TW202342014A - 1,3-benzodioxole derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I):

Description

1,3-Benzodioxolane derivatives

The present invention relates to 1,3-benzodioxolane derivatives, their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions, diseases and Use in Obstacles.

The glucagon-like peptide 1 receptor (GLP1R) belongs to the B1 family 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 [Endocrinology Reviews]. 20:876-913 (1999); Drucker, DJ, Endocrinology [Endocrinology] 142:521-7 (2001); Hoist, JJ, Diabetes Metab. Res. Rev. [Diabetes Metab. Reviews] 18:430-41 (2002); Regard JB, Cell 135:561-71 (2008)). The GLP1R natural agonist ligands GLP-1 (7-36, 30 aa) and oxyntomodulin (OXM, 37 aa), both derived from proglucagon. Upon activation, GLP1R couples to G _αs protein, followed by adenylyl cyclase activation and increased intracellular cAMP levels, thereby enhancing glucose-stimulated insulin secretion in pancreatic β-cells. Therefore, GLP1R is an attractive therapeutic target for lowering blood glucose in diabetic patients. Several GLP1R agonist peptides are under development (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide ), semaglutide) to treat patients with diabetes, NASH, and/or obesity.

Obesity is a highly prevalent chronic disease in modern society and is associated with many comorbidities, including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly associated with type 2 diabetes mellitus (T2DM) and insulin resistance, the latter of which is often accompanied by hyperinsulinemia or hyperglycemia, or both. Additionally, T2DM is associated with a twofold to fourfold increased risk of coronary artery disease. Currently, the most effective treatment for obesity is bariatric surgery, however, this is expensive and risky for patients. Therefore, pharmacological alternatives to surgery for obesity treatment are attractive alternatives. Even so, pharmacological interventions used to treat obesity have proven less effective than surgical obesity treatments and are also associated with side effects. Among the marketed GLP1R agonist peptides, liraglutide has been approved as a once-daily treatment for obesity. Semaglutide is currently in Phase 3 clinical trials as a once-weekly treatment for obesity. Currently, there are no approved pharmacologic therapies for the remission of type 2 diabetes in adults who are unable to maintain normal glycemic control with antidiabetic agents and/or insulin due to insulin resistance, and for heart failure with preserved ejection fraction (HFpEF) , there are no approved drug treatments. Alternatively, GLP1R agonists may be effective therapies for T2DM remission. GLP1R receptor agonists reduce the risk of cardiovascular death and hospitalization in patients with chronic HFpEF.

Therefore, metabolic disorders can potentially be treated with small molecule agonists of GLP1R.

In particular, the present invention provides compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein the component members are as defined herein.

As defined herein, compounds of formula (I) and pharmaceutically acceptable salts thereof are GLP1R agonists. Accordingly, the compounds are useful in the treatment of metabolic diseases, disorders and conditions, such as 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, dyslipidemia, and cardiovascular disease. The compounds may also be used to treat progressive liver disease and neuropathy.

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

Provided herein are methods of agonizing or activating the glucagon-like peptide 1 receptor (GLP1R), comprising contacting the GLP1R with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

Provided herein are methods of treating, preventing, or ameliorating a disease, disorder, or condition in a patient selected from the group consisting of 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), the method comprising administering (e.g., a therapeutically effective amount) of a compound of formula (I) or a pharmaceutical thereof to the patient. with an acceptable salt.

Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in any of the methods described herein.

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

The compounds of the invention may exhibit favorable ADME (absorption, distribution, metabolism and excretion) properties, e.g., in vivo exposure (in particular, when administered orally), e.g., by measuring certain pharmacokinetic parameters such as plasma It is presented for the highest concentration (C _max ) and/or total exposure (area under the curve (AUC) value).

Various aspects and embodiments of the invention are described herein. It will be appreciated that, for clarity (and/or brevity), certain features are specified in the context of individual embodiments, however, such embodiments may be combined with other specified features (e.g., in any suitable sub- combination) to provide additional embodiments of the invention.

The definitions of substituents apply to substituents provided herein having any formula, for example, formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb) , (V), (Va) and (Vb) compounds (as appropriate). The definition of substituents applies to the final product as well as to the corresponding intermediates (as appropriate).

In one aspect, provided herein are compounds of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein, It is a single bond or a double bond; department , in indicates the point of attachment to the rest of the molecule; W is O or _CH2 ; X is O or _CH2 ; ^R1 and ^R2 are each independently selected from H, _C1-3 -alkyl, halogen and CN; R ³ is selected from H and C _1-3 -alkyl; R ⁴ (a) is selected from 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-, halogen, CN, NO ₂ , OR ^4a , SR ^4a , C(O)R ^4b , C(O)NR ^4c R ^4d , C(O)NR ^4c (OR ^4a ), C(O)NR ^4c (S(O) ₂ R ^4b ), C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c OR ^4a , NR ^4c R ^4d , NR ^4c (C(O)R ^4b ), NR ^4c (C(O)OR ^4a ), N(OR ^4a ) (C(O)R ^4b ), NR ^4c (C(O)NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (C(O)R ^4b )), NR ^4c (S(O) ₂ R ^4b ), NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c (C(O) )NR ^4c (S(O) ₂ R ^4b )), OC(O)R ^4b , OC(O)NR ^4c R ^4d , ONR ^4c (C(O)R ^4b ), OS(O) ₂ R ^4b , OP (O)(OR ^4e )(OR ^4f )、S(O)OR ^4a 、S(O)R ^4b 、S(O) ₂ R ^4b 、S(O) ₂ NR ^4c R ^4d 、S(O) ₂ OR ^4a , S(=NR ^4g )(O)R ^4b , S(=NR ^4g )(O)NR ^4c NR ^4d , P(O)(OR ^4e )(OR ^4f ), and P(O)(OR ^4e ) (R ^4f ), wherein R ⁴ is C _1-6 -alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, benzene base, C _3-6 -cycloalkyl-C _1-3 -alkyl-, (4-10 membered heterocycloalkyl)-C _1-3 -alkyl-, and phenyl-C _1-3 -alkyl Groups - each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A ) (C(O)R ^4B ), NR ^4C (C(O) NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ) , NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS( O) ₂ R ^4B 、OP(O)(OR ^4E )(OR ^4F )、S(O)OR ^4A 、S(O)R ^4B 、S(O) ₂ R ^4B 、S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P (O)(OR ^4E )(R ^4F ), or R ⁴ is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5- 10-membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 -alkyl-are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1, 2, or 3 substituted with a group independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _{1-3 -alkyl, C 1-3 -alkyl} substituted by 1, 2 or 3 halogens, C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C ( S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C (O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ) , NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O ) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D ,P (O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ); R ⁵ (a) is selected from 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-, halogen, CN, NO ₂ , 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) ₂ R ^5b )、C(O)NR ^5c (S(O) ₂ NR ^5c R ^5d ) , NR ^5c OR ^5a , NR ^5c R ^5d , NR ^5c (C(O)R ^5b ), NR ^5c (C(O)OR ^5a ), N(OR ^5a ) (C(O)R ^5b ), NR ^5c ( C(O)NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (C(O)R ^5b )), NR ^5c (S(O) ₂ R ^5b ), NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (S(O) ₂ R ^5b )), OC(O)R ^5b , OC(O)NR ^5c R ^5d , ONR ^5c (C(O)R ^5b ), OS(O) ₂ R ^5b , OP(O)(OR ^5e )(OR ^5f ), S(O)OR ^5a , S(O)R ^5b , S(O) ₂ R ^5b , S(O) ₂ NR ^5c R ^5d 、S(O) ₂ OR ^5a 、S(=NR ^5g )(O)R ^5b 、S(=NR ^5g )(O)NR ^5c NR ^5d 、P(O)(OR ^5e )(OR ^5f ), and P(O)(OR ^5e )(R ^5f ), wherein R ⁵ is 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- are each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , 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) ₂ R ^5B )、C(O)NR ^5C (S(O ) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A )(C(O) R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ), OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ), S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B 、S(O) ₂ NR ^5C R ^5D 、S(O) ₂ OR ^5A 、S(=NR ^5G )(O)R ^5B 、S(=NR ^5G )(O)NR ^5C NR ^5D 、P(O) (OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), or R ⁵ is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _{1 -3} -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each isoselected by C(O)OR ^5A or carboxylic acid body and optionally substituted by 1, 2, or 3 groups independently selected from the following: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, by 1, 2 or 3 Halogen-substituted C _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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O) OR ^5A ), N(OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O) R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) , S(O)OR ^5A ,S(O)R ^5B ,S(O) ₂ R ^5B ,S(O) ₂ NR ^5C R ^5D ,S(O) ₂ OR ^5A ,S(=NR ^5G )(O)R ^5B ,S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); R ⁶ is selected from (4-10 membered heterocycloalkyl) )-C _1-3 -alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein R ⁶ is (4-10 membered heterocycloalkyl)-C _1-3 - Alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each independently selected from 1, 2, or 3, as appropriate, from C _1-6 -alkyl, -OH, and halogen Substituted with a group; R ^4a , R ^4b , R ^4c , and R ^4d are each independently selected from 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, wherein R ^4a , R ^4b , R ^4c , and R ^4d are C _1-6 -alkyl, C _{2 -6} alkenyl, and C _2-6 alkynyl are each optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; and R ^4a , R ^4b , R ^4c , and R ^4d Each of C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl is optionally independently selected from C _1-6 -alkanes. Substituted with radicals, -OH, and halogen; R ^4e , R ^4f , and R ^4g are each independently selected from H and C _1-6 -alkyl; R ^4A , R ^4B , R ^4C , and R ^4D are each independently selected is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycle Alkyl-C _1-3 -alkyl-, 5-10 membered heteroaryl, and phenyl, wherein R ^4A , R ^4B , R ^4C , and R ^4D are C _1-6 -alkyl, C _2-6 Alkenyl, and C _2-6 alkynyl are each optionally substituted with 1, 2, or 3 groups independently selected from -OH, halogen, and -OC(O)-C _1-15 -alkyl; and R C _3-6 -cycloalkyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkyl-C _1-3 -alkyl-, 5- of ^4A , R ^4B , R ^4C , and R ^4D 10-membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen; R ^4E , R ^4F , and R ^4G is each independently selected from H and C _1-6 -alkyl; R ^5a , R ^5b , R ^5c , and R ^5d are each independently selected from 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, wherein R ^5a , R ^5b , R ^5c , and R ^5d The C _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups are each optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; and R ^5a , R ^5b , R ^5c , and R ^5d , C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, and phenyl are each optionally replaced by 1, 2, or 3 Substituted with a group independently selected from C _1-6 -alkyl, -OH, and halogen; R ^5e , R ^5f , and R ^5g are each independently selected from H and C _1-6 -alkyl; R ^5A , R ^5B , R ^5C , and R ^5D are each independently selected from 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, wherein C of R ^5A , R ^5B , R ^5C , and R ^5D _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are each independently selected from -OH, halogen, and -OC(O)-C _1- by 1, 2, or 3 as appropriate. ₁₅ -alkyl group substitution; and C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl for R ^5A , R ^5B , R ^5C , and R ^5D - Each of C _1-3 -alkyl-, 5-10 membered heteroaryl, and phenyl is optionally selected from 1, 2, or 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen. group substitution; and R ^5E , R ^5F , and R ^5G are each independently selected from H and C _1-6 -alkyl.

In a preferred embodiment of the invention, this article provides a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein, It is a single bond or a double bond; department , in indicates the point of attachment to the rest of the molecule; W is O or _CH2 ; X is O or _CH2 ; ^R1 and ^R2 are each independently selected from H, _C1-3 -alkyl, halogen and CN; R ³ is selected from H and C _1-3 -alkyl; R ⁴ and R ⁵ are selected from: (aa) R ⁴ is selected from 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 base)-C _1-3 -alkyl-, phenyl-C _1-3 -alkyl-, halogen, CN, NO ₂ , OR ^4a , SR ^4a , C(O)R ^4b , C(O)NR ^4c R ^4d , C(O)NR ^4c (OR ^4a ), C(O)NR ^4c (S(O) ₂ R ^4b ), C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c OR ^4a , NR ^4c R ^4d , NR ^4c (C(O)R ^4b ), NR ^4c (C(O)OR ^4a ), N(OR ^4a )(C(O)R ^4b ), NR ^4c (C(O) )NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (C(O)R ^4b )), NR ^4c (S(O) ₂ R ^4b ), NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (S(O) ₂ R ^4b )), OC(O)R ^4b , OC(O)NR ^4c R ^4d , ONR ^4c (C(O)R ^4b ), OS (O) ₂ R ^4b 、OP(O)(OR ^4e )(OR ^4f )、S(O)OR ^4a 、S(O)R ^4b 、S(O) ₂ R ^4b 、S(O) ₂ NR ^4c R ^4d , S(O) ₂ OR ^4a , S(=NR ^4g )(O)R ^4b , S(=NR ^4g )(O)NR ^4c NR ^4d , P(O)(OR ^4e )(OR ^4f ), and P(O)(OR ^4e )(R ^4f ), wherein R ⁴ is 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 benzene The radicals - C _1-3 -alkyl - are each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ) , NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S( O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C( O)R ^4B )、OS(O) ₂ R ^4B 、OP(O)(OR ^4E )(OR ^4F )、S(O)OR ^4A 、S(O)R ^4B 、S(O) ₂ R ^4B 、S (O) ₂ NR ^4C R ^4D 、S(O) ₂ OR ^4A 、S(=NR ^4G )(O)R ^4B 、S(=NR ^4G )(O)NR ^4C NR ^4D 、P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), and R ⁵ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl- , wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^5A or by a carboxylic acid isostere and optionally by 1 , 2, or 3 substituted groups independently selected from the following: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, C _1- substituted by 1, 2 or 3 halogens 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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N( OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O ) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O )NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) , S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G )(O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); or (bb) R ⁴ is a 5-10 membered heteroaryl or (5-10 ((5-10-membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^4A may be substituted by a carboxylic acid isostere and optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl , C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O) NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ) ,NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C (O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O )R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), and R ⁵ is selected from 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-, halogen, CN, NO ₂ , 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) ₂ R ^5b ), C(O)NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c OR ^5a , NR ^5c R ^5d , NR ^5c (C(O)R ^5b ), NR ^5c (C(O)OR ^5a ), N(OR ^5a )(C(O)R ^5b ), NR ^5c (C(O)NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (C(O)R ^5b )), NR ^5c (S (O) ₂ R ^5b ), NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (S(O) ₂ R ^5b )), OC(O)R ^5b , OC (O)NR ^5c R ^5d 、ONR ^5c (C(O)R ^5b )、OS(O) ₂ R ^5b 、OP(O)(OR ^5e )(OR ^5f )、S(O)OR ^5a 、S(O )R ^5b , S(O) ₂ R ^5b , S(O) ₂ NR ^5c R ^5d , S(O) ₂ OR ^5a , S(=NR ^5g )(O)R ^5b , S(=NR ^5g )(O )NR ^5c NR ^5d , P(O)(OR ^5e )(OR ^5f ), and P(O)(OR ^5e )(R ^5f ), where R ⁵ is C _1-6 alkyl, C _2-6 alkene Base, 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- are each optionally substituted with 1, 2, or 3 groups independently selected from the following : Halogen, CN, NO ₂ , 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) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C (O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC (O)R ^5B 、OC(O)NR ^5C R ^5D 、ONR ^5C (C(O)R ^5B )、OS(O) ₂ R ^5B 、OP(O)(OR ^5E )(OR ^5F )、S(O )OR ^5A 、S(O)R ^5B 、S(O) ₂ R ^5B 、S(O) ₂ NR ^5C R ^5D 、S(O) ₂ OR ^5A 、S(=NR ^5G )(O)R ^5B 、S (=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); R ⁶ is selected from (4-10 members Cycloalkyl)-C _1-3 -alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl-, where R ⁶ is (4-10 membered heterocycloalkyl)-C _{1 -3} -alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each independently selected from 1, 2, or 3 C _1-6 -alkyl, -OH as appropriate , and halogen group substitution; R ^4a , R ^4b , R ^4c , and R ^4d are each independently selected from 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, wherein R ^4a , R ^4b , R ^4c , and R ^4d are C _1-6 -alkyl , C _2-6 alkenyl, and C _2-6 alkynyl are each optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; and R ^4a , R ^4b , R ^4c , and Each of the C _3-6 -cycloalkyl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl, and phenyl groups of R ^4d is independently selected from C _1- Group substitution of ₆ -alkyl, -OH, and halogen; R ^4e , R ^4f , and R ^4g are each independently selected from H and C _1-6 -alkyl; R ^4A , R ^4B , R ^4C , and R ^4D is each independently selected from 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, wherein R ^4A , R ^4B , R ^4C , and R ^4D are C _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are each optionally substituted with 1, 2, or 3 groups independently selected from -OH, halogen, and -OC(O)-C _1-15 -alkyl ; And R ^4A , R ^4B , R ^4C , and R ^4D are C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl-C _1-3 -alkyl- , 5-10 membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen; R ^4E , R ^4F , and R ^4G are each independently selected from H and C _1-6 -alkyl; R ^5a , R ^5b , R ^5c , and R ^5d are each independently selected from 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, wherein R ^5a , R ^5b , R ^5c , and R ^5d 's C _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups are each optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; And the C _3-6 -cycloalkyl group, 4-10-membered heterocycloalkyl group, 5-10-membered heteroaryl group, and phenyl group of R ^5a , R ^5b , R ^5c , and R ^5d are each optionally replaced by 1 or 2 , or substituted by 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen; R ^5e , R ^5f , and R ^5g are each independently selected from H and C _1-6 -alkyl; R ^5A , R ^5B , R ^5C , and R ^5D are each independently selected from 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, wherein R ^5A , R ^5B , R ^5C , and R The C _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups of ^5D are each independently selected from -OH, halogen, and -OC(O)- by 1, 2, or 3 as needed. C _1-15 -alkyl group substitution; and R ^5A , R ^5B , R ^5C , and R ^5D are C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycle Alkyl-C _1-3 -alkyl-, 5-10 membered heteroaryl, and phenyl are each optionally independently selected from 1, 2, or 3 C _1-6 -alkyl, -OH, and The group of halogen is substituted; and R ^5E , R ^5F , and R ^5G are each independently selected from H and C _1-6 -alkyl.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, ^R1 is halogen.

In embodiments of a compound of formula (I), or a pharmaceutically acceptable salt thereof, ^R1 is CN.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, ^R2 is halogen.

In embodiments of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, ^R1 is chlorine, fluorine, or CN; and ^R2 is chlorine or fluorine.

In embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, R ¹ is chlorine; and R ² is fluoro.

In embodiments of compounds of Formula (I), or a pharmaceutically acceptable salt thereof, ^R1 is CN; and ^R2 is chlorine or fluoro.

In embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, ^R1 is CN; and ^R2 is fluoro.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, ^R3 is H or _-CH3 .

In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, ^R3 is _-CH3 .

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ (a) is selected from 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-, halogen, CN, NO ₂ , OR ^4a , SR ^4a , C(O)R ^4b , C(O)NR ^4c R ^4d , C(O)NR ^4c (OR ^4a ), C(O)NR ^4c (S(O) ₂ R ^4b ), C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c OR ^4a , NR ^4c R ^4d 、NR ^4c (C(O)R ^4b )、NR ^4c (C(O)OR ^4a )、N(OR ^4a )(C(O)R ^4b )、NR ^4c (C(O)NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (C(O)R ^4b )), NR ^4c (S(O) ₂ R ^4b ), NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (S(O) ₂ R ^4b )), OC(O)R ^4b , OC(O)NR ^4c R ^4d , ONR ^4c (C(O)R ^4b ), OS(O) ₂ R ^4b 、OP(O)(OR ^4e )(OR ^4f )、S(O)OR ^4a 、S(O)R ^4b 、S(O) ₂ R ^4b 、S(O) ₂ NR ^4c R ^4d 、S (O) ₂ OR ^4a , S(=NR ^4g )(O)R ^4b , S(=NR ^4g )(O)NR ^4c NR ^4d , P(O)(OR ^4e )(OR ^4f ), and P(O )(OR ^4e )(R ^4f ), wherein R ⁴ is C _1-6 -alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, 4-10 membered hetero Cycloalkyl, phenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl-, (4-10 membered heterocycloalkyl)-C _1-3 -alkyl-, and phenyl-C _1-3 -Alkyl- each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C(O)R ^4B , C( O)NR ^4C R ^4D 、C(O)NR ^4C (OR ^4A )、C(O)NR ^4C (S(O) ₂ R ^4B )、C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A ) (C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D 、S(O) ₂ OR ^4A 、S(=NR ^4G )(O)R ^4B 、S(=NR ^4G )(O)NR ^4C NR ^4D 、P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), or R ⁴ is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl- , wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1 , 2, or 3 substituted groups independently selected from the following: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl, C _1- substituted by 1, 2 or 3 halogens 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 NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N( OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O ) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O )NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ) , OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ) , S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), where 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 are as defined herein.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ (a) is selected from C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and halogen, wherein R ⁴ is C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, Each of C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen and C _1-3 -alkyl, Or R ⁴ is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl Aryl) -C _1-3 -alkyl - each substituted by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1, 2, or 3 groups independently selected from: Halogen , C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^4A is selected from H and C _1-3 -alkyl.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, For example methyl, ethyl or trifluoromethyl.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl- , wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1 , 2 or 3 substituted groups independently selected from the following: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl, C _1-3 substituted by 1, 2 or 3 halogens -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 NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O) NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ) , OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ) , S(O)OR ^4A , S(O)R ^4B ,S(O) ₂ R ^4B ,S(O) ₂ NR ^4C R ^4D ,S(O) ₂ OR ^4A ,S(=NR ^4G )(O)R ^4B ,S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), where R ^4A , R ^4B , R ^4C , R ^4D , R ^4E , R ^4F and R ^4G is as defined herein.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁴ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl- , wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1 , 2, or 3 substituted with groups independently selected from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^4A is selected from H and C _1-3 -alkyl.

In embodiments having a compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R has the structure of formula H1 or H2: where: _X1 is C or N, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR4h , ^NR4i , O, or S; C(O)OR ^4A or carboxylic acid isostere; each is a single bond or a double bond; each R ^4h is independently selected from 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-, halogen, CN, NO ₂ , OR ^4a , SR ^4a , C(O)OR ^4a , C(O)R ^4b , C(O)NR ^4c R ^4d , C(O)NR ^4c (OR ^4a ), C(O)NR ^4c (S(O) ₂ R ^4b ), C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c OR ^4a , NR ^4c R ^4d , NR ^4c (C(O)R ^4b ), NR ^4c (C(O)OR ^4a ), N(OR ^4a )(C(O)R ^4b ), NR ^4c (C(O)NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (C(O)R ^4b )), NR ^4c (S (O) ₂ R ^4b ), NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (S(O) ₂ R ^4b )), OC(O)R ^4b , OC (O)NR ^4c R ^4d 、ONR ^4c (C(O)R ^4b )、OS(O) ₂ R ^4b 、OP(O)(OR ^4e )(OR ^4f )、S(O)OR ^4a 、S(O )R ^4b , S(O) ₂ R ^4b , S(O) ₂ NR ^4c R ^4d , S(O) ₂ OR ^4a , S(=NR ^4g )(O)R ^4b , S(=NR ^4g )(O )NR ^4c NR ^4d , P(O)(OR ^4e )(OR ^4f ), and P(O)(OR ^4e )(R ^4f ), wherein the 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-each optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, _NO2 , ^OR4A , ^SR4A , _C1-3 -alkyl, by 1, 2 or 3 halogen-substituted C _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) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O) R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A ) (C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ) , OS(O) ₂ R ^4B , OP(O)(OR ^4E ) (OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ); each R ⁴ⁱ is independently selected from 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) ₂ R ^4b ), and C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), where The C _1-6 -alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, benzene Base, C _3-6 -cycloalkyl-C _1-3 -alkyl-, (4-10 membered heterocycloalkyl)-C _1-3 -alkyl-, (5-10 membered heteroaryl)- Each of C _1-3 -alkyl-, and phenyl-C _1-3 -alkyl- is optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C(O)OR ^4A , C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O )OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )) , NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O )R ^4B 、OC(O)NR ^4C R ^4D 、ONR ^4C (C(O)R ^4B )、OS(O) ₂ R ^4B 、OP(O)(OR ^4E )(OR ^4F )、S(O)OR ^4A 、S(O)R ^4B 、S(O) ₂ R ^4B 、S(O) ₂ NR ^4C R ^4D 、S(O) ₂ OR ^4A 、S(=NR ^4G )(O)R ^4B 、S(= NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ); or R ^4h and R ⁴ⁱ can together form C _{3- 6} -cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, which may be further independently selected from the group consisting of C _1-6 -alkyl, -OH, and halogen. group substitution, wherein 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 are as defined herein. of.

In embodiments having a compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R has the structure of formula H1a or H2a: wherein the ring system is aromatic; wherein _X1 is C, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR4h , ^NR4i , O, _or S _, ^{wherein at} _{least one} of -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ⁴ⁱ is C _1-3 -alkyl.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, R ^is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^4A is selected from H and C _1-3 -alkyl. In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁵ (a) is selected from 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-, halogen, CN, NO ₂ , 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) ₂ R ^5b ), C(O)NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c OR ^5a , NR ^5c R ^5d 、NR ^5c (C(O)R ^5b )、NR ^5c (C(O)OR ^5a )、N(OR ^5a )(C(O)R ^5b )、NR ^5c (C(O)NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (C(O)R ^5b )), NR ^5c (S(O) ₂ R ^5b ), NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (S(O) ₂ R ^5b )), OC(O)R ^5b , OC(O)NR ^5c R ^5d , ONR ^5c (C(O)R ^5b ), OS(O) ₂ R ^5b 、OP(O)(OR ^5e )(OR ^5f )、S(O)OR ^5a 、S(O)R ^5b 、S(O) ₂ R ^5b 、S(O) ₂ NR ^5c R ^5d 、S( O) ₂ OR ^5a , S(=NR ^5g )(O)R ^5b , S(=NR ^5g )(O)NR ^5c NR ^5d , P(O)(OR ^5e )(OR ^5f ), and P(O) (OR ^5e )(R ^5f ), wherein R ⁵ is C _1-6 -alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycle Alkyl, phenyl, C _3-6 -cycloalkyl-C _1-3 -alkyl-, (4-10 membered heterocycloalkyl)-C _1-3 -alkyl-, and phenyl-C _{1 -3} -alkyl- each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , 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) ₂ R ^5B )、C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ) , NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C ( C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ), OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ), S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D 、S(O) ₂ OR ^5A 、S(=NR ^5G )(O)R ^5B 、S(=NR ^5G )(O)NR ^5C NR ^5D 、P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), or R ⁵ is (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^5A or carboxylic acid isosteres and optionally 1, 2, or 3 substituted groups independently selected from the following: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, C _1-3 substituted by 1, 2 or 3 halogens -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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O) NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) , S(O)OR ^5A , S(O)R ^5B ,S(O) ₂ R ^5B ,S(O) ₂ NR ^5C R ^5D ,S(O) ₂ OR ^5A ,S(=NR ^5G )(O)R ^5B ,S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), where 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 are as defined herein.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁵ (a) is selected from C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and halogen, wherein the C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _{3 -6} -Cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from halogen and C _1-3 -alkyl, or R ⁵ system (b) 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl )-C _1-3 -alkyl-each substituted by C(O)OR ^5A or by a carboxylic acid isostere and optionally by 1, 2, or 3 groups independently selected from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^5A is selected from H and C _1-3 -alkyl.

In embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, ^R5 is selected from halogen, _C1-3 -alkyl, and phenyl, wherein the _C1-3 -alkyl and phenyl Each group is optionally substituted with 1, 2, or 3 halogens.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R5 is selected from C _1-3 -alkyl, C _2-4 alkenyl, and C _3-6 -cycloalkyl, Wherein, the C _1-3 -alkyl, C _2-4 alkenyl, and C _3-6 -cycloalkyl groups of R ⁵ are each optionally substituted with 1, 2, or 3 halogens.

In embodiments of the compound of Formula (I), or _a pharmaceutically acceptable salt thereof, ^R5 is selected from _-CH3 , _-CF3 , F, _-CH2CH3 , and .

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁵ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, For example methyl, ethyl or trifluoromethyl.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R ⁵ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl- , wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl-are each replaced by C(O)OR ^5A or carboxylic acid isostere, optionally 1 , 2, or 3 substituted groups independently selected from the following: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, C _1- substituted by 1, 2 or 3 halogens 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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N( OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O ) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O )NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) , S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G )(O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), where R ^5A , R ^5B , R ^5C , R ^5D , R ^5E , R ^5F and R ^5G is as defined herein.

In embodiments having a compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R has the structure of formula H11 or H12: where: _X1 is C or N, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR5h , ^NR5i , O, or S; C(O)OR ^5A or carboxylic acid isostere; each is a single bond or a double bond; each R ^5h is independently selected from 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-, halogen, CN, NO ₂ , OR ^5a , SR ^5a , C (O)OR ^5a , C(O)R ^5b , C(O)NR ^5c R ^5d , C(O)NR ^5c (OR ^5a ) , C(O)NR ^5c (S(O) ₂ R ^5b ), C (O)NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c OR ^5a , NR ^5c R ^5d , NR ^5c (C(O)R ^5b ), NR ^5c (C(O)OR ^5a ), N (OR ^5a )(C(O)R ^5b ), NR ^5c (C(O)NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (C(O)R ^5b )), NR ^5c (S( O) ₂ R ^5b ), NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (S(O) ₂ R ^5b )), OC(O)R ^5b , OC( O)NR ^5c R ^5d 、ONR ^5c (C(O)R ^5b )、OS(O) ₂ R ^5b 、OP(O)(OR ^5e )(OR ^5f )、S(O)OR ^5a 、S(O) R ^5b , S(O) ₂ R ^5b , S(O) ₂ NR ^5c R ^5d , S(O) ₂ OR ^5a , S(=NR ^5g )(O)R ^5b , S(=NR ^5g )(O) NR ^5c NR ^5d , P(O)(OR ^5e )(OR ^5f ), and P(O)(OR ^5e )(R ^5f ), wherein the 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 base-, (4-10 membered heterocycloalkyl)-C _1-3 -alkyl-, (5-10 membered heteroaryl)-C _1-3 -alkyl-, and phenyl-C _1-3 -Alkyl-each optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, _NO2 , ^OR5A , ^SR5A , _C1-3 -Alkyl, by 1,2 Or 3 halogen-substituted C _1-3 -alkyl, C(O)OR ^5A , C(O)R ^5B , C(O)NR ^5C R ^5D , C(O)NR ^5C (OR ^5A ), C( O)NR ^5C (S(O) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ), OS(O) ₂ R ^5B , OP(O)(OR ^5E )( OR ^5F ), S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G ) (O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); each R ⁵ⁱ is independently selected from H, C _1-6 -alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-6 -cycloalkyl, _4-10 membered heterocycloalkyl, 5-10 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) ₂ R ^5b ), C(O)NR ^5c (S(O) ₂ NR ^5c R ^5d ), where the 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- are each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C(O)OR ^5A , C(O)R ^5B , C(O)NR ^5C R ^5D , C(O)NR ^5C (OR ^5A ), C(O)NR ^5C (S(O) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B ,OC(O)NR ^5C R ^5D ,ONR ^5C (C(O)R ^5B ),OS(O) ₂ R ^5B ,OP(O)(OR ^5E )(OR ^5F ) ,S(O)OR ^5A ,S (O)R ^5B 、S(O) ₂ R ^5B 、S(O) ₂ NR ^5C R ^5D 、S(O) ₂ OR ^5A 、S(=NR ^5G )(O)R ^5B 、S(=NR ^5G ) (O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); or R ^5h and R ⁵ⁱ can together form a C _3-6 -ring Alkyl, phenyl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, which may be further substituted by a group independently selected from C _1-6 -alkyl, -OH, and halogen, wherein 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 are as defined herein.

In embodiments having a compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R has the structure of formula H11a or H12a: wherein the ring system is aromatic; wherein _X1 is C, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR5h , ^NR5i , O, _or S _, ^{wherein at} _{least one} of -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ⁵ⁱ is C _1-3 -alkyl.

In embodiments of compounds having formula (I), or a pharmaceutically acceptable salt thereof, ^R5 has the structure of formula H11a, for example, wherein ^R5 is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^5A is selected from H and C _1-3 -alkyl.

In embodiments of the compound of formula (I) or a pharmaceutically acceptable salt thereof, ^R6 is selected from (4-6 membered heterocycloalkyl) _-CH2- and (5-6 membered heteroaryl)- CH ₂ -, wherein the (4-6 membered heterocycloalkyl)-CH ² _- and (5-6 membered heteroaryl)-CH ₂ - of R 6 are each independently replaced by 1, 2, or 3 as appropriate. Substituted with a group selected from C _1-6 -alkyl, -OH, and halogen.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, R ^is selected from the group consisting of: , , , , , , ,and , in Indicates the point of attachment to the rest of the molecule.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, ^R has the formula: , in Indicates the point of attachment to the rest of the molecule.

In embodiments of compounds of formula (I), or a pharmaceutically acceptable salt thereof, ^R has the formula: , in Indicates the point of attachment to the rest of the molecule.

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

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

In embodiments having a compound of Formula (I) or a pharmaceutically acceptable salt thereof, It is a single key.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Ia): (Ia), wherein A, W, X, ^R1 , ^R2 and ^R3 are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (II): (II), wherein A, R ¹ , R ² and R ³ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIa): (IIa), wherein A, R ¹ , R ² and R ³ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (III): (III), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIIa): (IIIa), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IIIb): (IIIb), wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IV): (IV), wherein R ¹ is chlorine or CN, and R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IVa): (IVa), wherein R ¹ is chlorine or CN, and R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IVb): (IVb), wherein R ¹ is chlorine or CN, and R ³ , R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (V): (V), wherein R ¹ is chlorine or CN, and R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Va): (Va), wherein R ¹ is chlorine or CN, and R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (Vb): (Vb), wherein R ¹ is chlorine or CN, and R ⁴ and R ⁵ are as defined herein, or a pharmaceutically acceptable salt thereof.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In embodiments of any compound, or a pharmaceutically acceptable salt thereof, R ⁴ is as defined herein.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In embodiments of any compound, or a pharmaceutically acceptable salt thereof, ^R is as defined herein.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In embodiments of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5 -10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl-are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and optionally by 1, 2, or 3 substituted groups independently selected from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^4A is selected from H and C _{1- 3} -alkyl; and R ⁵ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, ethyl or trifluoromethyl.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In embodiments of any compound or a pharmaceutically acceptable salt thereof, R ⁴ has a structure of formula H1 or H2 as defined herein; and R ⁵ is C _1-3 -alkyl or substituted by 1, 2 or 3 A halogen-substituted C _1-3 -alkyl group, such as methyl, ethyl or trifluoromethyl.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In embodiments of any compound or a pharmaceutically acceptable salt thereof, R ⁴ has a structure of formula H1a or H2a as defined herein; and R ⁵ is C _1-3 -alkyl or substituted by 1, 2 or 3 A halogen-substituted C _1-3 -alkyl group, such as methyl, ethyl or trifluoromethyl.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In the embodiment of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^4A is selected from H and C _1-3 -alkyl, and R ⁵ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, ethyl or trifluoromethyl.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In the embodiment of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, Ethyl or trifluoromethyl, and R ⁵ is a 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10 membered heteroaryl and ( 5-10 membered heteroaryl)-C _1-3 -alkyl-each is C(O)OR ^5A or a carboxylic acid isostere and optionally 1, 2, or 3 independently selected from the following Group substitution: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^5A is selected from H and C _1-3 -alkyl.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In the embodiment of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, ethyl or trifluoromethyl, and ^R has the structure of formula H11 or H12 as defined herein.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In the embodiment of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, ethyl or trifluoromethyl, and ^R has the structure of formula H11a or H12a as defined herein.

In formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) In the embodiment of any compound or a pharmaceutically acceptable salt thereof, R ⁴ is C _1-3 -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, such as methyl, ethyl or trifluoromethyl, and R ⁵ is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^5A is selected from H and C _1-3 -alkyl.

In embodiments, the compound of formula (I) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and , or its pharmaceutically acceptable salt.

In embodiments, the compound of formula (I) is selected from the group consisting of: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Methylethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl )ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Ethyl ethyl ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Methyl ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5- Methylethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- (Trifluoromethyl)ethazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- Methylethazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 2-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2 -Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2 -Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 5-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1, 3,4-Diazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -3-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -5-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2 -Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-formic acid, and 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Ethyl methylethazole-4-carboxylate, or a pharmaceutically acceptable salt thereof.

In embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from Table A: [ Table A] No. compound Name C-1 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Methylethazole-4-carboxylic acid C-2 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid C-3 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid C-4 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl )ethazole-4-carboxylic acid C-5 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid C-6 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid C-7 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 4-Formic acid C-8 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 5-Formic acid C-9 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid C-10 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Ethylethazole-4-carboxylic acid C-11 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Methylethazole-4-carboxylic acid C-12 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5- Methylethazole-4-carboxylic acid C-13 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 4-Formic acid C-14 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- (Trifluoromethyl)ethazole-5-carboxylic acid C-15 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- Methylethazole-5-carboxylic acid C-16 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid C-17 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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-18 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid C-19 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-3- Methylfuran-2-carboxylic acid C-20 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 2-Formic acid C-21 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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-22 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2 -Formic acid C-23 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) acid C-24 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2 -Formic acid C-25 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 5-Formic acid C-26 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1, 3,4-Diazole-2-carboxylic acid C-27 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -3-Formic acid C-28 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -5-Formic acid C-29 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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 C-30 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)acid C-31 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2 -Formic acid C-32 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid C-33 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Methylethazole-4-carboxylate

In embodiments of any of the formulas provided herein, or a pharmaceutically acceptable salt thereof, one or both of the optionally substituted variables ^R4 and ^R5 comprise a carboxylic acid, a carboxylic acid derivative (e.g., a carboxylic acid ester Derivatives such as methyl carboxylate or ethyl carboxylate) or carboxylic acid isosteres (see, e.g., J. Med. Chem. [ Journal of Medicinal Chemistry ] 2016, 59, 3183-3203). In a preferred embodiment, R ⁴ and R ⁵ are different. For example, in a preferred embodiment, only one of R ⁴ and R ⁵ contains carboxylic acid, carboxylic acid derivatives (for example, carboxylic acid ester derivatives such as carboxylic acid methyl ester or carboxylic acid ethyl ester) or carboxylic acid electrons, etc. Exhaust body.

A non-limiting list of example acyclic carboxylic acid isosteres is as follows: Name sample structure Sample format: carboxylic acid COOH Hydroxamic acid C(O)NH(OH) N(OH)(C(O)CH ₃ ) hydroxamates C(O)NH(OCH ₃ ) ONH(C(O)CH ₃ ) Phosphonic acid P(O)(OH) ₂ Phosphinic acid P(O)(OH)(H) Sulfonic acid S(O) _2OH Sulfinic acid S(O)OH Sulfonamide S(O) ₂ NH ₂ NH(S(O) ₂ CH ₃ ) acyl-sulfonamide C(O)NH(S(O) ₂ CH ₃ ) C(O)NH(S(O) ₂ N(CH ₃ ) ₂ ) Sulfonylurea NH(C(O)NH(S(O) ₂ CH ₃ )) acylurea NH(C(O)NH(C(O)CH ₃ )) iminosulfazone S(=NH)(O)CH ₃ sulfonamide S(=NH)(O)NH ₂

A non-limiting list of cyclic carboxylic acid isosteres is as follows: Name sample structure Tetrazole Tetrahydrothiazodione Azolidinedione Dioxadiazole-5(4H)-one Thiadiazole-5(4H)-one Thiadiazole-2-oxide Dioxadiazole-5(4H)-thione Isoethazole tetramic acid Cyclopentane 1,3-dione Cyclopentane 1,2-dione squaric acid derivatives Substituted phenols

Unless otherwise stated, the term "compounds of the invention, compound of the invention, compound of the invention or compounds of the invention" means compounds of formula (I), its subformulas (e.g., Formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb)) Compounds and Exemplary Compounds and their salts, as well as all stereoisomers (including diastereomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substitutions), and inherently formed parts.

Depending on the choice of starting materials and procedure, the compounds can be in the form of one of the possible stereoisomers or as a mixture thereof (e.g. as pure optical isomers or as mixtures of stereoisomers, such as racemates and non- Enantiomer mixtures) exist, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures and optically pure forms. Optically active ( R )- and ( S )-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains double bonds, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

The phrase "substituted as appropriate" means either unsubstituted or substituted. Substituents are independently selected, and substitution can be at any chemically accessible position. The term "substituted" means that a hydrogen atom is removed and replaced with a substituent. A single divalent substituent (eg, a pendant oxygen group) can replace two hydrogen atoms. It is understood that substitution at a given atom is limited by valency.

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

As used herein, "C _nm alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. In some embodiments, alkenyl groups contain from 2 to 6 carbon atoms, from 2 to 4 carbon atoms, or from 2 to 3 carbon atoms.

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

As used herein, "aryl" refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings). The term _Cnm aryl refers to an aryl group having from n to m ring carbon atoms. In some embodiments, an aryl group has from 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.

As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (eg, having two fused rings) groups, spiro rings, and bridged rings. The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted with pendant oxy groups or sulfido groups (eg, 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 cycloalkyl). In some embodiments, a cycloalkyl group has 3, 4, 5, or 6 ring-forming carbon atoms (i.e., C _3-6 cycloalkyl).

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

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 Replaced with heteroatoms selected from N, O, S, and B, and wherein the ring-forming carbon or heteroatom of the heterocycloalkyl group may be replaced by one or more pendant oxy or sulfide groups (e.g., C(O ), S(O), C(S), S(O) ₂ , etc.) are replaced as necessary. In some embodiments, the heterocycloalkyl group contains 4 to 10 ring-forming atoms (i.e., is 4-10 membered), wherein 1 to 4 atoms are heteroatoms independently selected from N, O, and S. .

As used herein, "C _op -cycloalkyl-C _nm- alkyl" refers to a group having the formula cycloalkyl-alkylene, wherein the cycloalkyl has o to p carbon atoms and the alkylene linkage A group has n to m carbon atoms.

As used herein, "heterocycloalkyl-C _nm -alkyl" refers to a group having the formula heterocycloalkyl-alkylene, wherein the alkylene linking group has n to m carbon atoms.

As used herein, "heteroaryl-C _nm- alkyl" refers to a group having the formula heteroaryl-alkylene, wherein the alkylene linking group has n to m carbon atoms.

As used herein, "aryl-C _nm- alkyl" (e.g., "phenyl-C _nm -alkyl") refers to a group having the formula aryl-alkylene, wherein the alkylene linking group has n to m carbon atoms.

As used herein, the term "salt or salts" refers to acid or base addition salts of the compounds provided herein. "Salt" specifically includes "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds provided herein, and such salts are typically not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of using basic nitrogen atoms (e.g., found in amine and pyridine groups or other groups similar thereto) and/or acidic protons (e.g., found in carboxylic acids or other groups similar thereto). The presence of ) in the group forms acid and/or base salts.

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

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

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, etc.

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

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the Periodic Table of Elements. 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.

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 and the like. Some organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

In another aspect, the compounds provided herein are in the following form: sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, choline salt, diethanolamine, diethylamine, lyoamine Acid, meglumine, piperazine or tromethamine salt.

In another aspect, the compounds provided herein are in the following forms: acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate Salt/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, ethylenedisulfonate, fumaric acid Salt, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate , lactate, lactosuronate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, mucinate, naphthalene Formate, naphthalene sulfonate, acid salt, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate , polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, toluenesulfonate, trifenatate ), trifluoroacetate or xinafoate.

Any formulas given herein are also intended to represent unlabeled as well as isotopically labeled forms of such compounds. Isotopically labeled compounds have structures described by the formulas given herein, except that one or more atoms are replaced by atoms of selected atomic weight or mass number. Isotopes that may be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen.

Additionally, incorporation of certain isotopes, particularly deuterium (i.e. ^{, H} or D) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or therapeutic index or tolerability improvement. It will be understood that deuterium in this context is considered a substituent of the compounds of the invention. The concentration of deuterium can be defined by the isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope and the natural abundance of a given isotope. If a substituent in a compound of the invention is indicated as deuterium, such compound has an isotope enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation per designated deuterium atom), At least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), At least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated). It will be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and sulfur, such as ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³⁵ S respectively. . Accordingly, it is to be understood that the present invention includes compounds incorporating one or more of any of the aforementioned isotopes, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically labeled compounds can be used for metabolic studies (with ¹⁴ C), reaction kinetic studies (for example with ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography Scanning (SPECT), including determination of tissue distribution of drugs or substrates, or for radiation therapy in patients. In particular, ^18F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of those previously employed. Unlabeled reagents are prepared.

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

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

The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that elicits a biological or medical response in a subject (e.g., agonizes GLP1R activity, ameliorates symptoms, alleviates a condition, slows or delays a disease, disorder or condition). progress, or prevention of a disease, disorder or condition). In one embodiment, the term "therapeutically effective amount" means that when administered to a subject, a compound of the invention is effective to at least partially alleviate, prevent and/or ameliorate a condition responsive to increased or agonistic GLP1R activity, or The amount of disorder or disease. In another embodiment, the term "therapeutically effective amount" refers to a compound of the invention that is effective to partially or fully agonize the activity of GLP1R when administered to a subject, cell, or tissue, or non-cellular biological material, or medium amount. In another embodiment, the term "therapeutically effective amount" refers to an observable level of a compound of the invention that, when administered to a subject, is effective in eliciting one or more desired biological or medical responses. The biological or medical response is, for example, selected from: lowering glucose levels (or improving glucose homeostasis), increasing insulin sensitivity, lowering triglyceride or cholesterol levels, losing weight, reducing food intake, and reducing body fat mass (e.g., peripheral fat and/or visceral fat).

As used herein, the term "subject" refers to primates (eg, 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 human.

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

As used herein, the term "treat, treating, or treatment" for any disease, disorder, or condition means to alleviate or ameliorate the disease, disorder, or condition (i.e., to slow or prevent the disease, disorder, or condition, or at least one clinical symptom thereof). development or progression); or alleviation or improvement of at least one physical parameter or biomarker associated with the disease, disorder or condition, including those physical parameters or biomarkers that the patient may not be able to discern.

As used herein, the term "prevent, preventing or prevention" of any disease, disorder or condition means preventive treatment of the disease, disorder or condition; or delaying the onset or progression of the disease, disorder or condition.

As used herein, a subject "is in need" of treatment if the subject will benefit from the treatment biologically, medically, or in terms of quality of life.

As used herein, the terms "a, an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) shall be construed to cover the singular and Both in the plural unless otherwise indicated herein or otherwise clearly contradicted by context.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention as otherwise claimed.

Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present invention may exist in a racemic or enantiomer-enriched form, such as ( R )-, ( S )-, or ( R,S )- Configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomer excess, at least 60% enantiomer excess, at least 70% enantiomer excess, at least 80% enantiomer excess, at least An ( R )- or ( S )-configuration of 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

Accordingly, as used herein, the compounds of the invention may be in one of the following forms: possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as essentially Pure diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, based on physicochemical differences of the components, for example by chromatography and/or fractional crystallization. substance, racemate.

Any resulting racemate of a compound or intermediate of the invention may be resolved into its optical antipodes by known methods, for example by separation of diastereomeric salts thereof obtained with optically active acids or bases. , and release optically active acidic or basic compounds. In particular, basic moieties can thus be used to resolve the compounds of the invention into their optical antipodes, for example by fractional crystallization with optically active acids such as tartaric acid, dibenzoyltartaric acid, diethyltartaric acid, Di- O,O' -p-tolyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid salts are used for separation. The racemic compound or racemic intermediate of the present invention can also be resolved by chiral chromatography (for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent).

Compounds provided herein (e.g., having formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), ( The compounds of Va) and (Vb) and their pharmaceutically acceptable salts) can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds provided herein may be synthesized using methods described in the Examples, as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof understood by those skilled in the art.

It is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general chemical principles. According to standard methods of organic synthesis (such as, for example, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons: New York, 1999 or Protecting Groups Groups], 3rd edition, Thieme, Stuttgart, 2004) operating protecting groups. Protecting groups are removed at a convenient stage in the synthesis of the compound using methods obvious to those skilled in the art.

One skilled in the art will recognize the presence or absence of stereocenters in the compounds disclosed herein. Resolution of final products, intermediates or starting materials may be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of formula (I) and compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), The compounds of any one of (V), (Va) and (Vb) and pharmaceutically acceptable salts thereof can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds provided herein may be synthesized using any one of General Synthetic Schemes A and B or as described in the Examples, as well as synthetic methods known in the art of synthetic organic chemistry or as understood by those skilled in the art. Variants are synthesized.

As described in Scheme A, intermediate II.A (wherein R ¹ , R ² and R ³ are as defined herein) is combined with intermediate III.A (wherein Y is Br or I and R ⁴ is as defined herein) reaction to provide intermediate IA . Intermediate IA (where Y is Br or I, and R ¹ , R ² , R ³ and R ⁴ are as defined herein) is then reacted with carboxylate derivative B1 in the presence of a Pd catalyst (e.g., Xphos Pd G2) and a base. Reaction in the presence of a solvent (eg, toluene) provides a compound of formula (I). In the carboxylate derivative B1 of this embodiment, R is C _1-3 -alkyl and H ^A is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl group-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each optionally selected from 1, 2, or 3 groups independently selected from the following groups Substitution: Halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^5B , C( O)NR ^5C R ^5D , C(O)NR ^5C (OR ^5A ), C(O)NR ^5C (S(O) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ), OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ), S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G )(O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), wherein R ^5A , R ^5B , R ^5C , R ^5D , R ^5E , R ^5F and R ^5G are as defined herein.

In another embodiment, intermediate IA (where Y is Br or I, and R ¹ , R ² , R ³ and R ⁴ are as defined herein) is reacted with carboxylate derivative B1 (where R is C _{1 - 3} -alkyl and H ^A is a 5-10-membered heteroaryl or (5-10-membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl Heteroaryl)-C _1-3 -alkyl-each protected by a boronic acid or dioxolaborane protecting group (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxo Heterocyclopentane-2-yl), and optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 - Alkyl, C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^5B , C(O)NR ^5C R ^5D , C(O)NR ^5C (OR ^5A ), C( O)NR ^5C (S(O) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ), OS(O) ₂ R ^5B , OP(O)(OR ^5E )( OR ^5F ), S(O)OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G ) (O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), where R ^5A , R ^5B , R ^5C , R ^5D , R ^5E , R ^5F and R ^5G are as defined herein) reaction.

In one embodiment, the compound of formula (I) so obtained is a carboxylate derivative, wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein, and H ^A′ is 5-10 Member heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkylene-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 - Alkylene - each optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, _NO2 , ^OR5A , ^SR5A , _C1-3 -alkyl, by 1,2 Or 3 halogen-substituted C _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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C (O)OR ^5A ), N(OR ^5A ) (C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC (O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) ,S(O )OR ^5A , S(O)R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G )(O)R ^5B ,S (=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ), where R ^5A , R ^5B , R ^5C , R ^5D , R ^5E , R ^5F and R ^5G are as defined herein, wherein the carboxylate derivatives can be prepared by adding The carboxylate moiety is hydrolyzed in water to the carboxylic acid moiety and converted into another compound of formula (I). Plan A

As described in Scheme B, intermediate II.A (wherein R ¹ , R ² and R ³ are as defined herein) is combined with intermediate III.B (wherein Y is Br or I and R ⁵ is as defined herein) reaction to provide intermediate IB . Intermediate IB (where R ¹ , R ² , R ³ and R ⁵ are as defined herein and Y is Br or I) is then reacted with carboxylate derivative B2 in the presence of a Pd catalyst (e.g., Xphos Pd G2) and a base The reaction is carried out in a solvent (eg, toluene) to provide a compound of formula (I). In the carboxylate derivative B2 of this embodiment, R is C _1-3 -alkyl and H ^B is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl group-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each optionally selected from 1, 2, or 3 groups independently selected from the following groups Substitution: Halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl, C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^4B , C( O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A ) (C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), wherein R ^4A , R ^4B , R ^4C , R ^4D , R ^4E , R ^4F and R ^4G are as defined herein.

In another embodiment, intermediate IB (wherein R ¹ , R ² , R ³ and R ⁵ are as defined herein and Y is Br or I) is reacted with carboxylate derivative B2 (where R is C _1-3 -Alkyl and H ^B is a 5-10-membered heteroaryl or (5-10-membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl Aryl) -C _1-3 -alkyl - each protected by a boronic acid or dioxolaborane protecting group (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxa cyclopentaborane-2-yl), and optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl Base, C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O )NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C ( C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )( O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), where R ^4A , R ^4B , R ^4C , R ^4D , R ^4E , R ^4F and R ^4G are as defined herein) reactions.

In one embodiment, the compound of formula (I) so obtained is a carboxylate derivative, wherein R ¹ , R ² , R ³ and R ⁵ are as defined herein and ^HB′ is 5-10 Member heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkylene-, wherein the 5-10 membered heteroaryl and (5-10 membered heteroaryl)-C _1-3 - Alkylene - each optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl, substituted by 1, 2 Or 3 halogen-substituted C _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 NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C (O)OR ^4A ), N(OR ^4A ) (C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC (O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ) , OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ) ,S(O )OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )(O)R ^4B ,S (=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), where R ^4A , R ^4B , R ^4C , R ^4D , R ^4E , R ^4F and R ^4G are as defined herein, wherein the carboxylate derivatives can be prepared by adding The carboxylate moiety is hydrolyzed in water to the carboxylic acid moiety and converted into another compound of formula (I). Plan B

Intermediate II.A is commercially available or can be produced by organic synthesis methods known to those skilled in the art. For example, Intermediate II.A can be prepared as described in Scheme C below.

As shown in Scheme C, intermediate II.1 (wherein R ¹ , R ² and R ³ are as defined herein) is reacted with 3-bromobenzene-1,2-diphenol in the presence of p-TsOH in a solvent (e.g. , toluene) to provide intermediate II.2 . Intermediate II.2 (where R ¹ , R ² and R ³ are as defined herein) is then reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxolabor Alk-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester in the presence of a Pd catalyst and a base (e.g., Na ₂ CO ₃ ) in a solvent (e.g., dihydropyridine) reaction to provide intermediate II.3 . Intermediate II.3 (wherein R ¹ , R ² and R ³ are as defined herein) is converted to intermediate II.3 in the presence of H ₂ in the presence of a catalyst (e.g., ((C ₆ H ₅ ) ₃ P) ₃ RhCl). II.4 . Intermediate II.4 (wherein R ¹ , R ² and R ³ are as defined herein) is then purified by SFC to intermediates II.5a and II.5b . Intermediates II.5a and II.5b (where R ¹ , R ² and R ³ are as defined herein) are converted to intermediates II.Aa and II, respectively, in the presence of HCl in a solvent (e.g., dimethacin). Ab (where R ¹ , R ² and R ³ are as defined herein). Plan C

Intermediates III.A and III.B are commercially available or can be produced by organic synthesis methods known to those skilled in the art. For example, intermediates III.A and III.B can be prepared as described in Scheme D below. Plan D

As shown in Scheme D, intermediate III.a (where Z is R ⁴ or R ⁵ as defined herein and Y is Br or I) is reacted with oxetan-2-ylmethyl 4-methyl The benzenesulfonate ester is reacted in the presence of cesium carbonate in a solvent (eg, acetonitrile). The residue is purified ^via chromatography to isolate the isomers to provide intermediates III.1a and III.1b (where R ^or R is as defined herein and Y is Br or I). Intermediates III.1a and III.1b (where R ^or R are as defined herein and Y is Br or ^I ) are independently reacted with LDA in a solvent (e.g., THF/heptane/ethylbenzene) to provide respectively Intermediates III.A and III.B.

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

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

In additional embodiments, the compositions include at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical compositions may be formulated for specific routes of administration, such as oral administration, parenteral administration (eg, by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention can be prepared 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 film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient and one or more of the following: a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) Lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; in the case of tablets, also c) Binders such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if required d) disintegrating agents such as starch, agar, alginic acid or sodium salts or effervescent mixtures thereof; and e) Adsorbents, colorants, flavorings and sweeteners.

Compounds of the invention (e.g., having formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), ( Compounds of IVa), (IVb), (V), (Va) and (Vb) and their pharmaceutically acceptable salts) exhibit valuable pharmacological properties, such as acting as GLP1R agonists, for example, as follows In vitro and in vivo tests are provided in one section as indicated, and are therefore indicated for use as therapeutics or for use as research chemicals, e.g. as tool compounds.

The compounds of the present invention (for example, having formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), ( The compounds of Va) and (Vb) and their pharmaceutically acceptable salts) are useful in the treatment of metabolic and related diseases, disorders and conditions. In particular, the compounds of the invention are 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 Various complications of diabetes (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).

The progressive liver disease may be, for example, non-alcoholic fatty liver disease (NAFLD), or, for example, non-alcoholic steatohepatitis (NASH).

For example, cardiovascular disease may be selected from: hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure (e.g., heart failure with reduced ejection fraction (HFrEF), intermediate ejection fraction heart failure (HFmrEF) and heart failure with preserved ejection fraction (HFpEF)), coronary artery disease, and cardiac arrhythmias (such as atrial arrhythmias and ventricular arrhythmias).

The compounds of the present invention may be used to treat several diseases, disorders or conditions that occur simultaneously in a subject (referred to as "comorbidities").

For example, comorbidities may be those in a subject who has type 2 diabetes and is otherwise obese and/or otherwise exhibits heart failure and/or NASH. For example, obese subjects may also exhibit type 2 diabetes and/or exhibit cardiovascular disease (eg, heart failure). Such subjects may also exhibit progressive liver disease (eg, NASH). For example, obese subjects may also exhibit type 2 diabetes and/or exhibit cardiovascular disease (eg, heart failure) and/or exhibit progressive liver disease (eg, NASH). Subjects may also have high blood pressure and/or high blood cholesterol levels. Subjects may also have peripheral neuropathy.

Accordingly, the compounds provided herein may be used to treat 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, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy , atrial fibrillation, heart failure (especially heart failure with reduced ejection fraction (HFrEF), heart failure with intermediate ejection fraction (HFmrEF), and heart failure with preserved ejection fraction (HFpEF)), coronary heart disease, cardiac arrhythmias ( especially atrial arrhythmias and ventricular arrhythmias) and neuropathy (especially peripheral neuropathy).

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

In embodiments, the disease, disorder or condition is selected from obesity, type 2 diabetes, atherosclerosis and heart failure (especially HFpEF).

Thus, as an additional aspect, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III), (IIIa) , a compound of any one of (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) in therapy. In additional embodiments, the therapy is treatment of a disease, disorder or condition treatable by agonism of GLP1R. In another embodiment, the therapy is the treatment of a disease, disorder or condition selected from the foregoing list, suitably selected from obesity, type 2 diabetes, atherosclerosis and heart failure (in particular heart failure with preserved ejection fraction), including such conditions as, for example, in subjects with type 2 diabetes who are also obese and/or in subjects with type 2 diabetes who are also suffering from heart failure and/or who have The presence of comorbidities in subjects with type 2 diabetes and NASH.

Thus, as an additional aspect, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III), (IIIa ), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof), for use in therapy use. In additional embodiments, the therapy is treatment of a disease, disorder or condition treatable by agonism of GLP1R. In another embodiment, the therapy is the treatment of a disease, disorder or condition selected from the foregoing list, suitably selected from obesity, type 2 diabetes, atherosclerosis and heart failure (in particular heart failure with preserved ejection fraction), including such conditions as, for example, in subjects with type 2 diabetes who are also obese and/or in subjects with type 2 diabetes who are also suffering from heart failure and/or who have The presence of comorbidities in subjects with type 2 diabetes and NASH.

In another aspect, provided herein is a method of treating a disease, disorder or condition treatable by agonism of GLP1R, comprising administering a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable form thereof Salts (including, for example, those of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (Iva), (Ivb), (V), (Va) and (Vb) a compound or a pharmaceutically acceptable salt thereof). In another embodiment, the invention provides a method of treating a disease, disorder or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from the foregoing list, suitably selected from obesity, type 2 diabetes, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), This includes, for example, subjects with type 2 diabetes and obesity and/or subjects with type 2 diabetes and heart failure, and/or subjects with type 2 diabetes and NASH. Presence of comorbidities among subjects.

In additional aspects, provided herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of Formula (Ia), (II), (IIa), (III), (IIIa), ( The compound of any one of IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) is used for the manufacture of medicines. In additional embodiments, the medicament is used to treat a disease treatable by agonism of GLP1R. In another embodiment, the disease is selected from the foregoing list, suitably selected from obesity, type 2 diabetes, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), including such as, for example, in Combination in subjects with type 2 diabetes and obesity and/or subjects with type 2 diabetes and heart failure and/or subjects with type 2 diabetes and NASH the presence of the disease.

The term "metabolic disorder or disease" refers to a group of related characteristics including, but not limited to, glucose intolerance, insulin resistance, hyperinsulinemia, obesity, excessive visceral adiposity, hypertension, and elevated triglycerides. Dyslipidemia characterized by 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.

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. This may be due to insufficient insulin production by the pancreas or peripheral insulin resistance.

As used herein, the term "insulin resistance" refers to a condition in which normal amounts of insulin fail to induce the expected physiological response and activate downstream pathways. In various instances, endogenously produced or exogenously administered insulin beyond the physiological range is sufficient to induce a complete or partial biological response to induce the desired physiological response.

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

The term "glucose intolerance" includes abnormalities characterized by elevated basal or postprandial glucose levels and/or elevated insulin levels or glucose-stimulated insulin release or HOMA-IR (homeostasis of insulin resistance) in subjects relative to healthy individuals. Any disorder characterized by clinical symptoms or combinations of clinical symptoms associated with (state model assessment). Elevated levels of glucose and/or insulin can manifest in the following diseases, disorders and conditions: obesity, metabolic syndrome, impaired glucose tolerance, type 2 diabetes, gestational diabetes, type 1 diabetes, insulin resistance, hyperinsulinemia , lipodystrophy, lipoatrophy, and various MODY (maturity-onset diabetes of the young) mutations. GLP1R agonists and compositions thereof provided herein may be used, for example, to achieve and/or maintain glucose homeostasis, such as to reduce glucose levels in the bloodstream and/or to reduce insulin levels to the range of healthy subjects.

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

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

The term "diabetic nephropathy" refers to a condition caused by diabetes and caused by damage to blood vessels and other cells in the kidneys, resulting in reduced kidney function.

The term "obesity" refers to a body mass index (BMI) of 30 or higher in human adults (Centers for Disease Control and Prevention). Such subjects may also be termed obese. This is called type I obesity. Obesity Class II includes individuals with a BMI of 35-39.9, and obesity Class III 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 calculation formula is BMI = weight (kg)/height ( ^m2 ).

In embodiments, the human subject with obesity has a BMI of ≥30 or ≥35 or a BMI in the range of ≥35 to <40 or ≥30 to <40. For example, an amount < 40 could be 39.9. In some embodiments, obesity is severe obesity or morbid obesity, wherein the human subject has a BMI ≥ 40.

The term "dyslipidemia" refers to complex disorders of lipoprotein metabolism, including excessive production or abnormal metabolism of lipoproteins. Dyslipidemia may manifest as increased total cholesterol, increased concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides, and decreased concentrations of high-density lipoprotein (HDL) cholesterol in the blood.

The term "atherosclerosis" refers to a vascular disease characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, sometimes leading to narrowing of the arterial lumen and eventual progression to fibrosis and calcification. Lesions are usually focal and progress slowly and intermittently. Restriction of blood flow is responsible for most clinical manifestations and varies with the distribution and severity of the disease.

The term "progressive liver disease" refers to progression from a benign state of hepatic steatosis to display of fibrosis and cirrhosis, which predisposes to hepatocellular carcinoma. The progression of obesity-related nonalcoholic fatty liver disease (NAFL) to NASH, fibrosis, and cirrhosis is well documented.

The term "non-alcoholic fatty liver disease (FLD)", also known as NAFLD, is a condition in which lipids accumulate excessively in liver cells, which can be caused by excessive de novo lipogenesis or abnormal clearance and oxidation of fatty acids in the liver. NAFLD was excluded as a cause of other liver diseases, including alcoholic liver disease and viral liver disease. NAFLD includes three histological entities that reflect disease progression: fatty liver, hepatic steatosis, and fibrosis or cirrhosis. The most common cause of NAFLD is obesity, although NAFLD can also occur in lean individuals. Accumulation of fat can progress inflammation with macrophage infiltration and histological changes in liver cells, including ballooning degeneration, which is known as steatohepatitis and is known as nonalcoholic steatohepatitis (NASH). NASH can progress to fibrosis or cirrhosis with interlobular bridging fibrosis. As used herein, the term NASH may encompass steatohepatitis, hepatocellular ballooning, and lobular inflammation.

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

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

The term "peripheral arterial disease" refers to a condition in which the accumulation of fatty deposits in the arteries limits the blood supply to the leg muscles.

The term "stroke" refers to a situation in which the blood supply to part of the brain is cut off.

The term "heart failure" refers to a condition in which the heart has a reduced ability to pump blood, and may include heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with intermediate ejection fraction (HFmrEF).

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

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

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

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

The pharmaceutical compositions or combinations provided herein may be presented in a unit dose of about 1-1000 mg of one or more active ingredients for a subject of about 50-70 kg. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age of the subject and the individual condition, disorder or disease being treated or its severity.

Compounds of the present invention (including, for example, compounds having formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), The compound of either (Va) and (Vb), or a pharmaceutically acceptable salt thereof) may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately by the same or different routes of administration as the other pharmaceutical agents, or administered together in the same pharmaceutical composition. Therapeutic agents are, for example, chemical compounds, peptides, peptide conjugates and fusions, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance when administered to a subject in combination with a compound of the invention. therapeutic activity.

Accordingly, in another aspect, provided herein is a combination (especially a pharmaceutical combination) comprising (e.g., a therapeutically effective amount) of a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, e.g., having Any of formulas (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) A compound or a pharmaceutically acceptable salt thereof), and one or more other therapeutically active agents.

In one embodiment, provided herein is a product comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of Formula (Ia), (II), (IIa), (III) ), a compound of any one of (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof), and At least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is treatment of a disease, disorder or condition selected from the foregoing list, suitably selected from the group consisting of type 2 diabetes, obesity, atherosclerosis and heart failure (especially radioactivity). heart failure with preserved blood fraction), including conditions where such conditions exist as comorbidities, for example, in subjects with type 2 diabetes who are also obese or in subjects with type 2 diabetes and who are also suffering from heart failure.

Products provided as combination preparations include compositions containing compounds of formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of formula (Ia), (II) together in the same pharmaceutical composition ), (IIa), (III), (IIIa), (IIIb), (IV), (Iva), (Ivb), (V), (Va) and (Vb) any one of the compounds or pharmaceuticals thereof an acceptable salt), and one or more other therapeutic agents, or a compound of the invention and one or more other therapeutic agents in separate form (eg, in the form of a kit).

In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, a compound of formula (Ia), (II), ( A compound of any one of Iia), (III), (IIIa), (IIIb), (IV), (Iva), (Ivb), (V), (Va) and (Vb) or a pharmaceutically acceptable compound thereof salt) and one or more additional therapeutic agents. If necessary, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described above.

In one embodiment, provided herein is a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound of the invention. In one embodiment, the kit includes means (eg, containers, separate bottles, or separate foil packets) for holding the compositions separately. An example of such a kit is a blister pack, as is typically used for the packaging of tablets, capsules, etc.

The set may be used to administer different dosage forms (eg, oral and parenteral dosage forms), to administer the individual compositions at different dosage intervals, or to titrate the individual compositions relative to each other. To aid compliance, the kits provided herein typically include instructions for administration.

In the combination therapies provided herein, compounds of formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of formula (Ia), (II), (Iia), (III), (IIIa), ( The compound of any one of IIIb), (IV), (Iva), (Ivb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof), and other therapeutic agents may be composed of the same or different Made and/or formulated by the manufacturer. In addition, compounds of formula (I), or pharmaceutically acceptable salts thereof, and other therapeutic agents may be incorporated into combination therapies: (i) upon release of the combination product to a physician (e.g., in a compound containing a compound of formula (I) compounds or pharmaceutically acceptable salts thereof, and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the direction of a physician); (iii) in the patient itself, for example during the sequential administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and another therapeutic agent.

Accordingly, provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of formula (Ia), (II), (Iia), (III), (IIIa), (IIIb) , a compound of any one of (IV), (Iva), (Ivb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for Treating a disease, disorder or condition selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), including the etc. as a comorbidity exists, for example in a subject with type 2 diabetes who is also obese or in a subject with type 2 diabetes who is also suffering from heart failure, where the drug is prepared for use with another treatment administered together.

Provided herein is the use of another therapeutic agent for the treatment of a disease, disorder or condition selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (in particular heart failure with preserved ejection fraction), including conditions where such conditions exist as comorbidities, for example, in subjects with type 2 diabetes who are also obese or in subjects with type 2 diabetes and who are also suffering from heart failure. , wherein the drug is administered together with a compound of the invention.

Provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), ( A compound of any one of IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) for use in a method of treating a disease, disorder or condition For use, the disease, disorder or condition is selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), including such as in patients with, e.g. There are cases where comorbidities exist in subjects with type 2 diabetes and obesity or subjects with type 2 diabetes and heart failure, wherein the compound of formula (I) is prepared or is pharmaceutically acceptable. Salts are accepted for administration with another therapeutic agent.

Also provided herein is another therapeutic agent for use in a method of treating a disease, disorder, or condition selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis, and Heart failure (especially heart failure with preserved ejection fraction), including such conditions as, for example, in a subject with type 2 diabetes and obesity or in a subject with type 2 diabetes and heart failure In the presence of comorbidities, the other therapeutic agent is prepared for use with a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III) ), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) administered together .

Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), A compound of any one of (IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) for use in a method of treating a disease, disorder or condition As used in, the disease, disorder or condition is selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), including such as, for example, in The presence of comorbidities in subjects with type 2 diabetes and obesity or in subjects with type 2 diabetes and heart failure, wherein the compound of formula (I) or its pharmaceutically acceptable The salts received are administered together with another therapeutic agent.

Also provided is another therapeutic agent for use in a method of treating a disease, disorder or condition selected from the foregoing list, suitably selected from the group consisting of type 2 diabetes, obesity, atherosclerosis and cardiac disease. Failure (especially heart failure with preserved ejection fraction), including such combinations as, for example, in a subject with type 2 diabetes who is also obese or in a subject with type 2 diabetes who is also suffering from heart failure In the presence of a disease, the other therapeutic agent is administered with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III), (IIIa), (IIIb), ( The use of a compound of any one of IV), (IVa), (IVb), (V), (Va) and (Vb) or a pharmaceutically acceptable salt thereof) for the treatment of a disease, disorder or condition, , disorder or condition selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (especially heart failure with preserved ejection fraction), including such as, for example, in patients with type 2 diabetes , the presence of comorbidities in subjects who are obese or who have type 2 diabetes and heart failure, where the patient has been previously (e.g., within 24 hours) treated with another therapeutic agent.

Also provided herein is the use of another therapeutic agent for the treatment of a disease, disorder or condition selected from the foregoing list, suitably selected from type 2 diabetes, obesity, atherosclerosis and heart failure (in particular heart failure with preserved ejection fraction), including those 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 is also suffering from heart failure Cases in which the patient has previously (e.g., within 24 hours) taken a compound of formula (I) or a pharmaceutically acceptable salt thereof (including, for example, compounds of formula (Ia), (II), (IIa), (III) , (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va) and (Vb) any one of the compounds or pharmaceutically acceptable salts thereof) treatment.

In one embodiment, the other therapeutic agents are selected from: 1. Antidiabetic agents, such as insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonamides (e.g., chlorpropamide, azepinamide tosilyl) , acetyl benzene sulfonamide, tolbutamide, glyburide, glimepiride, glipizide); glyburide and Amaryl; insulin-stimulating sulfonate urea receptor ligands, such as meglitazone, such as nateglinide and repaglinide; tetrahydrothiazodiones (such as rosiglitazone (AVANDIA), troglitazone (REZULIN), pioglitazone (ACTOS), balaglitazone, rivoglitazone, netoglitazone, troglitazone, englitazone, ciglitazone, ada adaglitazone, darglitazone), which enhance insulin action (e.g., by insulin sensitization), thereby promoting glucose utilization in peripheral tissues; protein tyrosine phosphatase-1B (PTP -1B) inhibitors, such as PTP-112; cholesteryl ester transfer protein (CETP) inhibitors, such as torcetrapib (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 co-transporter inhibitors such as canagliflozin and dapagliflozin net, empagliflozin, empagliflozin, ipagliflozin, rupagliflozin, repagliflozin etabonate, sopagliflozin, togliflozin; glycogen phosphorylase A inhibitors, such as BAY R3401; biguanides (e.g., metformin) and other agents that act by promoting glucose utilization, reducing hepatic glucose production, and/or reducing intestinal glucose output; alpha-glucosidase inhibitors (e.g., acarbose and migiitoi) and Other agents that slow carbohydrate digestion and therefore absorption from the intestine and reduce 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; and 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, such as lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velovastatin Statins, fluvastatin, darvastatin, atorvastatin, rosuvastatin, and rivastatin; squalene synthase inhibitors; FXR (bacterioconol X receptor) and LXR (liver X receptor) Ligands; bile acid sequestrants, such as cholestyramine and colesevelam; fibrates; acids and aspirin; 3. Anti-obesity agents, such as orlistat, rimonabant, phentermine, topiramate, qunexa and locaserin; GDF15 (such as variants, conjugates, fusions, analogs, mutants and fragments thereof, including other GFRAL modulators such as NGM386, NGM395); molecules described in: PCT Disclosure WO 2013/148117, WO 2014/120619 and all related patent family members (including but not limited to US Patent 9,161,966 B1), WO 2012/138919, WO 2013/113008, WO 2015/017710, WO 2015/200078, WO 2015/ 197446, WO 2015/198199 and WO 2017/109706, in particular conjugates of GDF15 with fatty acids (such as those described in PCT Publications WO 2015/200078 and WO 2017/109706) and GDF15 fusions (including for example GDF15 Fusions with human serum albumin (HSA)), such as those described in PCT Publications WO 2015/197446, WO 2015/198199 and WO 2017/109706; FGF21 mimics, such as PEG-FGF21, PegBev Pegbelfermin; ActRII antagonists, such as ramatercept; and Alk7 antagonists; 4. Antihypertensive agents, such as loop diuretics, such as ethacrynic acid, furosemide, and tolasel m; Angiotensin-converting enzyme (ACE) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinopril Nalapril, ramipril and trandolapril; Na-K-ATPase membrane pump inhibitors, such as digitonin; neutral endopeptidase (NEP) inhibitors; ACE/NEP inhibitors, such as Opacadril, sampadril, and facidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan , especially valsartan; angiotensin receptor-neprilysin inhibitors (ARNi), such as sacubitril/valsartan (Entresto); renin inhibitors, such as ditekiren (ditekiren), zankiren, terlakiren, aliskiren, RO 66-1132 and RO-66-1168; beta-adrenoceptor blockers such as acebutolol, Atenolol, betaxalol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol; inotropic agents, such as inotropes Xanthosides, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil (bepridil), diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; 5. Peroxisome proliferator-activator receptor agonists, such as fenofibrate, pioglitazone, rosin Glitazone, ticaglitazar, BMS-298585, L-796449, compounds specifically described in patent application WO 2004/103995 (i.e. compounds of examples 1 to 35 or compounds specifically listed in claim 21), or patents The compounds specifically described in application WO 03/043985 (i.e. the compounds of Examples 1 to 7 or the compounds specifically listed in claim 19) and especially ( R )-1-{4-[5-methyl-2-( 4-Trifluoromethyl-phenyl)-ethazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid or its salt; 6. Expert Opin Investig Drugs [Expert Opinion on Research Drugs] 2003 , 12(4): 623-633Specific antidiabetic compounds described in Figures 1 to 7. 7. Compounds that bind to corticotropin-releasing hormone receptors, such as urinary corticotropin 2.

Additionally, the present invention provides combination therapies with agents and methods that promote weight loss, such as agents that stimulate metabolism or reduce appetite, as well as improved dietary and/or exercise regimens to promote weight loss. Example

The following examples are intended to illustrate the invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods (e.g., microanalysis and spectroscopic characterization (e.g., MS, IR, NMR)). The abbreviations used are those conventional in the art.

All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used for the synthesis of the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. In addition, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art, as shown in the following examples.

The following examples and abbreviations used elsewhere in this article are: A ₀ Plateau of the Hill curve at low concentrations AC ₅₀ Concentration at half maximum compound effect A _inf Plateau of the Hill curve at high concentrations ACN Acetonitrile BSA Bovine serum albumin BOC tertiary butylcarboxybr broad peak BSA bovine serum albumin cAMP cyclic adenosine monophosphate CDI carbonyldiimidazole CO ₂ carbon dioxide d doublet dd double doublet DBU diazabicycloundecene DCM dichloromethane DIEA/DIPEA Diethylisopropylamine DMA Dimethylacetamide DMEM Dulbecco's modified Eagle's medium DMF N,N-dimethylformamide DMI Dimethylimidazolinone DMPU N,N-dimethylacrylamide DMSO Dimethyl sulfoxide EC Effective concentration EC ₀ Effective concentration of the compound that produced no response EC ₅₀ Effective concentration of the compound that produced a half-maximal response (AC ₅₀ in µM) EC ₁₀₀ Effective concentration of the compound that produced a maximum (100%) response Concentration EDTA Ethylenediaminetetraacetic acid E _max efficacy: the maximum achievable response to the administered agent ESI Electrospray ionization EtOAc Ethyl acetate ETOH Ethanol FA Formic acid FBS Fetal bovine serum G418 Geneticin, a selected antibiotic GLP1 Glucagon-like peptide 1 GLP1R glucagon-like peptide 1 receptor GPCR G protein-coupled receptor h hour HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4 ,5-b]pyridinium 3-oxide hexafluorophosphate) hGLP1R human glucagon 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 diisopropylamine LiOH Lithium hydroxide MeCN Acetonitrile MeOH Methanol MS Mass spectrometry m Multiplet peak mg mg min min mL ml mM mmol mmol millimole nM nanomolar m/z mass-to-charge ratio NMR ND Undetermined PBS Phosphate Buffered Saline Pd(OAc) _2Palladium (II) acetate PdCl ₂ (dppf) -CH ₂ Cl ₂ 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 benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate PyBroP bromotripyrrolidinylphosphonium hexafluorophosphate rac racemic R _t retention time rt chamber Temperature s single peak SFC superfluid carbon dioxide SM starting material (starting material / starting materials) SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride t triplet TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMS Trimethylsilyl TMSCl Trimethylsilyl Chloride Tol Toluene Turbo Grignard Isopropyl Magnesium Chloride Lithium Chloride Complex Solution v/v Volume/Volume µL Microliter µM Micromol General conditions: NMR

Reagents and solvents received from commercial suppliers were used unless otherwise noted. Proton nuclear magnetic resonance ( ¹ H NMR) spectra were recorded under the following conditions: (a) on a Bruker AVANCE 400 MHz or 500 MHz NMR spectrometer, using ICON-NMR, under the control of the TopSpin program; (b) on a Bruker AVANCE 400 MHz or 500 MHz NMR spectrometer ASCEND 400 MHz NMR spectrometer, using Console-Avance III 400, controlled by the TopSpin 3.2 program; or (c) on a Bruker ASCEND 400 MHz NMR spectrometer, using Console-Avance III HD, controlled by the TopSpin 3.2 program. Unless otherwise stated, spectra were measured at 293-298 K and referenced relative to solvent resonance. Spectra are given in ppm (δ) and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as internal standard. NMR-01 :

Reagents and solvents received from commercial suppliers were used unless otherwise noted. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker ASCEND 400 MHz NMR spectrometer using a Console-Avance III 400 under the control of the TopSpin 3.2 program. Unless otherwise stated, spectra were measured at 293 K-298 K and referenced relative to solvent resonance. Spectra are given in ppm (δ) and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as internal standard. NMR-02 :

Reagents and solvents received from commercial suppliers were used unless otherwise noted. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker ASCEND 400 MHz NMR spectrometer using Console-Avance III HD under the control of the TopSpin 3.2 program. Unless otherwise stated, spectra were measured at 293 K-298 K and referenced relative to solvent resonance. Spectra are given in ppm (δ) and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as internal standard. LCMS instrument

Mass spectra were acquired using an Agilent 1100 HPLC system equipped with an Agilent 6110 mass spectrometer. [M+H] ⁺ refers to a protonated molecular ion of a chemical species. The column temperature is 50°C. The flow rate is 1.0 mL/min. 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 execution time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: Solvent A from 0.1 to 1.8 min, 98% solvent B for 0.2 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 120-1250 (spray ionization); column, at 50°C; flow rate 1.0 mL/min. LCMS method 2 (alkaline):

Instrument: Waters Acquity UPLC, photodiode array detector; Column: AcQuity UPLC BEH C ₁₈ 1.7 µm, 21 × 50 mm; 2 min execution time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: Solvent A from 0.1 to 1.8 min, 98% solvent B for 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 (spray ionization); column, at 50°C; flow rate 1.0 mL/min. LCMS Method 3 (Product Analysis - Acidity):

Instrument: Waters Acquity UPLC, photodiode array detector; column AcQuity UPLC BEH C ₁₈ 1.7 µm, 21 × 30 mm; 5.2 min execution time, 2% → 98% Solvent B: Solvent A from 0 to 5.15 min, 98 % Solvent B from 5.15 to 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, at 50°C, flow rate 1.0 mL/min. 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 execution time, 2% → 98% Solvent B: Solvent A from 0 to 5.15 min, 98 % Solvent B from 5.15 to 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, at 50°C, flow rate 1.0 mL/min. HRMS Method 5 :

Instrument: Agilent 1200 LC/G1956A, diode array detector; Column: Chromolith Flash C ₁₈ , 1.6 μm, 2 × 25 mm; 1.5 min execution time, 5% → 95% Solvent B: Solvent A from 0 → 1.2 min And then 95% solvent B from 1.21 → 1.5 minutes. Solvents: Solvent A = 0.0375% TFA in water (v/v), Solvent B = 0.01875% TFA in acetonitrile (v/v). Injection volume 2-5 uL; UV detection 220 and 254 nM, mass detection 100-1000 (spray ionization); column, at 50°C; flow rate 1.5 mL/min. Chiral preparative HPLC method: Instrument: Shimadzu LC-20AP and UV detector. Column: CHIRALPAK IG, (250 × 21.0) mm, 5 micron, column flow rate: 16.0 mL/min. Mobile phase: (A) 0.1% DEA in methanol. UV spectra were recorded at λ _max of 276.0 nm.

The isocratic ratio is: time(min) %A 0.01 100 18.00 100 Example 1 : Synthesis of intermediates

Example 1-1 : (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolane-2-yl) Synthesis of benzonitrile 4-methylbenzenesulfonate ( II.B1 ).

Step 1: (S)-4-(2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine -Synthesis of tertiary butyl 1-carboxylate (I I.1b ).

Combine 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 Palladium(II)[2-(2'-amino-1,1'-biphenyl)]methanesulfonate (48.9 mg, 55.8 µmol) was dissolved in dry N,N-dimethyl under nitrogen formamide (5 mL). Water (0.1 mL) was added and the mixture was degassed by bubbling nitrogen. The reaction was heated to 150°C in the microwave for 25 minutes. By LCMS analysis, nearly complete conversion into the desired substance was found. Open the vial and pour a mixture of 1 N sodium hydroxide (30 mL) and ethyl acetate (75 mL). The mixture was stirred vigorously for 10 min and the phases were then separated. The organic phase was dried over sodium sulfate and evaporated to dryness under reduced pressure. Purification using ISCO (5%-60% ethyl acetate gradient in heptane) gave the desired II.1b as a white solid (445 mg, 1.02 mmol, 91% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.11 - 1.20 (m, 1 H) 1.30 - 1.38 (m, 9 H) 1.45 - 1.73 (m, 5 H) 1.89 - 1.95 (m, 3 H) 2.60 - 2.72 (m, 3 H) 4.03 - 4.15 (m, 2 H) 6.49 - 6.60 (m, 2 H) 6.60 - 6.69 (m, 1 H) 7.22 - 7.33 (m, 2 H) 7.53 - 7.59 (m, 1 H).

Step 2: (S)-3-fluoro-4-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxolane-2-yl)benzyl Synthesis of nitrile 4-toluenesulfonate ( II.B1 ).

To a solution of II.1b (445 mg, 1.02 mmol) in EtOAc (7 mL) was added Ts-OH.H ₂ O (231.6 mg, 1.218 mmol) at 25 °C. The mixture was heated to 45°C for 16 h, at which time LCMS analysis showed complete consumption of starting material and formation of the desired product. The crude product was evaporated to dryness under reduced pressure to obtain the tosylate salt of II.B1 as a white solid (518 mg, 1.02 mmol, 100% yield). LCMS method 1 (acidic): Rt = 0.75 min, MS (ESI+) m/z 339.1 (M+1) ⁺ .

Example 1-2 : ( S )-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piper Hydrochloride ( II.A1 ) and ( S )-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- Synthesis of 4-yl)piperidine 4-methylbenzenesulfonate ( II.B2 ).

Step 1: Synthesis of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane ( II.2a ).

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

Step 2: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)-3,6-dihydro Synthesis of tertiary butyl pyridine-1(2H)-carboxylate ( II.3a ).

To a solution of II.2a (150 g, 436.58 mmol) in dimethacin (1500 mL) at 25 °C was added 4-(4,4,5,5-tetramethyl-1,3,2- Dioxolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (162.00 g, 523.90 mmol), Na ₂ CO ₃ (254.50 g, 2401.19 mmol) and Pd(dppf)Cl ₂ (31.99 g, 43.66 mmol). The mixture was stirred at 90°C for 16 h. The reaction mixture was filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1) to obtain II.3a as a yellow oil (50 g, 112.11 mmol, 96% purity, 44% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (t, J = 8.3 Hz, 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 = 14.3 Hz, 2H), 2.08 (d, J = 0.6 Hz, 3H), 1.51 (s, 9H).

Step 3: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine-1-carboxylic acid tris Synthesis of grade butyl ester ( II.4a ).

To a solution of II.3a (50 g, 112.13 mmol) in MeOH (200 mL) was added ((C ₆ H ₅ ) ₃ P) ₃ RhCl (5.19 g, 5.61 mmol) at 25°C. The mixture was stirred at 50 °C under _H2 for 16 h. The reaction mixture was filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (SiO ₂ , PE: EA = 10: 1) to obtain II.4a as a yellow oil (37.5 g, 83.71 mmol, 98% purity, 75% yield) . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (t, J = 8.3 Hz, 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, 7.8 Hz, 1H), 4.25 (br s, 2H), 2.83 (tt, J = 3.7, 11.9 Hz, 3H), 2.06 (d, J = 0.7 Hz, 3H), 1.86 - 1.64 (m, 4H), 1.50 (s, 9H).

Step 4: SFC separation of II.6a and II.6b .

II.4a (170 g, 379.52 mmol, 96% purity) was analyzed by SFC (CAS-WH-ANA-SFC-A (Agilent-1260), column: Chiralpak AD-3 50 × 4.6 mm ID, 3 um; flow Phases: Phase A is _CO2 , and Phase B is IPA (0.05% DEA); Gradient elution: B in A from 5% to 40%; 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.

Step 5a: ( S )-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine 4 -Synthesis of toluene sulfonate ( II.B2 ).

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 equiv ). After 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 was obtained as a white solid (20.0 g, 36.9 mmol, 85.2% yield, 96.0% purity). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ) 8.58 (br d, J = 8.63 Hz, 1H), 8.31 (br d, J = 8.25 Hz, 1H), 7.49 (d, J = 8.00 Hz, 2H ), 7.56 - 7.65 (m, 2H), 7.34 (dd, J = 8.38, 1.75 Hz, 1H), 7.12 (d, J = 7.88 Hz, 2H), 6.82 - 6.87 (m, 2H), 6.68 - 6.74 ( m, 1H), 3.37 (br d, J = 12.51 Hz, 2H), 2.94 - 3.07 (m, 3H), 2.03 (s, 3H), 2.29 (s, 3H), 1.84 - 1.94 (m, 4H).

Step 5b: ( S )-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine salt Synthesis of acid salt ( II.A1 ).

To a solution of II.6b (67 g, 149.58 mmol) in dimethicone (670 mL) was added HCl (670 mL, 1 M in dimethicone) at 25 °C. The mixture was stirred at 25°C for 16 h. The mixture was concentrated to give crude product. The crude product was triturated with MTBE:MeOH = 10:1 (700 mL) to give II.A1 as a white solid (71 g, 204.13 mmol, 98% purity, 99.27% ee quantification). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.98 - 9.43 (m, 2H), 7.57 (t, J = 8.3 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.87 - 6.65 (m, 3H), 3.96 (s, 1H), 3.64 (br d, J = 10.9 Hz, 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).

Example 1-3 : 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]dioxolane-4-yl)piperidine ( I .A1 ) synthesis.

Step 1: (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole (2a) and (S)-5-bromo-4-methyl Synthesis of 1-(oxetan-2-ylmethyl)-1H-imidazole ( III.2b ).

To a solution of 4-bromo-5-methyl-1H-imidazole ( III.a1 ) (2.000 g, 12.4 mmol) in acetonitrile (50 mL) at room temperature was added (S)-oxetane- 2-ylmethyl 4-methylbenzenesulfonate (3.33 g, 13.0 mmol) and cesium carbonate (10.1 g, 31.1 mmol). The mixture was stirred at 80°C for 16 hours using a findenser 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 via chromatography (0-100% EtOAc/Heptane, 0-5% MeOH/EtOAc) to isolate the isomers to provide (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) ⁺ ).

Step 2: Synthesis of (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde ( III.3 )

(S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole ( III.2a ) (580 mg, 2.51 mmol) at -78°C ) to a solution in THF (12 mL) was slowly added LDA in THF/heptane/ethylbenzene (2.51 mL, 2 M, 5.02 mmol). The reaction was stirred at -78°C for 40 min, then N,N-dimethylformamide (972 µL, 12.5 mmol) was added. The reaction was stirred from -78 °C to room temperature for 2 h. The reaction was quenched with saturated aqueous _NH4Cl and extracted three times with diethyl ether. _The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated to provide (S)-4-bromo-5-methyl-1-(oxetane-2- (Methyl)-1H-imidazole-2-carboxaldehyde ( III.3 ) (588.9 mg, 90.6% yield). The crude product was used in the next step without further purification. LCMS method 2 (basic): Rt = 1.02 min, MS (ESI+) m/z 259.1 (M+H) ⁺ .

Step 3: 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]dioxolane-4-yl)piperidine ( I.A1 ) Synthesis.

To (S)-4-bromo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde (1.6 g, 6.18 mmol) ( III.3 ) in To a solution in DCM (40 mL) was added (S)-4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-onium 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, then sodium triacetyloxyborohydride (1.36 g, 6.43 mmol) was added. The reaction was stirred at room temperature for an additional 2 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous _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 foamy solid. This crude product was further purified by normal phase chromatography (0-100% EtOAc/heptane) to provide 1-((4-bromo-5-methyl-1-(((S)- Oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methyl ylbenzo[d][1,3]dioxolane-4-yl)piperidine ( I.A1 ) (1.7 g, 58.2% yield). LCMS Method 4: (Product Analysis - Basic): Rt = 3.42 min, MS (ESI+) m/z 592.3 (M+H) ⁺ . ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 7.58 (t, J = 8.4 Hz, 1H), 7.24 - 7.13 (m, 2H), 6.85 - 6.77 (m, 1H), 6.74 (s, 2H), 5.07 (qd, J = 7.3, 2.9 Hz, 1H), 4.64 (td, J = 8.0, 5.8 Hz, 1H), 4.53 - 4.37 (m, 2H), 4.29 (d, J = 15.0 Hz, 1H), 3.67 (d, J = 13.5 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 3.07 - 2.84 (m, 2H), 2.76 (dtd, J = 11.4, 8.0, 5.9 Hz, 2H), 2.46 ( ddt, J = 11.3, 9.3, 7.2 Hz, 1H), 2.23 (s, 3H), 2.21 (br,s, 2H), 2.08 (d, J = 1.2 Hz, 3H), 1.84 (d, J = 23.4 Hz , 4H).

Example 2 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) -Synthesis of 5-methylethazole-4-carboxylic acid ( C-1 ).

Step 1: (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl) -1H -imidazole ( III.3a ) and ( S )-5-iodo- Synthesis of 4-methyl-1-(oxetan-2-ylmethyl) -1H -imidazole ( III.3b) .

To ( S )-oxetan-2-ylmethyl 4-methylbenzenesulfonate (2.17 g, 8.96 mmol) and 5-iodo-4-methyl-1 H -imidazole (CAS No. 15813- 07-72, 2.049 g, 9.85 mmol) to a solution in ACN (50 mL) was added Cs ₂ CO ₃ (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 to 20%) to isolate the positional isomers and provide intermediates III.3a and III.3b . (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl) -1H -imidazole ( III.3a ): ^1H 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 ): ^1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 5.12 - 4.98 (m, 1H), 4.74 - 4.58 (m, 1H), 4.37 (td, J = 6.0, 9.2 Hz, 1H), 4.18 - 4.06 (m, 2H), 2.69 (dtd , J = 6.0, 8.0, 11.6 Hz, 1H), 2.35 (tdd, J = 7.2, 9.2, 11.2 Hz, 1H), 2.26 (s, 3H).

Step 2 Synthesis of: ( S )-5-iodo-4-methyl-1-(oxetan-2-ylmethyl) -1H -imidazole-2-carbaldehyde ( III.4 ).

To a solution of III.3b (0.222 g, 0.8 mmol) in THF (4 mL) at -78 °C, LDA (1.600 mL, 1.600 mmol) was slowly added. The reaction was stirred at -78 °C for 30 min, then DMF (0.310 mL, 4.00 mmol) was added. The reaction was stirred from -78 °C to room temperature for 2 h. Afterwards, the reaction was quenched with saturated aqueous _NH4Cl solution 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) ⁺ .

Step 3: 4-(( S )-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)-1- ((5-iodo-4-methyl-1-((( S )-oxetan-2-yl)methyl)-1 H -imidazol-2-yl)methyl)piperidine ( I. Synthesis of B1 ).

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, then sodium triacetoxyborohydride (170 mg, 0.800 mmol) was added. The reaction was stirred at room temperature for 1.5 h before being cooled to 0 °C, quenched with saturated _aqueous NaHCO and extracted twice with DCM. The combined organic layers were concentrated and the residue was purified by FCC (EA/Hep = 0 to 100%) to provide I.B1 . LCMS method 1 (acidic): Rt = 1.23 min, MS (ESI+) m/z 638.2 (M+H) ⁺ .

Step 4: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) -Synthesis of ethyl 5-methylethazole-4-carboxylate ( I.1 ).

To a solution of I.B1 (2.3 g, 3.61 mmol) and ethyl 5-methylethazole-4-carboxylate (1.12 g, 7.21 mmol) in toluene (16 mL) was added Xphos Pd G2 ( 283.7 mg, 360.5 µmol) and Cs ₂ CO ₃ (2.35 g, 7.21 mmol). The reaction was heated to 120°C for 16 h, at which time LCMS analysis showed 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 to 10%) to afford 1.1 (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) ⁺ .

Step 5: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) -Synthesis of 5-methylethazole-4-carboxylic acid ( C-1 ).

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 1 M in H ₂ O (9.622 mL, 9.622 mmol). The reaction mixture was stirred overnight, at which time LCMS analysis showed complete consumption of the starting ester and formation of the desired product. The reaction was then acidified with 1 M citric acid to pH = 4 and extracted three times with ethyl acetate. _The combined organic layers were washed with brine and dried over _Na2SO4 . After filtration and concentration, the residue was purified by RP ISCO (2 × 150 g C18 column, 10%-70% ACN in water, 0.1% concentrated NH ₄ OH as modifier) to provide the presentation after lyophilization Compound C-1 was a white solid (155.0 mg, 0.24 mmol, 10% yield).

C-1 : ¹ H NMR (400 MHz, DMSO) δ 7.57 - 7.39 (m, 2H), 7.27 (dd, J = 8.4, 2.1 Hz, 1H), 6.74 - 6.59 (m, 3H), 4.93 - 4.80 ( m, 2H), 4.72 - 4.57 (m, 1H), 4.38 - 4.29 (m, 1H), 4.23 (dt, J = 8.9, 6.0 Hz, 1H), 3.69 (d, J = 13.4 Hz, 1H), 3.49 (d, J = 13.4 Hz, 1H), 2.90 (d, J = 11.2 Hz, 1H), 2.79 (d, J = 11.3 Hz, 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 = 27.9 Hz, 4H). LCMS method 2 (basic): Rt = 0.79 min, MS (ESI+) m/z 637.5 (M+H) ⁺ . HRMS calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2401.

Example 2-1 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-5-carboxylic acid ( C-2 ).

Compound C-2 used the same procedure as described in Example 2 but used (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate in step 1 and in step 4 Synthesized from ethyl ethyl ethazole-5-carboxylate.

C-2 : ¹ H NMR (400 MHz, MeOD) δ 7.53 - 7.45 (m, 2H), 7.18 (dd, J = 11.0, 2.1 Hz, 1H), 7.11 (dd, J = 8.4, 2.1 Hz, 1H) , 6.76 - 6.60 (m, 3H), 5.17 - 5.06 (m, 1H), 4.90 - 4.80 (m, 2H), 4.60 (td, J = 8.1, 5.8 Hz, 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), 2.72 - 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 calculated value for C ₃₂ H ₃₃ ClFN ₄ O ₆ (M+H) ⁺ is 623.2073, found value is 623.2139.

Example 2-2 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-4-carboxylic acid ( C-3 ).

Compound C-3 used the same procedure as described in Example 2 except that in step 1 (R)-oxetan-2-ylmethyl 4-methylbenzenesulfonate was used and in step 4 Synthesized from ethyl ethazole-4-carboxylate.

C-3 : ¹ H NMR (400 MHz, MeOD) δ 8.23 (s, 1H), 7.49 (t, J = 8.3 Hz, 1H), 7.19 (dd, J = 10.9, 2.1 Hz, 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 = 14.9 Hz, 3H), 2.74 - 2.61 (m, 1H ), 2.43 (s, 3H), 2.41 - 2.30 (m, 1H), 1.98 - 1.86 (m, 7H). HRMS calculated value for C32H33ClFN4O6 (M+H) ⁺ is 623.2073, and the measured value is 623.2103.

Example 2-3 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H- Synthesis of imidazol-5-yl)ethazole-4-carboxylic acid ( C-4 ).

Compound C-4 used the same procedure as described in Example 2 but used 5-iodo-4-(trifluoromethyl)-1H-imidazole in step 1 and ethyl ethazole-4-carboxylate in step 4. synthesized from esters.

C-4 : ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 1.90 - 2.13 (m, 7 H) 2.31 - 2.57 (m, 1 H) 2.62 - 3.04 (m, 4 H) 3.32 - 3.46 (m , 2 H) 4.02 - 4.33 (m, 2 H) 4.34 - 4.49 (m, 1 H) 4.53 - 4.68 (m, 1 H) 4.88 - 4.98 (m, 1 H) 5.02 - 5.30 (m, 2 H) 6.66 - 6.76 (m, 2 H) 6.76 - 6.84 (m, 1 H) 7.17 - 7.24 (m, 1 H) 7.24 - 7.32 (m, 1 H) 7.53 - 7.62 (m, 1 H) 8.10 - 8.79 (m, 1H). HRMS calculated value for C ₃₂ H ₃₀ ClF ₄ N ₄ O ₆ (M+H) ⁺ is 677.1790, found value is 677.1899.

Example 2-4 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-4-carboxylic acid ( C-5 ).

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 ethazole-4-carboxylate in step 4.

C-5 : ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 1.27 (t, J = 7.52 Hz, 3 H) 1.91 - 2.14 (m, 8 H) 2.41 - 2.51 (m, 1 H) 2.73 - 2.81 (m, 1 H) 2.87 - 2.96 (m, 5 H) 3.44 - 3.52 (m, 2 H) 4.28 - 4.33 (m, 2 H) 4.46 - 4.53 (m, 1 H) 4.64 - 4.70 (m, 1 H) 4.99 - 5.08 (m, 2 H) 5.17 - 5.24 (m, 1 H) 6.72 - 6.82 (m, 3 H) 7.18 - 7.24 (m, 1 H) 7.25 - 7.32 (m, 1 H) 7.54 - 7.63 (m, 1 H) 8.27 - 8.34 (m, 1 H). HRMS calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2405.

Example 2-5 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-5-carboxylic acid ( C-6 ).

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 ethazole-5-carboxylate in step 4.

C-6 : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.15 - 1.23 (m, 3 H) 1.65 - 1.82 (m, 4 H) 2.02 (s, 3 H) 2.07 - 2.40 (m, 4 H) 2.62 - 2.68 (m, 2 H) 2.79 - 2.90 (m, 3 H) 2.96 - 3.02 (m, 1 H) 3.59 (br d, J =13.45 Hz, 1 H) 3.76 - 3.87 (m, 1 H ) 4.27 - 4.46 (m, 2 H) 4.53 - 4.78 (m, 1 H) 4.79 - 5.06 (m, 2 H) 6.73 - 6.81 (m, 3 H) 7.31 - 7.37 (m, 1 H) 7.51 - 7.61 ( m, 2 H). HRMS calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2264.

Example 2-6 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-4-carboxylic acid ( C-7 ).

Compound C-7 was prepared using the same procedure as described in Example 2 but using 4-ethyl-5-iodo-1H-imidazole and (R)-oxetan-2-ylmethyl4- in step 1 Tosylate, and was synthesized in step 4 using ethyl ethazole-4-carboxylate.

C-7 : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.12 - 1.22 (m, 3 H) 1.68 - 1.82 (m, 4 H) 1.98 - 2.04 (m, 3 H) 2.06 - 2.25 (m , 2 H) 2.25 - 2.37 (m, 1 H) 2.57 - 2.68 (m, 2 H) 2.72 - 2.82 (m, 2 H) 2.82 - 2.91 (m, 1 H) 2.93 - 3.02 (m, 1 H) 3.54 - 3.65 (m, 1 H) 3.72 - 3.87 (m, 1 H) 4.23 - 4.33 (m, 1 H) 4.34 - 4.44 (m, 1 H) 4.63 - 4.76 (m, 1 H) 4.86 - 5.03 (m, 2 H) 6.70 - 6.82 (m, 3 H) 7.30 - 7.37 (m, 1 H) 7.51 - 7.61 (m, 2 H) 8.74 - 8.79 (m, 1 H). HRMS calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2377.

Example 2-7 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-5-carboxylic acid ( C-8 ).

Compound C-8 was prepared using the same procedure as described in Example 2 but using 4-ethyl-5-iodo-1H-imidazole and (R)-oxetan-2-ylmethyl4- in step 1 Tosylate, and was synthesized using ethyl ethazole-5-carboxylate in step 4.

C-8 : ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.11 - 1.21 (m, 3 H) 1.69 - 1.80 (m, 4 H) 2.02 (s, 3 H) 2.08 - 2.28 (m, 2 H) 2.29 - 2.37 (m, 1 H) 2.59 - 2.68 (m, 2 H) 2.70 (br s, 3 H) 2.95 - 3.05 (m, 1 H) 3.59 - 3.65 (m, 1 H) 3.77 - 3.86 ( m, 1 H) 4.27 - 4.46 (m, 2 H) 4.56 - 4.75 (m, 1 H) 4.75 - 5.06 (m, 2 H) 6.72 - 6.82 (m, 3 H) 7.31 - 7.37 (m, 1 H) 7.52 - 7.60 (m, 2 H) 7.76 - 8.03 (m, 1 H). HRMS calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2351.

Example 2-8 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethazole-4-carboxylic acid ( C-9 ).

Compound C-9 was synthesized using the same procedure as described in Example 2 but using ethyl ethazole-4-carboxylate in step 4.

C-9 : ¹ H NMR (400 MHz, MeOD) δ 8.30 (s, 1H), 7.60 - 7.56 (m, 1H), 7.28 (dd, J = 11.2 Hz, 2 Hz, 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) ⁺ .

Example 2-9 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of ethyl)-5-ethylethazole-4-carboxylic acid ( C-10 ).

Compound C-10 was synthesized using the same procedure as described in Example 2 but using ethyl 5-ethylethazole-4-carboxylate in step 4.

C-10 : ¹ H NMR (400 MHz, DMSO) δ 7.56 - 7.43 (m, 2H), 7.27 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 - 6.63 (m, 3H), 4.86 (dd, J = 10.2, 3.4 Hz, 2H), 4.73 - 4.56 (m, 1H), 4.34 (q, J = 6.8 Hz, 1H), 4.24 (dt, J = 8.9, 6.0 Hz, 1H), 3.69 (d, J = 13.3 Hz, 1H), 3.49 (d, J = 13.4 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.90 (d, J = 11.0 Hz, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.56 (dd, J = 16.3, 11.7 Hz, 2H), 2.31 - 2.20 (m, 4H), 2.15 - 1.98 (m, 2H), 1.95 (s, 3H), 1.77 - 1.53 (m, 4H), 1.13 (t, J = 7.4 Hz, 3H). HRMS calculated value for C ₃₄ H ₃₇ ClFN ₄ O ₆ (M+H) ⁺ is 651.2386, found value is 651.2513.

Example 2-10 : 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy Pentyl)-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5 -Synthesis of -5-methylethazole-4-carboxylic acid ( C-11 ).

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 : ¹ H NMR (400 MHz, DMSO) δ 7.91 (d, J = 11.2 Hz, 1H), 7.67 (d, J = 6.5 Hz, 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, 6.3 Hz, 1H), 4.24 (dt, J = 8.8, 6.0 Hz, 1H), 3.70 (d, J = 13.5 Hz, 1H), 3.50 (d, J = 13.5 Hz, 1H), 2.90 (d, J = 11.1 Hz, 1H), 2.79 (d, J = 11.0 Hz, 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 calculated value for C ₃₄ H ₃₅ FN ₅ O ₆ (M+H) ⁺ is 628.2571, and the found value is 628.2587.

Example 3 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) -Synthesis of 5-methylethazole-4-carboxylic acid ( C-12 ).

Step 1 Synthesis of: (S)-4-iodo-5-methyl-1-(oxetan-2-ylmethyl)-1H-imidazole-2-carbaldehyde ( III.5 ).

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) ⁺ .

Step 2: 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)-1- ((4-iodo-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine ( I.A2 ) Synthesis.

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) ⁺ .

Step 3: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) -Synthesis of ethyl 5-methylethazole-4-carboxylate ( I.2 ).

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) ⁺ .

Step 4: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) -Synthesis of 5-methylethazole-4-carboxylic acid ( C-12 ).

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 (400 MHz, DMSO) δ 7.55 - 7.44 (m, 2H), 7.27 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 - 6.60 (m, 3H), 4.96 (dd, J = 8.8, 6.3 Hz, 1H), 4.49 - 4.29 (m, 3H), 4.23 (dd, J = 15.2, 2.8 Hz, 1H), 3.66 (d, J = 13.5 Hz, 1H), 3.42 (d, J = 13.4 Hz, 1H), 2.91 (d, J = 11.1 Hz, 1H), 2.76 (d, J = 11.3 Hz, 1H), 2.61 (td, J = 17.4, 8.7 Hz, 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 calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2288.

Example 3-1 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of ethazole-4-carboxylic acid ( C-13 ).

Compound C-13 was synthesized using the same procedure as described in Example 3 but using ethyl ethazole-4-carboxylate in step 3.

C-13 : ¹ H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 7.58 - 7.53 (m, 2H), 7.33 (dd, J = 8.4, 1.6 Hz, 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 = 13.2 Hz, 1H) , 3.50 (d, J = 5 Hz, 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)+.

Example 3-2 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of methyl)-4-(trifluoromethyl)ethazole-5-carboxylic acid ( C-14 ).

Compound C-14 was synthesized using the same procedure as described in Example 3 but using ethyl 4-(trifluoromethyl)ethazole-5-carboxylate in step 3.

C-14 : 1H NMR (400 MHz, DMSO) δ 7.54 - 7.44 (m, 2H), 7.28 (dd, J = 8.5, 2.1 Hz, 1H), 6.77 - 6.60 (m, 3H), 5.04 - 4.88 (m , 1H), 4.49 - 4.29 (m, 3H), 4.24 (d, J = 14.4 Hz, 1H), 3.67 (d, J = 13.6 Hz, 1H), 3.43 (d, J = 13.3 Hz, 1H), 2.92 (d, J = 11.1 Hz, 1H), 2.78 (d, J = 11.3 Hz, 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 calculated value for C ₃₃ H ₃₂ ClF ₄ N ₄ O ₆ (M+H) ⁺ is 691.1947, found value is 691.1964.

Example 3-3 : 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of methyl)-4-methylethazole-5-carboxylic acid ( C-15 ).

Compound C-15 was synthesized using the same procedure as described in Example 3 but using ethyl 4-methylethazole-5-carboxylate in step 3.

C-15 : ¹ H NMR (400 MHz, DMSO) δ 7.55 - 7.46 (m, 2H), 7.28 (dd, J = 8.4, 2.1 Hz, 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, 2.9 Hz, 1H), 3.65 (d, J = 13.3 Hz, 1H), 3.41 (d, J = 13.3 Hz, 1H), 2.92 (d, J = 11.2 Hz, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.65 - 2.54 (m, 2H), 2.48 (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 calculated value for C ₃₃ H ₃₅ ClFN ₄ O ₆ (M+H) ⁺ is 637.2229, found value is 637.2372.

Example 4 : 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) Synthesis of ethazole-2-carboxylic acid ( C-16 ).

Step 1: 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) Synthesis of ethyl ethyl ethazole-2-carboxylate ( I.3 ).

To 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]dioxolane-4-yl)piperidine ( I.A1 ) ( To a solution of 50.00 mg, 84.61 µmol) in 1,4-dioxolaborate (1.000 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Ethyl alk-2-yl)ethazole-2-carboxylate (29.38 mg, 110.0 µmol), K ₃ PO ₄ (126.9 µL, 2.000 M, 253.8 µmol), and Pd 118 (5.515 mg, 8.461 µmol). Microwave the reaction mixture at 120°C for 30 min. LCMS showed the reaction was complete. The crude product was diluted with DCM and washed with saturated _NaHCO3 . The separated organic layer was filtered to remove water and concentrated via rotary evaporator to provide a brown oil ( 1.3 ), which was used "as is" in the next step. LCMS method 2 (basic): Rt = 1.37 min, MS (ESI+) m/z 651.2 (M+H) ⁺ .

Step 2: 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) Synthesis of ethazole-2-carboxylic acid ( C-16 ).

To 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole To a solution of -ethyl-2-formate ( 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 M, 337.9 µmol). The reaction mixture was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The crude product was loaded directly onto a 50 g C18 column and purified by ISCO (10%-100% ACN in water, modified with 0.1% concentrated NH ₄ OH) to provide 5-(2-( after lyophilization (4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine-1- methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole-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) ⁺ . ¹ H NMR (400 MHz, MeOD) δ 7.48 (t, J = 8.3 Hz, 1H), 7.21 - 7.06 (m, 3H), 6.72 - 6.54 (m, 3H), 5.08 (qd, J = 7.4, 2.5 Hz , 1H), 4.61 - 4.46 (m, 2H), 4.41 (dt, J = 9.2, 5.9 Hz, 1H), 4.30 (dd, J = 15.3, 2.6 Hz, 1H), 3.70 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 2.92 (d, J = 11.3 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.71 (ddd, J = 11.5, 5.5, 2.7 Hz, 1H ), 2.65 - 2.51 (m, 1H), 2.47 (s, 3H), 2.40 (dt, J = 11.2, 8.0 Hz, 1H), 2.10 (dtd, J = 30.6, 11.4, 2.9 Hz, 2H), 1.93 ( s, 3H), 1.77 (dddd, J = 25.3, 17.4, 12.7, 7.0 Hz, 4H).

Example 4-1 : 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of 1-methyl-1H-pyrazole-5-carboxylic acid ( C-17 ).

Compound C-17 Use the same procedure as described in Example 4 but use 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxetane in step 1 Pentaborane-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester.

C-17 : ¹ H NMR (400 MHz, MeOD) δ 7.48 (t, J = 8.3 Hz, 1H), 7.18 (dd, J = 11.0, 2.1 Hz, 1H), 7.11 (dd, J = 8.3, 2.0 Hz , 1H), 6.76 (s, 1H), 6.71 - 6.53 (m, 3H), 5.07 (qd, J = 7.3, 2.6 Hz, 1H), 4.59 - 4.33 (m, 3H), 4.28 (dd, J = 15.4 , 2.7 Hz, 1H), 4.05 (s, 3H), 3.67 (d, J = 13.5 Hz, 1H), 3.54 (d, J = 13.5 Hz, 1H), 2.93 (d, J = 11.3 Hz, 1H), 2.83 (d, J = 11.5 Hz, 1H), 2.69 (dtd, J = 11.2, 8.0, 6.0 Hz, 1H), 2.58 (ddd, J = 11.8, 7.6, 3.4 Hz, 1H), 2.47 - 2.38 (m, 1H), 2.36 (s, 3H), 2.10 (dtd, J = 26.9, 11.4, 2.9 Hz, 2H), 1.93 (s, 3H), 1.87 - 1.63 (m, 4H). HRMS calculated value for C ₃₃ H ₃₆ ClFN ₅ O ₅ (M+H) ⁺ is 636.2389, found value is 636.2411.

Example 4-2 : 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of ethazole-2-carboxylic acid ( C-18 ).

Compound C-18 Use the same procedure as described in Example 4 but use 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2 in step 1 -ethyl)ethyl ethazole-2-carboxylate.

C-18 : ¹ H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.48 (t, 1H), 7.18 (dd, J = 10.8, 2.0 Hz, 1H), 7.11 (dd, J = 8.5, 2.0 Hz, 1H), 6.73 - 6.53 (m, 3H), 5.13 - 4.98 (m, 1H), 4.59 - 4.44 (m, 2H), 4.40 (dt, J = 9.2, 5.9 Hz, 1H), 4.28 (dd , J = 15.3, 2.7 Hz, 1H), 3.69 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 2.93 (d, J = 11.3 Hz, 1H), 2.82 (d , J = 11.4 Hz, 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) ⁺ .

Example 4-3 : 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-4- Synthesis of methyl)-3-methylfuran-2-carboxylic acid ( C-19 ).

Compound C-19 Use the same procedure as described in Example 4 but use 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxetane in step 1 Synthesized from pentaborane-2-yl)furan-2-carboxylic acid methyl ester.

C-19 : ¹ H NMR (400 MHz, MeOD) δ 7.57 (t, J = 8.3 Hz, 1H), 7.26 (dd, J = 10.8, 2.0 Hz, 1H), 7.18 (dd, J = 8.5, 2.1 Hz , 1H), 6.81 - 6.74 (m, 1H), 6.70 (dd, J = 7.1, 5.5 Hz, 2H), 6.51 (s, 1H), 5.15 (qd, J = 7.4, 2.4 Hz, 1H), 4.64 ( td, J = 7.8, 5.6 Hz, 1H), 4.59 - 4.51 (m, 1H), 4.48 (dt, J = 9.1, 5.9 Hz, 1H), 4.37 (dd, J = 15.6, 2.5 Hz, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 3.24 (s, 1H), 3.11 (d, J = 12.3 Hz, 1H), 2.86 - 2.66 (m, 2H) , 2.53 (s, 3H), 2.57 - 2.32 (m, 3H), 2.36 (s, 3H), 2.02 (s, 3H), 2.05 - 1.75 (m, 4H). HRMS calculated value for C ₃₄ H ₃₆ ClFN ₃ O ₆ (M+H) ⁺ is 636.2277, found value is 636.2281.

Example 5 : 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) Synthesis of ethazole-2-carboxylic acid ( C-20 ).

Step 1: 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) Synthesis of ethyl ethyl ethazole-2-carboxylate ( I.4 ).

To 4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)-1-(( 5-iodo-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)piperidine ( I.B1 ) ( To a solution of 60.00 mg, 94.06 µmol) in 1,4-dioxolaborate (1.000 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxolabor Ethyl alk-2-yl)ethazole-2-carboxylate (75.36 mg, .2 µmol), K ₂ CO ₃ (211.6 µL, 2.000 M, 4423.3 µmol), and XPhos Pd G2 (7.400 mg, 9.406 µmol). The reaction mixture was purged with nitrogen for 5 min and then heated in the microwave at 110°C for 30 min. LCMS showed formation of 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Ethyl)ethyl ethazole-2-carboxylate ( I.4 ). Hydrolyzed acid PDT (Rt = 0.81 min) and a considerable amount of doubly coupled side PDT (Rt = 1.27 min) were also observed. The crude product was acidified (to pH = 4) by 1 M citric acid, diluted with brine and extracted with EtOAc (2×). The isolated 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) ⁺ .

Step 2: 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) Synthesis of ethazole-2-carboxylic acid ( C-20 ).

To 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole To a solution of -ethyl-2-formate ( 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 M, 374.7 µmol). The resulting mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The crude product was purified directly on a 50 g C18 column using ISCO (10%-100% ACN in water, 0.1% concentrated _NH4OH as buffer) to provide 4-(2-((4- ((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidin-1-yl)methane methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole-2-carboxylic acid 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 (400 MHz, MeOD) δ 7.94 (s, 1H), 7.48 (t, J = 8.3 Hz, 1H), 7.18 (dd, J = 11.0, 2.0 Hz, 1H), 7.11 (dd, J = 8.3 , 2.1 Hz, 1H), 6.72 - 6.54 (m, 3H), 4.95 (dt, J = 7.4, 3.8 Hz, 1H), 4.85 (dd, J = 15.0, 7.6 Hz, 1H), 4.56 (dd, J = 15.1, 2.9 Hz, 1H), 4.45 (td, J = 7.9, 5.8 Hz, 1H), 4.30 (dt, J = 9.2, 5.9 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.55 ( d, J = 13.6 Hz, 1H), 2.94 (d, J = 11.2 Hz, 1H), 2.83 (d, J = 11.4 Hz, 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).

Example 5-1 : 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of 1-methyl-1H-pyrazole-5-carboxylic acid ( C-21 ).

Compound C-21 Use the same procedure as described in Example 5 but use 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxetane in step 1 Pentaborane-2-yl)-1H-pyrazole-5-carboxylic acid methyl ester.

C:21 : ¹ H NMR (400 MHz, MeOD) δ 7.48 (t, J = 8.3 Hz, 1H), 7.18 (dd, J = 10.8, 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.1 Hz , 1H), 6.73 - 6.54 (m, 4H), 4.91 (qd, J = 7.0, 3.3 Hz, 1H), 4.71 (dd, J = 15.0, 6.8 Hz, 1H), 4.52 - 4.43 (m, 2H), 4.30 (dt, J = 9.2, 5.9 Hz, 1H), 4.06 (s, 3H), 3.75 (d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.5 Hz, 1H), 2.94 (d, J = 11.6 Hz, 1H), 2.87 (d, J = 11.5 Hz, 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 calculated value for C ₃₃ H ₃₆ ClFN ₅ O ₅ (M+H) ⁺ is 636.2389, found value is 636.2394.

Example 5-2 : 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of furan-2-carboxylic acid ( C-22 ).

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 (400 MHz, MeOD) δ 7.48 (t, J = 8.3 Hz, 1H), 7.18 (dd, J = 10.9, 2.2 Hz, 1H), 7.11 (dd, J = 8.3, 2.2 Hz , 1H), 6.93 (d, J = 3.4 Hz, 1H), 6.74 - 6.54 (m, 3H), 6.43 (d, J = 3.4 Hz, 1H), 4.93 (qd, J = 7.1, 3.0 Hz, 1H) , 4.84 - 4.73 (m, 1H), 4.52 (dd, J = 15.1, 3.1 Hz, 1H), 4.45 (td, J = 7.9, 5.7 Hz, 1H), 4.31 (dt, J = 9.0, 6.0 Hz, 1H ), 3.74 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.6 Hz, 1H), 2.93 (d, J = 11.3 Hz, 1H), 2.83 (d, J = 11.4 Hz, 1H), 2.67 - 2.50 (m, 2H), 2.27 (ddt, J = 11.4, 9.2, 7.0 Hz, 1H), 2.19 - 2.01 (m, 5H), 1.93 (s, 3H), 1.88 - 1.60 (m, 4H). HRMS calculated value for C ₃₃ H ₃₄ ClFN ₃ O ₆ (M+H) ⁺ is 622.21, found value is 622.2185.

Example 5-3 : 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane Cycl-4-yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazole-5- Synthesis of thiazole-2-carboxylic acid ( C-31 ).

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 (400 MHz, DMSO) δ 7.91 (s, 1H), 7.63 - 7.53 (m, 2H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H), 6.80 (d, J = 4.5 Hz, 2H ), 6.78 - 6.72 (m, 1H), 4.89 - 4.68 (m, 2H), 4.52 (dd, J = 14.6, 3.3 Hz, 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).

Example 6 : 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) Synthesis of acid ( C-23 ).

To 1-((4-bromo-5-methyl-1-((S)-oxetan-2-yl) prepared using the same procedure as described in steps 1 to 3 of Example 1-3 )methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1, To a solution of 3]dioxolane-4-yl)piperidine ( I.A1 ) (39 mg, 66 µmol) in 1,4-dichloromethane (0.7 mL) was added 5-carboxypyridine-3-boronic acid (13 mg, 79 µmol), K ₃ PO ₄ (0.30 mL, 1 M, 0.30 mmol), and Pd 118 (4.3 mg, 6.6 µmol). The mixture was degassed _under N and then microwaved at 120 °C for 20 min. The reaction mixture was diluted with water, filtered through a plug and purified on basic HPLC to provide 5-(2-((4-((S))-2-(4-chloro-2-fluorophenyl)-2-methyl Benzo[d][1,3]dioxolane-4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetane-2 Synthesis of -methyl)-1H-imidazol-4-yl) 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 (400 MHz, DMSO) δ 8.91 (d, J = 2.3 Hz, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.42 (t, J = 2.1 Hz, 1H), 7.62 - 7.50 ( m, 2H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 6.83 - 6.71 (m, 3H), 5.04 (qd, J = 7.4, 2.8 Hz, 1H), 4.58 - 4.39 (m, 3H) , 4.30 (dd, J = 15.2, 2.9 Hz, 1H), 3.76 (d, J = 13.4 Hz, 1H), 3.52 (d, J = 13.3 Hz, 1H), 3.05 - 2.96 (m, 1H), 2.88 ( dq, J = 12.5, 4.2 Hz, 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, 3.5 Hz, 4H).

Example 7 : 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) Furan-2-carboxylic acid ( C-24 ).

To 5-borofuran-2-carboxylic acid (1.3 mg, 8.46 µmol) was added 1-((4-bromo-5-methyl-) containing PdCl ₂ (dtbpf) (1.4 mg, 2.1 µmol) at room temperature. 1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-2-yl)methyl)-4-((S)-2-(4-chloro-2- Fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidine ( I.A1 ) (5 mg, 85 µL, 8.46 µmol) (Use as in Example 1 -3) 0.1 M solution in DMA prepared by the same procedure described in steps 1 to 3. To this solution was added tripotassium phosphate (5.4 mg, 25.4 µL, 25.4 µmol) in 1 M water. The mixture was stirred at 110°C for 18 hours. After this time, the solvent was removed under reduced pressure in the genevac. The crude product was dissolved in 7:2:1 acetonitrile:water:dimethylsulfoxide, passed through a metal scavenger filter (SiliCycle SiliaPrep 96-well dimercaptotrifluoroethylene, 40-63 µm, 60 Å), and prepared by HPLC Method MC-1 was purified and immediately quantified by LCMS equipped with CAD (LCMS Method MC-1). The solvent was removed under a Porvair Sciences Ultravap Mistral evaporator and the purified solid was immediately reconstituted in DMSO to provide 5-(2-((4-((S)-2-(4- Chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl)piperidin-1-yl)methyl)-5-methyl-1- (((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2-carboxylic acid ( C-24 ). 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] ⁺ . Biological Assays and Data

Compounds of formula (I) according to the invention were tested in cellular assays measuring intracellular cAMP concentration, β-arrestin recruitment and receptor internalization. cAMP is produced by activation of GLP1R. The cAMP data obtained are shown in Table 1 . GLP1R activation recruits β-arrestin and the data obtained are shown in Table 2 . After activation, the extent to which GLP1R is internalized into cells and dissociated from the plasma membrane is also shown in Table 2 . The _EC50 for each assay was defined as the compound concentration that resulted in half the maximum response (after baseline correction). _Emax is defined as the maximum response observed for a test compound normalized to the maximum response observed to the endogenous ligand (GLP1(7-36)) for GLP1R. Human GLP1R cAMP agonist assay

The agonist activity of compounds was determined using the GloSensor™ cAMP assay (Promega Corp.), which measures changes in intracellular cAMP concentration following ligand activation of GPCRs. This assay uses a biosensor encoded by the pGloSensor™-22F cAMP plasmid (Promega, Cat. No. E2301) in which the cAMP binding domain is fused to a mutant form of firefly 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 expressing human GLP1 receptor (hGLP1R) and pGloSensor™-22F were seeded in white 384-well poly-D-lysine-coated plates (Greiner Bio) One), Cat. No. 781945) in CO2 _- independent medium (Gibco Cat. No. 18045-088, containing 1.0% FBS, 2 mM L-glutamic acid, penicillin, and streptomycin) and incubate overnight at 37°C, 5% _CO2 , and humidity. The next morning, start the assay by adding an equal volume of _CO2- independent medium containing a 4% v/v dilution of GloSensor substrate (Promega, Cat. No. E1291) to all wells. The cell plate was incubated in the dark at room temperature for 2 h. A Biomek i7 (Beckman Coulter) instrument was used for the liquid handling step. To generate duplicate dose-response curves, add 3-fold serial dilutions of compounds to cell assay plates in a final volume of 60 µL in _CO2 -independent medium containing 0.1% BSA, 0.5 mM IBMX, and 0.4% DMSO The final concentration range is 30 µM to 0.06 pM. EC ₁₀₀ control wells containing the GLP1(7-36) peptide (Bachem, Cat. No. H-6795) at a final concentration of 2 nM and EC ₀ control wells without the peptide in the same plate as the compounds tested and in assay buffer. After adding compounds to the cells, the plate was incubated in the dark at room temperature for 12 min. Then an Envision 2104 Multilabel reader (PerkinElmer) with a "TRF light unit, 337 nm" was used to set up a "384-well US luminescence detector" using an ultra-sensitive solution with 384-well luminescence holes. 0.1 sec/well to measure luminescence. cAMP activity was calculated as a percentage of GLP1 (7-36) EC ₁₀₀ control wells: [(sample signal - average EC ₀ signal)/(average GLP1 (7-36) EC ₁₀₀ signal - average EC ₀ signal)]*100. Curve fitting for EC ₅₀ determination was performed in the Helios module of the suite software DAVID. A 4-parameter logistic model Hill slope was used: y = A _inf + (A ₀ - A _inf ) / (1 + (x / AC ₅₀ ) ^{Hill slope} ), where y is the functional response; x is the compound concentration; A ₀ is the minimum value (at 0 dose); A _inf is the maximum value (at infinite dose); AC ₅₀ corresponds to the inflection point (i.e., the point on the S-shaped curve halfway between A ₀ and A _inf ). The _EC50 value is expressed in µM by the _AC50 value calculated from Helios. E _max is the maximum activity detected within the concentration range and is derived from the fitted curve. Generation of HEK293-SNAP-hGLP1R cell line

Mix 327 µL of Opti-MEM medium (Gibco, Cat. No. 31985-062) with 12 µL of FuGENE® HD (Promega, Cat. No. E2311) and incubate at room temperature for 5 min. Then 8.2 µL (4 µg, 0.485 µg/µL solution) of the SNAP-tagged pSNAP-hGLP1R plasmid (Cisbio) encoding human GLP1R (NCBI reference sequence: NM_002062.3) fused to Si Biotechnology Co., Ltd., catalog number PSNAP-GLP1) was added to the Fugene HD/Opti-MEM mixture and incubated at room temperature for 20 min. Prepare a suspension of HEK293 cells (ATCC® CRL-1573™) at 800,000 cells/mL. Then, add the plasmid/FuGene HD mixture to 8 mL of cells and mix gently. Add 2 mL of new mixture to 4 wells of the 6-well plate and 2 mL of untransfected cells to two wells as a control. The plates were incubated at 37°C until 100% confluent. Antibiotic selection [800 µg/mL G418 (Geneticin, Gibco, Cat. No. 10131-035)] was performed at a dilution of 2500 cells/mL after trypsinization of cells. Add 1 mL of cell suspension to 20 mL of selection medium in a 10 cm dish (2500 cells total), and in parallel, add 4 mL of the diluted cell suspension to 20 mL of selection medium in a 10 cm dish (10,000 cells in total). The remaining cells were cultured in T150 flasks. Additionally, HEK293 cells were cultured in selection medium in T75 flasks as a negative control. Finally, individual plants were picked from the 10 cm culture dish and cultured until there were enough cells for gene expression analysis and HTRF cAMP determination. Plant 2 showed the highest GLP1R-dependent cAMP response and was expanded to generate the GloSensor stable cell line. Generation of HEK293-SNAP-hGLP1R-GloSensor Stable Cell Line

Stabilized HEK293 cells expressing SNAP-hGLP1R (as described above) were plated at a density of 3 million cells in DMEM complete growth medium containing 17 mL of DMEM (Gibco, Cat. No. 11965-092) + 10% fetal calf serum ( FBS, Gibco Corporation, catalog number 16140-071) in a 10 cm Petri dish. The next day, cells were transfected as follows. The DNA complex was prepared as 0.020 µg/µL pGloSensor™-22F cAMP plasmid (Promega Corporation, catalog number E2301; GenBank® accession no. for GU174434). Then, mixing carefully, add 112 µL FuGENE® HD Reagent. After incubation for 5-10 min at room temperature, add 850 µL of complex per well to the cells and mix thoroughly. After 24 h of incubation at 37°C, 5% CO and _humidity , remove the medium and rinse the cells with PBS. Then, select medium [600 µg/mL G418 and 600 µg/mL hygromycin B (Gibco, Cat. No. 10687010)] was added. Change the medium twice a week until dead cells are no longer observed. Once the cell plant is visible, single cells are isolated. To do this, add 10 µL of 0.05% trypsin-EDTA solution to the single cells by pipetting up and down. The single cell-derived plants were then cultured in six-well plates with selective medium (600 µg/mL G418 + 600 µg/mL Hygromycin B) until sufficient cells were available for testing in the GloSensor luminescence assay. cAMP agonist response. HEK293-SNAP-hGLP1R stable cell lines producing the desired response were used in the human GLP1R cAMP agonist assay. [ Table 1.] Compound number EC ₅₀ average ( µM ) E _max average ( % ) C-1 5.60E-05 110 C-2 1.49E-04 108 C-3 4.84E-05 105 C-4 2.98E-04 120 C-5 4.18E-05 123 C-6 4.64E-04 123 C-7 3.51E-05 118 C-8 3.53E-04 101 C-9 1.03E-04 107 C-10 1.42E-04 108 C-11 4.28E-05 105 C-12 5.75E-04 114 C-13 3.76E-04 102 C-14 4.92E-04 104 C-15 1.12E-04 103 C-16 1.71E-04 108 C-17 7.54E-04 113 C-18 1.88E-04 115 C-19 3.77E-04 109 C-20 2.40E-04 112 C-21 8.36E-04 117 C-22 3.50E-04 119 C-23 6.13E-04 106 C-24 1.02E-04 113 Human GLP1R beta - arrestin recruitment assay

The extent of β-arrestin recruitment by agonists was measured using the PathHunter® β-arrestin assay (DiscoverX Inc.). This assay measures beta-arrestin binding to the receptor using an enzyme complementation method. The two inactive parts of beta-galactosidase (called Prolink and enzyme receptor, or "EA") are tagged so that human GLP1R (hGLP1R) contains the Prolink part and beta-arrestin contains the EA part. When beta-arrestin is recruited to the receptor, the enzyme becomes active and produces light in the presence of a chemiluminescent substrate (PathHunter® Assay Kit, DiscoverX Inc. Cat. No. 93-0001). Luminescence can be measured on an associated detector. Stabilized CHO-hGLP1R-β-arrestin blood cells expressing Prolink-tagged hGLP1R and EA-tagged β-arrestin were inoculated into a white 384-well poly-D-lysine acid-coated plate at 20 µL per well. Plating Reagent 2 (DiscoverX, Cat. No. 93-0563R2A) (Greiner BioOne, Cat. No. 781945) and incubate overnight at 37°C, 5 _% CO, and humidity. The next day, prepare the agonist at 5 times the final desired 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 added to the cell assay plate to a final volume of 25 µL and starting at Final maximum concentration of 30 µM. EC ₁₀₀ control wells containing GLP1(7-36) peptide (Bachem, Cat. No. H-6795) at a final concentration of 1 µM and EC ₀ control wells without compound in the same plate and assay buffer as the compound tested liquid. After adding the compounds to the cells, the plates were incubated for 2 h at 37°C, ₅ % CO, and humidity. Then prepare detection reagents (19 parts Cell Assay Buffer, 5 parts Substrate Reagent 1, and 1 part Substrate Reagent 2, according to manufacturer's recommendations, DiscoverX Inc. Cat. No. 93-0001) and add to each well of the cell assay plate. 12 µL. The plate was incubated for an additional hour at room temperature in the dark. Then an Envision 2104 Multilabel reader (Perkin Elmer) with a "TRF light unit, 337 nm" was used to set up a "384-well US luminescence detector" using an ultra-sensitive protocol with 384-well luminescence wells. , 0.1 sec/well to measure luminescence. β-arrestin recruitment was calculated and expressed as percentage of GLP1(7-36)EC ₁₀₀ control wells: [(sample signal - mean EC ₀ signal)/(mean GLP1(7-36)EC ₁₀₀ signal - mean EC ₀ signal) ]*100, using Microsoft Excel. Curve fitting for EC ₅₀ determination was performed using GraphPad Prism. A 4-parameter logistic model Hill slope was used: Y = floor + (top - floor)/(1 + 10 ^ ((Log EC ₅₀ - X) * Hill slope)), where Y is the functional response; is the concentration of the compound; the bottom value is A ₀ or the minimum value (at 0 dose); the top value is A _inf or the maximum value (at infinite dose); EC ₅₀ is the inflection point (that is, the S-shaped curve between A ₀ and A _inf halfway between points). EC ₅₀ values are calculated in µM. _Emax is the maximum activity detected over the concentration range and is derived from a fitted curve relative to GLP1(7-36). The reference compound is 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (WO 2019/ 239319, Example 7). Generation of CHO-hGLP1R-beta- arrestin blood cell line

PathHunter CHO-K1-EA parental cells (DiscoverX, Cat. No. 93-0164) ^were plated in 22 ^mL of complete medium (Assay Complete Cell Culture Kit 107, DiscoverX Corporation, catalog number 92-3107G). The next day, replace the medium with 22 mL of fresh medium without antibiotics and transfect the cells as follows. Prepare plasmid/Fugene® HD transfection mix in Opti-MEM medium (3:1 ratio of reagents: DNA). Add 25 µg (34 µL) of pCMV-PK1-GLP1R plasmid [Discover (Thermo Fisher Scientific)] was added to 1129 µL Opti-MEM for a total volume of 1163 µL. Then, add 74 µL FuGENE® HD Reagent by mixing carefully. Incubate at room temperature for 5-10 min, 1125 µL of the complex solution was added to the cells and incubated at 37°C for 48 h. Then, the medium was removed and added containing 300 µg/mL hygromycin (Gibco, Cat. No. 10687010) and 500 µg /mL geneticin (Gibco, Cat. No. 10131035) selection medium. Change the medium every 2-3 days until dead cells are no longer observed. Cells were detached, resuspended at 300,000 cells/mL, and incubated with 40 µm filter. Cells were then FACS sorted using an Aria G instrument into single cells in 100 µL culture medium in black, clear bottom poly-D-lysine-coated 96-well plates. Every 2-3 days by Change the medium as follows: Remove up to 80 µL and add fresh medium containing the selection antibiotic. Expand and test surviving single strains. Select single strain 1 for β-arrestin assay based on best signal and profile. Human GLP1R DERET internalization assay

The extent of agonist internalization of human GLP1R was determined based on an optimized version of the real-time FRET-based "DERET" (dissociation enhanced resonance energy transfer) assay. This technology relies on labeling SNAP-tagged GPCRs with SNAP-Lumi-Terbium (donor fluorophore, Xisi Biotechnology Co., Ltd., catalog number SSNPTBD). Compounds are incubated with cells expressing the GPCR of interest in the presence of excess luciferin (acceptor fluorophore). When the GPCR is on the cell surface, the donor signal is quenched by the receptor, and the donor/acceptor ratio is lower. As the GPCR is internalized, the donor signal is no longer quenched and the receptor is no longer excited, so the donor/acceptor ratio increases.

HEK293-SNAP-hGLP1R-GloSensor cells (stable expressing SNAP-tagged hGLP1R) were seeded in regular DMEM in white 384-well poly-D-lysine-coated plates (Greiner BioOne, Cat. No. 781945) Growth medium (Gibco, Cat. No. 11965-092, 10% heat-inactivated FBS, 10 mM HEPES, 1 × Penicillin/Streptomycin, 0.5 mg/mL Geneticin (Gibco, Cat. No. 10131- 035) and 0.25 mg/mL hygromycin B (Invitrogen, Cat. No. 10687010) overnight. On the day of the assay, remove the cell culture medium and add 100 nM SNAP-Lumi-Tb reagent to the Opti-MEM solution. Place Cells were incubated for 1 h at 37°C. Cells were washed with a plate washer in assay buffer [1 15630-080), 1 mM CaCl ₂ (Fluka, Cat. No. 21114-1L), 1 mM MgCl ₂ (Ambion, Cat. No. AM9530G) pH 7.4] and wash 20 µL Buffer containing 0.1% BSA was added to each well. After allowing cells to equilibrate at 37°C for approximately 15 min, add 10 µL of luciferin (sodium salt, Sigma, catalog No. F6377, diluted in buffer). To generate triplicate dose-response curves, compounds were serially diluted 3-fold in assay buffer and added to the cell assay plate to a final volume of 40 µL and starting at 30 Final maximum concentration of 1 µM. In the same plate and assay buffer as the compounds tested, including the GLP1(7-36) peptide (Bachem, Cat. No. H-6795) control curve, the final maximum concentration was 1 µM, to Establish EC _100. Also include EC ₀ wells with buffer only. Use a Percolator with LANCE/DELFIA D400 single lens, excitation filter X320 and emission filters M615_203 (donor emission) and M515 (acceptor emission) KingElmer Envision measured plate FRET fluorescence immediately and then every 30 min. In-peak integration was achieved at 120 min. The plate was maintained at 37°C between reads. Data were expressed using Microsoft Excel are the ratios of donor/acceptor emission and plotted in GraphPad Prism. To determine _EC50 and _Emax of internalization, data were calculated and expressed as percentage of GLP1(7-36) _EC100 control wells: [(Sample signal - average EC ₀ signal)/(average GLP1 (7-36) EC ₁₀₀ signal - average EC ₀ signal)] * 100, using Microsoft Excel. Curve fitting for EC ₅₀ determination was performed using GraphPad Prism. A 4-parameter logistic model Hill slope was used: Y = floor + (top - floor)/(1 + 10^((Log EC ₅₀ -X) * Hill slope)), where Y is the functional response; is the concentration of the compound; the bottom value is A ₀ or the minimum value (at 0 dose); the top value is A _inf or the maximum value (at infinite dose); EC ₅₀ is the inflection point (that is, the S-shaped curve between A ₀ and A _inf halfway between points). EC ₅₀ values are calculated in µM. _Emax is the maximum activity measured over the concentration range and is derived from a fitted curve relative to GLP1(7-36). [ Table 2.] Compound number β- arrestin assay DERET internalization assay EC ₅₀ average ( µM ) E _max ( % ) EC ₅₀ average ( uM ) E _max ( % ) C-1 ＞30 2 ＞30 8 C-4 ＞30 0 ＞30 1 C-5 ＞30 0 ＞30 6 C-7 ＞30 5 0.03 51 C-9 ＞30 0 ＞30 11 C-10 ＞30 0 ＞30 7 C-12 ＞30 10 ＞30 45 C-13 ＞30 12 1.279 42 C-14 ＞30 0 ＞30 20 C-16 ＞30 11 2.943 50 C-17 ＞30 2 ＞30 6 C-18 ＞30 16 2.376 86 C-19 ＞30 7 ＞30 34 C-20 ＞30 0 ＞30 5 C-21 ＞30 0 ＞30 2 C-23 ND ND ＞30 10 C-24 ＞30 1 0.49 19 Reference compound 0.123 27 0.015 87

without

without

without

Claims (25)

A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein, It is a single bond or a double bond; department , in indicates the point of attachment to the remainder of the molecule; W is O or _CH2 ; X is O or _CH2 ; ^R1 and ^R2 are each independently selected from H, _C1-3 -alkyl, halogen and CN; R ³ is selected from H and C _1-3 -alkyl; R ⁴ and R ⁵ are selected from: (aa) R ⁴ is selected from 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 base)-C _1-3 -alkyl-, phenyl-C _1-3 -alkyl-, halogen, CN, NO ₂ , OR ^4a , SR ^4a , C(O)R ^4b , C(O)NR ^4c R ^4d , C(O)NR ^4c (OR ^4a ), C(O)NR ^4c (S(O) ₂ R ^4b ), C(O)NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c OR ^4a , NR ^4c R ^4d , NR ^4c (C(O)R ^4b ), NR ^4c (C(O)OR ^4a ), N(OR ^4a )(C(O)R ^4b ), NR ^4c (C(O) )NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (C(O)R ^4b )), NR ^4c (S(O) ₂ R ^4b ), NR ^4c (S(O) ₂ NR ^4c R ^4d ), NR ^4c (C(O)NR ^4c (S(O) ₂ R ^4b )), OC(O)R ^4b , OC(O)NR ^4c R ^4d , ONR ^4c (C(O)R ^4b ), OS (O) ₂ R ^4b 、OP(O)(OR ^4e )(OR ^4f )、S(O)OR ^4a 、S(O)R ^4b 、S(O) ₂ R ^4b 、S(O) ₂ NR ^4c R ^4d , S(O) ₂ OR ^4a , S(=NR ^4g )(O)R ^4b , S(=NR ^4g )(O)NR ^4c NR ^4d , P(O)(OR ^4e )(OR ^4f ), and P(O)(OR ^4e )(R ^4f ), wherein R ⁴ is the 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- are each optionally substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O)NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S (O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C (O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D 、S(O) ₂ OR ^4A 、S(=NR ^4G )(O)R ^4B 、S(=NR ^4G )(O)NR ^4C NR ^4D 、P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), and R ⁵ is 5-10 membered heteroaryl or (5-10 membered heteroaryl)-C _1-3 -alkyl -, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^5A or by a carboxylic acid isostere and optionally by Substituted with 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^5A , SR ^5A , C _1-3 -alkyl, C ₁ substituted with 1, 2 or 3 halogens _-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 NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N (OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O)R ^5B )), NR ^5C (S( O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )), OC(O)R ^5B , OC( O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) , S(O)OR ^5A ,S(O) R ^5B , S(O) ₂ R ^5B , S(O) ₂ NR ^5C R ^5D , S(O) ₂ OR ^5A , S(=NR ^5G )(O)R ^5B , S(=NR ^5G )(O) NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); or (bb) R ⁴ is a 5-10-membered heteroaryl or (5- (10-membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O) OR ^4A may be substituted by a carboxylic acid isostere and optionally substituted by 1, 2, or 3 groups independently selected from: halogen, CN, NO ₂ , OR ^4A , SR ^4A , C _1-3 -alkyl Base, C _1-3 -alkyl substituted by 1, 2 or 3 halogens, C(O)R ^4B , C(O)NR ^4C R ^4D , C(O)NR ^4C (OR ^4A ), C(O )NR ^4C (S(O) ₂ R ^4B ), C(O)NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C OR ^4A , NR ^4C R ^4D , NR ^4C (C(O)R ^4B ), NR ^4C (C(O)OR ^4A ), N(OR ^4A )(C(O)R ^4B ), NR ^4C (C(O)NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C ( C(O)R ^4B )), NR ^4C (S(O) ₂ R ^4B ), NR ^4C (S(O) ₂ NR ^4C R ^4D ), NR ^4C (C(O)NR ^4C (S(O) ₂ R ^4B )), OC(O)R ^4B , OC(O)NR ^4C R ^4D , ONR ^4C (C(O)R ^4B ), OS(O) ₂ R ^4B , OP(O)(OR ^4E )(OR ^4F ), S(O)OR ^4A , S(O)R ^4B , S(O) ₂ R ^4B , S(O) ₂ NR ^4C R ^4D , S(O) ₂ OR ^4A , S(=NR ^4G )( O)R ^4B , S(=NR ^4G )(O)NR ^4C NR ^4D , P(O)(OR ^4E )(OR ^4F ), and P(O)(OR ^4E )(R ^4F ), and R ⁵ is selected From 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-, halogen, CN, NO ₂ , 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) ₂ R ^5b ) , C(O)NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c OR ^5a , NR ^5c R ^5d , NR ^5c (C(O)R ^5b ), NR ^5c (C(O)OR ^5a ) , N(OR ^5a )(C(O)R ^5b ), NR ^5c (C(O)NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (C(O)R ^5b )), NR ^5c ( S(O) ₂ R ^5b ), NR ^5c (S(O) ₂ NR ^5c R ^5d ), NR ^5c (C(O)NR ^5c (S(O) ₂ R ^5b )), OC(O)R ^5b , OC(O)NR ^5c R ^5d 、ONR ^5c (C(O)R ^5b )、OS(O) ₂ R ^5b 、OP(O)(OR ^5e )(OR ^5f )、S(O)OR ^5a 、S( O)R ^5b , S(O) ₂ R ^5b , S(O) ₂ NR ^5c R ^5d , S(O) ₂ OR ^5a , S(=NR ^5g )(O)R ^5b , S(=NR ^5g )( O)NR ^5c NR ^5d , P(O)(OR ^5e )(OR ^5f ), and P(O)(OR ^5e )(R ^5f ), wherein the C _1-6 -alkyl, C _2- of R ⁵ 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- are each optionally independently selected from the following groups: 1, 2, or 3 Group substitution: halogen, CN, NO ₂ , 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) ₂ R ^5B ), C(O)NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C OR ^5A , NR ^5C R ^5D , NR ^5C (C(O)R ^5B ), NR ^5C (C(O)OR ^5A ), N(OR ^5A )(C(O)R ^5B ), NR ^5C (C(O)NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (C(O) R ^5B )), NR ^5C (S(O) ₂ R ^5B ), NR ^5C (S(O) ₂ NR ^5C R ^5D ), NR ^5C (C(O)NR ^5C (S(O) ₂ R ^5B )) , OC(O)R ^5B , OC(O)NR ^5C R ^5D , ONR ^5C (C(O)R ^5B ) , OS(O) ₂ R ^5B , OP(O)(OR ^5E )(OR ^5F ) ,S (O)OR ^5A 、S(O)R ^5B 、S(O) ₂ R ^5B 、S(O) ₂ NR ^5C R ^5D 、S(O) ₂ OR ^5A 、S(=NR ^5G )(O)R ^5B , S(=NR ^5G )(O)NR ^5C NR ^5D , P(O)(OR ^5E )(OR ^5F ), and P(O)(OR ^5E )(R ^5F ); R ⁶ is selected from (4-10 (membered heterocycloalkyl)-C _1-3 -alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl-, wherein R ⁶ is the (4-10 membered heterocycloalkyl )-C _1-3 -alkyl- and (5-10 membered heteroaryl)-C _1-3 -alkyl- are each independently selected from C _1-6 -alkanes, as appropriate. substituted with groups such as -OH, and halogen; R ^4a , R ^4b , R ^4c , and R ^4d are each independently selected from 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, wherein the C ₁ of R ^4a , R ^4b , R ^4c , and R ^4d _-6 -Alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are each optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; and R ^4a , R ^4b The C _3-6 -cycloalkyl group, 4-10-membered heterocycloalkyl group, 5-10-membered heteroaryl group, and phenyl group of R ^4c and R ^4d are each optionally replaced by 1, 2, or 3 independently Substituted with a group independently selected from C _1-6 -alkyl, -OH, and halogen; R ^4e , R ^4f , and R ^4g are each independently selected from H and C _1-6 -alkyl; R ^4A , R ^4B , R ^4C , and R ^4D are each optionally substituted with 1, 2, or 3 groups independently selected from -OH, halogen, and -OC(O)-C _1-15 -alkyl; and R ^4A , R The C _3-6 -cycloalkyl, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkyl-C _1-3 -alkyl-, 5-10-membered of ^4B , R ^4C , and R ^4D Heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen; each of R ^4E , R ^4F , and R ^4G Independently selected from H and C _1-6 -alkyl; R ^5a , R ^5b , R ^5c , and R ^5d are each independently selected from 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, where R ^5a , R ^5b , R ^5c , and R ^5d are Each of C _1-6 -alkyl, C _2-6 alkenyl, and C _2-6 alkynyl is optionally substituted with 1, 2, or 3 groups independently selected from -OH and halogen; and R ^5a , The C _3-6 -cycloalkyl group, 4-10-membered heterocycloalkyl group, 5-10-membered heteroaryl group, and phenyl group of R ^5b , R ^5c , and R ^5d are each optionally replaced by 1, 2, or 3 Substituted with a group independently selected from C _1-6 -alkyl, -OH, and halogen; R ^5e , R ^5f , and R ^5g are each independently selected from H and C _1-6 -alkyl; R ^5A , R ^5B , R ^5C , and R ^5D are each optionally substituted with 1, 2, or 3 groups independently selected from -OH, halogen, and -OC(O)-C _1-15 -alkyl; and R ^5A , R ^5B , R ^5C , and the C _3-6 -cycloalkyl ^, 4-10-membered heterocycloalkyl, 4-10-membered heterocycloalkyl-C _1-3 -alkyl-, 5- The 10-membered heteroaryl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen; and R ^5E , R ^5F , and Each R ^5G is independently selected from H and C _1-6 -alkyl. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is chlorine, fluorine or CN, R ² is chlorine or fluorine, and R ³ is -CH ₃ . The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, and halogen, wherein R ⁴ is the C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 -cycloalkyl, 4-10 membered heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from halogen and C _1-3 -alkyl , and R ⁵ is a 5-10-membered heteroaryl or (5-10-membered heteroaryl)-C _1-3 -alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl )-C _1-3 -alkyl-each substituted by C(O)OR ^5A or by a carboxylic acid isostere and optionally by 1, 2, or 3 groups independently selected from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^5A is selected from H and C _1-3 -alkyl. The compound as described in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C _1-3 -alkyl or C _1- substituted by 1, 2 or 3 halogens ₃ -alkyl. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 5-10-membered heteroaryl group or (5-10-membered heteroaryl group)-C _1-3 - Alkyl-, wherein the 5-10-membered heteroaryl and (5-10-membered heteroaryl)-C _1-3 -alkyl- are each replaced by C(O)OR ^4A or by a carboxylic acid isostere and viewed Needs to be substituted by 1, 2, or 3 groups independently selected from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^4A is selected from H and C _1-3 -alkyl, and R ⁵ is selected from C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 -cycloalkyl, 4- 10-membered heterocycloalkyl, phenyl, and halogen, wherein the C _1-3 -alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 -cycloalkyl, 4-10 membered Heterocycloalkyl, and phenyl are each optionally substituted with 1, 2, or 3 groups independently selected from halogen and C _1-3 -alkyl. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-3 -alkyl group or a C _1-3 -alkyl group substituted by 1, 2 or 3 halogens. The compound as claimed in claim 5 or claim 6, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is C(O)OR ^4A and optionally 1, 2, or 3 independently selected from the following 5-10 membered heteroaryl substituted by groups: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^4A is selected from H and C _{1 -3} -alkyl. The compound as described in any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof, wherein R ⁴ has the structure of formula H1a or H2a: wherein the ring system is aromatic; wherein _X1 is C, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR4h , ^NR4i , O, _or S _, ^{wherein at} _{least one} of -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ⁴ⁱ is C _1-3 -alkyl. The compound as described in any one of claims 5 to 8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^4A is selected from H and C _1-3 -alkyl. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is C(O)OR ^5A and 1, 2, or 3 are independently selected as needed. 5-10 membered heteroaryl substituted from: halogen, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens; wherein R ^5A is selected from H and C _1-3 -alkyl. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R ⁵ has the structure of formula H11a or H12a: wherein the ring system is aromatic; wherein _X1 is C, and each of _X2 , _X3 , _X4 , _X5 , and _X6 is independently C=O, ^CR5h , ^NR5i , O, _or S _, ^{wherein at} _{least one} of -alkyl or C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ⁵ⁱ is C _1-3 -alkyl. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt thereof, wherein ^R5 is selected from the group consisting of: , , , , , , , , , , ,and , wherein Ra, Rb and Rc are independently selected from H, C _1-3 -alkyl and C _1-3 -alkyl substituted by 1, 2 or 3 halogens, and R ^5A is selected from H and C _1-3 -alkyl. The compound as described in any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from (4-6 membered heterocycloalkyl)-CH ₂ - and (5-6 membered heterocycloalkyl) Heteroaryl)-CH ₂ -, wherein the (4-6 membered heterocycloalkyl)-CH ₂ - and (5-6 membered heteroaryl)-CH ₂ - of R ⁶ are each optionally replaced by 1, 2, Or substituted by 3 groups independently selected from C _1-6 -alkyl, -OH, and halogen. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R ⁶ has the following formula: , in Indicates the point of attachment to the rest of the molecule. The compound as described in any one of claims 1 to 14, which compound is a compound of formula (IIa): (IIa) or a pharmaceutically acceptable salt thereof. The compound as described in any one of claims 1 to 15, which compound is a compound of formula (IIIa): (IIIa), or a pharmaceutically acceptable salt thereof. The compound as described in claim 1, which compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and , or its pharmaceutically acceptable salt. The compound described in claim 1, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Methylethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl )ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-ethyl-1-(((R)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethyl- 5-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5- Ethyl ethyl ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Methyl ethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-5- Methylethazole-4-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 4-Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- (Trifluoromethyl)ethazole-5-carboxylic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-4- Methylethazole-5-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 2-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 2-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)furan-2 -Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl) acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)furan-2 -Formic acid, 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)ethazole- 5-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)-1, 3,4-Diazole-2-carboxylic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -3-Formic acid, 3-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-5-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-4-yl)isoethazole -5-Formic acid, 5-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-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]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl) acid, 4-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)thiazole-2 -Formic acid, and 2-(2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4-yl )piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)ethazole- 5-formic acid, and 2-(2-((4-((S)-2-(4-cyano-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxolane-4- yl)piperidin-1-yl)methyl)-4-methyl-1-(((S)-oxetan-2-yl)methyl)-1H-imidazol-5-yl)-5 -Ethyl methylethazole-4-carboxylate, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. A combination comprising a compound as described in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents. The compound described in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, is used as a medicine. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of disorders or diseases selected from the group consisting of: obesity, type 2 diabetes, insulin resistance, hypertension Insulinemia, glucose intolerance, hyperglycemia, one or more complications of diabetes, diabetic nephropathy, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, atherosclerosis Sclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy. The use of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder or disease selected from: obesity, type 2 diabetes, Insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more complications of diabetes, diabetic nephropathy, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hyperlipidemia blood pressure, atherosclerosis, peripheral arterial disease, stroke, cardiomyopathy, atrial fibrillation, heart failure, coronary heart disease, and neuropathy. A method of stimulating GLP1R activity in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound as described in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. A method of treating a disorder or disease in a subject selected from the group consisting of obesity, type 2 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, one or more complications of diabetes, diabetes Kidney disease, 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, the method includes administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.