulae (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease, disorder or condition selected from the foregoing list, suitably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including where these exist as comorbidities, for example in a subject with type 2 diabetes who is also obese, or in a subject with type 2 diabetes who also has heart failure.

[0188] Products provided as combined preparations include a compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., including a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) and another therapeutic agent combined in the same pharmaceutical composition, or a composition comprising a compound of the invention and the other therapeutic agent in separate form, e.g., in the form of a kit.

[0189] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof (e.g., a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), and (Vb), or a pharma- ceutically acceptable salt thereof) and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharma- ceutically acceptable carrier as described herein.

[0190] In one embodiment, a kit is provided herein that comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention.In one embodiment, the kit comprises a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil pouch.An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, etc.

[0191] Kits may be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To aid in compliance, kits provided herein typically include directions for administration.

[0192] In the combination therapy provided herein, the compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. In addition, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the other therapeutic agent may be incorporated into the combination therapy (i) prior to delivery of the combination product to the physician (e.g., in the case of a kit comprising the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the other therapeutic agent); (ii) by the physician (or under the guidance of the physician) immediately prior to administration; or (iii) in the patient himself, for example, during sequential administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the other therapeutic agent.

[0193] Thus, there is provided herein the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) in the preparation of a medicament for treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including those present as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the medicament is prepared for administration with another therapeutic agent.

[0194] Provided herein is the use of another therapeutic agent to treat a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein a medicament is administered together with a compound of the invention.

[0195] Provided herein is a compound of formula (I) or a pharma- ceutically acceptable salt thereof (including, for example, a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) for use in a method of treating a disease, disorder or condition selected from the foregoing list, suitably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is formulated for administration with another therapeutic agent.

[0196] Also provided herein is another therapeutic agent for use in a method of treating a disease, disorder or condition, including when present as a comorbidity in a subject with type 2 diabetes mellitus who is also obese, or who has type 2 diabetes mellitus who also has heart failure, suitably selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), wherein the other therapeutic agent is formulated for administration with a compound of Formula (I) or a pharmacologic acceptable salt thereof (including, for example, a compound of any of Formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmacologic acceptable salt thereof).

[0197] Also provided herein is a compound of formula (I) or a pharma- ceutically acceptable salt thereof (including, for example, a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) for use in a method of treating a disease, disorder or condition selected from the foregoing list, suitably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as a comorbidity, for example in a subject with type 2 diabetes who is also obese, or in a subject with type 2 diabetes who also has heart failure, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with another therapeutic agent.

[0198] There is also provided another therapeutic agent for use in a method of treating a disease, disorder or condition, including when present as a comorbidity in a subject with type 2 diabetes mellitus who is also obese, or who has type 2 diabetes mellitus who also has heart failure, preferably selected from the foregoing list, wherein the other therapeutic agent is administered together with a compound of formula (I), or a pharma- ceutical acceptable salt thereof.

[0199] Also provided herein is the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof (e.g., comprising a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharma- ceutically acceptable salt thereof) for treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including when these are present as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, and wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent.

[0200] Also provided herein is the use of another therapeutic agent for treating a disease, disorder or condition selected from the foregoing list, preferably type 2 diabetes, obesity, atherosclerosis and heart failure (particularly heart failure with preserved ejection fraction), including where these exist as comorbidities, for example in a subject with type 2 diabetes who is also obese, or a subject with type 2 diabetes who also has heart failure, where the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I) or a pharmacologic acceptable salt thereof (including, for example, a compound of any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb), or a pharmacologic acceptable salt thereof).

[0201] In one embodiment, the other therapeutic agent is selected from: 1. Antidiabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as sulfonylureas (e.g., chlorpropamide, tolazamide, acetohexamide, tolbutamide, glyburide, glimepiride, glipizide); glyburide and amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; thiazolidinediones 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), balaglitazone, rivoglitazone, netoglitazone, troglitazone, englitazone, ci ... protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as PTP-112; cholesteryl ester transfer protein (CETP) inhibitors such as torcetrapib, GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN-194204; sodium-dependent glucose cotransporter inhibitors such as canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sotagliflozin, and tofogliflozin; glycogen phosphorylase A inhibitors such as R3401; biguanides such as metformin and other agents that act by promoting glucose utilization, decreasing hepatic glucose production and / or decreasing intestinal glucose output; alpha-glucosidase inhibitors such as acarbose and migiitoi and other agents that slow carbohydrate digestion and consequently absorption from the intestine, reducing postprandial hyperglycemia; GIPR modulators such as trizepatide, CT-868, CT-388, AMG133, HM15211, NN9423, TAK-094, LBT-6030, ZP-I-98, NN9709, RG7685, RG7697, SAR438335;as well as DPPIV (dipeptidyl peptidase IV) inhibitors such as vildagliptin; 2. Lipid-lowering agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; bile acid sequestrants such as cholestyramine and colesevelam; fibrates; nicotinic acid and aspirin; 3. Anti-obesity agents such as orlistat, rimonabant, phentermine, topiramate, qunexa, and lorcaserin; GDF15 (including variants, conjugates, fusions, analogs, mutants, and fragments thereof, including other GFRAL modifiers such as NGM386, NGM395, etc.); PCT publications WO 2013 / 148117, WO 2014 / 120619 and related patent family members (including, but not limited to, U.S. Pat. No. 9,161,966 B1), WO 2012 / 138919, WO 2013 / 113008, WO 2015 / 017710, WO 2015 / 200078, WO 2015 / 197446 GDF15 fusions such as GDF15 conjugates with fatty acids (such as those described in PCT publications WO 2015 / 200078 and WO 2017 / 109706) and fusions described in PCT publications WO 2015 / 197446, WO 2015 / 198199 and WO 2017 / 109706 (including, for example, GDF15 fusions with human serum albumin (HSA)); FGF21 mimetics such as PEG-FGF21, pegbelfermin; ActRII antagonists such as ramatercept; and Alk7 antagonists; 4. Antihypertensive drugs, for example, loop diuretics such as ethacrynic acid, furosemide and torsemide; Angiotensin-converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; Inhibitors of the Na-K-ATPase membrane pump such as digoxin; Neutral endopeptidase (NEP) inhibitors; ACE / NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, especially valsartan; angiotensin receptor-neprilysin inhibitors (ARNi) such as sacubitril / valsartan (Entresto); ditekiren, zankiren, terlaquilen, aliskiren, RO renin inhibitors such as 66-1132 and RO-66-1168; beta-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropes such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; 5. Agonists of peroxisome proliferator-activated receptors, such as fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585, L-796449, the compounds specifically described in patent application WO 2004 / 103995, i.e. the compounds of Examples 1 to 35 or the compounds specifically listed in claim 21, or the compounds specifically described in patent application WO 03 / 043985, i.e. the compounds of Examples 1 to 7 or the compounds specifically listed in claim 19, and in particular (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxy or a salt thereof; 6. Certain antidiabetic compounds described in Expert Opin Investig Drugs 2003, 12(4):623-633, Figures 1-7. 7. Compounds that bind to the corticotropin-releasing hormone receptor, such as Urocortin 2.

[0202] Additionally, the present invention provides combination therapy with agents that stimulate metabolism or reduce appetite, as well as agents and methods for promoting weight loss, such as dietary modifications and / or exercise regimes to promote weight loss. EXAMPLES

[0203] The following examples are intended to illustrate the invention and should not be construed as limiting thereto. Temperatures are given in degrees Celsius. Unless otherwise indicated, all evaporations are carried out under reduced pressure, usually at about 15 mmHg to 100 mmHg (=20 to 133 mbar). The structures of final products, intermediates and starting materials are confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0204] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0205] Abbreviations used in the examples below and elsewhere in the specification are as follows: Plateau value of Hill curve at low A0 concentration AC 50 Concentration of half-maximal compound effect A inf Hill curve plateau value at high concentration ACN Acetonitrile BSA Bovine Serum Albumin BOC Tertiary butyl carboxy br Broad BSA Bovine Serum Albumin cAMP cyclic adenosine monophosphate CDI Carbonyldiimidazole CO2 Carbon Dioxide d double line dd Double line double line DBU Diazabicycloundecene DCM Dichloromethane DIEA / DIPEA Diethylisopropylamine DMA Dimethylacetamide DMEM Dulbecco's Modified Eagle's Medium DMF N,N-Dimethylformamide DMI Dimethylimidazolidinone DMPU N,N-Dimethylpropylene urea DMSO Dimethyl sulfoxide EC Effective Concentration Effective concentration of compound that does not produce an EC0 response EC 50 The effective concentration of compound that produces a half-maximal response (AC in μM) 50 ) EC 100Effective concentration of compound that produces a maximum (100%) response EDTA Ethylenediaminetetraacetic acid E max Efficacy: The maximum response achievable from a given drug. ESI Electrospray Ionization EtOAc Ethyl acetate EtOH Ethanol FA Formic Acid FBS Fetal Bovine Serum G418 Geneticin, a selective antibiotic GLP1 Glucagon-like peptide 1 GLP1R Glucagon-like peptide 1 receptor GPCR G protein-coupled receptor h time HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) hGLP1R Human glucagon-like peptide 1 receptor HPLC High Pressure Liquid Chromatography HRMS high resolution mass spectrometry HTRF homogeneous time-resolved fluorescence IBMX 3-isobutyl-1-methylxanthine KHMDS Potassium bis(trimethylsilyl)amide LCMS Liquid Chromatography and Mass Spectrometry LDA Lithium diisopropylamide LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MS mass spectrometry m multiplet mg milligram min ml milliliter mM millimolar concentration mmol nM nanomolar m / z mass-to-charge ratio NMR nuclear magnetic resonance ND Not decided PBS Phosphate Buffered Saline Pd(OAc)2Palladium(II) Acetate PdCl2(dppf)-CH2Cl2 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex Pd(OAc)2Palladium(II) Acetate ppm parts per million p-TsOH p-Toluenesulfonic acid PyBOP Benzotriazole-1-oxytripyrrolidinophosphonium hexafluorophosphate PyBroP Bromotripyrrolidinophosphonium hexafluorophosphate rac Racemic R t retention time rt room temperature s single line SFC Superfluid Carbon Dioxide SM Starting material / Starting material(s) SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride t triple line TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl TMSCl Trimethylsilyl chloride Tol Toluene Turbo Grignard Isopropylmagnesium chloride Lithium chloride complex solution v / v volume / volume μL microliter μM micromolar

[0206] General conditions: NMR Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. 1H NMR (H NMR) spectra were recorded on (a) a Bruker AVANCE 400 MHz or 500 MHz NMR spectrometer using an ICON-NMR under TopSpin program control; (b) a Bruker ASCEND 400 MHz NMR spectrometer using a Console-Avance III 400 under TopSpin 3.2 program control; or (c) a Bruker ASCEND 400 MHz NMR spectrometer using a Console-Avance III HD under TopSpin 3.2 program control. Spectra were measured at 293-298 K unless otherwise specified and were referenced to the solvent resonance. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0207] NMR-01: Unless otherwise stated, reagents and solvents were used as received from commercial 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 293-298 K and referenced to solvent resonances unless otherwise specified. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0208] NMR-02: Unless otherwise stated, reagents and solvents were used as received from commercial 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 293-298 K and referenced to solvent resonances unless otherwise specified. Spectra are given in ppm (δ) and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0209] LCMS equipment Mass spectra were obtained using an Agilent 1100 HPLC system equipped with an Agilent 6110 mass spectrometer. [M+H] + refers to the protonated molecular ion of the species. The column temperature was 50° C. The flow rate was 1.0 ml / min.

[0210] LCMS method 1 (acidic): Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; 2 min run time, 2% solvent B 0–0.1 min, 2 → 98% solvent B: solvent A 0.1–1.8 min, 98% solvent B 0.2 min. Solvents: solvent A = 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 °C; flow rate 1.0 mL / min.

[0211] LCMS method 2 (basic): Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C 18 1.7 μm, 21 × 50 mm; 2 min run time, 2% solvent B 0–0.1 min, 2→98% solvent B:solvent A 0.1–1.8 min, 98% solvent B 0.2 min. Solvents: solvent A = 5 mM ammonium hydroxide in water, solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume 2–5 uL; UV detection array 210–400, mass detection 120–1250 (electrospray ionization); column 50 °C; flow rate 1.0 mL / min.

[0212] LCMS method 3 (product analysis - acidic): Instrument: Waters Acquity UPLC, photodiode array detector; column AcQuity UPLC BEH C 181.7 μm, 21 × 30 mm; 5.2 min run time, 2 → 98% solvent B: solvent A 0–5.15 min, 98% solvent B 5.15–5.20 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2–5 uL; UV detection array 210–400, mass detection 120–1600; column 50 °C, flow rate 1.0 mL / min.

[0213] LCMS method 4 (product analysis - basic): Instrument: Waters Acquity UPLC, photodiode array detector; column AcQuity UPLC BEH C 18 1.7 μm, 21 × 30 mm; 5.2 min run time, 2 → 98% solvent B: solvent A 0–5.15 min, 98% solvent B 5.15–5.20 min. Solvents: solvent A = 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.

[0214] HRMS method 5: Instrument: Agilent 1200 LC / G1956A, diode array detector; Column: Chromolith Flash C 18 , 1.6 micron 2 x 25 mm; 1.5 min run time, 5 → 95% solvent B: solvent A 0 → 1.2 min followed by 95% solvent B 1.21 → 1.5 min. Solvents: Solvent A = 0.0375% TFA (v / v) in water, Solvent B = 0.01875% TFA (v / v) in acetonitrile. Injection volume 2-5 uL; UV detection 220 and 254 nM, mass detection 100-1000 (electrospray ionization); column 50 °C; flow rate 1.5 mL / min.

[0215] Chiral Preparative HPLC Method: Equipment: Shimadzu LC-20AP and UV detector. Column: CHIRALPAK IG, (250x21.0)mm, 5 micron, Column flow rate: 16.0 ml / min. Mobile phase: (A) 0.1% DEA in methanol. UV spectra were recorded at 276.0 nm lambda max. The uniform concentration ratio was:

[0216] [Table 12]

[0217] Example 1: Synthesis of intermediates Example 1-1: Synthesis of 4-methylbenzenesulfonic acid (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)benzonitrile (II.B1) [ka] Step 1: Synthesis of (S)-tert-butyl 4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (II.1b) [ka] Intermediate II.2b (0.500 g, 1.12 mmol), zinc cyanide (144 mg, 77.9 μL, 1.23 mmol), and (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (48.9 mg, 55.8 μmol) were dissolved in dry N,N-dimethylformamide (5 mL) under nitrogen. Water (0.1 mL) was added and the mixture was degassed by bubbling nitrogen through it. The reaction was heated to 150° C. in a microwave for 25 min. Near complete conversion to the desired mass was found by LCMS analysis. The vial was opened and poured into a mixture of 1N sodium hydroxide (30 mL) and ethyl acetate (75 mL). The mixture was stirred vigorously for 10 min and then the phases were separated. The organic phase was dried over sodium sulfate and evaporated to dryness under reduced pressure. Purification using ISCO (5-60% ethyl acetate in heptane gradient) afforded the desired II.1b (445 mg, 1.02 mmol, 91% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ ppm 1.11-1.20(m,1H)1.30-1.38(m,9H)1.45-1.73(m,5H)1.89-1.95(m,3H)2.60-2.72(m,3H) 4.03-4.15(m,2H)6.49-6.60(m,2H)6.60-6.69(m,1H)7.22-7.33(m,2H)7.53-7.59(m,1H).

[0218] Step 2: Synthesis of 4-methylbenzenesulfonic acid (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxol-2-yl)benzonitrile (II.B1) [ka] To a solution of II.1b (445 mg, 1.02 mmol) in EtOAc (7 mL) was added Ts-OH.H2O (231.6 mg, 1.218 mmol) at 25 °C. The mixture was heated to 45 °C for 16 h, when LCMS analysis indicated complete consumption of starting material and formation of the desired product. The crude product was evaporated to dryness under reduced pressure to give the tosylate salt of II.B1 (518 mg, 1.02 mmol, 100% yield) as a white solid. LCMS Method 1 (acidic): Rt = 0.75 min, MS (ESI+) m / z 339.1 (M+1). + .

[0219] Example 1-2: Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.A1) and (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonate (II.B2) [ka]

[0220] Step 1: Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole (II.2a). [ka] To a solution of 1-(4-chloro-2-fluorophenyl)ethan-1-one (150 g, 793.61 mmol) in toluene (1500 mL) was added 3-bromobenzene-1,2-diol (123.27 g, 714.25 mmol) and p-TsOH (27.33 g, 158.72 mmol) at 25 °C. The mixture was stirred at 140 °C for 48 h. TLC (petroleum ether: ethyl acetate = 30: 1) showed that 1-(4-chloro-2-fluorophenyl)ethan-1-one was completely consumed and a new spot (Rf = 0.4) was detected. The mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether) to give II.2a (175 g, crude) as a black oil, which was used for the next step without further purification. 1 H-NMR(400MHz,CDCl3)δ 2.04(s,3H),7.47(t,J=8.38Hz,1H),7.05-7.09(m,2H),6.88(dd,J=7.88,1.13Hz,1H),6.57-6.71(m,2H),2.04(s,3H).

[0221] Step 2: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (II.3a) [ka] To a solution of II.2a (150 g, 436.58 mmol) in dioxane (1500 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (162.00 g, 523.90 mmol), Na2CO3 (254.50 g, 2401.19 mmol) and Pd(dppf)Cl2 (31.99 g, 43.66 mmol) at 25 °C. The mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO2, petroleum ether:ethyl acetate = 10:1) to give II.3a (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).

[0222] Step 3: Synthesis of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine-1-carboxylate (II.4a) [ka] To a solution of II.3a (50 g, 112.13 mmol) in MeOH (200 mL) was added ((C6H5)3P)3RhCl (5.19 g, 5.61 mmol) at 25 °C. The mixture was stirred under H2 at 50 °C for 16 h. The reaction mixture was filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (SiO2, PE:EA = 10:1) to give II.4a (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).

[0223] Step 4: SFC separation of II.6a and II.6b. [ka] II.4a (170 g, 379.52 mmol, 96% purity) was purified by SFC (CAS-WH-ANA-SFC-A (Agilent-1260), column: Chiralpak AD-3 50×4.6 mm ID, 3 um; mobile phase: phase A with CO2 and phase B with IPA (0.05% DEA); gradient elution: 5% to 40% B in A; flow rate: 3 mL / min; detector: DAD; column temperature: 35° C.; back pressure: 100 Bar) to give II.6a (77 g, 171.90 mmol, 100% ee) and II.6b (75 g, 167.44 mmol, 100% ee). SFC: Rt=0.884 min, II.6a peak 1. SFC: Rt=1.118 min, II.6b peak 2.

[0224] Step 5a: Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine 4-methylbenzenesulfonic acid (II.B2). [ka] To a solution of compound II.6b (19.4 g, 43.3 mmol) in EtOAc (200 mL) was added TsOH.H2O (9.88 g, 51.9 mmol, 1.20 eq). After the addition, the pale yellow suspension was stirred at 45 °C for 12 h. The reaction mixture was poured into petroleum ether (400 mL), filtered, collected and dried. II.B2 (20.0 g, 36.9 mmol, 85.2% yield, 96.0% purity) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ)8.58(br d,J=8.63Hz,1H),8.31(br d,J=8.25Hz,1H),7.49(d,J=8.00Hz,2H),7.56-7.65(m,2H),7.34(dd,J=8.38,1. 75Hz,1H),7.12(d,J=7.88Hz,2H),6.82-6.87(m,2H),6.68-6.74(m,1H),3.37(br d,J=12.51Hz,2H),2.94-3.07(m,3H),2.03(s,3H),2.29(s,3H),1.84-1.94(m,4H).

[0225] Step 5b: Synthesis of (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine hydrochloride (II.A1). [ka] To a solution of II.6b (67 g, 149.58 mmol) in dioxane (670 mL) was added HCl (670 mL, 1 M in dioxane) at 25° C. The mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give the crude product. The crude product was triturated with MTBE:MeOH=10:1 (700 mL) to give II.A1 (71 g, 204.13 mmol, 98% purity, 99.27% ​​ee quantitative) as a white solid. 1H NMR(400MHz,CDCl3)δ 9.98-9.43(m,2H),7.57(t,J=8.3Hz,1H),7.19-7.09(m,2H),6.87-6.65(m,3H),3.96(s,1H),3.64(br d,J=10.9Hz,2H),3.50(s,2H),3.22(s,1H),3.12-2.90(m,3H),2.39-2.19(m,2H),2.15-1.98(m,5H),1.20(s,1H).

[0226] Example 1-3: Synthesis of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) [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 (III.2b) [ka] To a solution of 4-bromo-5-methyl-1H-imidazole (III.a1) (2.000 g, 12.4 mmol) in acetonitrile (50 mL) was added (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (3.33 g, 13.0 mmol) and cesium carbonate (10.1 g, 31.1 mmol) at room temperature. The mixture was stirred at 80° C. using a findenser for 16 h and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography (0-100% EtOAc / heptane, 0-5% MeOH / EtOAc) and the isomers were separated to give (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.2a) (1.2 g, 42%) (LCMS Method 2 (basic): Rt = 0.67 min, MS (ESI+) m / z 233.0 [M+1] + ), and (S)-5-bromo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.2b) (0.35 g, 12%) (LCMS Method 2 (basic): Rt = 0.68 min, MS (ESI+) m / z 231.3 (M+1) + ) was obtained.

[0227] Step 2: Synthesis of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (III.3) [ka] To a solution of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.2a) (580 mg, 2.51 mmol) in THF (12 mL) was slowly added LDA (2.51 mL, 2 molar, 5.02 mmol) in THF / heptane / ethylbenzene at -78 °C. The reaction was stirred at -78 °C for 40 min followed by the addition of N,N-dimethylformamide (972 μL, 12.5 mmol). The reaction was stirred from -78 °C to room temperature for 2 h. The reaction was quenched with a saturated aqueous solution of NH4Cl and extracted three times with ethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (III.3) (588.9 mg, 90.6% yield) as a brownish solid. The crude was used for the next step without further purification. LCMS Method 2 (basic): Rt=1.02 min, MS (ESI+) m / z 259.1 (M+H). + .

[0228] Step 3: Synthesis of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) [ka] To a solution of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldeyde (1.6 g, 6.18 mmol) (III.3) in DCM (40 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-ium chloride (II.A1) (1.9 g, 4.94 mmol) and TEA (1.72 mL, 12.4 mmol). The reaction was stirred at room temperature for 15-25 min followed by the addition of sodium triacetoxyborohydride (1.36 g, 6.43 mmol). The reaction was stirred at room temperature for an additional 2 h. 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 give an off-white foam solid. The crude was further purified by normal phase chromatography (0-100% EtOAc / heptane) to give 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) as a white foam solid (1.7 g, 58.2% yield). LCMS Method 4: (Product Analysis - Basic: Rt=3.42 min, MS(ESI+) m / z 592.3 (M+H) + . 1H 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).

[0229] Example 2: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid (C-1) [ka] Step 1: Synthesis of (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.3a) and (S)-5-iodo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.3b) [ka] To a solution of (S)-oxetan-2-ylmethyl 4-methylbenzenesulfonate (2.17 g, 8.96 mmol) and 5-iodo-4-methyl-1H-imidazole (CAS#15813-07-72, 2.049 g, 9.85 mmol) in ACN (50 mL) was added Cs2CO3 (2.92 g, 8.96 mmol). The reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by FCC (MeOH / ethyl acetate=0-20%) and the regioisomers were separated to give intermediates III.3a and III.3b. (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.3a): 1 H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 5.03-4.95 (m, 1H), 4.64-4.56 (m, 1H), 4.32 (td, J = 6.0, 9.2 Hz, 1H), 4.11-4.05 (m, 2H), 2.68 (dtd, J = 6.0, 8.0, 11.6 Hz, 1H), 2.34-2.26 (m, 1H), 2.20 (s, 3H). (S)-5-Iodo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (III.3b): 1 H NMR(400MHz,CDCl3)δ 7.80(s,1H),5.12-4.98(m,1H),4.74-4.58(m,1H),4.37(td,J=6.0,9.2Hz,1H),4.18-4.06( m,2H),2.69(dtd,J=6.0,8.0,11.6Hz,1H),2.35(tdd,J=7.2,9.2,11.2Hz,1H),2.26(s,3H).

[0230] Step 2: Synthesis of (S)-5-iodo-4-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (III.4) [ka] To a solution of III.3b (0.222 g, 0.8 mmol) in THF (4 mL) was added LDA (1.600 mL, 1.600 mmol) slowly at -78 °C. The reaction was stirred at -78 °C for 30 min, followed by the addition of DMF (0.310 mL, 4.00 mmol). The reaction was stirred at -78 °C to room temperature for 2 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted three times with ether. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue of III.4 was used in the next step without purification. LCMS Method 2 (basic): Rt = 0.69 min, MS (ESI+) m / z = 306.9 (M+1) + .

[0231] Step 3: Synthesis of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((5-iodo-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine (I.B1) [ka] To a solution of III.4 (245 mg, 0.800 mmol) and intermediate II.A1 (215 mg, 0.560 mmol) in DCM (5 mL) was added pyridine (64.7 μl, 0.800 mmol). The reaction was stirred at room temperature for 15 min followed by the addition of sodium triacetoxyborohydride (170 mg, 0.800 mmol). The reaction was stirred at room temperature for 1.5 h before being cooled to 0° C. and quenched with saturated aqueous NaHCO3 and extracted twice with DCM. The combined organic layers were concentrated and the residue was purified by FCC (EA / Hep=0-100%) to give I.B1. LCMS Method 1 (acidic): Rt=1.23 min, MS (ESI+) m / z 638.2 (M+H) + .

[0232] Step 4: Synthesis of ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylate (I.1) [ka] To a solution of I.B1 (2.3 g, 3.61 mmol) and ethyl 5-methyloxazole-4-carboxylate (1.12 g, 7.21 mmol) in toluene (16 mL) was added Xphos Pd G2 (283.7 mg, 360.5 μmol) and Cs2CO3 (2.35 g, 7.21 mmol) under nitrogen atmosphere. The reaction was heated to 120 °C for 16 h, when LCMS analysis indicated the presence of the desired product. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by FCC (DCM / MeOH=0-10%) to give I.1 (1.6 g, 2.4 mmol, 66.7% yield). LCMS method 2 (basic): Rt=1.41 min, MS(ESI+) m / z 665.5(M+H) + .

[0233] Step 5: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid (C-1) [ka] To a solution of I.1 (1.6 g, 2.405 mmol) in a mixed solvent of THF-MeOH (7 mL / 4 mL) was added LiOH 1M in HO (9.622 mL, 9.622 mmol). The reaction mixture was stirred overnight when LCMS analysis indicated complete consumption of the starting ester and formation of the desired product. The reaction was then acidified to pH=4 with 1 M citric acid and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over NaSO. After filtration and concentration, the residue was purified by RP ISCO (2×150 g C18 column, 10-70% ACN in water, 0.1% NHOH as modifier) ​​to give compound C-1 (155.0 mg, 0.24 mmol, 10% yield) as a white solid after lyophilization. C-1: 1 H NMR(400MHz,DMSO)δ 7.57-7.39(m,2H),7.27(dd,J=8.4,2.1Hz,1H),6.74-6.59(m,3H),4.93-4.80(m,2H),4.72-4.5 7(m,1H),4.38-4.29(m,1H),4.23(dt,J=8.9,6.0Hz,1H),3.69(d,J=13.4Hz,1H),3.49(d,J=13. 4Hz,1H),2.90(d,J=11.2Hz,1H),2.79(d,J=11.3Hz,1H),2.62-2.48(m,5H),2.32-2.21(m,4H), 2.16-1.99(m,2H),1.95(s,3H),1.66(d,J=27.9Hz,4H).LCMS method 2 (basic): Rt=0.79 min, MS(ESI+)m / z 637.5(M+H) + .HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229, and the actual value was 637.2401.

[0234] Example 2-1: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid (C-2) [ka] Compound C-2 was synthesized using the same procedure as described in Example 2, but using (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1 and ethyl oxazole-5-carboxylate in step 4. C-2: 1 H NMR(400MHz,MeOD)δ 7.53-7.45(m,2H),7.18(dd,J=11.0,2.1Hz,1H),7.11(dd,J=8.4,2.1Hz,1H),6.76-6.6 0(m,3H),5.17-5.06(m,1H),4.90-4.80(m,2H),4.60(td,J=8.1,5.8Hz,1H),4.47-4.36( m,2H),4.36-4.28(m,1H),3.64-3.51(m,2H),3.11-2.95(m,2H),2.90-2.85(m,1H),2.7 2-2.59(m,1H),2.48(s,3H),2.44-2.32(m,1H),2.07-1.95(m,4H),1.93(s,3H).HRMS is C 32 H 33 ClFN4O6(M+H) + The calculated value was 623.2073, and the actual value was 623.2139.

[0235] Example 2-2: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid (C-3) [ka] Compound C-3 was synthesized using the same procedure as described in Example 2, but using (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1 and ethyl oxazole-4-carboxylate in step 4. C-3: 1 H NMR(400MHz,MeOD)δ 8.23(s,1H),7.49(t,J=8.3Hz,1H),7.19(dd,J=10.9,2.1Hz,1H),7.11(dd,J=8.4,2.1 Hz,1H),6.75-6.68(m,1H),6.68-6.59(m,2H),5.15-5.05(m,1H),4.95-4.90(m,2H),4 .61-4.51(m,1H),4.44-4.34(m,1H),4.20(s,2H),3.43-3.35(m,2H),2.83(d,J=14.9H z,3H),2.74-2.61(m,1H),2.43(s,3H),2.41-2.30(m,1H),1.98-1.86(m,7H).HRMS is C 32 H 33 ClFN4O6(M+H) + The calculated value was 623.2073, and the actual value was 623.2103.

[0236] Example 2-3: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid (C-4). [ka] Compound C-4 was synthesized using the same procedure as described in Example 2, but using 5-iodo-4-(trifluoromethyl)-1H-imidazole in step 1 and ethyl oxazole-4-carboxylate in step 4. C-4: 1H NMR (400MHz, methanol-d4) δ ppm 1.90-2.13(m,7H)2.31-2.57(m,1H)2.62-3.04(m,4H)3.32-3.46(m,2 H)4.02-4.33(m,2H)4.34-4.49(m,1H)4.53-4.68(m,1H)4.88-4.98(m ,1H)5.02-5.30(m,2H)6.66-6.76(m,2H)6.76-6.84(m,1H)7.17-7.24(m,1H)7.24-7.32(m,1H)7.53-7.62(m,1H)8.10-8.79(m,1H).HRMS is C 32 H 30 ClF4N4O6(M+H) + The calculated value was 677.1790 and the actual value was 677.1899.

[0237] Example 2-4: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid (C-5). [ka] Compound C-5 was synthesized using the same procedure as described in Example 2, but using 4-ethyl-5-iodo-1H-imidazole in step 1 and ethyl oxazole-4-carboxylate in step 4. C-5: 1H NMR(400MHz, methanol-d4)δ ppm 1.27(t,J=7.52Hz,3H)1.91-2.14(m,8H)2.41-2.51(m,1H)2.73-2.81(m,1 H)2.87-2.96(m,5H)3.44-3.52(m,2H)4.28-4.33(m,2H)4.46-4.53(m,1H)4 .64-4.70(m,1H)4.99-5.08(m,2H)5.17-5.24(m,1H)6.72-6.82(m,3H)7.18 -7.24(m,1H)7.25-7.32(m,1H)7.54-7.63(m,1H)8.27-8.34(m,1H)HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229, and the actual value was 637.2405.

[0238] Example 2-5: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid (C-6). [ka] Compound C-6 was synthesized using the same procedure as described in Example 2, but using 4-ethyl-5-iodo-1H-imidazole in step 1 and ethyl oxazole-5-carboxylate in step 4. C-6: 1H NMR(400MHz,DMSO-d6)δ ppm 1.15-1.23(m,3H)1.65-1.82(m,4H)2.02(s,3H)2.07-2.40(m,4H)2.62-2.68(m,2H)2.79-2.90(m,3H)2.96-3.02(m,1H)3.59(br d,J=13.45Hz,1H)3.76-3.87(m,1H)4.27-4.46(m,2H)4.53-4.78(m,1H)4.79 -5.06(m,2H)6.73-6.81(m,3H)7.31-7.37(m,1H)7.51-7.61(m,2H).HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229, and the actual value was 637.2264.

[0239] Example 2-6: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid (C-7). [ka] Compound C-7 was synthesized using the same procedure as described in Example 2, but using 4-ethyl-5-iodo-1H-imidazole and (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1, and ethyl oxazole-4-carboxylate in step 4. C-7: 1H NMR(400MHz,DMSO-d6)δ ppm 1.12-1.22(m,3H)1.68-1.82(m,4H)1.98-2.04(m,3H)2.06-2.25(m,2H)2.25-2.37(m,1 H)2.57-2.68(m,2H)2.72-2.82(m,2H)2.82-2.91(m,1H)2.93-3.02(m,1H)3.54-3.65(m ,1H)3.72-3.87(m,1H)4.23-4.33(m,1H)4.34-4.44(m,1H)4.63-4.76(m,1H)4.86-5.03 (m,2H)6.70-6.82(m,3H)7.30-7.37(m,1H)7.51-7.61(m,2H)8.74-8.79(m,1H).HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229 and the actual value was 637.2377.

[0240] Example 2-7: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid (C-8). [ka] Compound C-8 was synthesized using the same procedure as described in Example 2, but using 4-ethyl-5-iodo-1H-imidazole and (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1, and ethyl oxazole-5-carboxylate in step 4. C-8: 1H NMR(400MHz,DMSO-d6)δ ppm 1.11-1.21(m,3H)1.69-1.80(m,4H)2.02(s,3H)2.08-2.28(m,2H)2.29-2.37(m,1H)2.59-2.68(m,2H)2.70(br s,3H)2.95-3.05(m,1H)3.59-3.65(m,1H)3.77-3.86(m,1H)4.27-4.46(m,2H)4.56-4.75(m,1H)4 .75-5.06(m,2H)6.72-6.82(m,3H)7.31-7.37(m,1H)7.52-7.60(m,2H)7.76-8.03(m,1H).HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229, and the actual value was 637.2351.

[0241] Example 2-8: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid (C-9). [ka] Compound C-9 was synthesized using the same procedure as described in Example 2, but using ethyl oxazole-4-carboxylate in step 4. C-9: 1H NMR(400MHz,MeOD)δ 8.30(s,1H),7.60-7.56(m,1H),7.28(dd,J=11.2Hz,2Hz,1H),7.23-7.20(m,1H),6.82- 6.78(m,1H),6.75-6.71(m,2H),5.22-5.20(m,1H),5.06-5.04(m,2H),4.68-4.66(m,1H ),4.5-4.48(m,1H),4.26(s,2H),3.47-3.43(m,2H),2.88-2.77(m,4H),2.52(s,3H),2. 51-2.47(m,1H),2.03(s,3H),2.02-1.99(m,4H).LCMS method 1 (acidic): Rt=1.57 min, MS(ESI+)m / z 623.2(M+H) + .

[0242] Example 2-9: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-ethyloxazole-4-carboxylic acid (C-10). [ka] Compound C-10 was synthesized using the same procedure as described in Example 2, but using ethyl 5-ethyloxazole-4-carboxylate in step 4. C-10: 1H NMR(400MHz,DMSO)δ 7.56-7.43(m,2H),7.27(dd,J=8.5,2.1Hz,1H),6.76-6.63(m,3H),4.86(dd,J=10.2,3.4Hz,2H),4.73-4 .56(m,1H),4.34(q,J=6.8Hz,1H),4.24(dt,J=8.9,6.0Hz,1H),3.69(d,J=13.3Hz,1H),3.49(d,J=13.4Hz ,1H),2.99(q,J=7.6Hz,2H),2.90(d,J=11.0Hz,1H),2.79(d,J=11.2Hz,1H),2.56(dd,J=16.3,11.7Hz,2 HRMS is C 34 H 37 ClFN4O6(M+H) + The calculated value was 651.2386 and the actual value was 651.2513.

[0243] Example 2-10: Synthesis of 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid (C-11). [ka] Compound C-11 was synthesized using the same procedure as described in Example 2, but using intermediate II.B1 instead of II.A1 in step 3. C-11: 1H NMR(400MHz,DMSO)δ 7.91(d,J=11.2Hz,1H),7.67(d,J=6.5Hz,2H),6.82-6.62(m,3H),4.94-4.78(m,2H),4.71-4.53(m,1H),4.34(dt,J=8.5,6.3Hz,1H),4.24(d t,J=8.8,6.0Hz,1H),3.70(d,J=13.5Hz,1H),3.50(d,J=13.5Hz,1H),2.90(d,J=11.1Hz,1H),2.79(d,J=11.0Hz,1H),2.63-2.51(m,5H),2.33 -2.19(m,4H),2.17-1.91(m,5H),1.76-1.55(m,4H).HRMS is C 34 H 35 FN5O6(M+H) + The calculated value was 628.2571 and the actual value was 628.2587.

[0244] Example 3: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-methyloxazole-4-carboxylic acid (C-12). [ka] Step 1: Synthesis of (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (III.5). [ka] Intermediate III.5 was synthesized using the same procedure as described in step 2 of Example 2, but using III.3a instead of III.3b. LCMS Method 2 (basic): Rt = 0.69 min, MS (ESI+) m / z 306.9 (M+H). + .

[0245] Step 2: Synthesis of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((4-iodo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine (I.A2). [ka] Intermediate I.A2 was synthesized using the same procedure as described in step 3 of Example 2, but using III.5 instead of III.4. LCMS Method 2 (basic): Rt = 1.43 min, MS (ESI+) m / z 638.0 (M+H). + .

[0246] Step 3: Synthesis of ethyl 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-methyloxazole-4-carboxylate (I.2). [ka] Intermediate I.2 was synthesized using the same procedure as described in step 4 of Example 2, but using I.A2 instead of I.B1. LCMS Method 2 (basic): Rt=1.38 min, MS (ESI+) m / z 665.5 (M+H). + .

[0247] Step 4: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-methyloxazole-4-carboxylic acid (C-12). [ka] Compound C-12 was synthesized using the same procedure as described in step 5 of Example 2, but using I.2 instead of I.1. C-12: 1 H NMR(400MHz,DMSO)δ 7.55-7.44(m,2H),7.27(dd,J=8.5,2.1Hz,1H),6.76-6.60(m,3H),4.96(dd,J=8.8,6.3Hz,1H),4.49- 4.29(m,3H),4.23(dd,J=15.2,2.8Hz,1H),3.66(d,J=13.5Hz,1H),3.42(d,J=13.4Hz,1H),2.91(d,J= 11.1Hz,1H),2.76(d,J=11.3Hz,1H),2.61(td,J=17.4,8.7Hz,2H),2.51(s,3H),2.49(s,3H),2.39-2. 31(m,1H),2.13-1.99(m,2H),1.96(s,3H),1.75-1.47(m,4H).LCMS method 2 (basic): Rt=0.87 min, MS(ESI+)m / z 637.5(M+H) + .HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229 and the actual value was 637.2288.

[0248] Example 3-1: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-4-carboxylic acid (C-13). [ka] Compound C-13 was synthesized using the same procedure as described in Example 3, but using ethyl oxazole-4-carboxylate in step 3. C-13: 1H NMR(400MHz,MeOD)δ 8.64(s,1H),7.58-7.53(m,2H),7.33(dd,J=8.4,1.6Hz,1H),6.79-6.78(m,2H),6.76-6.73(m, 1H),5.05-5.03(m,1H),4.51-4.42(m,3H),4.33-4.29(m,1H),3.74(d,J=13.2Hz,1H),3.50(d, J=5Hz,1H),3.0-2.97(m,1H),2.85-2.83(m,1H),2.69-2.67(m,2H),2.58(s,3H),2.49-2.32(m ,1H),2.18-2.01(m,3H),2.02(s,3H),1.76-1.66(m,4H).LCMS method 1 (acidic): Rt=1.12 min, MS(ESI+)m / z 623.2(M+H) + .

[0249] Example 3-2: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid (C-14). [ka] Compound C-14 was synthesized using the same procedure as described in Example 3, but using ethyl 4-(trifluoromethyl)oxazole-5-carboxylate in step 3. C-14:1H NMR(400MHz,DMSO)δ 7.54-7.44(m,2H),7.28(dd,J=8.5,2.1Hz,1H),6.77-6.60(m,3H),5.04-4.88(m,1H) ),4.49-4.29(m,3H),4.24(d,J=14.4Hz,1H),3.67(d,J=13.6Hz,1H),3.43(d,J=13. 3Hz,1H),2.92(d,J=11.1Hz,1H),2.78(d,J=11.3Hz,1H),2.67-2.54(m,2H),2.49(s ,3H),2.37-2.31(m,1H),2.15-1.97(m,2H),1.96(s,3H),1.77-1.44(m,4H).HRMS is C 33 H 32 ClF4N4O6(M+H) + The calculated value was 691.1947, and the actual value was 691.1964.

[0250] Example 3-3: Synthesis of 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-methyloxazole-5-carboxylic acid (C-15). [ka] Compound C-15 was synthesized using the same procedure as described in Example 3, but using ethyl 4-methyloxazole-5-carboxylate in step 3. C-15: 1H NMR(400MHz,DMSO)δ 7.55-7.46(m,2H),7.28(dd,J=8.4,2.1Hz,1H),6.77-6.62(m,3H),4.97(qd,J=7.4,2.9 Hz,1H),4.50-4.29(m,3H),4.20(dd,J=15.5,2.9Hz,1H),3.65(d,J=13.3Hz,1H),3.41(d ,J=13.3Hz,1H),2.92(d,J=11.2Hz,1H),2.79(d,J=11.2Hz,1H),2.65-2.54(m,2H),2.4 8(s,3H),2.38-2.29(m,1H),2.24(s,3H),2.13-1.89(m,5H),1.79-1.51(m,4H).HRMS is C 33 H 35 ClFN4O6(M+H) + The calculated value was 637.2229, and the actual value was 637.2372.

[0251] Example 4: Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid (C-16). [ka] Step 1: Synthesis of ethyl 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylate (I.3). [ka]

[0252] To a solution of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) (50.00 mg, 84.61 μmol) in 1,4-dioxane (1.000 mL) was added ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (29.38 mg, 110.0 μmol), KPO (126.9 μL, 2.000 molar, 253.8 μmol) and Pd (5.515 mg, 8.461 μmol). The reaction mixture was microwaved at 120° C. for 30 min. LCMS showed the reaction was complete. The crude was diluted with DCM and washed with saturated NaHCO3. The separated organic layer was filtered to remove water and concentrated by rotovap to give a brown oil (I.3) which is used "as is" in the next step. LCMS Method 2 (basic): Rt=1.37 min, MS(ESI+) m / z 651.2 (M+H). + .

[0253] Step 2: Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid (C-16) [ka] To a solution of ethyl 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylate (I.3) (55.00 mg, 84.47 μmol) in THF (0.500 mL) and methanol (0.25 mL) was added LiOH (0.337 mL, 1.000 molar, 337.9 μmol). The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The crude was loaded directly onto a 50 g C18 column and purified by ISCO (10-100% ACN in water, modified with 0.1% concentration of NH4OH) to give, after lyophilization, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid lithium salt (C-16) (12.00 mg, 22%). C-16: LCMS method 2 (basic): Rt=0.89 min, MS(ESI+) m / z 623.2(M+H) + . 1H NMR(400MHz,MeOD)δ 7.48(t,J=8.3Hz,1H),7.21-7.06(m,3H),6.72-6.54(m,3H),5.08(qd,J=7.4,2.5Hz,1H),4.61-4.46(m,2H),4.4 1(dt,J=9.2,5.9Hz,1H),4.30(dd,J=15.3,2.6Hz,1H),3.70(d,J=13.6Hz,1H),3.53(d,J=13.6Hz,1H),2.92(d,J =11.3Hz,1H),2.85-2.74(m,1H),2.71(ddd,J=11.5,5.5,2.7Hz,1H),2.65-2.51(m,1H),2.47(s,3H),2.40(dt,J =11.2,8.0Hz,1H),2.10(dtd,J=30.6,11.4,2.9Hz,2H),1.93(s,3H),1.77(dddd,J=25.3,17.4,12.7,7.0Hz,4H).

[0254] Example 4-1: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (C-17). [ka] Compound C-17 was synthesized using the same procedure as described in Example 4, but using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-methyl carboxylate in step 1. C-17: 1H NMR(400MHz,MeOD)δ 7.48(t,J=8.3Hz,1H),7.18(dd,J=11.0,2.1Hz,1H),7.11(dd,J=8.3,2.0Hz,1H),6.76(s,1H),6.71-6.53(m,3H),5.07( qd,J=7.3,2.6Hz,1H),4.59-4.33(m,3H),4.28(dd,J=15.4,2.7Hz,1H),4.05(s,3H),3.67(d,J=13.5Hz,1H),3.54(d,J=1 3.5Hz,1H),2.93(d,J=11.3Hz,1H),2.83(d,J=11.5Hz,1H),2.69(dtd,J=11.2,8.0,6.0Hz,1H),2.58(ddd,J=11.8,7.6,3 .4Hz,1H),2.47-2.38(m,1H),2.36(s,3H),2.10(dtd,J=26.9,11.4,2.9Hz,2H),1.93(s,3H),1.87-1.63(m,4H).HRMS is C 33 H 36 ClFN5O5(M+H) + The calculated value was 636.2389, and the actual value was 636.2411.

[0255] Example 4-2: Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid (C-18). [ka] Compound C-18 was synthesized using the same procedure as described in Example 4, but using ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate in step 1. C-18: 1H NMR(400MHz,MeOD)δ 7.92(s,1H),7.48(t,1H),7.18(dd,J=10.8,2.0Hz,1H),7.11(dd,J=8.5,2.0Hz,1H),6.73-6.53(m,3H),5.13-4.9 8(m,1H),4.59-4.44(m,2H),4.40(dt,J=9.2,5.9Hz,1H),4.28(dd,J=15.3,2.7Hz,1H),3.69(d,J=13.6Hz,1H),3.5 3(d,J=13.6Hz,1H),2.93(d,J=11.3Hz,1H),2.82(d,J=11.4Hz,1H),2.77-2.65(m,1H),2.63-2.53(m,1H),2.50(s, 3H),2.46-2.34(m,1H),2.21-1.99(m,2H),1.93(s,3H),1.86-1.61(m,4H).LCMS method 2 (basic): Rt=0.81 min, MS(ESI+)m / z 623.2(M+H) + .

[0256] Example 4-3: Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-3-methylfuran-2-carboxylic acid (C-19). [ka] Compound C-19 was synthesized using the same procedure as described in Example 4, but using methyl 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carboxylate in step 1. C-19: 1H NMR(400MHz,MeOD)δ 7.57(t,J=8.3Hz,1H),7.26(dd,J=10.8,2.0Hz,1H),7.18(dd,J=8.5,2.1Hz,1H),6.81-6.74(m,1H),6.70(dd,J=7.1 ,5.5Hz,2H),6.51(s,1H),5.15(qd,J=7.4,2.4Hz,1H),4.64(td,J=7.8,5.6Hz,1H),4.59-4.51(m,1H),4.48(dt,J=9. 1,5.9Hz,1H),4.37(dd,J=15.6,2.5Hz,1H),3.90(d,J=13.8Hz,1H),3.79(d,J=14.0Hz,1H),3.24(s,1H),3.11(d,J=1 HRMS is C 34 H 36 ClFN3O6(M+H) + The calculated value was 636.2277, and the actual value was 636.2281.

[0257] Example 5: Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylic acid (C-20). [ka] Step 1: Synthesis of ethyl 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylate (I.4). [ka] To a solution of 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1-((5-iodo-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine (I.B1) (60.00 mg, 94.06 μmol) in 1,4-dioxane (1.000 mL) was added ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole-2-carboxylate (75.36 mg, .2 μmol), KCO (211.6 μL, 2.000 molar, 4423.3 μmol) and XPhos Pd G (7.400 mg, 9.406 μmol). The reaction mixture was purged with nitrogen for 5 min and then microwaved at 110° C. for 30 min. LCMS showed the formation of ethyl 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylate (I.4). Hydrolyzed acid pdt (Rt=0.81 min) and a significant amount of terminal bis-conjugated pdt (Rt=1.27 min) were also observed. The crude was acidified with 1M citric acid (~pH=4), diluted with brine and extracted with EtOAc (2×). The separated organics were filtered, concentrated and used in the next step without further purification. LCMS method 2 (basic): Rt=1.34 min, MS(ESI+) m / z 651.3(M+H) + .

[0258] Step 2: Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylic acid (C-20). [ka] To a solution of ethyl 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylate (I.4) (61.00 mg, 93.68 μmol) in THF (0.500 mL) and MeOH (0.250 mL) was added LiOH (374.7 μL, 1.000 molar, 374.7 μmol). The resulting mixture was stirred at room temperature overnight. LCMS indicated the reaction was complete. The crude material was directly purified by ISCO (10-100% ACN in water, 0.1% concentration of NH4OH as buffer) on a 50 g C18 column to give, after lyophilization, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylate lithium salt (C-20) (7.000 mg, 12%). C-20: LCMS method 2 (basic): Rt=0.78 min, MS(ESI+) m / z 623.4(M+H) + . 1 H NMR(400MHz,MeOD)δ 7.94(s,1H),7.48(t,J=8.3Hz,1H),7.18(dd,J=11.0,2.0Hz,1H),7.11(dd,J=8.3,2.1Hz,1H),6.72-6.54(m,3H ),4.95(dt,J=7.4,3.8Hz,1H),4.85(dd,J=15.0,7.6Hz,1H),4.56(dd,J=15.1,2.9Hz,1H),4.45(td,J=7.9,5.8 Hz,1H),4.30(dt,J=9.2,5.9Hz,1H),3.76(d,J=13.6Hz,1H),3.55(d,J=13.6Hz,1H),2.94(d,J=11.2Hz,1H),2. 83(d,J=11.4Hz,1H),2.71-2.45(m,2H),2.37-2.23(m,1H),2.20-2.00(m,5H),1.93(s,3H),1.89-1.61(m,4H).

[0259] Example 5-1: Synthesis of 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (C-21). [ka] Compound C-21 was synthesized using the same procedure as described in Example 5, but using 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-5-methyl carboxylate in step 1. C:21: 1 H NMR(400MHz,MeOD)δ 7.48(t,J=8.3Hz,1H),7.18(dd,J=10.8,2.0Hz,1H),7.11(dd,J=8.4,2.1Hz,1H),6.73-6.54(m,4H),4.91(q d,J=7.0,3.3Hz,1H),4.71(dd,J=15.0,6.8Hz,1H),4.52-4.43(m,2H),4.30(dt,J=9.2,5.9Hz,1H),4.06(s,3 H),3.75(d,J=13.7Hz,1H),3.59(d,J=13.5Hz,1H),2.94(d,J=11.6Hz,1H),2.87(d,J=11.5Hz,1H),2.65-2. 54(m,1H),2.54-2.44(m,1H),2.29-2.20(m,1H),2.19-2.02(m,5H),1.93(s,3H),1.89-1.61(m,4H).HRMS is C 33 H 36 ClFN5O5(M+H) + The calculated value was 636.2389 and the actual value was 636.2394.

[0260] Example 5-2: Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxylic acid (C-22). [ka] Compound C-22 was synthesized using the same procedure as described in Example 5, but using (5-(ethoxycarbonyl)furan-2-yl)boronic acid in step 1. C-22: 1 H NMR(400MHz,MeOD)δ 7.48(t,J=8.3Hz,1H),7.18(dd,J=10.9,2.2Hz,1H),7.11(dd,J=8.3,2.2Hz,1H),6.93(d,J=3.4Hz,1H),6.74-6.54(m,3H) ,6.43(d,J=3.4Hz,1H),4.93(qd,J=7.1,3.0Hz,1H),4.84-4.73(m,1H),4.52(dd,J=15.1,3.1Hz,1H),4.45(td,J=7.9,5.7H z,1H),4.31(dt,J=9.0,6.0Hz,1H),3.74(d,J=13.7Hz,1H),3.56(d,J=13.6Hz,1H),2.93(d,J=11.3Hz,1H),2.83(d,J=11.4 Hz,1H),2.67-2.50(m,2H),2.27(ddt,J=11.4,9.2,7.0Hz,1H),2.19-2.01(m,5H),1.93(s,3H),1.88-1.60(m,4H).HRMS is C 33 H 34 ClFN3O6(M+H) + The calculated value was 622.21, and the actual value was 622.2185.

[0261] Example 5-3: Synthesis of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2-carboxylic acid (C-31). [ka] Compound C-31 was synthesized using the same procedure as described in Example 5, but using (2-(ethoxycarbonyl)thiazol-4-yl)boronic acid in step 1. C-31: LCMS method 2 (basic): Rt=0.83 min, MS(ESI+) m / z 639.2(M+H) + . 1 H NMR(400MHz,DMSO)δ 7.91(s,1H),7.63-7.53(m,2H),7.34(dd,J=8.5,2.1Hz,1H),6.80(d,J=4.5Hz,2H),6.78-6.72(m,1H),4.89-4.68(m,2H),4.52(dd,J=14. 6,3.3Hz,1H),4.44-4.34(m,1H),4.34-4.20(m,1H),3.31(s,6H),2.74(s,1H),2.54(s,1H),2.20(s,4H),2.03(s,3H),1.94-1.68(m,4H).

[0262] Example 6: Synthesis of 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid (C-23). [ka] To a solution of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) (39 mg, 66 μmol), prepared using the same procedure as described in steps 1-3 of Example 1-3, in 1,4-dioxane (0.7 mL), was added 5-carboxypyridine-3-boronic acid (13 mg, 79 μmol), K3PO4 (0.30 mL, 1 molar, 0.30 mmol) and Pd118 (4.3 mg, 6.6 μmol). The mixture was degassed under N2 and subsequently microwaved at 120 °C for 20 min. The reaction mixture was diluted with water, filtered through a plug, and purified by basic HPLC to give 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid (C-23). C-23: LCMS method 4 (product analysis - basic): Rt=1.79 min, MS(ESI+) m / z 633.5(M+H) + . 1 H NMR(400MHz,DMSO)δ 8.91(d,J=2.3Hz,1H),8.86(d,J=2.0Hz,1H),8.42(t,J=2.1Hz,1H),7.62-7.50(m,2H),7.34(dd,J=8.4 ,2.0Hz,1H),6.83-6.71(m,3H),5.04(qd,J=7.4,2.8Hz,1H),4.58-4.39(m,3H),4.30(dd,J=15.2,2.9H z,1H),3.76(d,J=13.4Hz,1H),3.52(d,J=13.3Hz,1H),3.05-2.96(m,1H),2.88(dq,J=12.5,4.2Hz,1H) ,2.76-2.58(m,2H),2.44(s,4H),2.21-2.05(m,2H),2.02(s,3H),1.73(dqd,J=28.3,11.3,3.5Hz,4H).

[0263] Example 7: 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid (C-24) [ka] To 5-boronofuran-2-carboxylic acid (1.3 mg, 8.46 μmol) was added a 0.1 M solution of 1-((4-bromo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidine (I.A1) (5 mg, 85 μL, 8.46 μmol), prepared using the same procedure as described in steps 1-3 of Example 1-3, containing PdCl2(dtbpf) (1.4 mg, 2.1 μmol) in DMA, at room temperature. To this solution was added a 1 M aqueous solution of potassium phosphate tribasic (5.4 mg, 25.4 μL, 25.4 μmol). The mixture was stirred at 110° C. for 18 hours. After this time, the solvent is removed under reduced pressure in a Genevac. After this time, the solvent is removed under reduced pressure in a Genevac. The crude product is dissolved in 7:2:1 acetonitrile:water:dimethylsulfoxide, passed through a metal scavenger filter (SiliCycle SiliaPrep 96-well dimercaptotriazine, 40-63 μm, 60 Å), purified by HPLC prep method MC-1, and immediately quantified by LCMS with CAD (LCMS method MC-1). The solvent was removed under a Porvair Sciences Ultravap Mistral evaporator and the purified solid was then immediately reconstituted in DMSO to give 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid (C-24) as a solution in DMSO. LCMS Method MC-1: Rt=1.23 min; MS m / z 622.8[M+1]+. LCMS Method MC-2: Rt=1.16 min; MS m / z 622.0[M+1]+.

[0264] Biological Assays and Data Compounds of formula (I) of the present invention were tested in the following cellular assays measuring intracellular cAMP concentration, beta-arrestin recruitment and receptor internalization. cAMP is generated upon activation of GLP1R. The cAMP data obtained are shown in Table 1. Beta-arrestin is recruited upon activation of GLP1R and the data obtained are shown in Table 2. The extent to which GLP1R is internalized into the cell and leaves the cell membrane after activation is also shown in Table 2. The EC for each assay 50 E is defined as the concentration of compound that produces half the maximal response (after baseline correction). max is defined as the maximal response observed for a test compound normalized to the maximal response observed for the endogenous ligand for GLP1R (GLP1(7-36)).

[0265] Human GLP1R cAMP agonist assay Agonist activity of the compounds is determined using the GloSensor™ cAMP assay (Promega Corp.), which measures the change in intracellular concentration of cAMP following ligand activation of a GPCR. The assay uses a biosensor encoded by the pGloSensor™-22F cAMP plasmid (Promega, cat#E2301) with a cAMP binding domain fused to a mutant form of Photinus pyralis luciferase. Binding to cAMP results in a conformational change that promotes a large increase in light output, which can be measured by a luminescence detector. HEK293-SNAP-hGLP1R-GloSensor cells stably overexpressing the human GLP1 receptor (hGLP1R) and pGloSensor™-22F were seeded in white 384-well poly-D-lysine coated plates (Greiner Bio One, cat#781945) in CO2-independent medium (Gibco cat#18045-088 with 1.0% FBS, 2 mM L-glutamine, penicillin and streptomycin) and incubated overnight at 37° C., 5% CO2 with humidity. The assay was initiated the next morning by adding an equal volume of CO2-independent medium containing a 4% v / v dilution of GloSensor substrate (Promega, cat#E1291) to all wells. The cell plates were incubated for 2 hours at room temperature in the dark. A Biomek i7 (Beckman Coulter) instrument was used for liquid handling steps. To generate duplicate dose-response curves, 3-fold serial dilutions of compounds were added to the cell assay plate at final concentrations ranging from 30 μM to 0.06 pM in CO2-independent medium containing 0.1% BSA, 0.5 mM IBMX and 0.4% DMSO in a final volume of 60 μL. EC 100Control wells contained GLP1(7-36) peptide (Bachem, cat#H-6795) at a final concentration of 2 nM and EC0 control wells contained no peptide. After compound was added to the cells, the plate was incubated for 12 minutes at room temperature in the dark. Luminescence was then measured on an Envision 2104 Multilabel reader with a "TRF Light Unit, 337 nm" (PerkinElmer) using the Ultra-Sensitive protocol setting "384-well US Luminescence Detector" with a 384-well emission aperture at 0.1 seconds per well. cAMP activity was measured using the GLP1(7-36)EC0 100 Calculated as a percentage of control wells: [(sample signal-mean EC0 signal) / (mean EC0 signal for GLP1(7-36) signal 100 -Average EC0 signal)*100. EC 50 Curve fitting for the determination was performed in the Helios module of the software package DAVID. A four-parameter logistic model, Hill slope, was used: y = A inf +(A0-A inf ) / (1+(x / AC 50 ) ヒル勾配 ), y is the functional response; x is the compound concentration; A0 is the minimum value (at 0 dose); A inf is the maximum value (at infinite dose); AC 50 is the inflection point (i.e., A0 and A inf The EC corresponds to the midpoint of the sigmoid curve between 50 Values ​​are calculated from Helios in μM. 50 Represented by the value E max is the maximum activity detected within the concentration range derived from the fitted curve.

[0266] Generation of HEK293-SNAP-hGLP1R cell line 327 μL of Opti-MEM medium (Gibco, cat#31985-062) was mixed with 12 μL of FuGENE® HD (Promega, cat#E2311) and incubated at room temperature for 5 min. Then, 8.2 μL (4 μg, 0.485 μg / μL solution) of pSNAP-hGLP1R plasmid encoding human GLP1R fused with SNAP tag (NCBI reference sequence: NM_002062.3) from Cisbio (Cisbio, cat#PSNAP-GLP1) was added to the Fugene HD / Opti-MEM mixture and incubated at room temperature for 20 min. A suspension of HEK293 cells (ATCC® CRL-1573™) was prepared at 800,000 cells / mL. The plasmid / FuGene HD mixture was then added to 8 mL of cells and gently mixed. 2mL of the new mixture was added to 4 wells in a 6-well plate, and 2mL of untransfected cells were added to 2 wells as a control. The plate was incubated at 37°C until 100% confluence. Antibiotic selection [800μg / mL G418 (Geneticin, Gibco, cat#10131-035)] was done after cell trypsinization at a dilution of 2500 cells / mL. 1mL of cell suspension was added to 20mL of selection medium in a 10cm culture dish (total of 2500 cells), and in parallel 4mL of the diluted cell suspension was added to 20mL of selection medium in a 10cm culture dish (total of 10000 cells). The rest of the cells were cultured in a T150 flask. In addition, HEK293 cells were cultured in a T75 flask in selection medium as a negative control. Finally, a single clone was selected from a 10 cm culture dish and cultured until there were enough cells for gene expression analysis and HTRF cAMP assay. Clone 2 showed the highest GLP1R-dependent cAMP response and was expanded for the generation of GloSensor stable cell lines.

[0267] Generation of HEK293-SNAP-hGLP1R-GloSensor stable cell lines HEK293 cells stably overexpressing SNAP-hGLP1R (above) were seeded at a density of 3 million cells in a 10 cm dish containing 17 mL of DMEM complete growth medium (Gibco, cat#11965-092) + 10% fetal bovine serum (FBS, Gibco, cat#16140-071). The next day, cells were transfected as follows: DNA complex was prepared as 0.020 μg / μL pGloSensor™-22F cAMP plasmid (Promega, cat#E2301; GenBank® accession number is GU174434) by adding 37 μg of plasmid DNA in 1758 μL of Opti-MEM solution. Then, 112 μL of FuGENE® HD reagent was added to it by mixing carefully. After 5-10 min incubation at room temperature, 850 μL of complex per well was added to the cells and mixed thoroughly. After 24 h incubation at 37°C, 5% CO2 with humidity, the medium was removed and the cells were rinsed with PBS. Selection medium [600 μg / mL G418 and 600 μg / mL Hygromycin B (Gibco, cat#10687010)] was then added. The medium was changed twice a week until no further dead cells were observed. Once cell clones were visible, single cells were isolated. For that, 10 μL of 0.05% trypsin-EDTA solution was added to single cells by pipetting up and down. These single cell-derived clones were then cultured in 6-well plates with selection medium (600 μg / mL G418 + 600 μg / mL Hygromycin B) until enough cells were available to be tested for cAMP agonist response in the GloSensor luminescence assay. HEK293-SNAP-hGLP1R stable cell clones that produced the desired responses were used for human GLP1R cAMP agonist assays.

[0268] [Table 13]

[0269] Human GLP1R β-arrestin recruitment assay The degree to which agonists recruited β-arrestin was measured using the PathHunter® β-arrestin assay (DiscoverX). This assay uses an enzyme complementation approach to measure the binding of β-arrestin to the receptor. Two inactive moieties of the β-galactosidase enzyme (Prolink and enzyme acceptor, or "EA") are tagged, such that human GLP1R (hGLP1R) contains the Prolink moiety and β-arrestin contains the EA moiety. When β-arrestin is recruited to the receptor, the enzyme becomes active and generates luminescence in the presence of a chemiluminescent substrate (PathHunter® Detection Kit, DiscoverX cat#93-0001). Luminescence can be measured on an appropriate detector. CHO-hGLP1R-β-arrestin cells stably overexpressing Prolink-tagged hGLP1R and EA-tagged β-arrestin were seeded at 20 μL per well in white 384-well poly-D-lysine coated plates (Greiner Bio One, cat#781945) in plating reagent 2 (DiscoverX, cat#93-0563R2A) and incubated overnight at 37° C., 5% CO2 with humidity. The next day, agonists were prepared at 5x the final required concentration. To generate triplicate dose-response curves, compounds were serially diluted 3-fold in assay buffer (HBSS, 10 mM Hepes and 0.1% BSA) and subsequently added to the cell assay plate in a final volume of 25 μL and starting at 30 μM up to the final highest concentration. EC 100Control wells contained GLP1(7-36) peptide (Bachem, cat#H-6795) at a final concentration of 1 μM and EC0 control wells contained no compound. After compound was added to the cells, the plate was incubated at 37° C., 5% CO2 with humidity for 2 hours. Detection reagent was then prepared (19 parts Cell Assay Buffer, 5 parts Substrate Reagent 1 and 1 part Substrate Reagent 2 as per manufacturer's recommendations, DiscoverX cat#93-0001) and 12 μL was added per well to the cell assay plate. The plate was incubated for an additional hour at room temperature in the dark. Luminescence was then measured on an Envision 2104 Multilabel reader with a "TRF Light Unit, 337 nm" (Perkin Elmer) using the Ultra-Sensitive protocol setting "384-well US Luminescence Detector" with a 384-well emission aperture at 0.1 seconds per well. β-arrestin recruitment was measured using Microsoft Excel to calculate the GLP1(7-36)EC0 concentration. 100 Calculated and expressed as a percentage of control wells: [(sample signal-mean EC0 signal) / (mean EC0 signal for GLP1(7-36) signal] 100 -Average EC0 signal)*100. EC 50 Curve fitting for the determination of was performed using GraphPad Prism. A 4-parameter logistic model, Hill slope, was used: Y=Bottom+(Top-Bottom) / (1+10^((Log EC 50 -X)*Hill slope), Y is the functional response; X is the compound concentration; bottom is A0 or the minimum value (at 0 dose); top is A inf or maximum value (at infinite dose);EC 50 is the inflection point (i.e., A0 and A inf The EC is the midpoint of the sigmoid curve between 50 Values ​​were calculated in μM. maxis the maximum activity detected within the concentration range derived from the curve fitted to GLP1(7-36). The reference compound is 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-benzo[d]imidazole-6-carboxylic acid (WO 2019 / 239319, Example 7).

[0270] Generation of CHO-hGLP1R-β-arrestin cell line PathHunter CHO-K1-EA parental cells (DiscoverX, cat#93-0164) were cultured at T75cm in 22mL of complete medium (AssayComplete Cell Culture Kit 107, DiscoverX, cat#92-3107G). 2 Winning 2 x 10 6The cells were seeded at a density of 1000 x 100 cells / well. The next day, the medium was replaced with 22 mL of fresh medium without antibiotics, and the cells were transfected as follows: Plasmid / Fugene® HD transfection mixture was prepared in Opti-MEM medium (3:1 ratio of reagent:DNA). 25 μg (34 μL) of pCMV-PK1-GLP1R plasmid [DiscoverX pCMV PK vector bundle with inserted sequence encoding full-length human GLP1R-NCBI reference sequence, cat#93-0491:NM_002062, synthesized by GeneArt (Thermo Fisher Scientific)] was added to 1129 μL of Opti-MEM for a total volume of 1163 μL. Then, 74 μL of FuGENE® HD reagent was added by careful mixing. After 5-10 min of incubation at room temperature, 1125 μL of complex solution was added to the cells and incubated at 37 °C for 48 h. The medium was then removed and selection medium containing 300 μg / mL hygromycin (Gibco, cat#10687010) and 500 μg / mL geneticin (Gibco, cat#10131035) was added. The medium was changed every 2-3 days until no further dead cells were observed. The cells were detached, resuspended at 300000 cells / mL and filtered through a 40 μm filter. The cells were then FACS sorted into single cells in black clear bottom poly-D-lysine coated 96 well plates in 100 μL medium using an Aria G instrument. The medium was changed every 2-3 days by removing up to 80 μL and adding fresh medium containing the selection antibiotic. Surviving single clones were expanded and tested. Single clone 1 was selected for the β-arrestin assay based on optimal signal and curve profile.

[0271] Human GLP1R DERET internalization assay The extent to which agonists internalize human GLP1R was determined based on an optimized version of a real-time FRET-based "DERET" (Dissociation Enhanced Resonance Energy Transfer) assay. This technique relies on labeling of SNAP-tagged GPCRs with SNAP-Lumi-Terbium (donor fluorophore, Cisbio, cat#SSNPTBD). Compounds are incubated with cells overexpressing the GPCR of interest in the presence of excess fluorescein (acceptor fluorophore). When the GPCR is on the cell surface, the donor signal is quenched by the acceptor and the donor / acceptor ratio is low. As the GPCR internalizes, the donor signal is no longer quenched and the acceptor is no longer excited, thus increasing the donor / acceptor ratio.

[0272] HEK293-SNAP-hGLP1R-GloSensor cells (stably overexpressing SNAP-tagged hGLP1R) were seeded overnight in white 384-well poly-D-lysine coated plates (Greiner Bio One, cat#781945) in regular DMEM growth medium (Gibco, cat#11965-092, 10% heat-inactivated FBS, 10 mM HEPES, 1x penicillin / streptomycin, 0.5 mg / mL geneticin (Gibco, cat#10131-035) and 0.25 mg / mL hygromycin B (Invitrogen, cat#10687010). On the day of assay, cell medium was removed and 100 nM SNAP-Lumi-Tb reagent was added to the Opti-MEM solution. Cells were incubated for 1 hour at 37°C. Cells were washed in assay buffer [1X HBSS (10X Gibco, cat#14065-056), 20 mM Hepes (Gibco, cat#15630-080), 1 mM CaCl2 (Fluka, cat#21114-1L), 1 mM MgCl2 (Ambion, cat#AM9530G) pH 7.4] using a plate washer and 20 μL of 0.1% BSA were added. Buffer was added to each well. Cells were left to equilibrate at 37° C. for approximately 15 minutes before adding 10 μL of fluorescein (sodium salt, Sigma, cat#F6377, diluted in buffer) to a final concentration of 25 μM. To generate triplicate dose-response curves, compounds were serially diluted 3-fold in assay buffer and then added to the cell assay plate in a final volume of 40 μL and starting at 30 μM to the final highest concentration. A GLP1 (7-36) peptide (Bachem, cat#H-6795) control curve, in the same plate and assay buffer as the tested compounds, showed an EC 100EC0 wells containing buffer alone were also included. Plate FRET fluorescence was measured immediately and then every 30 min using a Perkin Elmer Envision equipped with a LANCE / DELFIA D400 single mirror, excitation filter X320, and emission filters M615_203 (donor emission) and M515 (acceptor emission). Peak internalization was reached at 120 min. Plates were maintained at 37°C between readings. Data were expressed as ratios of donor / acceptor emission using Microsoft Excel and plotted in GraphPad Prism. EC for internalization 50 and E max The data was calculated to determine the GLP1(7-36)EC 100 Expressed as a percentage of control wells: [(sample signal-mean EC0 signal) / (mean EC0 of GLP1(7-36) signal 100 -Average EC0 signal)*100. EC 50 Curve fitting for the determination of was performed using GraphPad Prism. A 4-parameter logistic model, Hill slope, was used: Y=Bottom+(Top+Bottom) / (1+10^((LogEC 50 -X)*Hill slope) Y is the functional response; X is the compound concentration; bottom is A0 or the minimum value (at 0 dose); top is A inf or maximum value (at infinite dose);EC 50 is the inflection point (i.e., A0 and A inf The EC is the midpoint of the sigmoid curve between 50 Values ​​were calculated in μM. max is the maximum activity measured within the concentration range derived from the curve fitted to GLP1(7-36).

[0273] [Table 14]

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, During the ceremony, 【Chemistry 2】 is a single bond or a double bond; 【Chemistry 3】 teeth, 【Chemistry 4】 and 【Chemistry 5】 indicates the point of attachment to the remainder of the molecule; W is O or CH ２ and X is O or CH ２ and R １ and R ２ are each independently H, C １～３ selected from alkyl, halo, and CN; R ３ is H and C １～３ - alkyl; R ４ and R ５ teeth, (aa)R ４ is H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -Alkyl-, Phenyl-C １～３ -Alkyl-, halo, CN, NO ２ , OR ４ａ , S.R. ４ａ , C(O)R ４ｂ , C(O)NR ４ｃ R ４ｄ , C(O)NR ４ｃ (OR ４ａ ), C(O)NR ４ｃ (S(O) ２ R ４ｂ ), C(O)NR ４ｃ (S(O) ２ N.R. ４ｃ R ４ｄ ), N.R. ４ｃ OR ４ａ , N.R. ４ｃ R ４ｄ , N.R. ４ｃ (C(O)R ４ｂ ), N.R. ４ｃ (C(O)OR ４ａ ), N(OR ４ａ ) (C(O)R ４ｂ ), N.R. ４ｃ (C(O)NR ４ｃ R ４ｄ ), N.R. ４ｃ (C(O)NR ４ｃ (C(O)R ４ｂ ) ) NR ４ｃ (S(O) ２ R ４ｂ ), N.R. ４ｃ (S(O) ２ N.R. ４ｃ R ４ｄ ), N.R. ４ｃ (C(O)NR ４ｃ (S(O) ２ R ４ｂ )), O.C.(O)R ４ｂ , O.C.(O)NR ４ｃ R ４ｄ , O.N.R. ４ｃ (C(O)R ４ｂ ), OS(O) ２ R ４ｂ , OP(O)(OR ４ｅ ) (OR ４ｆ ), S(O)OR ４ａ , S(O)R ４ｂ , S(O) ２ R ４ｂ , S(O) ２ N.R. ４ｃ R ４ｄ , S(O) ２ OR ４ａ , S (=NR ４ｇ ) (O) R ４ｂ , S (=NR ４ｇ ) (O) N.R. ４ｃ N.R. ４ｄ , P(O)(OR ４ｅ ) (OR ４ｆ ), and P(O)(OR ４ｅ ) (R ４ｆ ) selected from R ４ The above C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl- and phenyl-C １～３ -Alkyl- is halo, CN, NO ２ , OR ４Ａ , S.R. ４Ａ , C(O)R ４Ｂ , C(O)NR ４Ｃ R ４Ｄ , C(O)NR ４Ｃ (OR ４Ａ ), C(O)NR ４Ｃ (S(O) ２ R ４Ｂ ), C(O)NR ４Ｃ (S(O) ２ N.R. ４Ｃ R ４Ｄ ), N.R. ４Ｃ OR ４Ａ , N.R. ４Ｃ R ４Ｄ , N.R. ４Ｃ (C(O)R ４Ｂ ), N.R. ４Ｃ (C(O)OR ４Ａ ), N(OR ４Ａ ) (C(O)R ４Ｂ ), N.R. ４Ｃ (C(O)NR ４Ｃ R ４Ｄ ), N.R. ４Ｃ (C(O)NR ４Ｃ (C(O)R ４Ｂ ) ) NR ４Ｃ (S(O) ２ R ４Ｂ ), N.R. ４Ｃ (S(O) ２ N.R. ４Ｃ R ４Ｄ ), N.R. ４Ｃ (C(O)NR ４Ｃ (S(O) ２ R ４Ｂ )), O.C.(O)R ４Ｂ , O.C.(O)NR ４Ｃ R ４Ｄ , O.N.R. ４Ｃ (C(O)R ４Ｂ ), OS(O) ２ R ４Ｂ , OP(O)(OR ４Ｅ ) (OR ４Ｆ ), S(O)OR ４Ａ , S(O)R ４Ｂ , S(O) ２ R ４Ｂ , S(O) ２ N.R. ４Ｃ R ４Ｄ , S(O) ２ OR ４Ａ , S (=NR ４Ｇ ) (O) R ４Ｂ , S (=NR ４Ｇ ) (O) N.R. ４Ｃ N.R. ４Ｄ , P(O)(OR ４Ｅ ) (OR ４Ｆ ), and P(O)(OR ４Ｅ ) (R ４Ｆ Optionally substituted with 1, 2, or 3 groups independently selected from R ５ is 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C １～３ -alkyl-, and the 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C １～３ -alkyl- is C(O)OR ５Ａ or substituted with a carboxylic acid isostere and halo, CN, NO ２ , OR ５Ａ , S.R. ５Ａ , C １～３ - alkyl, C substituted with 1, 2 or 3 halo １～３ -alkyl, C(O)R ５Ｂ , C(O)NR ５Ｃ R ５Ｄ , C(O)NR ５Ｃ (OR ５Ａ ), C(O)NR ５Ｃ (S(O) ２ R ５Ｂ ), C(O)NR ５Ｃ (S(O) ２ N.R. ５Ｃ R ５Ｄ ), N.R. ５Ｃ OR ５Ａ , N.R. ５Ｃ R ５Ｄ , N.R. ５Ｃ (C(O)R ５Ｂ ), N.R. ５Ｃ (C(O)OR ５Ａ ), N(OR ５Ａ ) (C(O)R ５Ｂ ), N.R. ５Ｃ (C(O)NR ５Ｃ R ５Ｄ ), N.R. ５Ｃ (C(O)NR ５Ｃ (C(O)R ５Ｂ ) ) NR ５Ｃ (S(O) ２ R ５Ｂ ), N.R. ５Ｃ (S(O) ２ N.R. ５Ｃ R ５Ｄ ), N.R. ５Ｃ (C(O)NR ５Ｃ (S(O) ２ R ５Ｂ )), O.C.(O)R ５Ｂ , O.C.(O)NR ５Ｃ R ５Ｄ , O.N.R. ５Ｃ (C(O)R ５Ｂ ), OS(O) ２ R ５Ｂ , OP(O)(OR ５Ｅ ) (OR ５Ｆ ), S(O)OR ５Ａ , S(O)R ５Ｂ , S(O) ２ R ５Ｂ , S(O) ２ N.R. ５Ｃ R ５Ｄ , S(O) ２ OR ５Ａ , S (=NR ５Ｇ ) (O) R ５Ｂ , S (=NR ５Ｇ ) (O) N.R. ５Ｃ N.R. ５Ｄ , P(O)(OR ５Ｅ ) (OR ５Ｆ ), and P(O)(OR ５Ｅ ) (R ５Ｆ or (bb) R ４ is 5- to 10-membered heteroaryl or (5- to 10-membered heteroaryl)-C １～３ -alkyl-, and the 5- to 10-membered heteroaryl and (5- to 10-membered heteroaryl)-C １～３ -alkyl- is C(O)OR substituted with ４Ａ or substituted with a carboxylic acid isostere and halo, CN, NO ２ , OR ４Ａ , S.R. ４Ａ , C １～３ - alkyl, C substituted with 1, 2 or 3 halo １～３ -alkyl, C(O)R ４Ｂ , C(O)NR ４Ｃ R ４Ｄ , C(O)NR ４Ｃ (OR ４Ａ ), C(O)NR ４Ｃ (S(O) ２ R ４Ｂ ), C(O)NR ４Ｃ (S(O) ２ N.R. ４Ｃ R ４Ｄ ), N.R. ４Ｃ OR ４Ａ , N.R. ４Ｃ R ４Ｄ , N.R. ４Ｃ (C(O)R ４Ｂ ), N.R. ４Ｃ (C(O)OR ４Ａ ), N(OR ４Ａ ) (C(O)R ４Ｂ ), N.R. ４Ｃ (C(O)NR ４Ｃ R ４Ｄ ), N.R. ４Ｃ (C(O)NR ４Ｃ (C(O)R ４Ｂ ) ) NR ４Ｃ (S(O) ２ R ４Ｂ ), N.R. ４Ｃ (S(O) ２ N.R. ４Ｃ R ４Ｄ ), N.R. ４Ｃ (C(O)NR ４Ｃ (S(O) ２ R ４Ｂ )), O.C.(O)R ４Ｂ , O.C.(O)NR ４Ｃ R ４Ｄ , O.N.R. ４Ｃ (C(O)R ４Ｂ ), OS(O) ２ R ４Ｂ , OP(O)(OR ４Ｅ ) (OR ４Ｆ ), S(O)OR ４Ａ , S(O)R ４Ｂ , S(O) ２ R ４Ｂ , S(O) ２ N.R. ４Ｃ R ４Ｄ , S(O) ２ OR ４Ａ , S (=NR ４Ｇ ) (O) R ４Ｂ , S (=NR ４Ｇ ) (O) N.R. ４Ｃ N.R. ４Ｄ , P(O)(OR ４Ｅ ) (OR ４Ｆ ), and P(O)(OR ４Ｅ ) (R ４Ｆ Optionally substituted with 1, 2, or 3 groups independently selected from R ５ is H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl, (4- to 10-membered heterocycloalkyl)-C １～３ -Alkyl-, Phenyl-C １～３ -Alkyl-, halo, CN, NO ２ , OR ５ａ , S.R. ５ａ , C(O)R ５ｂ , C(O)NR ５ｃ R ５ｄ , C(O)NR ５ｃ (OR ５ａ ), C(O)NR ５ｃ (S(O) ２ R ５ｂ ), C(O)NR ５ｃ (S(O) ２ N.R. ５ｃ R ５ｄ ), N.R. ５ｃ OR ５ａ , N.R. ５ｃ R ５ｄ , N.R. ５ｃ (C(O)R ５ｂ ), N.R. ５ｃ (C(O)OR ５ａ ), N(OR ５ａ ) (C(O)R ５ｂ ), N.R. ５ｃ (C(O)NR ５ｃ R ５ｄ ), N.R. ５ｃ (C(O)NR ５ｃ (C(O)R ５ｂ ) ) NR ５ｃ (S(O) ２ R ５ｂ ), N.R. ５ｃ (S(O) ２ N.R. ５ｃ R ５ｄ ), N.R. ５ｃ (C(O)NR ５ｃ (S(O) ２ R ５ｂ )), O.C.(O)R ５ｂ , O.C.(O)NR ５ｃ R ５ｄ , O.N.R. ５ｃ (C(O)R ５ｂ ), OS(O) ２ R ５ｂ , OP(O)(OR ５ｅ ) (OR ５ｆ ), S(O)OR ５ａ , S(O)R ５ｂ , S(O) ２ R ５ｂ , S(O) ２ N.R. ５ｃ R ５ｄ , S(O) ２ OR ５ａ , S (=NR ５ｇ ) (O) R ５ｂ , S (=NR ５ｇ ) (O) N.R. ５ｃ N.R. ５ｄ , P(O)(OR ５ｅ ) (OR ５ｆ ), and P(O)(OR ５ｅ ) (R ５ｆ ) selected from R ５ The above C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, C ３～６ -Cycloalkyl-C １～３ -alkyl-, (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl- and phenyl-C １～３ -Alkyl- is halo, CN, NO ２ , OR ５Ａ , S.R. ５Ａ , C(O)R ５Ｂ , C(O)NR ５Ｃ R ５Ｄ , C(O)NR ５Ｃ (OR ５Ａ ), C(O)NR ５Ｃ (S(O) ２ R ５Ｂ ), C(O)NR ５Ｃ (S(O) ２ N.R. ５Ｃ R ５Ｄ ), N.R. ５Ｃ OR ５Ａ , N.R. ５Ｃ R ５Ｄ , N.R. ５Ｃ (C(O)R ５Ｂ ), N.R. ５Ｃ (C(O)OR ５Ａ ), N(OR ５Ａ ) (C(O)R ５Ｂ ), N.R. ５Ｃ (C(O)NR ５Ｃ R ５Ｄ ), N.R. ５Ｃ (C(O)NR ５Ｃ (C(O)R ５Ｂ ) ) NR ５Ｃ (S(O) ２ R ５Ｂ ), N.R. ５Ｃ (S(O) ２ N.R. ５Ｃ R ５Ｄ ), N.R. ５Ｃ (C(O)NR ５Ｃ (S(O) ２ R ５Ｂ )), O.C.(O)R ５Ｂ , O.C.(O)NR ５Ｃ R ５Ｄ , O.N.R. ５Ｃ (C(O)R ５Ｂ ), OS(O) ２ R ５Ｂ , OP(O)(OR ５Ｅ ) (OR ５Ｆ ), S(O)OR ５Ａ , S(O)R ５Ｂ , S(O) ２ R ５Ｂ , S(O) ２ N.R. ５Ｃ R ５Ｄ , S(O) ２ OR ５Ａ , S (=NR ５Ｇ ) (O) R ５Ｂ , S (=NR ５Ｇ ) (O) N.R. ５Ｃ N.R. ５Ｄ , P(O)(OR ５Ｅ ) (OR ５Ｆ ), and P(O)(OR ５Ｅ ) (R ５Ｆ Optionally substituted with 1, 2, or 3 groups independently selected from ６ is (4 to 10 membered heterocycloalkyl)-C １～３ -alkyl- and (5- to 10-membered heteroaryl)-C １～３ -alkyl-, wherein R6 is selected from the (4- to 10-membered heterocycloalkyl)-C １～３ -alkyl- and (5- to 10-membered heteroaryl)-C １～３ -alkyl- is C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo; and R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４ｅ , R ４ｆ , and R ４ｇ are each independently H and C １～６ - alkyl; R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is, respectively, —OH, halo, and —OC(O)—C １～１５ -alkyl; and R ４Ａ , R ４Ｂ , R ４Ｃ , and R ４Ｄ The above C ３～６ -cycloalkyl, 4- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl-C １～３ - alkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ４Ｅ , R ４Ｆ , and R ４Ｇ are each independently H and C １～６ - alkyl; R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ are each independently H, C １～６ -Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ - selected from cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl; R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Each alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from —OH and halo, and R ５ａ , R ５ｂ , R ５ｃ , and R ５ｄ The above C ３～６ -Cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ５ｅ , R ５ｆ , and R ５ｇ are each independently H and C １～６ - alkyl; R ５Ａ , R ５Ｂ , R ５Ｃ , and R ５Ｄ The above C １～６ -Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is, respectively, —OH, halo, and —OC(O)—C １～１５ -alkyl; and R ５Ａ , R ４Ｂ , R ５Ｃ , and R ５Ｄ The above C ３～６ -cycloalkyl, 4- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl-C １～３ - alkyl, 5- to 10-membered heteroaryl, and phenyl are each C １～６ -optionally substituted with 1, 2, or 3 groups independently selected from alkyl, -OH, and halo; R ５Ｅ , R ５Ｆ , and R ５Ｇ are each independently H and C １～６ - selected from alkyl; Selected from A compound, or a pharma- ceutically acceptable salt thereof.

2. R １ is chloro, fluoro or CN; and R ２ is chloro or fluoro, and R ３ But -CH ３ 2. The compound of claim 1, wherein:

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

4. R ４ But, C １～３ - C substituted with alkyl or 1, 2 or 3 halo １～３ -alkyl, or a pharma- ceutically acceptable salt thereof.

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

6. R ５ But, C １～３ - C substituted with alkyl or 1, 2 or 3 halo １～３ -alkyl, or a pharma- ceutically acceptable salt thereof.

7. R ４ But C(O)OR ４Ａ and substituted with halo, C １～３ - C substituted with alkyl and 1, 2 or 3 halo １～３ -alkyl; ４Ａ But H and C １～３ 7. The compound according to claim 5 or claim 6, or a pharma- ceutically acceptable salt thereof, wherein:

8. R ４ Formula H1a or H2a 【Chemistry 6】 having the structure: The ring is aromatic, X １ is C and X ２ , X ３ , X ４ , X ５ , and X ６ each independently represents C=O, CR ４ｈ , N.R. ４ｉ , O, or S; X ２ ~X ６ at least one of is N, O, or S; R ４Ａ But H and C １～３ - alkyl; and If present, R ４ｈ But, Halo, C １～３ - C substituted with alkyl or 1, 2 or 3 halo １～３ -alkyl and R ４ｉ But, C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

9. R ４ but, 【Chemistry 7】 is selected from the group consisting of Ra, Rb and Rc are H, C １～３ - C substituted with alkyl and 1, 2 or 3 halo １～３ -alkyl, and R ４Ａ But H and C １～３ 6. The compound of claim 5, or a pharma- ceutically acceptable salt thereof, wherein:

10. R ５ But C(O)OR ５Ａ and substituted with halo, C １～３ - C substituted with alkyl and 1, 2 or 3 halo １～３ -alkyl; R ５Ａ But H and C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein:

11. R ５ Formula H11a or H12a: 【Chemistry 8】 The structure is The ring is aromatic, X １ is C and X ２ , X ３ , X ４ , X ５ , and X ６ each independently represents C=O, CR ５ｈ , N.R. ５ｉ , O, or S; X ２ ~X ６ at least one of is N, O, or S; R ５Ａ But H and C １～３ - alkyl; and If present, R ５ｈ But, Halo, C １～３ - C substituted with alkyl or 1, 2 or 3 halo １～３ -alkyl and R ５ｉ But, C １～３ -alkyl), or a pharma- ceutically acceptable salt thereof.

12. R ５ but, 【Chemistry 9】 Selected from the group consisting of: Ra, Rb and Rc are H, C １～３ - C substituted with alkyl and 1, 2 or 3 halo １～３ -alkyl, and R ５Ａ But H and C １～３ 12. The compound of claim 10 or claim 11, or a pharma- ceutically acceptable salt thereof, wherein:

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

14. R ６ But the formula: 【Chemistry 10】 and 【Chemistry 11】 14. The compound of claim 13, or a pharma- ceutically acceptable salt thereof, wherein indicates the point of attachment to the remainder of the molecule.

15. Compound of formula (IIa): 【Chemistry 12】 2. The compound of claim 1, wherein:

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

17.

14. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 2. The compound of claim 1, selected from the group consisting of:

18. 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-ethyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5-methyloxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-(trifluoromethyl)oxazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4-methyloxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-3-methylfuran-2-carboxylic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-2-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-1-methyl-1H-pyrazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)nicotinic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)oxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1,3,4-oxadiazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-3-carboxylic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoxazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1-methyl-1H-pyrazole-3-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)nicotinic acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2-carboxylic acid, and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)oxazole-5-carboxylic acid, and ethyl 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5-methyloxazole-4-carboxylate, 2. The compound of claim 1, selected from the group consisting of:

19. 10. A pharmaceutical composition comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers.

20. 13. A combination comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and one or more therapeutically active agents.

21. A pharmaceutical comprising the compound of claim 1, or a pharma- ceutically acceptable salt thereof.

22. A pharmaceutical for the treatment of a disorder or disease selected from obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more diabetic complications, diabetic nephropathy, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy, comprising the compound of claim 1 or a pharma-ceutical acceptable salt thereof.

23. A pharmaceutical composition for use in a method of stimulating GLP1R activity in a subject, comprising a compound according to claim 1, or a pharma- ceutically acceptable salt thereof, said method comprising administering to said subject a therapeutically effective amount of said compound, or a pharma- ceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound of claim 1, or a pharma- ceutically acceptable salt thereof, for use in a method for treating a disorder or disease selected from 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 in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound, or a pharma- ceutically acceptable salt thereof.

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