Tetrahydropyrazolo-pyrazinyl-dihydroimidazolone or tetrahydropyrazolo-pyridinyl-dihydroimidazolone compounds and methods of using the same

Abstract

To provide a compound for treating or preventing a disease in which a GLP-1 receptor plays a role.SOLUTION: Provided are compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising a compound of Formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to International Application No. PCT / CN2020 / 102955, filed July 20, 2020, and International Application No. PCT / CN2021 / 070120, filed January 4, 2021, both of which are incorporated herein by reference in their entireties. [Background technology]

[0002] background Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino acid incretin secreted by L-cells in the small intestine. GLP-1 exerts a wide range of effects through the GLP-1 receptor, including stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, delaying gastric emptying, and suppressing food intake. Therefore, GLP-1 analogs have demonstrated potent effects in lowering HbA1c and reducing body weight, and are being developed as effective therapeutic agents for the treatment of diabetes and obesity. GLP-1 analogs also demonstrate efficacy in improving cardiovascular outcomes and preserving renal function in diabetic patients, providing therapeutic opportunities for various metabolic disorders and related comorbidities. Recently, liraglutide and semaglutide treatments have been shown to reduce liver fat and promote the resolution of NASH in clinical trials, suggesting their potential usefulness for NASH. However, most of these GLP-1 analogs require invasive subcutaneous administration. Semaglutide in certain formulations can be administered orally, but still suffers from inconvenient dosing regimens and poor bioavailability. Improving the metabolic stability and bioavailability of GLP-1 analogues is difficult due to their peptide nature.

[0003] Currently, there are no small molecule GLP-1 receptor agonists approved for the treatment of diabetes or other metabolic disorders in which the GLP-1 receptor plays a role. Thus, there is a need for small molecule GLP-1 receptor agonists as a therapeutic option for the treatment of these disorders. The present application addresses this need. Summary of the Invention

[0004] overview The present application provides novel GLP-1 receptor ligands useful in the treatment of diseases or disorders in which the GLP-1 receptor plays a role, such as those described herein, including, but not limited to, diabetes, obesity, an overweight condition, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, arrhythmias, diabetic kidney disease, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0005] A first aspect of the present application is a compound of formula (I): The compound of TIFF2026035735000001.tif41128, wherein A, X, Y, T, L, R2, and R4 are as detailed below: compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

[0006] Another aspect of the present application relates to a pharmaceutical composition comprising a compound of Formula (I) or any compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0007] Another aspect of the present application relates to methods of treating or preventing a GLP-1 receptor-mediated disease or disorder described herein (e.g., a disease or disorder in which the GLP-1 receptor plays a role, or a disease or disorder associated with modulation of the GLP-1 receptor) (e.g., diabetes, obesity, an overweight condition, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, hypertension, stroke, coronary heart disease, congestive heart failure, cardiac arrhythmias, diabetic kidney disease, dementia, Parkinson's disease, Alzheimer's disease, and liver diseases such as NAFLD and NASH). The method includes administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0008] Another aspect of the present application relates to a method of modulating (e.g., activating or stimulating) a GLP-1 receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0009] Another aspect of the present application relates to a compound of formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a compound described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, for use in a method of treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating (e.g., activating or stimulating) a GLP-1 receptor.

[0010] Another aspect of the present application relates to the use of a compound of formula (I) or a compound as described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of formula (I) or a compound as described herein, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, in the manufacture of a medicament for treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating (e.g., activating or stimulating) a GLP-1 receptor.

[0011] The present application provides modulators (e.g., agonists) of the GLP-1 receptor that are therapeutic agents in the treatment of diseases such as diabetes, obesity, metabolic diseases, cardiovascular diseases, liver diseases, NASH, renal diseases, neurodegenerative diseases, and other diseases or disorders associated with modulation of the GLP-1 receptor.

[0012] The present application further provides compounds and compositions that exhibit improved therapeutic profiles (e.g., efficacy, pharmacodynamics, safety) compared to known GLP-1 receptor agonists and alternative routes of administration for the treatment of various types of diseases, including diabetes, obesity, metabolic diseases, cardiovascular diseases, liver diseases, NASH, renal diseases, neurodegenerative diseases, and other diseases associated with modulation of the GLP-1 receptor. [The present invention 1001] Formula (I): The compound of TIFF2026035735000002.tif41128, During the ceremony, TIFF2026035735000003.tif14128 TIFF2026035735000004.tif20128; R1 is (CR C R C ) 0~2 -C3-C6 cycloalkyl, (CR C R C ) 0~2 -phenyl, or one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (CR C R C ) 0~2 -heteroaryl, wherein the cycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl, where the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl; Each R C are independently H, C1-C3 alkyl, or C1-C3 haloalkyl; R2 is C3~C 10cycloalkyl, phenyl, heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2, and wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl; TIFF2026035735000005.tif13128 a bicyclic heteroaryl ring selected from TIFF2026035735000006.tif81132; Each R3 is independently halogen, C3-C 10 cycloalkyl, phenyl, heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, OH, halogen, NH, NH-(C-C alkyl), N(C-C alkyl), CN, and NO, wherein the cycloalkyl is a spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl, with the proviso that at least one R is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl; R4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, or CN; L is TIFF2026035735000007.tif9128 or phenylenyl, wherein the phenylenyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and halogen, or, when the phenylenyl is substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, the two substituents may, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O, and S; R5 and R6 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen; and T is C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or heteroaryl containing one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo; and L is TIFF2026035735000008.tif9128, T is not C(O)OH; or when L is phenylenyl substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, and the two substituents together with the carbon atoms to which they are attached form a 5- or 6-membered ring, then T is H; however, TIFF2026035735000009.tif14128 TIFF2026035735000010.tif19128, TIFF2026035735000011.tif12128 TIFF2026035735000012.tif16128, T is oxadiazolonyl, each R3 is independently F, heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted, and L is TIFF2026035735000013.tif9128, and when R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, the C3-C6 cycloalkyl is unsubstituted; however, TIFF2026035735000014.tif14128 TIFF2026035735000015.tif19128, TIFF2026035735000016.tif12128 TIFF2026035735000017.tif16128, T is oxadiazolonyl, and L is TIFF2026035735000018.tif9128, and R5 and R6 together with the carbon atoms to which they are attached form an unsubstituted C3-C6 cycloalkyl, and R3 is a heterocyclyl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, then R3 is substituted; however, TIFF2026035735000019.tif14128 TIFF2026035735000020.tif19128, TIFF2026035735000021.tif12128 TIFF2026035735000022.tif16128, T is oxadiazolonyl, and L is TIFF2026035735000023.tif9128, and when R5 and R6 are each methyl, R3 is not a heteroaryl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S; and however, TIFF2026035735000024.tif14128 TIFF2026035735000025.tif19128, TIFF2026035735000026.tif12128 TIFF2026035735000027.tif16128, and L is TIFF2026035735000028.tif9128, and when R5 and R6 are each H, and R3 is heterocyclyl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, R3 is substituted; compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. [The present invention 1002] Formula (Ia1), (Ia2), (Ia3), (Ia4), (Ia5), (Ia6), (Ia7), (Ia8), (Ia9), (Ia10), or (Ia11): The structure of TIFF2026035735000029.tif189143TIFF2026035735000030.tif116131, During the ceremony, each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and Each R 11are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, or C3-C6 cycloalkyl; structure or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: [The present invention 1003] Formula (Ib1), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (Ib10), or (Ib11): The structure of TIFF2026035735000031.tif189144TIFF2026035735000032.tif116132, During the ceremony, each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and Each R 11 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, O2, or C3-C6 cycloalkyl; structure or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein: [The present invention 1004] TIFF2026035735000033.tif14128 TIFF2026035735000034.tif19128, compound of the present invention 1001. [The present invention 1005] TIFF2026035735000035.tif14128 TIFF2026035735000036.tif19128, compound of the present invention 1001. [The present invention 1006] R1 may be substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl (CR C R C ) 0~2 -phenyl. [The present invention 1007] Any of compounds 1001 to 1005 of the present invention, wherein R1 is phenyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl. [The present invention 1008] R1 may be substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl (CR C R C ) 0~2 The compound of any one of claims 1001 to 1005, wherein the cycloalkyl is -C3-C6 cycloalkyl, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl. [The present invention 1009] Any of compounds 1001 to 1005 of the present invention, wherein R1 is C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl, wherein the cycloalkyl is spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl. [The present invention 1010] Any of compounds 1001 to 1005 of the present invention, wherein R1 is cyclohexyl or bicyclopentanyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl. [The present invention 1011] R1 contains one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (CR C R C ) 0~2 -heteroaryl, wherein cycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl. [The present invention 1012] Compounds of any of claims 1001 to 1011 of the present invention, wherein R1 is substituted with one, two, or three substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl, linear C1-C4 haloalkyl or branched C3-C4 haloalkyl, linear C1-C4 alkoxy or branched C3-C4 alkoxy, linear C1-C4 haloalkoxy or branched C3-C4 haloalkoxy, and halogen. [The present invention 1013] R2 is a C3-C alkyl group optionally substituted by one or more substituents independently selected from C1-C6 alkyl optionally substituted by C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2; 10 The compound of any one of claims 1001 to 1012, wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl. [The present invention 1014] Any of the compounds of the present invention 1001 to 1012, wherein R2 is bicyclooctanyl substituted by one or more substituents independently selected from C1-C6 alkyl optionally substituted by C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. [The present invention 1015] Any of compounds 1001 to 1012 of the present invention, wherein R2 is phenyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl optionally substituted by C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. [The present invention 1016] Any of the compounds of the present invention 1001 to 1012, wherein R2 is heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. [The present invention 1017] R2, Heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2 The compound of any one of claims 1001 to 1012 of the present invention, [The present invention 1018] R2, Heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2 The compound of any one of claims 1001 to 1012 of the present invention, [The present invention 1019] Any of the compounds of the present invention 1001 to 1012, wherein R2 is indazolyl or imidazopyridinyl, each of which may be substituted by one or more substituents independently selected from C1-C6 alkyl optionally substituted by C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. [The present invention 1020] Any of compounds 1001 to 1019 of the present invention, wherein R2 is substituted with one, two, or three substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl, linear C1-C4 haloalkyl or branched C3-C4 haloalkyl, linear C1-C4 alkoxy or branched C3-C4 alkoxy, linear C1-C4 haloalkoxy or branched C3-C4 haloalkoxy, and halogen. [The present invention 1021] TIFF2026035735000037.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000038.tif60132. [The present invention 1022] TIFF2026035735000039.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000040.tif60159. [The present invention 1023] TIFF2026035735000041.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000042.tif58145. [The present invention 1024] TIFF2026035735000043.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000044.tif62155. [The present invention 1025] TIFF2026035735000045.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000046.tif62155. [The present invention 1026] TIFF2026035735000047.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000048.tif21138. [The present invention 1027] TIFF2026035735000049.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000050.tif21128. [The present invention 1028] TIFF2026035735000051.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000052.tif21128. [The present invention 1029] TIFF2026035735000053.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000054.tif21128. [The present invention 1030] TIFF2026035735000055.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000056.tif21128. [The present invention 1031] TIFF2026035735000057.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000058.tif21128. [The present invention 1032] TIFF2026035735000059.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000060.tif53145. [The present invention 1033] TIFF2026035735000061.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000062.tif35132. [The present invention 1034] TIFF2026035735000063.tif12128 Any of compounds 1001 to 1020 of the present invention, which is a bicyclic heteroaryl ring selected from TIFF2026035735000064.tif54136. [This invention 1035] At least one R3 is a C3-C alkyl group optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. 10 The compound of any one of claims 1001 to 1034, wherein said cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl. [The present invention 1036] Any of compounds 1001 to 1034 of the present invention, wherein at least one R3 is phenyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. [This invention 1037] At least one R3 is Heterocyclyl containing one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2 The compound of any one of claims 1001 to 1034 of the present invention, [The present invention 1038] At least one R3 is Tetrahydropyranyl optionally substituted by one or more substituents selected from N, O, and S, optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. The compound of any one of claims 1001 to 1034 of the present invention, [This invention 1039] At least one R3 is Heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2. The compound of any one of claims 1001 to 1034 of the present invention, [The present invention 1040] At least one R3 is pyridyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2, and optionally substituted by one or more substituents selected from N, O, and S; The compound of any one of claims 1001 to 1034 of the present invention, [This invention 1041] Any of compounds 1001 to 1034 of the present invention, wherein at least one R3 is substituted with one or more substituents independently selected from straight chain C1-C4 alkyl or branched C3-C4 alkyl, straight chain C1-C4 haloalkyl or branched C3-C4 haloalkyl, straight chain C1-C4 alkoxy or branched C3-C4 alkoxy, straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy, and halogen. [The present invention 1042] The compound of any one of claims 1001 to 1041, wherein R4 is a linear C1 to C6 alkyl or a branched C3 to C6 alkyl. [This invention 1043] L Any of compounds 1001 to 1042 of the present invention, which is TIFF2026035735000065.tif9128. [This invention 1044] Any of the compounds of 1001 to 1042 of the present invention, wherein L is phenylenyl optionally substituted by one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and halogen. [This invention 1045] Any of the compounds of claims 1001 to 1042, wherein L is phenylenyl substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, and wherein the two substituents, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O, and S. [The present invention 1046] The compound of any one of claims 1001 to 1045, wherein R5 and R6 are each H. [This invention 1047] The compound of any one of claims 1001 to 1045, wherein one of R5 and R6 is C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, OH, or halogen. [This invention 1048] Any of the compounds of claims 1001 to 1045, wherein R5 and R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen. [This invention 1049] Any of compounds 1001 to 1045 of the present invention, wherein R5 and R6, together with the carbon atom to which they are attached, form a cyclopropyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen. [The present invention 1050] The compound of any one of claims 1001 to 1049, wherein T is C(O)OH. [This invention 1051] The compound of any one of claims 1001 to 1049, wherein T is (CH2)NHS(O)2-(C1-C6 alkyl). [This invention 1052] T, Heteroaryl containing one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo. The compound of any one of claims 1001 to 1049 of the present invention, [This invention 1053] T, Heteroaryl containing one 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, OH, halogen, or oxo. The compound of any one of claims 1001 to 1049 of the present invention, [This invention 1054] T, Heteroaryl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 alkoxy, C1 to C6 haloalkoxy, OH, halogen, or oxo. The compound of any one of claims 1001 to 1049 of the present invention, [This invention 1055] T, heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolonyl, and thiadiazolonyl, each of which may be substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo; The compound of any one of claims 1001 to 1049 of the present invention, [This invention 1056] The compound of any one of claims 1001 to 1049, wherein T is oxadiazolonyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen. [This invention 1057] 1001 Compounds of the present invention selected from Table A. [This invention 1058] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1057, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient. [This invention 1059] A method for treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating a GLP-1 receptor, comprising administering to a subject in need thereof a therapeutically effective amount of any of compounds 1001 to 1057 of the present invention, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of compound 1058 of the present invention. [The present invention 1060] 1059. The method of claim 1059, wherein said disease or disorder is selected from diabetes, diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic kidney disease. [This invention 1061] A compound of any of claims 1001 to 1057, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of claim 1058, for use in a method for treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating a GLP-1 receptor. [This invention 1062] Use of any of the compounds of inventions 1001 to 1057, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of invention 1058, in the manufacture of a medicament for treating or preventing a GLP-1 receptor-mediated disease or disorder or modulating a GLP-1 receptor. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description Compounds of the present application The present application relates to compounds and compositions thereof that can modulate the activity of the GLP-1 receptor. The present application features a method for treating, preventing, or ameliorating a disease or disorder in which the GLP-1 receptor plays a role by administering to a subject in need thereof a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. The compounds of the present application can be used in the treatment of various GLP-1 receptor-mediated diseases and disorders by stimulating the GLP-1 receptor. Activation or stimulation of the GLP-1 receptor results in the treatment, prevention, or amelioration of diseases, including, but not limited to, diabetes, obesity, metabolic disease, cardiovascular disease, liver disease, nonalcoholic steatohepatitis (NASH), and other diseases associated with modulation of the GLP-1 receptor.

[0014] In a first aspect of the present application, a compound of formula (I): The compound of TIFF2026035735000066.tif41128, During the ceremony, TIFF2026035735000067.tif14128 TIFF2026035735000068.tif20128; R1 is (CR C R C ) 0~2 -C3-C6 cycloalkyl, (CR C R C ) 0~2 -phenyl, or one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S (CR C R C ) 0~2-heteroaryl, wherein the cycloalkyl, phenyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, and C3-C6 cycloalkyl, where the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl; Each R C are independently H, C1-C3 alkyl, or C1-C3 haloalkyl; R2 is C3~C 10 cycloalkyl, phenyl, heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, and NO2, and wherein the cycloalkyl is a spirocycloalkyl, a bridged cycloalkyl, or a monocycloalkyl; TIFF2026035735000069.tif12128 a bicyclic heteroaryl ring selected from TIFF2026035735000070.tif81133; Each R3 is independently halogen, C3-C 10cycloalkyl, phenyl, heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, OH, halogen, NH, NH-(C-C alkyl), N(C-C alkyl), CN, and NO, wherein the cycloalkyl is a spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl, with the proviso that at least one R is a cycloalkyl, phenyl, heterocyclyl, or heteroaryl; R4 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, or CN; L is TIFF2026035735000071.tif9128 or phenylenyl, wherein the phenylenyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and halogen, or, when the phenylenyl is substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, the two substituents may, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring optionally containing 1 to 3 heteroatoms selected from N, O, and S; R5 and R6 are each independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen, or R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen; and T is C(O)OH, (CH2)NHS(O)2-(C1-C6 alkyl), or heteroaryl containing one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, or oxo; and L is TIFF2026035735000072.tif9128, then T is not C(O)OH; or when L is phenylenyl substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, and the two substituents together with the carbon atoms to which they are attached form a 5- or 6-membered ring, then T is H; however, TIFF2026035735000073.tif14128 TIFF2026035735000074.tif19128, TIFF2026035735000075.tif11128 TIFF2026035735000076.tif16128, T is oxadiazolonyl, each R3 is independently F, heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, or heteroaryl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted, and L is TIFF2026035735000077.tif9128, and when R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl, the C3-C6 cycloalkyl is unsubstituted; however, TIFF2026035735000078.tif14128 TIFF2026035735000079.tif19128, TIFF2026035735000080.tif12128 TIFF2026035735000081.tif16128, T is oxadiazolonyl, and L is TIFF2026035735000082.tif9128, and when R5 and R6 together with the carbon atoms to which they are attached form an unsubstituted C3-C6 cycloalkyl, and R3 is a heterocyclyl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, then R3 is substituted; however, TIFF2026035735000083.tif14128 TIFF2026035735000084.tif19128, TIFF2026035735000085.tif12128 TIFF2026035735000086.tif16128, T is oxadiazolonyl, and L is TIFF2026035735000087.tif9128, and when R5 and R6 are each methyl, R3 is not a heteroaryl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S; and however, TIFF2026035735000088.tif14128 TIFF2026035735000089.tif19128, TIFF2026035735000090.tif12128 TIFF2026035735000091.tif16128, and L is TIFF2026035735000092.tif9128, and when R5 and R6 are each H, and R3 is heterocyclyl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, R3 is substituted; compound, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof is described.

[0015] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, has the formula (Ia1), (Ia2), (Ia3), (Ia4), (Ia5), (Ia6), (Ia7), (Ia8), (Ia9), (Ia10), or (Ia11): The structure of TIFF2026035735000093.tif190144TIFF2026035735000094.tif116128, During the ceremony, each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and Each R 11 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, NO2, or C3-C6 cycloalkyl; structure It has.

[0016] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, has the formula (Ib1), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (Ib10), or (Ib11): The structure of TIFF2026035735000095.tif190144TIFF2026035735000096.tif116129, During the ceremony, each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, or halogen; and Each R 11 are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, NH2, NH-(C1-C6 alkyl), N(C1-C6 alkyl)2, CN, O2, or C3-C6 cycloalkyl; structure It has.

[0017] For each formula described herein, where applicable:

[0018] In some embodiments, TIFF2026035735000097.tif14128 TIFF2026035735000098.tif19128.

[0019] In some embodiments, TIFF2026035735000099.tif14128 The file is TIFF2026035735000100.tif19128.

[0020] In some embodiments, R1 is selected from the group consisting of a linear C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a linear C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a linear C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a linear C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., one or more halogen atoms). (CR) substituted with one or more substituents independently selected from methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each of which is substituted with several halogens (e.g., F, Cl). C R C ) 0~2 -phenyl.

[0021] In some embodiments, R1 is selected from the group consisting of a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), a straight chain C1-C4 haloalkoxy or a branched C3-C4 haloalkoxy (e.g., one or more halogen atoms). (CR) substituted with one or more substituents independently selected from methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), each substituted with several halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl); C R C ) 0~2 -phenyl.

[0022] In some embodiments, R1 is selected from the group consisting of straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogens (e.g., F, Cl)), and halogens (e.g., F, Cl, Br, or I) (CR C R C ) 0~2 -phenyl.

[0023] In some embodiments, R1 is substituted with 1, 2, or 3 substituents as described herein (CR C R C ) 0~2 -phenyl.

[0024] In some embodiments, R1 is substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~2 -phenyl.

[0025] In some embodiments, R1 is substituted with one or more substituents described herein (CR C R C ) 0~1 -phenyl.

[0026] In some embodiments, R1 is substituted with 1, 2, or 3 substituents as described herein (CR C R C ) 0~1 -phenyl.

[0027] In some embodiments, R1 is substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~1 -phenyl.

[0028] In some embodiments, R1 is phenyl substituted with one or more substituents described herein.

[0029] In some embodiments, R1 is phenyl substituted with 1, 2, or 3 substituents described herein.

[0030] In some embodiments, R1 is phenyl substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl.

[0031] In some embodiments, R is CR substituted with one or more substituents described herein. C R C -phenyl.

[0032] In some embodiments, R is CR substituted with 1, 2, or 3 substituents as described herein. C R C -phenyl.

[0033] In some embodiments, R is CR substituted with 1, 2, or 3 substituents selected from methyl, CF, F, and Cl. C R C -phenyl.

[0034] In some embodiments, R1 is selected from the group consisting of a linear C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a linear C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a linear C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a linear C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., one or more and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each of which is substituted with a halogen (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each of which is substituted with a halogen (e.g., F, Cl), (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0035] In some embodiments, R1 is selected from the group consisting of a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), a straight chain C1-C4 haloalkoxy or a branched C3-C4 haloalkoxy (e.g., one or more and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each of which is substituted with a halogen (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), each of which is substituted with a halogen (e.g., F, Cl), (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0036] In some embodiments, R1 is optionally substituted with 1, 2, or 3 substituents described herein (CR C R C ) 0~2-C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0037] In some embodiments, R1 is optionally substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0038] In some embodiments, R1 is optionally substituted with one or more substituents described herein (CR C R C ) 0~1 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0039] In some embodiments, R1 is optionally substituted with 1, 2, or 3 substituents described herein (CR C R C ) 0~1 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0040] In some embodiments, R1 is optionally substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~1 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0041] In some embodiments, R1 is cyclohexyl or bicyclopentanyl, each optionally substituted with one or more substituents described herein.

[0042] In some embodiments, R1 is cyclohexyl or bicyclopentanyl, each optionally substituted with 1, 2, or 3 substituents described herein.

[0043] In some embodiments, R1 is cyclohexyl or bicyclopentanyl, each optionally substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl.

[0044] In some embodiments, R1 is selected from the group consisting of a linear C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a linear C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a linear C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a linear C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., each substituted with one or more halogens (e.g., F, Cl)), methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), containing one 5- or 6-membered ring and one to three heteroatoms selected from N, O, and S (CR C R C ) 0~2 -heteroaryl.

[0045] In some embodiments, R1 is selected from the group consisting of a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), a straight chain C1-C4 haloalkoxy or a branched C3-C4 haloalkoxy (e.g., each substituted with one or more halogens (e.g., F, Cl)). methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN, NO, and C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) (CR C R C ) 0~2 -heteroaryl.

[0046] In some embodiments, R1 contains one 5-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~2 -heteroaryl.

[0047] In some embodiments, R1 contains one 5-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~1 -heteroaryl.

[0048] In some embodiments, R1 is a heteroaryl containing one 5-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein.

[0049] In some embodiments, R1 contains one 6-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~2 -heteroaryl.

[0050] In some embodiments, R1 contains one 6-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~1 -heteroaryl.

[0051] In some embodiments, R1 is heteroaryl containing one 6-membered ring and 1-3 heteroatoms selected from N, O, and S, which may be substituted as described herein.

[0052] In some embodiments, each R C is H.

[0053] In some embodiments, at least one R C is C1-C3 alkyl (e.g., methyl, ethyl, propyl, or i-propyl) or C1-C3 haloalkyl (e.g., methyl, ethyl, propyl, or i-propyl, each substituted with one or more halogens (e.g., F, Cl)).

[0054] In some embodiments, each R C is independently C1-C3 alkyl (e.g., methyl, ethyl, propyl, or i-propyl) or C1-C3 haloalkyl (e.g., methyl, ethyl, propyl, or i-propyl, each substituted with one or more halogens (e.g., F, Cl)).

[0055] In some embodiments, R2 is a heterocyclyl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, or a heteroaryl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is a straight chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy). C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with one or more halogens (e.g., F, Cl), methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)); linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), linear C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), and N(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0056] In some embodiments, R2 is a heterocyclyl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is a C1-C6 alkyl (e.g., methyl) optionally substituted with a straight chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy). , ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., and optionally substituted with one or more substituents independently selected from F, Cl, Br, or I), NH, NH—(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0057] In some embodiments, R2 is a heterocyclyl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents described herein.

[0058] In some embodiments, R2 is a heterocyclyl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents described herein.

[0059] In some embodiments, R2 is a heterocyclyl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents described herein.

[0060] In some embodiments, R2 is heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, where the heteroaryl is C1-C6 alkyl (e.g., methyl) optionally substituted with straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy). , ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., and optionally substituted with one or more substituents independently selected from F, Cl, Br, or I), NH, NH—(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0061] In some embodiments, R2 is a heteroaryl containing two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0062] In some embodiments, R2 is a heteroaryl containing two 5- or 6-membered rings and 1-3 heteroatoms selected from N and O, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0063] In some embodiments, R2 is a heteroaryl containing two 5- or 6-membered rings and 1-3 heteroatoms selected from N, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0064] In some embodiments, R2 is a heteroaryl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0065] In some embodiments, R2 is a heteroaryl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0066] In some embodiments, R2 is a heteroaryl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more substituents described herein.

[0067] In some embodiments, R2 is a C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with a straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight-chain C1 -C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., and imidazolyl or imidazopyridinyl, each optionally substituted by one or more substituents independently selected from N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0068] In some embodiments, R2 is selected from the group consisting of C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, and hexyl ... alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, and hexyloxy), and C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), indazolyl or imidazopyridinyl, each optionally substituted with one or more substituents independently selected from OH, and halogens (e.g., F, Cl, Br, or I).

[0069] In some embodiments, R2 is indazolyl or imidazopyridinyl, each optionally substituted with one or more substituents independently selected from C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), and halogen (e.g., F, Cl, Br, or I).

[0070] In some embodiments, R2 is indazolyl or imidazopyridinyl, each optionally substituted with 1, 2, or 3 substituents described herein.

[0071] In some embodiments, R2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy); linear C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)); linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy); , t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C spiro C3-C6 alkyl optionally substituted with one or more substituents independently selected from N(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO2; 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0072] In some embodiments, R2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy); linear C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)); linear C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy); , t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C and bicyclooctanyl substituted by one or more substituents independently selected from N(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0073] In some embodiments, R2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy). , straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, methoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C-C haloalkoxy or branched C-C haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), NH, NH—(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and phenyl substituted by one or more substituents independently selected from NO.

[0074] In some embodiments, R2 is selected from the group consisting of C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 halo, alkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyl); xyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i- and N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), indazolyl, imidazopyridinyl, phenyl, or bicyclooctanyl, each of which is optionally substituted independently with one or more substituents independently selected from N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO2.

[0075] In some embodiments, R2 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl) optionally substituted with straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or indazolyl, imidazopyridinyl, phenyl, or bicyclooctanyl, each of which is optionally independently substituted with one or more substituents independently selected from branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy, or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, and halogen (e.g., F, Cl, Br, or I).

[0076] In some embodiments, R2 is indazolyl, imidazopyridinyl, phenyl, or bicyclooctanyl, each optionally independently substituted with 1, 2, or 3 substituents described herein.

[0077] In some embodiments, TIFF2026035735000101.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000102.tif60144.

[0078] In some embodiments, TIFF2026035735000103.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000104.tif60160.

[0079] In some embodiments, TIFF2026035735000105.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000106.tif59160.

[0080] In some embodiments, TIFF2026035735000107.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000108.tif61155.

[0081] In some embodiments, TIFF2026035735000109.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000110.tif62155.

[0082] In some embodiments, TIFF2026035735000111.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000112.tif60132.

[0083] In some embodiments, TIFF2026035735000113.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000114.tif58145.

[0084] In some embodiments, TIFF2026035735000115.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000116.tif60155.

[0085] In some embodiments, TIFF2026035735000117.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000118.tif21138.

[0086] In some embodiments, TIFF2026035735000119.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000120.tif21128.

[0087] In some embodiments, TIFF2026035735000121.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000122.tif21128.

[0088] In some embodiments, TIFF2026035735000123.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000124.tif21128.

[0089] In some embodiments, TIFF2026035735000125.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000126.tif21128.

[0090] In some embodiments, TIFF2026035735000127.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000128.tif21128.

[0091] In some embodiments, TIFF2026035735000129.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000130.tif52145.

[0092] In some embodiments, TIFF2026035735000131.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000132.tif35144.

[0093] In some embodiments, TIFF2026035735000133.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000134.tif35159.

[0094] In some embodiments, TIFF2026035735000135.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000136.tif35159.

[0095] In some embodiments, TIFF2026035735000137.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000138.tif37155.

[0096] In some embodiments, TIFF2026035735000139.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000140.tif37155.

[0097] In some embodiments, TIFF2026035735000141.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000142.tif35133.

[0098] In some embodiments, TIFF2026035735000143.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000144.tif33144.

[0099] In some embodiments, TIFF2026035735000145.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000146.tif35155.

[0100] In some embodiments, TIFF2026035735000147.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000148.tif16128.

[0101] In some embodiments, TIFF2026035735000149.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000150.tif16128.

[0102] In some embodiments, TIFF2026035735000151.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000152.tif17128.

[0103] In some embodiments, TIFF2026035735000153.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000154.tif16128.

[0104] In some embodiments, TIFF2026035735000155.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000156.tif17128.

[0105] In some embodiments, TIFF2026035735000157.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000158.tif17128.

[0106] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight-chain C1-C6 haloalkoxy, or spiro C3-C6 alkyl optionally substituted with one or more substituents independently selected from branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO2; 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0107] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, spiro C3-C alkyl alkoxy groups optionally substituted with one or more substituents independently selected from ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), and halogens (e.g., F, Cl, Br, or I). 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0108] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), spiro C3-C haloalkoxy optionally substituted by one or more substituents independently selected from methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogens (e.g., F, Cl)), and halogens (e.g., F, Cl, Br, or I). 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0109] In some embodiments, at least one R3 is a spiro C3-C alkyl, optionally substituted with one or more substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), linear C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), and halogen (e.g., F, Cl, Br, or I). 10Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0110] In some embodiments, at least one R is a spiro C-C group, optionally substituted with one or two substituents as described herein. 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0111] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight-chain C1-C6 haloalkoxy, or and phenyl optionally substituted with one or more substituents independently selected from branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH—(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO.

[0112] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), and phenyl optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I).

[0113] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), and phenyl optionally substituted by one or more substituents independently selected from halogen (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogen (e.g., F, Cl)), and halogen (e.g., F, Cl, Br, or I).

[0114] In some embodiments, at least one R3 is phenyl optionally substituted with one or more substituents independently selected from straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), and halogen (e.g., F, Cl, Br, or I).

[0115] In some embodiments, at least one R3 is phenyl optionally substituted with one or two substituents described herein.

[0116] In some embodiments, at least one R3 is phenyl substituted with one or two substituents described herein.

[0117] In some embodiments, at least one R3 is selected from the group consisting of a straight chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl ... each substituted with one or more halogens (e.g., F, Cl), -butyl, t-butyl, pentyl, or hexyl), straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 halo ... each substituted with one or more halogens (e.g., F, Cl) , i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), OH, halogen (e.g., F, Cl, Br, or I), NH2, NH-(C1-C6 alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C1-C6 alkyl)2 (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, and heterocyclyl containing one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from alkyl, aryl, butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO, wherein the heterocyclyl containing two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S may be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0118] In some embodiments, at least one R3 is selected from the group consisting of a straight chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy). ), a straight-chain C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which is substituted with one or more halogens (e.g., F, Cl)), and a heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I), wherein the heterocyclyl containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S may be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0119] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy ...), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or and a branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is substituted with one or more halogens (e.g., F, Cl)), and a heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from a halogen (e.g., F, Cl, Br, or I), wherein the heterocyclyl containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S may be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0120] In some embodiments, at least one R3 is a heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), linear C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), and halogen (e.g., F, Cl, Br, or I), wherein the heterocyclyl containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S can be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0121] In some embodiments, at least one R3 is a heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or two substituents described herein, wherein the heterocyclyl containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S can be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0122] In some embodiments, at least one R3 is a heterocyclyl containing one or two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S, substituted with one or two substituents described herein, wherein the heterocyclyl containing two 3- to 6-membered rings and one to three heteroatoms selected from N, O, and S can be a spirocyclic heterocyclyl or a fused-ring heterocyclyl.

[0123] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight-chain C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., one or more and heterocyclyl containing one or two five- or six-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted by one or more substituents independently selected from methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), OH, halogen (e.g., F, Cl, Br, or I), NH, NH—(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO, each substituted by one or more halogens (e.g., F, Cl).

[0124] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy). , i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), and heterocyclyl containing one or two five- or six-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I).

[0125] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- and heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from halogen (e.g., halogen, methyl, methyl, propyl, methyl, propyl, propyl) and halogen (e.g., halogen, methyl, propyl ...

[0126] In some embodiments, at least one R3 is a heterocyclyl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), linear C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), and halogens (e.g., F, Cl, Br, or I).

[0127] In some embodiments, at least one R3 is a heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or two substituents described herein.

[0128] In some embodiments, at least one R3 is a heterocyclyl containing one or two 5- or 6-membered rings and one to three heteroatoms selected from N, O, and S, substituted with one or two substituents described herein.

[0129] In some embodiments, at least one R3 is a heterocyclyl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0130] In some embodiments, at least one R3 is a heterocyclyl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0131] In some embodiments, at least one R3 is a heterocyclyl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0132] In some embodiments, at least one R3 is a heterocyclyl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0133] In some embodiments, at least one R3 is a heterocyclyl containing a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0134] In some embodiments, at least one R3 is a heterocyclyl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0135] In some embodiments, at least one R3 is a heterocyclyl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0136] In some embodiments, at least one R3 is a heterocyclyl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0137] In some embodiments, at least one R3 is a heterocyclyl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0138] In some embodiments, at least one R3 is tetrahydropyranyl optionally substituted with one or more substituents described herein.

[0139] In some embodiments, at least one R3 is tetrahydropyranyl optionally substituted with one or two substituents described herein.

[0140] In some embodiments, at least one R3 is tetrahydropyranyl substituted with one or two substituents described herein.

[0141] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight-chain C1-C6 haloalkoxy or a branched C3-C6 haloalkoxy (e.g., one or more and heteroaryl containing one or two five- or six-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted by one or more substituents independently selected from methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), OH, halogen (e.g., F, Cl, Br, or I), NH, NH—(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, and NO, each substituted by one or more halogens (e.g., F, Cl).

[0142] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a straight-chain C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy). , i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl), and heteroaryl containing one or two five- or six-membered rings and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I).

[0143] In some embodiments, at least one R3 is selected from the group consisting of a straight-chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight-chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n- and heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from halogen (e.g., halogen, methyl, methyl, propyl, methyl, propyl, propyl) and halogen (e.g., halogen, methyl, propyl ...

[0144] In some embodiments, at least one R3 is a heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from linear C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), linear C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), and halogens (e.g., F, Cl, Br, or I).

[0145] In some embodiments, at least one R3 is a heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or two substituents described herein.

[0146] In some embodiments, at least one R3 is a heteroaryl containing one or two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S, substituted with one or two substituents described herein.

[0147] In some embodiments, at least one R3 is a heteroaryl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0148] In some embodiments, at least one R3 is a heteroaryl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0149] In some embodiments, at least one R3 is a heteroaryl containing a 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0150] In some embodiments, at least one R3 is a heteroaryl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0151] In some embodiments, at least one R3 is a heteroaryl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0152] In some embodiments, at least one R3 is a heteroaryl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0153] In some embodiments, at least one R3 is a heteroaryl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0154] In some embodiments, at least one R3 is a heteroaryl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with 1 or 2 substituents as described herein.

[0155] In some embodiments, at least one R3 is a heteroaryl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, substituted with 1 or 2 substituents as described herein.

[0156] In some embodiments, at least one R3 is pyridyl optionally substituted with one or more substituents described herein.

[0157] In some embodiments, at least one R3 is pyridyl optionally substituted with one or two substituents described herein.

[0158] In some embodiments, at least one R3 is pyridyl substituted with one or two substituents described herein.

[0159] In some embodiments, R4 is a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight-chain C1-C6 alkoxy, or a branched C3-C6 Alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, or halogen (e.g., F, Cl, Br, or I).

[0160] In some embodiments, R4 is a straight-chain C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight-chain C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), or a halogen (e.g., F, Cl, Br, or I).

[0161] In some embodiments, R4 is a straight chain C1-C6 alkyl or a branched C3-C6 alkyl (eg, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0162] In some embodiments, R4 is a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (eg, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0163] In some embodiments, L is The file is TIFF2026035735000159.tif9128.

[0164] In some embodiments, L is selected from the group consisting of straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, propoxy). and phenylenyl optionally substituted by one or more substituents independently selected from alkyl, alkylphenyl, alkoxy, alkylethoxy, alkylpropoxy, alkyln-butoxy, alkyls-butoxy, alkyls-s-butoxy, alkoxy, alkylt-but ...

[0165] In some embodiments, L is phenylenyl substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, and the two substituents, together with the carbon atoms to which they are attached, may form a 5- or 6-membered ring that optionally contains 1 to 3 heteroatoms selected from N, O, and S.

[0166] In some embodiments, R5 and R6 are each H.

[0167] In some embodiments, one of R5 and R6 is a straight chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C6 alkoxy, or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)). branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy, or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, or halogen (e.g., F, Cl, Br, or I).

[0168] In some embodiments, R5 and R6, together with the carbon atom to which they are attached, are selected from a linear C1-C6 alkyl or a branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a linear C1-C6 haloalkyl or a branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl), a linear C1-C6 alkoxy or a branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, alkoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, and C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I).

[0169] In some embodiments, R5 and R6, together with the carbon atom to which they are attached, are selected from a linear C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a linear C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a linear C1-C4 alkoxy or a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i -propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogens (e.g., F, Cl)), OH, and a C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more substituents independently selected from halogens (e.g., F, Cl, Br, or I).

[0170] In some embodiments, R5 and R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0171] In some embodiments, R5 and R6, together with the carbon atom to which they are attached, form a cyclopropyl optionally substituted with one or two straight chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).

[0172] In some embodiments, R5 and R6, together with the carbon atom to which they are attached, form a cyclopropyl optionally substituted with one or two straight chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0173] In some embodiments, R5 and R6 together with the carbon atom to which they are attached form a cyclopropyl.

[0174] In some embodiments, T is C(O)OH.

[0175] In some embodiments, T is (CH2)NHS(O)2-(C1-C6 alkyl).

[0176] In some embodiments, T is selected from the group consisting of straight-chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), straight-chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s- butoxy, t-butoxy, pentoxy, or hexyloxy), straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), heteroaryl containing a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from OH, halogens (e.g., F, Cl, Br, or I), and oxo (i.e., ═O).

[0177] In some embodiments, T is selected from the group consisting of straight-chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), straight-chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), straight-chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy). and heterocyclyl containing one 5- or 6-membered ring and one to three heteroatoms selected from N, O, and S, optionally substituted with one or more substituents independently selected from OH, halogen (e.g., methyl, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogen (e.g., F, Cl)), OH, halogen (e.g., F, Cl, Br, or I), and oxo (i.e., ═O).

[0178] In some embodiments, T is heteroaryl containing a 5-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0179] In some embodiments, T is heteroaryl containing a 6-membered ring and 1-3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0180] In some embodiments, T is heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolonyl, and thiadiazolonyl, each optionally substituted with one or more substituents described herein.

[0181] In some embodiments, at least one R7 is a straight chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C6 alkoxy, or a branched C 3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy, each substituted with one or more halogens (e.g., F, Cl)), OH, or halogen (e.g., F, Cl, Br, or I).

[0182] In some embodiments, at least one R7 is selected from the group consisting of a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or a branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy, or is a branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), a straight chain C1-C4 haloalkoxy, or a branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogens (e.g., F, Cl)), OH, or a halogen (e.g., F, Cl, Br, or I).

[0183] In some embodiments, at least one R7 is a straight chain C1-C4 alkyl or a branched C3-C4 alkyl (eg, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0184] In some embodiments, at least one R 11is a straight chain C1-C6 alkyl or branched C3-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), a straight chain C1-C6 haloalkyl or branched C3-C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C6 alkoxy or branched C3-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), a straight chain C1-C6 haloalkoxy or branched C3-C6 haloalkoxy (e.g., For example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), each substituted with one or more halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), CN, NO, or C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0185] In some embodiments, at least one R 11is a straight chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy or branched C3-C4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), a straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., For example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), each substituted with one or more halogens (e.g., F, Cl), OH, halogen (e.g., F, Cl, Br, or I), NH, NH-(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), N(C-C alkyl) (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN, O, or C-C cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0186] In some embodiments, at least one R 11is a straight chain C1-C4 alkyl or branched C3-C4 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), a straight chain C1-C4 haloalkyl or branched C3-C4 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, each substituted with one or more halogens (e.g., F, Cl)), a straight chain C1-C4 alkoxy or branched C3-C4 alkyl alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy), straight chain C1-C4 haloalkoxy or branched C3-C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each substituted with one or more halogens (e.g., F, Cl)), or halogen (e.g., F, Cl, Br, or I).

[0187] In some embodiments, at least one R 11 is F.

[0188] In some embodiments, at least one R 11 is F and at least one R 11 is methyl.

[0189] As described herein TIFF2026035735000160.tif16128, L, T, R1, R C , R 11 , R2, R3, R4, R5, R6, and R7, any moiety of which may be any of the groups described herein. TIFF2026035735000161.tif15128, L, T, R1, R C , R 11 , R2, R3, R4, R5, R6, and R7.

[0190] In some embodiments, TIFF2026035735000162.tif16128, L, T, R1, R C , R 11 , R2, R3, R4, R5, R6, and R7 can be combined as follows:

[0191] (A-1') In some embodiments, TIFF2026035735000163.tif14128 TIFF2026035735000164.tif19128; TIFF2026035735000165.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000166.tif81132.

[0192] (A-1) In some embodiments, TIFF2026035735000167.tif14128 TIFF2026035735000168.tif19128; TIFF2026035735000169.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000170.tif79144.

[0193] (A-2) In some embodiments, TIFF2026035735000171.tif14128 TIFF2026035735000172.tif19128; TIFF2026035735000173.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000174.tif60144.

[0194] (A-3') In some embodiments, TIFF2026035735000175.tif14128 TIFF2026035735000176.tif19128; TIFF2026035735000177.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000178.tif59160.

[0195] (A-3) In some embodiments, TIFF2026035735000179.tif14128 TIFF2026035735000180.tif19128; TIFF2026035735000181.tif11128 and a bicyclic heteroaryl ring selected from TIFF2026035735000182.tif60159.

[0196] (A-4) In some embodiments, TIFF2026035735000183.tif14128 TIFF2026035735000184.tif19128; TIFF2026035735000185.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000186.tif59160.

[0197] (A-5') In some embodiments, TIFF2026035735000187.tif14128 TIFF2026035735000188.tif19128; TIFF2026035735000189.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000190.tif80153.

[0198] (A-5) In some embodiments, TIFF2026035735000191.tif14128 TIFF2026035735000192.tif19128; TIFF2026035735000193.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000194.tif62153.

[0199] (A-6) In some embodiments, TIFF2026035735000195.tif14128 TIFF2026035735000196.tif19128; TIFF2026035735000197.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000198.tif61155.

[0200] (A-7) In some embodiments, TIFF2026035735000199.tif14128 TIFF2026035735000200.tif19128; TIFF2026035735000201.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000202.tif21143.

[0201] (A-8) In some embodiments, TIFF2026035735000203.tif14128 TIFF2026035735000204.tif19128; TIFF2026035735000205.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000206.tif21128.

[0202] (A-9) In some embodiments, TIFF2026035735000207.tif14128 TIFF2026035735000208.tif19128; TIFF2026035735000209.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000210.tif21128.

[0203] (A-10) In some embodiments, TIFF2026035735000211.tif14128 TIFF2026035735000212.tif19128; TIFF2026035735000213.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000214.tif21128.

[0204] (A-11) In some embodiments, TIFF2026035735000215.tif14128 TIFF2026035735000216.tif19128; TIFF2026035735000217.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000218.tif21130.

[0205] (A-12) In some embodiments, TIFF2026035735000219.tif14128 TIFF2026035735000220.tif19128; TIFF2026035735000221.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000222.tif21128.

[0206] (A-13) In some embodiments, TIFF2026035735000223.tif14128 TIFF2026035735000224.tif19128; TIFF2026035735000225.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000226.tif35128.

[0207] (A-14) In some embodiments, TIFF2026035735000227.tif14128 TIFF2026035735000228.tif19128; TIFF2026035735000229.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000230.tif35128.

[0208] (A-15) In some embodiments, TIFF2026035735000231.tif14128 TIFF2026035735000232.tif19128; TIFF2026035735000233.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000234.tif36128.

[0209] (A-16') In some embodiments, TIFF2026035735000235.tif14128 TIFF2026035735000236.tif19128; TIFF2026035735000237.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000238.tif16128.

[0210] (A-16) In some embodiments, TIFF2026035735000239.tif14128 TIFF2026035735000240.tif19128; TIFF2026035735000241.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000242.tif16128.

[0211] (A-17') In some embodiments, TIFF2026035735000243.tif14128 TIFF2026035735000244.tif19128; TIFF2026035735000245.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000246.tif16128.

[0212] (A-17) In some embodiments, TIFF2026035735000247.tif14128 TIFF2026035735000248.tif19128; TIFF2026035735000249.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000250.tif16128.

[0213] (A-18') In some embodiments, TIFF2026035735000251.tif14128 TIFF2026035735000252.tif19128; TIFF2026035735000253.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000254.tif17128.

[0214] (A-18) In some embodiments, TIFF2026035735000255.tif14128 TIFF2026035735000256.tif19128; TIFF2026035735000257.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000258.tif16128.

[0215] (B-1') In some embodiments, TIFF2026035735000259.tif14128 TIFF2026035735000260.tif19128; TIFF2026035735000261.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000262.tif81132.

[0216] (B-1) In some embodiments, TIFF2026035735000263.tif14128 TIFF2026035735000264.tif19128; TIFF2026035735000265.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000266.tif80145.

[0217] (B-2') In some embodiments, TIFF2026035735000267.tif14128 TIFF2026035735000268.tif19128; TIFF2026035735000269.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000270.tif60159.

[0218] (B-2) In some embodiments, TIFF2026035735000271.tif14128 TIFF2026035735000272.tif19128; TIFF2026035735000273.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000274.tif60160.

[0219] (B-3') In some embodiments, TIFF2026035735000275.tif14128 TIFF2026035735000276.tif19128; TIFF2026035735000277.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000278.tif80153.

[0220] (B-3) In some embodiments, TIFF2026035735000279.tif14128 TIFF2026035735000280.tif19128; TIFF2026035735000281.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000282.tif62153.

[0221] (B-4) In some embodiments, TIFF2026035735000283.tif14128 TIFF2026035735000284.tif19128; TIFF2026035735000285.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000286.tif21139.

[0222] (B-5) In some embodiments, TIFF2026035735000287.tif14128 TIFF2026035735000288.tif19128; TIFF2026035735000289.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000290.tif21128.

[0223] (B-6) In some embodiments, TIFF2026035735000291.tif14128 TIFF2026035735000292.tif19128; TIFF2026035735000293.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000294.tif21128.

[0224] (B-7) In some embodiments, TIFF2026035735000295.tif14128 TIFF2026035735000296.tif19128; TIFF2026035735000297.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000298.tif35128.

[0225] (B-8) In some embodiments, TIFF2026035735000299.tif14128 TIFF2026035735000300.tif19128; TIFF2026035735000301.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000302.tif35128.

[0226] (B-9) In some embodiments, TIFF2026035735000303.tif14128 TIFF2026035735000304.tif19128; TIFF2026035735000305.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000306.tif36128.

[0227] (B-10') In some embodiments, TIFF2026035735000307.tif14128 TIFF2026035735000308.tif19128; TIFF2026035735000309.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000310.tif16128.

[0228] (B-10) In some embodiments, TIFF2026035735000311.tif14128 TIFF2026035735000312.tif19128; TIFF2026035735000313.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000314.tif16128.

[0229] (B-11') In some embodiments, TIFF2026035735000315.tif14128 TIFF2026035735000316.tif19128; TIFF2026035735000317.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000318.tif16128.

[0230] (B-11) In some embodiments, TIFF2026035735000319.tif14128 TIFF2026035735000320.tif19128; TIFF2026035735000321.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000322.tif16128.

[0231] (B-12') In some embodiments, TIFF2026035735000323.tif14128 TIFF2026035735000324.tif19128; TIFF2026035735000325.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000326.tif17128.

[0232] (B-12) In some embodiments, TIFF2026035735000327.tif14128 TIFF2026035735000328.tif19128; TIFF2026035735000329.tif12128 and a bicyclic heteroaryl ring selected from TIFF2026035735000330.tif16128.

[0233] (C-1) In some embodiments, TIFF2026035735000331.tif15128 is as described in any one of (A-1') to (B-12), and R1 is (CR C R C )0~2 -phenyl.

[0234] (C-2) In some embodiments, TIFF2026035735000332.tif15128 is as described in any one of (A-1') to (B-12), and R1 is a substituted (CR C R C ) 0~2 -phenyl.

[0235] (C-3) In some embodiments, TIFF2026035735000333.tif15128 is as described in any one of (A-1') to (B-12), and R1 is substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~2 -phenyl.

[0236] (C-4) In some embodiments, TIFF2026035735000334.tif15128 is as described in any one of (A-1′) to (B-12), wherein R1 is phenyl substituted with one or more substituents described herein.

[0237] (C-5) In some embodiments, TIFF2026035735000335.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is phenyl substituted with one, two, or three substituents as described herein.

[0238] (C-6) In some embodiments, TIFF2026035735000336.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is phenyl substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl.

[0239] (C-7) In some embodiments, TIFF2026035735000337.tif15128 is as described in any one of (A-1') to (B-12), and R1 is a CR substituted with one or more substituents as described herein. C R C -phenyl.

[0240] (C-8) In some embodiments, TIFF2026035735000338.tif15128 is as described in any one of (A-1') to (B-12), and R1 is a CR substituted with one, two, or three substituents as described herein. C R C -phenyl.

[0241] (C-9) In some embodiments, TIFF2026035735000339.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is CR substituted with one, two, or three substituents selected from methyl, CF3, F, and Cl. C R C -phenyl.

[0242] (C-10) In some embodiments, TIFF2026035735000340.tif15128 is as described in any one of (A-1') to (B-12), and R1 may be substituted with one or more substituents described herein (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0243] (C-11) In some embodiments, TIFF2026035735000341.tif15128 is as described in any one of (A-1') to (B-12), and R1 is optionally substituted with one, two, or three substituents as described herein (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0244] (C-12) In some embodiments, TIFF2026035735000342.tif15128 is as described in any one of (A-1') to (B-12), and R1 is optionally substituted with one, two, or three substituents selected from methyl, methoxy, CF3, F, and Cl (CR C R C ) 0~2 -C3-C6 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl).

[0245] (C-13) In some embodiments, TIFF2026035735000343.tif15128 is as described in any one of (A-1') to (B-12), and R1 is cyclohexyl or bicyclopentanyl, each of which may be substituted with one or more substituents described herein.

[0246] (C-14) In some embodiments, TIFF2026035735000344.tif15128 is as described in any one of (A-1') to (B-12), and R1 is cyclohexyl or bicyclopentanyl, each optionally substituted with one, two, or three substituents as described herein.

[0247] (C-15) In some embodiments, TIFF2026035735000345.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is cyclohexyl or bicyclopentanyl, each optionally substituted with 1, 2, or 3 substituents selected from methyl, methoxy, CF3, F, and Cl.

[0248] (C-16) In some embodiments, TIFF2026035735000346.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 contains one 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~2 -heteroaryl.

[0249] (C-17) In some embodiments, TIFF2026035735000347.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is heteroaryl containing one 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, which may be substituted as described herein.

[0250] (C-18) In some embodiments, TIFF2026035735000348.tif15128 is as described in any one of (A-1') to (B-12), and R1 contains one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, which may be substituted as described herein (CR C R C ) 0~2 -heteroaryl.

[0251] (C-19) In some embodiments, TIFF2026035735000349.tif15128 is as described in any one of (A-1') to (B-12), wherein R1 is heteroaryl containing one 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, which may be substituted as described herein.

[0252] (D-1) In some embodiments, TIFF2026035735000350.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heterocyclyl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0253] (D-2) In some embodiments, TIFF2026035735000351.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heterocyclyl containing a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0254] (D-3) In some embodiments, TIFF2026035735000352.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heterocyclyl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0255] (D-4) In some embodiments, TIFF2026035735000353.tif15128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0256] (D-5) In some embodiments, TIFF2026035735000354.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heteroaryl containing a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0257] (D-6) In some embodiments, TIFF2026035735000355.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heteroaryl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0258] (D-7) In some embodiments, TIFF2026035735000356.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is heteroaryl containing two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0259] (D-8) In some embodiments, TIFF2026035735000357.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is indazolyl or imidazopyridinyl, each of which may be substituted with one or more substituents described herein.

[0260] (D-9) In some embodiments, TIFF2026035735000358.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is a spiro C3-C6 alkyl group optionally substituted with one or more substituents as described herein. 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0261] (D-10) In some embodiments, TIFF2026035735000359.tif16128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is bicyclooctanyl optionally substituted with one or more substituents described herein.

[0262] (D-11) In some embodiments, TIFF2026035735000360.tif15128, and R1, if applicable, is as described in any one of (A-1') to (C-19), and R2 is phenyl optionally substituted with one or more substituents described herein.

[0263] (E-1) In some embodiments, TIFF2026035735000361.tif16128, R1 and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is optionally substituted with one or more substituents described herein; 10 Cycloalkyl, bridged C3-C 10 Cycloalkyl or mono C3-C 10 Cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which can be spirocycloalkyl, bridged cycloalkyl, or monocycloalkyl).

[0264] (E-2) In some embodiments, TIFF2026035735000362.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is phenyl optionally substituted with one or more substituents described herein.

[0265] (E-3) In some embodiments, TIFF2026035735000363.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is a heterocyclyl containing one or two 3- to 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0266] (E-4) In some embodiments, TIFF2026035735000364.tif15128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is heterocyclyl containing a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0267] (E-5) In some embodiments, TIFF2026035735000365.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is heterocyclyl containing a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0268] (E-6) In some embodiments, TIFF2026035735000366.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is heterocyclyl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0269] (E-7) In some embodiments, TIFF2026035735000367.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is tetrahydropyranyl optionally substituted with one or more substituents described herein.

[0270] (E-8) In some embodiments, TIFF2026035735000368.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is a heteroaryl containing one or two 5- or 6-membered rings and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0271] (E-9) In some embodiments, TIFF2026035735000369.tif16128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is heteroaryl containing a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0272] (E-10) In some embodiments, TIFF2026035735000370.tif15128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is a heteroaryl containing a 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0273] (E-11) In some embodiments, TIFF2026035735000371.tif15128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is a heteroaryl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0274] (E-12) In some embodiments, TIFF2026035735000372.tif15128, R1, and R2, if applicable, are as described in any one of (A-1') to (D-11), and at least one R3 is pyridyl optionally substituted with one or more substituents described herein.

[0275] (F-1) In some embodiments, TIFF2026035735000373.tif16128, R1, R2, and R3 are as described in any one of (A-1') to (E-12), if applicable, and L is TIFF2026035735000374.tif9128, and R5 and R6 are H.

[0276] (F-2) In some embodiments, TIFF2026035735000375.tif15128, R1, R2, and R3 are as described in any one of (A-1') to (E-12), if applicable, and L is TIFF2026035735000376.tif9128, and R5 and R6, together with the carbon atom to which they are attached, form a C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more substituents described herein.

[0277] (F-3) In some embodiments, TIFF2026035735000377.tif15128, R1, R2, and R3 are as described in any one of (A-1') to (E-12), if applicable, and L is TIFF2026035735000378.tif9128, and R5 and R6 together with the carbon atom to which they are attached form a cyclopropyl group which may be substituted with one or more substituents described herein.

[0278] (G-1) In some embodiments, TIFF2026035735000379.tif15128, R1, R2, R3, R5, R6, and L, if applicable, are as described in any one of (A-1') to (F-3), and T is heteroaryl containing one 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0279] (G-2) In some embodiments, TIFF2026035735000380.tif15128, R1, R2, R3, R5, R6, and L, if applicable, are as described in any one of (A-1') to (F-3), and T is heteroaryl containing one 5-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0280] (G-3) In some embodiments, TIFF2026035735000381.tif15128, R1, R2, R3, R5, R6, and L, if applicable, are as described in any one of (A-1') to (F-3), and T is heteroaryl containing a 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents described herein.

[0281] (G-4) In some embodiments, TIFF2026035735000382.tif16128, R1, R2, R3, R5, R6, and L, where applicable, are as described in any one of (A-1') to (F-3), and T is heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, oxadiazolonyl, and thiadiazolonyl, each of which may be substituted with one or more substituents described herein.

[0282] Non-limiting exemplary compounds of the present application are listed in Table A. As shown in Table A, other compound tables, examples, schemes, and compounds throughout this application, "or 1" (or "Or 1") and "or 2" (or "Or 2") indicate one stereoisomeric configuration, but the absolute stereochemical configuration of the specified chiral carbon atom is not determined, and "&1" indicates a mixture of stereoisomers of the specified chiral carbon atom.

[0283] (Table A) TIFF2026035735000383.tif150161TIFF2026035735000384.tif206161TIFF2026035735000385.tif216161TIFF2026035735000386.tif220161TIFF2026035735000387.tif216161TIFF2026035735000388.tif220161TIFF2026035735000389.tif220161TIFF2026035735000390.tif220161TIFF2026035735000391.tif211161TIFF2026035735000392.tif214161TIFF2026035735000393.tif161161TIFF2026035735000394.tif220161TIFF2026035735000395.tif215161TIFF2026035735000396.tif155161TIFF2026035735000397.tif212161TIFF2026035735000398.tif200161TIFF2026035735000399.tif204161TIFF2026035735000400.tif208161TIFF2026035735000401.tif215161TIFF2026035735000402.tif220161TIFF2026035735000403.tif210161TIFF2026035735000404.tif204161TIFF2026035735000405.tif204161TIFF2026035735000406.tif208161TIFF2026035735000407.tif208161TIFF2026035735000408.tif208161TIFF2026035735000409.tif208161TIFF2026035735000410.tif207161TIFF2026035735000411.tif207161TIFF2026035735000412.tif207161TIFF2026035735000413.tif207161TIFF2026035735000414.tif207161TIFF2026035735000415.tif207161TIFF2026035735000416.tif207161TIFF2026035735000417.tif207161TIFF2026035735000418.tif78161.

[0284] The compounds of the present application have advantageous properties compared to known compounds, such as known GLP-1 agonists. For example, the compounds of the present application have more potent GLP-1 agonist activity, more favorable pharmacokinetic properties (e.g., C max , T max and / or AUC) and / or exhibits less interaction with other cellular targets (e.g., hepatocyte transporters such as OATP1B1), and therefore improved safety (e.g., drug-drug interactions). These beneficial properties of the compounds of the present application can be measured according to methods generally available in the art, such as those exemplified herein.

[0285] The compounds of the present application may be in the cis or trans configuration, or in the Z or E configuration, due to the presence of double bonds. Although one configuration may be shown in the structure of a compound or formula of the present application, it will be understood that the present application encompasses the other configuration. For example, the compounds or formula of the present application may be shown in the cis or trans configuration, or in the Z or E configuration.

[0286] In one embodiment, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) are pharmaceutically acceptable salts. In another embodiment, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) are solvates. In another embodiment, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) are hydrates.

[0287] Details of the present application are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, exemplary methods and materials are described herein. Other features, objects, and advantages of the present application will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0288] definition In this application, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0289] In this application, the term "and / or" is used to mean "and" or "or" unless otherwise indicated.

[0290] The present application also includes pharmaceutical compositions comprising an effective amount of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein) and a pharmaceutically acceptable carrier.

[0291] The term "alkyl," as used herein, refers to a saturated straight- or branched-chain hydrocarbon group containing, in certain embodiments, 1 to 6 carbon atoms. Examples of C1-C8 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl groups.

[0292] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety containing from 2 to 6 carbon atoms, in certain embodiments, with at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0293] The term "alkoxy" refers to an --O-alkyl group.

[0294] The terms "hal," "halo," and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0295] The term "aryl" as used herein means a monocyclic or polycyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

[0296] The term "aralkyl," as used herein, refers to an alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0297] As used herein, the term "cycloalkyl" refers to a monovalent group derived from a monocyclic or polycyclic saturated or partially saturated carbocyclic ring compound (fused, bridged, or spirocyclic). Examples of C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl; 12 Examples of -cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Monovalent groups derived from monocyclic or polycyclic carbocyclic ring compounds having at least one carbon-carbon double bond by the removal of a hydrogen atom are also contemplated. Examples of these groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

[0298] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic or higher), fused or unfused, group or ring system having at least one aromatic ring having 5 to 10 ring atoms, of which one ring atom is selected from S, O, and N, zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N, and the remaining ring atoms are carbon. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, and the like.

[0299] The term "heteroaralkyl," as used herein, refers to an alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl, and the like.

[0300] The term "heterocyclyl" or "heterocycloalkyl," as used herein, refers to a saturated or unsaturated non-aromatic 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic ring system, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring system (fused, bridged, or spirocyclic), or 11-, 12-, 13-, or 14-membered tricyclic ring system (fused, bridged, or spirocyclic), in which (i) each ring contains 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, (ii) each 5-membered ring has 0 to 1 double bond and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms are optionally oxidized, and (iv) the nitrogen heteroatom is optionally quaternized.Representative heterocycloalkyl groups include [1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-pyridone, oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and 2,6-diazaspiro[3.3]heptanyl. nyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 2-azaspiro[3.3]heptan-5-amine, 1-azaspiro[3.3]heptan-5-amine, 1-oxa-6-azaspiro[3.3]heptan-3-amine, 2-azaspiro[3.3]heptan-6-amine, 1-azaspiro[3.3]heptan-6-amine, 6-azaspiro[3.4]octan-2-amine, 5-azaspiro[3.4]octan-2-amine, 6-azaspiro[3.4]octan-1-amine, 5-azaspiro[3.4]octan-1-amine, 5-oxa-2-azaspiro[3.4]octan-7-amine, 7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, 5-oxa-2-azaspiro[3.4]octan-8-amine, 8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, and the like.

[0301] The term "alkylamino" refers to a group having the structure, for example, NH(C1-C6 alkyl), where C1-C6 alkyl is as previously defined.

[0302] The term "dialkylamino" refers to a group having the structure, for example, N(C1-C6 alkyl)2, where C1-C6 alkyl is as previously defined.

[0303] According to the present application, any aryl, substituted aryl, heteroaryl, and substituted heteroaryl described herein can be any aromatic group, which can be substituted or unsubstituted.

[0304] As described herein, the compounds of the present application may be substituted with one or more substituents, for example, those generally exemplified above or those exemplified by specific classes, subclasses, and species of the present application. It will be recognized that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, means that a hydrogen radical in a given structure is replaced with a specified substituent radical. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. As used herein, the terms "optionally substituted," "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted cycloalkyl," "optionally substituted cycloalkenyl," "optionally substituted aryl," "optionally substituted heteroaryl," "optionally substituted aralkyl," "optionally substituted heteroaralkyl," "optionally substituted heterocyclyl," and any other optionally substituted group, mean a group that is substituted or unsubstituted by having one, two, three, or more hydrogen atoms thereof independently replaced with substituents including, but not limited to, the following: -F, -CI, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH2, protected amino, -NH-C1-C 12 -Alkyl, -NH-C2~C 12 -Alkenyl, -NH-C 12 -Alkenyl, -NH-C3-C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -Alkyl, -O-C2~C 12 -Alkenyl, -O-C2-C 12 -alkenyl, -O-C3-C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -Alkyl, -C(O)-C2-C 12 -Alkenyl, -C(O)-C 12 -Alkenyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH, -CONH-C 12 -Alkyl, -CONH-C2~C 12 -alkenyl, -CONH-C2~C 12 -Alkenyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -Alkyl, -OCO2-C2~C 12 -Alkenyl, -OCO2-C2~C 12 -alkenyl, -OCO2-C3~C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -OCONH2, -OCONH-C1~C 12 -Alkyl, -OCONH-C2~C 12 -Alkenyl, -OCONH-C2-C 12 -alkenyl, -OCONH-C3~C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C1~C 12 -Alkyl, -NHC(O)-C2-C 12 -Alkenyl, -NHC(O)-C 12 -alkenyl, -NHC(O)-C3~C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1~C 12 -Alkyl, -NHCO2-C2~C 12 -Alkenyl, -NHCO2-C2~C 12 -alkenyl, -NHCO2-C3~C 12 -cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1~C 12 -Alkyl, -NHC(O)NH-C2-C 12 -alkenyl, -NHC(O)NH-C2~C 12 -Alkenyl, -NHC(O)NH-C 12 -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, -NHC(S)NH2, -NHC(S)NH-C1~C 12 -Alkyl, -NHC(S)NH-C2~C 12 -alkenyl, -NHC(S)NH-C2~C 12 -Alkenyl, -NHC(S)NH-C3-C 12 -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1~C 12 -Alkyl, -NHC(NH)NH-C2-C 12 -Alkenyl, -NHC(NH)NH-C 12-alkenyl, -NHC(NH)NH-C3~C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH heterocycloalkyl, -NHC(NH)-C 12 -Alkyl, -NHC(NH)-C2-C 12 -alkenyl, -NHC(NH)-C2~C 12 -Alkenyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -alkyl, -C(NH)NH-C~C 12 -Alkenyl, -C(NH)NH-C 12 -Alkenyl, C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NHheterocycloalkyl, -S(O)-C1~C 12 -Alkyl, -S(O)-C2-C 12 -Alkenyl, -S(O)-C2-C 12 -alkenyl, -S(O)-C3~C 12 -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1~C 12 -Alkyl, -SO2NH-C2~C 12 -Alkenyl, -SO2NH-C2~C 12 -alkenyl, -SO2NH-C3~C 12 -cycloalkyl, -SONH-aryl, -SONH-heteroaryl, -SONH-heterocycloalkyl, -NHSO2-C1~C 12 -Alkyl, -NHSO2-C2~C12 -Alkenyl, -NHSO2-C2~C 12 -alkenyl, -NHSO2-C3~C 12 -cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3~C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1~C 12 -Alkyl, -S-C2~C 12 -Alkenyl, -S-C2-C 12 -Alkenyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl.

[0305] The term "carrier" as used in this application encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting an agent from one organ or part of the body of a subject to another organ or part of the body.

[0306] The compounds of the present application can form salts that are also within the scope of the present application, and unless otherwise indicated, reference to compounds of the formulae described herein is understood to include reference to salts thereof.

[0307] Representative "pharmaceutically acceptable salts" include, for example, water-soluble salts and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, and isothiocyanate. salts, lactate, lactobionate, laurate, magnesium salts, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salts, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0308] The compounds of the present application (including, for example, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers of the compounds) can exist in unsolvated or solvated forms or in solvated forms with other solvent molecules.

[0309] "Solvate" refers to a solvent adduct containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds or salts have a tendency to form solvates by trapping a fixed molar ratio of solvent molecules in a crystalline solid. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance in which the water maintains its molecular state as HO.

[0310] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the present compounds (including stereoisomers of salts, solvates, esters, and prodrugs of the present compounds, and salts, solvates, and esters of the prodrugs), including, for example, enantiomeric forms (which may exist even in the absence of an asymmetric carbon), rotamer forms, atropisomers, and diastereoisomeric forms, that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of the present application, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl). For example, when a compound of formula (I) contains a double bond or a fused ring, both the cis- and trans-forms, and mixtures thereof, are encompassed within the scope of the present application. Individual stereoisomers of the compounds of the present application may be, for example, substantially free of other isomers, or may be mixed, for example, as a racemate, or mixed with all or selected other stereoisomers. The chiral centers of the present application can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salt," "solvate," "ester," "prodrug," and the like are intended to apply equally to salts, solvates, esters, and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the present invention.

[0311] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural differences may exist in terms of chemical structure (geometric isomers) or ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, or individual enantiomers or diastereomers.

[0312] In this specification, the structural formula of the present compound may in some cases conveniently represent a specific isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, and tautomers.

[0313] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers," or sometimes optical isomers. A mixture containing equal amounts of individual enantiomers of opposite chirality is called a "racemic mixture."

[0314] The compounds of the present application may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present application, and mixtures thereof, including racemic mixtures, are intended to form part of this application. Furthermore, this application encompasses all geometric and positional isomers. For example, if a compound of the present application contains a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are encompassed within the scope of this application. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or any other form with respect to stereochemical configuration. Assay results may reflect data collected for racemic, enantiomerically pure, or any other form with respect to stereochemical configuration.

[0315] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."

[0316] "Chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center may exist as an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the ranking rules of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0317] "Geometric isomers" refers to diastereomers that exist due to restricted rotation about double bonds. These configurations are distinguished in designations by the prefixes cis and trans or Z and E, which indicate that groups are on the same or opposite sides of a double bond in a molecule, according to the Cahn-Ingold-Prelog rules.

[0318] In another embodiment of the present application, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) are enantiomers. In some embodiments, the compounds are (S)-enantiomers. In other embodiments, the compounds are (R)-enantiomers. In still other embodiments, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) can be (+) or (-) enantiomers. The compounds can contain two or more stereocenters.

[0319] In another embodiment of the present application, the compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) are diastereomers. In some embodiments, the compounds are syn diastereomers. In other embodiments, the compounds are anti diastereomers.

[0320] Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral alcohol or a chiral auxiliary such as Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using chiral HPLC columns.

[0321] The compounds of the present application may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present application. Also included within the application are, for example, all keto-enol and imine-enamine forms of the compounds.

[0322] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are easily converted from one isomer to another. This conversion involves the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In solid form, one tautomer usually predominates. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept that tautomers are interconvertible by tautomerization is called tautomerism.

[0323] Of the various possible types of tautomerism, two are commonly observed: keto-enol tautomerism, which involves the simultaneous transfer of an electron and a hydrogen atom; and ring-chain tautomerism, as illustrated by glucose, which occurs when an aldehyde group (-CHO) in a sugar molecule reacts with a hydroxyl group (-OH) in the same molecule, resulting in a cyclic (ring-shaped) form of the molecule.

[0324] Common tautomeric pairs are ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomers, amine-enamine, and enamine-imine in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine).

[0325] The present application relates to compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, that are capable of modulating (e.g., activating or stimulating) the GLP-1 receptor, and are useful for treating diseases and disorders associated with modulation of the GLP-1 receptor. The present application further relates to compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, that are useful for modulating (e.g., activating or stimulating) the GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0326] In some aspects, the present application provides compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) that have advantageous properties, such as increased potency, improved oral bioavailability, or desirable pharmacodynamic / pharmacokinetic profiles, compared to one or more known GLP-1 receptor ligands (e.g., incretins or small molecule GLP-1 receptor agonists).

[0327] The potency of agonists / activators / stimulators is determined by the EC 50 The EC value determined under substantially similar conditions can be used to determine the 50 Compounds with lower EC 50 Compounds with higher values ​​are more potent agonists / activators / stimulators than compounds with higher values.

[0328] Compounds of the present application can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperbenzoic acid (m-CPBA) and / or hydrogen peroxide) to provide other compounds of the present application. Accordingly, all depicted and claimed nitrogen-containing compounds, where valence and structure permit, include the depicted compounds and their N-oxide derivatives (N→O or N + -O- (which may be depicted as N-hydroxy or N-alkoxy). Additionally, in other cases, nitrogens in the compounds of the present application can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine with an oxidizing agent such as m-CPBA. All depicted and claimed nitrogen-containing compounds are also considered to encompass both the depicted compound and its N-hydroxy (i.e., N—OH) and N-alkoxy (i.e., N—OR, where R is substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3- to 14-membered carbocyclic, or 3- to 14-membered heterocyclic) derivatives, where valence and structure permit.

[0329] The term "prodrug," as used in this application, means a compound that is convertible in vivo by metabolic means (eg, hydrolysis) to a disclosed compound.

[0330] Because prodrugs are known to enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturability, etc.), compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can be delivered in prodrug form. Thus, the present application is intended to cover prodrugs of compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, methods of delivering the same, and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo upon administration of the prodrug to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present application having a hydroxyl or amino group attached to any group that cleaves to form a free hydroxyl or free amino group, respectively, upon administration of the prodrug of the present application to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of each formula described herein, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0331] The terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystalline form to predominate.

[0332] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., one atom is replaced with an atom of a different element, or a particular functional group is present, or one functional group is replaced with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but not in structure or origin.

[0333] The present application also encompasses isotopically labeled compounds that are identical to the compounds set forth in each formula set forth herein except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, fluorine, e.g., 3 H, 11 C. 14 C. 2 H, and 18 F is one example.

[0334] Compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, that contain the above isotopes, and / or other isotopes of other atoms, are within the scope of the present application. Isotopically labeled compounds of the present application, e.g., 3 H, 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritium-labeled isotopes, i.e. 3 H, and carbon-14 isotopes, i.e. 14 C is useful because of its ease of preparation and detectability. 11 C and 18 F isotopes are useful in PET (positron emission tomography), which is useful in brain imaging. In addition, deuterium, i.e. 2Substitution with heavier isotopes, such as H, can realize certain therapeutic advantages resulting from increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some situations. Generally, isotopically labeled compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can be prepared by performing the procedures disclosed in the schemes and / or examples set forth herein by substituting a readily available isotopically labeled reagent for an isotopically unlabeled reagent. In one aspect, a compound of the present application (e.g., compounds of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, is not isotopically labeled.

[0335] The terms "administer," "administering," or "administration" as used in this application mean administering a disclosed compound or a pharmaceutically acceptable salt of the disclosed compound, or a composition directly to a subject, or administering to a subject a prodrug, derivative, or analog of the compound or a pharmaceutically acceptable salt of the compound, or a composition that is capable of forming an equivalent amount of the active compound in the subject's body.

[0336] A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0337] An "effective amount" or "therapeutically effective amount" when used with respect to a compound or pharmaceutical composition is an amount effective to treat or prevent a disease in a subject as described herein.

[0338] The term "treating" with respect to a subject means improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0339] The compounds of the present application, or pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers thereof, can also be used to prevent a disease, condition, or disorder. As used herein, "preventing" or "prevent" refers to reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.

[0340] Unless otherwise indicated, the term "disorder" is used in this application to mean, and is used interchangeably with, the terms disease, condition, or illness.

[0341] As used herein, the term "GLP-1 receptor-mediated" disease or disorder refers to any disease or other adverse condition in which the GLP-1 receptor or a variant thereof is known to play a role. Accordingly, another aspect of the present application relates to treating or reducing the severity of one or more diseases in which the GLP-1 receptor or a variant thereof is known to play a role. Specifically, the present application relates to a method of treating or reducing the severity of a disease or condition described herein, comprising administering to a subject in need thereof a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a composition of the present application.

[0342] Methods for preparing the compounds The compounds of the present application can be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes shown below.

[0343] The compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein) can be prepared by methods known in the art of organic synthesis, as described in part by the following synthetic schemes. In the schemes described below, it will be fully understood that protecting groups for sensitive or reactive groups are used as necessary in accordance with general principles or chemical reactions. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage in the compound synthesis using methods that are obvious to those skilled in the art. The selected processes, as well as the reaction conditions and order for their implementation, shall be consistent with the preparation of the compounds of the present application.

[0344] Those skilled in the art will recognize whether a stereocenter exists in the compounds of the present application (e.g., compounds of any formula disclosed herein or any individual compound). Accordingly, the present application includes both possible stereoisomers (unless specified in the synthesis), including not only the racemate but also the individual enantiomers and / or diastereomers. When a compound as a single enantiomer or diastereomer is desired, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0345] The compounds described herein may be made from commercially available starting materials or may be synthesized using known organic, inorganic, and / or enzymatic processes.

[0346] The compounds of the present application can be prepared in several ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present application can be synthesized by using the methods described below, together with synthetic methods known in the art of organic synthetic chemistry, or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. Compounds of the present application (i.e., compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein)) can be synthesized according to the steps outlined in the examples, schemes, procedures, and / or synthetic methods (e.g., Examples) described herein. Starting materials are commercially available or made by known procedures reported in the literature or as exemplified.

[0347] The mixtures of enantiomers, diastereomers, and cis / trans isomers obtained by the above methods can be separated into single components by chiral salt techniques, chromatography using normal-phase, reverse-phase, or chiral columns, depending on the nature of the separation.

[0348] Analytical methods, materials, and instrument configurations Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz on a Bruker or Varian spectrometer. Spectra are reported in ppm (δ), and coupling constants (J) are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Liquid chromatography-mass spectrometry (LC / MS) was collected using a SHIMADZU LCMS-2020EV or an Agilent 1260-6125B LCMS. Purity and low-resolution mass spectral data were measured using an Agilent 1260-6125B LCMS system (equipped with a diode array detector and an Agilent G6125BA mass spectrometer) or a Waters Acquity UPLC system (equipped with a diode array detector and a Waters 3100 mass detector). Purity was characterized by UV wavelengths of 214 nm, 220 nm, 254 nm, and ESI. Column: poroshell 120 EC-C18 2.7 μm 4.6 x 100 mm; flow rate 0.8 mL / min; solvent A (100 / 0.1 water / formic acid), solvent B (100 acetonitrile); gradient: 5% B until 0.3 min, 5 to 95% B from 0.3 to 2 min, 95% B until 4.8 min, 95 to 5% B from 4.8 to 5.4 min, then 5% B until 6.5 min. Alternatively, Column: Acquity UPLC BEH C18 1.7 μm 2.1 × 50 mm; Flow rate 0.5 mL / min; Solvent A (0.1% formic acid / water), Solvent B (acetonitrile); Gradient: 5% B hold 0.2 min, 5 to 95% B from 0.2 to 2.0 min, 95% B hold until 3.1 min, then 5% B at 3.5 min.

[0349] Abbreviations used in the examples below and elsewhere in this specification are as follows: DIEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMSO dimethyl sulfoxide DEAD Diethyl azodicarboxylate EA Ethyl acetate IPA Isopropyl Alcohol IPE Di-Isopropyl Ether MeCN acetonitrile THF tetrahydrofuran m-CPBA 3-chlorobenzenecarboperoxy acid DCM dichloromethane LC / MS Liquid Chromatography Mass Spectrometry MeOH Methanol MS mass spectrometry PE Petroleum Ether NMP N-methylpyrrolidinone NMR nuclear magnetic resonance ppm parts per million TEA Triethylamine

[0350] Biological assays The biological activity of the compounds of the present application can be assessed by methods and assays known in the art. Exemplary methods, such as the GLP1R cAMP assay and the human GLP-1 activity assay, are described in the Examples.

[0351] The compounds of the present application also have favorable pharmacokinetic properties and / or activity profiles against hepatic drug transporters (e.g., OATP1B1, OATP1B3) compared to known small molecule GLP-1 receptor agonists, and these properties can be assessed by methods and assays available in the art, such as those described and / or exemplified herein.

[0352] Methods of Using the Compounds The compounds of the present application are useful for modulating (e.g., activating or stimulating) GLP-1 receptors.Therefore, the compounds of the present application are useful for treating diseases or disorders associated with GLP-1 receptors, including metabolic diseases such as diabetes and obesity, cardiovascular diseases, liver diseases such as NASH, kidney diseases, neurodegenerative diseases, and other diseases or disorders associated with the modulation of GLP-1 receptors.For example, diseases or disorders associated with GLP-1 receptors include, but are not limited to, diabetes (non-insulin-dependent diabetes mellitus (type 2 diabetes) or insulin-dependent diabetes mellitus (type 1 diabetes)), diabetic complications, obesity, impaired glucose tolerance, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, hypertension, coronary heart disease such as myocardial infarction and angina pectoris, congestive heart failure, arrhythmia, cerebral infarction, stroke, liver diseases such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), dementia, Parkinson's disease, and diabetic kidney disease.

[0353] "Diabetes" refers to a condition or disease in which the body is unable to maintain adequate blood glucose levels, resulting in an incomplete metabolism to produce and use glucose, and includes insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes).

[0354] "Dementia" includes, for example, Alzheimer's disease, vascular dementia, and diabetic dementia.

[0355] "Diabetic complications" refer to complications caused by diabetes or hyperglycemia, and include ketoacidosis, infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), microangiopathy (e.g., nephropathy and retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, and autonomic neuropathy), and gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0356] Liver diseases (e.g., GLP-1 receptor-associated liver diseases) include, but are not limited to, NASH, NAFLD, hepatitis, liver fibrosis, cirrhosis, autoimmune liver disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune cholangitis, and alcoholic liver disease.

[0357] Another aspect of the present application relates to a method for treating, preventing, inhibiting, or eliminating a disease or disorder associated with GLP-1 receptor modulation (e.g., activation or stimulation of the GLP-1 receptor). The method includes administering to a subject in need of treatment for a disease or disorder associated with GLP-1 receptor modulation an effective amount of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein). In one embodiment, the GLP-1 receptor-mediated disorder is a disease or disorder described herein. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0358] Another aspect of the present application relates to a method for modulating a GLP-1 receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein). In one embodiment, modulating a GLP-1 receptor is activating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0359] Another aspect of the present application relates to a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for treating a GLP-1 receptor-mediated disease or disorder. In one embodiment, the GLP-1 receptor-mediated disorder is a disease or disorder described herein. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0360] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in a method for treating a GLP-1 receptor-mediated disease or disorder. In one embodiment, the GLP-1 receptor-mediated disorder is a disease or disorder described herein. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0361] Another aspect of the present application relates to a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating a GLP-1 receptor. In one embodiment, modulating a GLP-1 receptor is activating or stimulating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0362] In another aspect, the present application relates to a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, for use in modulating a GLP-1 receptor. In one embodiment, modulating a GLP-1 receptor is activating or stimulating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0363] Another aspect of the present application relates to the use of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a GLP-1 receptor-mediated disease or disorder. In one embodiment, the GLP-1 receptor-mediated disorder is a disease or disorder described herein. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0364] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a GLP-1 receptor-mediated disease or disorder. In one embodiment, the GLP-1 receptor-mediated disorder is a disease or disorder described herein. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0365] Another aspect of the present application relates to the use of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for modulating a GLP-1 receptor. In one embodiment, modulating a GLP-1 receptor is activating or stimulating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0366] In another aspect, the present application relates to the use of a pharmaceutical composition of a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for modulating a GLP-1 receptor. In one embodiment, modulating a GLP-1 receptor is activating or stimulating a GLP-1 receptor. In some embodiments, the GLP-1 receptor is a wild-type GLP-1 receptor. In other embodiments, the GLP-1 receptor is a mutant GLP-1 receptor.

[0367] The disclosed compounds of the present application can be administered in an amount effective to treat or prevent a disorder and / or prevent its progression in a subject.

[0368] The compounds of the present application can be administered in therapeutically effective amounts in combination therapy (pharmaceutical combination) with one or more therapeutic agents, or in combination therapy with one or more therapeutic modalities, such as non-drug therapies. For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory, or anti-inflammatory substances. In some embodiments, the compounds of the present application (e.g., compounds of any formula disclosed herein or any individual compound) are administered in combination with an additional therapeutic agent selected from anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, agents for treating cardiovascular disease, agents for treating liver disease, agents for treating lung disease, agents for treating kidney disease, agents for treating eye disease, agents for treating skin disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, and agents for treating immunodeficiency disorders. When the compounds of the present application are administered in combination with other therapeutic agents, the dosage of the co-administered compound will naturally vary depending on the type of co-administered agent used, the specific drug used, the condition being treated, etc.

[0369] Combination therapy includes administering the present compound in further combination with other biologically active ingredients (such as, but not limited to, anti-inflammatory agents, immunomodulatory agents, chemotherapeutic agents, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, agents for treating immunodeficiency disorders, and agents for treating pain) and non-drug therapies (such as, but not limited to, surgery or radiation treatment). For example, the compounds of the present application can be used in combination with other pharmaceutically effective compounds, preferably in combination with compounds that can improve the effects of the compounds of the present application. The compounds of the present application can be administered simultaneously (in a single formulation or in separate formulations) or sequentially with other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during one treatment cycle or course of treatment.

[0370] Pharmaceutical Compositions The present application also provides pharmaceutical compositions comprising a compound of the present application (e.g., a compound of any formula or any individual compound disclosed herein), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, in combination with at least one pharmaceutically acceptable excipient or carrier.

[0371] A "pharmaceutical composition" refers to a formulation comprising a compound of the present application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof) in a unit dosage form of the composition is an effective amount and will vary depending on the specific treatment involved. Those skilled in the art will recognize that it is sometimes necessary to make routine modifications to the dosage depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, intrapulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0372] As used herein, the phrase "pharmaceutically acceptable" means compounds, ingredients, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0373] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and more than one such excipient.

[0374] The pharmaceutical compositions of the present application are formulated to be compatible with the intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate, and an agent for adjusting osmolality such as sodium chloride or glucose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials.

[0375] The compound or pharmaceutical composition of the present application can be administered to the subject by many well-known methods currently used for chemotherapy treatment.The dose selected should be sufficient to constitute effective treatment, but not so high as to cause unacceptable side effects.It should be preferable to carefully monitor the state of disease state and the health of the patient during treatment and for a considerable period after treatment.

[0376] As used herein, "therapeutically effective amount" refers to the amount of a drug that treats, alleviates, or prevents a identified disease or condition, or that exhibits a detectable therapeutic or regulatory effect. The effect can be detected by any assay known in the art. The exact effective amount for a subject depends on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation, which is within the skill and judgment of the clinician. In one aspect, the disease or disorder is a disease or disorder described herein.

[0377] For any compound, the therapeutically effective amount can be estimated first in cell culture assays, such as neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.Animal models can also be used to determine the appropriate concentration range and administration route.This information can then be used to determine the useful dose and administration route in humans.Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED 50 (therapeutic effective dose in 50% of the population) and LD 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0378] Dosage and administration are adjusted to provide a sufficient level of the active agent or to maintain the desired effect.Factors that can be taken into consideration include the severity of the disease state, the subject's overall health, the subject's age, weight, and sex, diet, administration time and frequency, drug combinations, reaction sensitivity, and tolerance / response to treatment.Long-acting pharmaceutical compositions can be administered every 3-4 days, once a week, or once every 2 weeks, depending on the half-life and clearance rate of the specific formulation.

[0379] Pharmaceutical compositions comprising the active compounds of the present application (i.e., compounds of the present application (e.g., compounds of any formula or any individual compound disclosed herein)) can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions can be formulated in a conventional manner using pharmaceutically acceptable carriers containing one or more excipients and / or auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. Of course, appropriate formulation will depend upon the chosen route of administration.

[0380] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as aluminum monostearate and gelatin.

[0381] Sterile injectable solution can be prepared by incorporating the required amount of active compound in suitable solvent with one or combination of the components listed above as needed, and then sterilize by filtration.Generally, dispersion is prepared by incorporating active compound into the sterile medium that contains basic dispersion medium and other components listed above as necessary.For the sterile powder that is used to prepare sterile injectable solution, preparation method includes vacuum drying and freeze-drying, which obtains the powder of active compound and any other required components from the solution that has already been sterilized and filtered.

[0382] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions used as mouthwashes may also be prepared using fluid carriers. In mouthwashes, the compound in the fluid carrier is orally applied, swished, and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavoring.

[0383] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0384] Systemic administration can be via transmucosal or transdermal means.For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.These penetrants are generally known in the art, and for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives are included.Transmucosal administration can be achieved through the use of nasal sprays or suppositories.For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams that are generally known in the art.

[0385] The active compounds can be prepared as controlled-release formulations, including implants and microencapsulated delivery systems, with pharmaceutically acceptable carriers that protect the compounds against rapid elimination from the body. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing these formulations will be apparent to those skilled in the art. Materials may be commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (containing liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0386] It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form because of the ease of administration and uniformity of dosage.As used herein, unit dosage form refers to a physically discrete unit suitable as a unit dosage form for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect and a required pharmaceutical carrier combination.The specifications of unit dosage form in this application are determined and directly depend on the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0387] For therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present application will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors influencing the selected dosage. Dosages may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of an agent is an amount that provides an objectively identifiable improvement noted by a clinician or other qualified observer. As used herein, the term "dosage effective manner" refers to an amount of an effective compound that produces a desired biological effect in a subject or cell.

[0388] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0389] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present application in which the parent compound has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, these common non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, Included are, but are not limited to, salts derived from inorganic and organic acids selected from maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0390] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, etc. The present application also encompasses salts formed when an acidic proton present in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or is coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0391] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt as defined herein.

[0392] The compounds of the present application can also be prepared as esters, such as pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, such as a methyl ester, ethyl ester, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, such as an acetate ester, propionate ester, or other ester.

[0393] The compounds of the present application can also be prepared as prodrugs, e.g., pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein to refer to any compound that releases an active parent drug in vivo. Because prodrugs are known to enhance many desirable properties of drugs (e.g., solubility, bioavailability, manufacturability, etc.), the compounds of the present application can be delivered in prodrug form. Accordingly, the present application is intended to cover prodrugs of the compounds claimed herein, methods of delivering the same, and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo upon administration of the prodrug to a subject. Prodrugs in the present application are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present application having a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group bonded to any group that can be cleaved in vivo to form a free hydroxyl, amino, sulfhydryl, carboxy, or carbonyl group, respectively.

[0394] Examples of prodrugs include, but are not limited to, esters (e.g., acetate, dialkylaminoacetate, formate, phosphate, sulfate, and benzoate derivatives) and carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds of the present application, esters (e.g., ethyl ester, morpholinoethanol ester) of carboxyl functional groups, N-acyl derivatives (e.g., N-acetyl) of amino functional groups, N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups, etc. See Bundegaard, H., Design of Prodrugs, p. 1-92, Elsevier, New York-Oxford (1985).

[0395] The compound or its pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative can be administered orally, intranasally, transdermally, intrapulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.In one embodiment, the compound or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer or tautomer can be administered orally.Those skilled in the art will recognize the advantages of certain administration routes.

[0396] The dosage regimen utilizing the present compounds is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound used, or its pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer. A physician or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, combat, or stop the progression of the condition.

[0397] Techniques for formulating and administering the compounds disclosed in this application are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or inert diluents, and sterile aqueous or organic solutions. The compound, or its pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or tautomers, are present in the pharmaceutical composition in an amount sufficient to provide the desired dosage in the range described herein.

[0398] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present application will become apparent from the different examples. The examples provided illustrate different components and methodologies useful in carrying out the present application. The examples do not limit the claimed application. Those skilled in the art can identify and use other components and methodologies useful for carrying out the present application based on the present application. [Example]

[0399] The present application is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the spirit or scope of the present application to the specific procedures described therein. It should be understood that the examples are presented to illustrate particular embodiments and are not intended to limit the scope of the present application. Furthermore, it should be understood that various other embodiments, modifications, and equivalents of the present application are available and may occur to those skilled in the art without departing from the spirit of the present application and / or the scope of the appended claims.

[0400] Example 1 Synthesis of intermediate 1 TIFF2026035735000419.tif18140

[0401] Process 1: 1-B To a solution of 1-A (20.0 g, 0.16 mol) in MeCN (500 mL) was added NBS (31.3 g, 0.176 mol) in several portions at 10 °C. The resulting mixture was warmed to 25 °C and stirred for 30 min. After cooling to 10 °C, saturated aqueous NaSO (500 mL) was slowly added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was washed with petroleum ether to give 1-B (19.2 g, 58.88% yield). MS: m / z = 204 (M + 1).

[0402] Process 2: 1-C To a solution of 1-B (19.2 g, 89.3 mmol) in AcOH (600 mL) was added NaNO (7.39 g, 107 mmol) at 10 °C. The mixture was stirred at 25 °C for 4 h. After cooling to 10 °C, aqueous NaOH (50% w / w) was slowly added to the reaction mixture until the pH reached 7–8. The aqueous layer was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with water (100 mL x 3) and brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (9% dichloromethane in ethyl acetate) to give 1-C (9.2 g, 45.47% yield). MS: m / z = 215 (M + 1).

[0403] Step 3: Intermediate 1 To a solution of 1-C (9.2 g, 42.0 mmol) in DMF (50 mL) was added t-BuOK (4.7 g, 42.0 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 40 min. CHCl (3.1 mL, 50.3 mmol) was added dropwise at 0 °C. After stirring at 25 °C for 18 h, the reaction mixture was quenched with saturated aqueous NHCl (200 mL), and the aqueous layer was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated aqueous NHCl (100 mL × 3), water (100 mL × 3), and brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (25% petroleum ether in ethyl acetate) to give intermediate 1 (5.5 g, 56.12% yield). TIFF2026035735000420.tif12149

[0404] Example 2 Synthesis of intermediate 2 TIFF2026035735000421.tif46142

[0405] Process 1: 2-B To a stirred mixture of 2-A (28.23 g, 0.375 mol) in ethyl acetate (200 mL) was added dropwise a solution of (Boc)O (86.13 g, 0.395 mol) in ethyl acetate (200 mL) at 0 °C over 30 min. A solution of TMEDA (59.6 mL, 0.395 mol) in ethyl acetate (50 mL) was then added dropwise at 0 °C. MsCl (30.6 mL, 0.395 mol) was then added dropwise over 46 min at 0 °C. The reaction mixture was stirred at 0 °C for 3.2 h. After filtration, the filtrate was concentrated to approximately half its volume, poured into hexane (800 mL), and stirred at 0 °C for 2 h. 2-B (79.6 g, 83.9% yield) was obtained after filtration. TIFF2026035735000422.tif12133

[0406] Process 2: 2-C To a stirred mixture of sodium cyanide (47.2 g, 0.407 mol) in DMF (500 mL), TBAB (10.2 g, 31.3 mmol) was added and stirred at 35 °C for 2 h. 2-B (79.6 g, 0.313 mol) was then added and stirred for an additional 48 h. Water (500 mL) was added, and the aqueous layer was extracted with ethyl acetate (1000 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to give 2-C (43 g, 74% yield). TIFF2026035735000423.tif19156

[0407] Process 3: 2-D To a mixture of 2-C (43 g, 0.232 mol) in THF (500 mL) was added methanesulfonic acid (37.6 mL, 0.580 mol) at 0 °C and stirred for 20 min. The reaction mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was then cooled to 25 °C and filtered. The cake was dissolved in DCM (200 mL), and the mixture was adjusted to pH 13 with aqueous sodium carbonate and NaOH (6 M). After separation, the aqueous layer was extracted with DCM (300 mL × 3), and the combined organic layers were dried over sodium sulfate and concentrated to give 2-D (10.1 g, 51% yield). TIFF2026035735000424.tif12128

[0408] Step 4: 2-E To a solution of 2-D (10.1 g, 120.2 mmol) in ethanol (60 mL) were added ethyl acrylate (14.4 g, 144.2 mmol) and EtN (20 mL, 144.2 mmol). The reaction solution was heated at 70 °C for 3 h. After cooling to 25 °C, N-methylpiperazine (4 mL, 36.1 mmol) and (Boc)O (33.1 mL, 144.2 mmol) were added and the mixture was stirred at 25 °C for 14 h. Water (100 mL) was added, and the aqueous layer was extracted with toluene (100 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated to give 2-E (34.1 g, crude product). MS: m / z = 285 (M + 1).

[0409] Step 5: Intermediate 2 To a mixture of 2-E (34.1 g) in THF (500 mL) was added t-BuOK (13.5 g, 120.2 mmol) at 25 °C and stirred for 2 hours. 2N HCl (90 mL) was added and stirred for 30 minutes. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel column (PE / EA = 20 / 1) to give intermediate 2 (9.2 g, 32% yield). TIFF2026035735000425.tif12165

[0410] Example 3 Synthesis of intermediate 3 TIFF2026035735000426.tif61143

[0411] Process 1: 3-B To a solution of 3-A (2 g, 9.85 mmol) in THF (20 mL) was added n-BuLi (2.5 M, 3.94 mL, 9.85 mmol) at −78 °C. The reaction mixture was stirred at −70 °C for 1 h. Di-tert-butyl-diazene-1,2-dicarboxylate (2.27 g, 9.85 mmol) was added, and the reaction mixture was stirred at −40 °C for 30 min and then warmed to 25 °C for an additional 2 h. Aqueous NH4Cl solution (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over sodium sulfate, concentrated, and purified on a silica gel column (PE / EA = 10 / 1) to give 3-B (2.58 g, 74% yield). TIFF2026035735000427.tif12128

[0412] Process 2: 3-C To a solution of 3-B (2.58 g, 7.29 mmol) in NMP (20 mL) was added methanesulfonic acid (1.40 g, 14.58 mmol). The reaction mixture was heated to 80 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was poured into toluene (20 mL) and the pH was adjusted to approximately 9 with aqueous KCO solution. The organic layer was collected and dried over sodium sulfate. Intermediate 2 (1.73 g, 7.29 mmol) and pyridine hydrochloride (84.3 mg, 0.73 mmol) were then added to the organic layer, and the resulting mixture was heated at 90 °C for 1 h. The reaction mixture was poured into water (40 mL), the pH was adjusted to approximately 9 with aqueous NaOH solution, and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give a residue, which was purified on a silica gel column (PE / EA = 4 / 1) to give 3-C (1.80 g, 66% yield). MS: m / z = 375 (M + 1).

[0413] Process 3: 3-D To a solution of N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (1.29 g, 6.47 mmol) and 3-C (2.2 g, 5.88 mmol) in DMA (30 mL) was added t-BuOK (1.98 g, 17.65 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL x 3), dried over sodium sulfate, and concentrated to give a residue, which was purified on a silica gel column (DCM / EA = 3 / 1) to give 3-D (1.34 g, 45% yield). MS: m / z = 506 (M + 1).

[0414] Step 4: 3-E To a solution of 3-D (1.29 g, 2.55 mmol) in THF (20 mL) was added methanesulfonic acid (196 mg, 2.04 mmol). The reaction mixture was stirred at 60 °C for 2 h. Then, the reaction mixture was cooled, and the pH was adjusted to approximately 9 with aqueous KPO. To the reaction mixture was added BocO (222.7 mg, 1.02 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then poured into water (40 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine (20 mL × 3), dried over sodium sulfate, and concentrated to give a residue, which was purified on a silica gel column to give 3-E (729 mg, 65% yield). MS: m / z = 442 (M + 1).

[0415] Process 5: 3-F To a solution of 3-E (700 mg, 1.59 mmol), Intermediate 1 (727 mg, 3.17 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (112.7 mg, 0.79 mmol), and K2CO3 (657 mg, 4.76 mmol) in NMP (15 mL) was added CuI (60.5 mg, 0.32 mmol). The reaction mixture was stirred at 130 °C under argon for 3 h. After cooling to room temperature, the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine (20 mL x 3), dried over sodium sulfate, concentrated, and purified on a silica gel column to give 3-F (774 mg, 82.6% yield). MS: m / z = 590 (M + 1).

[0416] Step 6: Intermediate 3 To a solution of 3-F (400 mg, 678.39 μmol) in DCM (3 mL) was added HCl / dioxane (4 M, 3 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. Excess solvent was removed under reduced pressure to give crude product Intermediate 3 (396 mg, HCl salt). MS: m / z = 490 (M + 1).

[0417] Example 4 Synthesis of intermediates 4-7 Intermediates 4-7 in Table 1 were prepared according to the procedure for Intermediate 3.

[0418] (Table 1) TIFF2026035735000428.tif161144

[0419] Example 5 Synthesis of intermediate 8 TIFF2026035735000429.tif104151

[0420] Process 1: 8-B To a solution of 8-A (10 g, 104.07 mmol) in methanol (60 mL) was added 2-aminoethanol (7.63 g, 124.89 mmol) and stirred for 1 h. Sodium borohydride (4.72 g, 124.89 mmol) was then added slowly at 0 °C. The resulting mixture was stirred for an additional 1 h and then poured into water (100 mL), to which benzyl chloroformate (21.29 g, 124.80 mmol) was added dropwise. The resulting mixture was stirred for an additional 2 h. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and concentrated to give a residue. The residue was purified by flash chromatography (DCM / MeOH = 10 / 1) to give 8-B (16 g, 55.88% yield). TIFF2026035735000430.tif18161

[0421] Step 2: 8-C A solution of 8-B (15 g, 54.49 mmol) and triphenylphosphine (42.87 g, 163.46 mmol) in THF (200 mL) was added dropwise to a solution of di-tert-butyl azodicarboxylate (25.52 g, 110.8 mmol) in THF (200 mL) at 0 °C. The resulting mixture was stirred for 16 h. The mixture was concentrated, and the residue was redissolved in DCM (50 mL) and TFA (30 mL). After stirring for 0.5 h, the mixture was concentrated, redissolved in DCM (100 mL), and basified to pH 7-8 with saturated NaHCO3. After separation, the organic layer was washed with brine (50 mL) and concentrated to give the crude product. The crude product was dissolved in DCM (30 mL), and petroleum ether was added until a white precipitate formed. The mixture was filtered, and the filtrate was concentrated and purified by flash chromatography (PE / EA = 1 / 1) to give 8-C (10 g, 38.87 mmol, 71.33% yield). TIFF2026035735000431.tif19154

[0422] Process 3: 8-D To a solution of 8-C (6 g, 23.32 mmol) in MeCN (150 mL) was added dropwise a solution of NIS (7.87 g, 34.98 mmol) in MeCN (150 mL) at 0 °C. The mixture was stirred for 16 h, then poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated NaSO solution (100 mL), brine (100 mL), and concentrated to give 8-D (8.2 g, 91.76% yield). MS: m / z = 383.6 (M + 1).

[0423] Step 4: 8-E A mixture of 8-D (8 g, 20.88 mmol), diphenylmethanimine (7.57 g, 41.76 mmol), potassium tert-butoxide (7.03 g, 62.63 mmol), Pd(dba) (1.91 g, 2.09 mmol), and Xantphos (2.42 g, 4.18 mmol) in toluene (100 mL) was stirred and refluxed for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (DCM / MeOH = 15 / 1) to give 1,1-diphenyl-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)methanimine (3.3 g). This intermediate was dissolved in DCM (100 mL), TEA (3.3 g, 32.7 mmol) was added, followed by the dropwise addition of benzyl chloroformate (2 g, 11.7 mmol). After stirring for 1 h, the mixture was washed with brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography (PE / EA = 1 / 1) to give 8-E (3.9 g, 42.79% yield). MS: m / z = 436.7 (M +1).

[0424] Process 5: 8-F A mixture of 8-E (2.16 g, 4.95 mmol), 1-bromo-4-fluorobenzene (1.73 g, 9.90 mmol), Pd(OAc) (333.29 mg, 1.48 mmol), 1,10-phenanthroline (891.73 mg, 4.95 mmol), and CsCO (4.84 g, 14.85 mmol) in toluene (50 mL) was stirred at 140 °C for 12 h. The reaction mixture was concentrated to give the crude product, which was purified by flash chromatography (PE / EA = 1 / 1) to give 8-F (280 mg, 10.66% yield). MS: m / z = 558.7 (M + 1).

[0425] Step 6: 8-G To a solution of 8-F (160 mg, 301.55 μmol) in ethyl acetate (2 mL) was added HCl / dioxane (4 M, 2 mL). The reaction mixture was stirred for 1 h. The mixture was diluted with ethyl acetate (10 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (PE / EA = 1 / 1) to give 8-G (110 mg, 99.56% yield). MS: m / z = 367.2 (M + 1).

[0426] Step 7: 8-H To a solution of triphosgene (90 mg, 300.23 μmol) in THF (10 mL) was added a solution of 8-G (110 mg, 300.23 μmol) in THF (5 mL) at 0°C, followed by a solution of TEA (152 mg, 1.50 mmol) in THF (5 mL). The reaction mixture was stirred for 1 h. Next, a solution of 2,2-dimethoxyethanamine (158 mg, 1.50 mmol) in THF (5 mL) was added at 0°C. The reaction mixture was stirred for another 1 h. The mixture was diluted with brine (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried and concentrated to give 8-H (140 mg, 93.73% yield). MS: m / z = 497.7 (M + 1).

[0427] Step 8: 8-I To a solution of 8-H (140 mg, 281.40 μmol) in DCM (2 mL) was added HCl / dioxane (4 M, 1 mL). The resulting mixture was stirred for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (10 mL) and DCM (10 mL). The organic layer was dried over sodium sulfate and concentrated to give the crude product, which was purified by preparative TLC (PE / EA = 1 / 2) to give 8-I (105 mg, 86.09% yield). MS: m / z = 434.2 (M + 1).

[0428] Step 9: 8-J A mixture of 8-I (105 mg, 242.25 μmol), Intermediate 1 (83 mg, 363.38 μmol), (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (34 mg, 242.25 μmol), CuI (46 mg, 242.25 μmol), and KCO (100 mg, 726.75 μmol) in dioxane (5 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by flash chromatography (PE / EA = 1 / 1) to give 8-J (55 mg, 39.04% yield). MS: m / z = 582.1 (M + 1).

[0429] Step 10: Intermediate 8 To a solution of 8-J (55 mg, 94.57 μmol) in DCM (2 mL) was added a solution of boron trichloride in DCM (2 mL, 1 M) at 0 °C, and the resulting mixture was stirred for 2 h. The reaction was quenched with MeOH (2 mL) and diluted with saturated aqueous NaHCO3 (20 mL) and DCM (10 mL). After separation, the organic layer was washed with brine, dried over sodium sulfate, and concentrated to give intermediate 8 (45 mg, crude). MS: m / z = 448.2 (M + 1).

[0430] Example 6a Synthesis of intermediate 9 A mixture of TIFF2026035735000433.tif301289-A (7.83 g, 58.38 mmol), tert-butyl N-aminocarbamate (7.72 g, 58.38 mmol), and hexane (100 mL) was stirred at reflux for 1 h. The white solid was filtered and washed with hexane. 1 M borane in THF (58.35 mL) was added to the solid to give a clear mixture, which was stirred at room temperature until hydrogen evolution ceased. 6 M HCl (58.35 mL) was added, and the mixture was heated to reflux for 45 min. The mixture was concentrated under reduced pressure and washed with THF to give Intermediate 9 (9.36 g, 99% yield, HCl salt). TIFF2026035735000434.tif12149

[0431] Example 6b Synthesis of intermediate 10 TIFF2026035735000435.tif21138

[0432] Process 1: 10-B To a stirred, cooled mixture (-50 °C) of 10-A (20 g, 67.38 mmol) in pentane (15 mL) and diethyl ether (3 mL) in a 500 mL three-neck RBF (fitted with a nitrogen line, thermometer, and addition funnel) was slowly added an ethereal solution of methyllithium-lithium bromide complex (1 M, 161.72 mL). After the addition was complete, the mixture was allowed to warm to 0 °C. After 2 h, the addition funnel was replaced with a distillation head fitted with a 200 mL RBF in a -78 °C bath. Vacuum was slowly applied to the system, and the distillate was collected. A diethyl ether solution of 10-B (130 mL, approximately 0.3 M) was obtained, which was used in the next step without further purification. TIFF2026035735000436.tif5128

[0433] Step 2: 10-C Under a nitrogen atmosphere, Mn(dpm)3 (435.41 mg, 720.0 μmol) was dissolved in isopropanol (200 mL) and cooled to 0 °C. A solution of phenylsilane (3.90 g, 36.0 mmol) and tert-butyl (NE)-N-tert-butoxycarbonyliminocarbamate (12.43 g, 54.0 mmol) in DCM (200 mL) was added, followed by a solution of 10-B (0.3 M, 120 mL) in ether / pentane. The resulting mixture was stirred at 0 °C for 21 h. The reaction was quenched by the addition of water (200 mL) and brine (500 mL). The mixture was stirred for 5 min and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a residue which was purified by silica gel column (PE / EA = 10 / 1) to give 10-C (8.3 g, yield 77.27%). TIFF2026035735000437.tif5146

[0434] Step 3: Intermediate 10 To a solution of 10-C (8.3 g, 27.82 mmol) in DCM (20 mL) was added HCl / dioxane (4 M, 69.54 mL) at 25° C. The reaction was stirred at 25° C. for 16 h. After filtration, the solid was collected and dried to give intermediate 10 (3.3 g, 69.35% yield, HCl salt).

[0435] Example 7 Synthesis of intermediate 11 TIFF2026035735000438.tif65142

[0436] Process 1: 11-A To a solution of intermediate 2 (1.2 g, 5.04 mmol) in ethanol (11 mL) was added intermediate 9 (1.12 g, 5.04 mmol) and HCl (2 M, 4 mL) at 25 °C. The resulting mixture was warmed to 50 °C and stirred for 1 h. The mixture was quenched with saturated aqueous KCO and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by combi-flash eluting with DCM / MeOH = 20 / 1 to give 11-A (0.998 g, 53% yield). MS: m / z = 371.0 (M + 1).

[0437] Process 2: 11-B To a solution of triphosgene (480 mg, 1.62 mmol) in THF (66 mL) were added 11-A (600 mg, 1.62 mmol) and triethylamine (819 mg, 8.1 mmol). The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was then cooled to 0 °C, and 2,2-dimethoxyethanamine (851 mg, 8.1 mmol) was added. The mixture was warmed to room temperature and stirred for an additional 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 11-B (1.46 g, crude). MS: m / z = 501.8 (M + 1).

[0438] Step 3: 11-C To a solution of 11-B (1.36 g) in DCM (14 mL) was added HCl in dioxane (4 M, 7.46 mL). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was then adjusted to pH 10 with aqueous NaOH. BocO (710 mg, 3.25 mmol) was added, and the reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (15 mL × 3). The organic layer was washed with brine (15 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified on a silica gel column (DCM / methanol = 20 / 1) to give 11-C (378 mg, 31% yield). MS: m / z = 437.8 (M + 1).

[0439] Step 4: 11-D To a solution of Intermediate 1 (275.37 mg, 1.20 mmol), 11-C (338 mg, 1.0 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (342.02 mg, 2.40 mmol), and CuI (228.97 mg, 1.20 mmol) in dioxane (17 mL) was added K2CO3 (332.33 mg, 2.40 mmol). The reaction mixture was stirred at 100 °C under argon for 16 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by combi-flash (eluting with DCM / methanol = 20 / 1) to give 11-D (309 mg, 52% yield). MS: m / z = 585.7 (M + 1).

[0440] Step 5: Intermediate 11 A mixture of 11-D (309 mg, 0.527 mmol) and HCl in dioxane (4 M, 10.55 mL) was stirred for 0.5 h. The solvent was removed under reduced pressure to give intermediate 11 (250 mg, 97% yield). MS: m / z = 485.8 (M + 1).

[0441] Example 8 Synthesis of intermediates 12-16 Intermediates 12-16 in Table 2 were prepared according to the procedure for Intermediate 11.

[0442] (Table 2) TIFF2026035735000439.tif212143

[0443] Example 9 Synthesis of intermediate 17 TIFF2026035735000440.tif107148

[0444] Process 1: 17-B To a solution of 17-A (10 g, 72.39 mmol) in isopropyl alcohol (80 mL) was added tert-butyl N-aminocarbamate (9.57 g, 72.39 mmol) at 25 °C. The resulting mixture was heated to 90 °C for 2 h. Petroleum ether (160 mL) was added to the reaction mixture at 25 °C, and the resulting mixture was stirred for 10 min, filtered, and the residue was washed with petroleum ether (40 mL x 2) and dried to give 17-B (12 g, 65% yield). MS: m / z = 197.2 (M + 1 - 56).

[0445] Step 2: 17-C Palladium (843 mg, 7.93 mmol) was added to a solution of 17-B (10 g, 39.64 mmol) in methanol (150 mL) under a hydrogen atmosphere at 25°C. The resulting mixture was stirred at 25°C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give 17-C (9 g, 89% yield). MS: m / z = 277.2 (M + 23).

[0446] Process 3: 17-D To a solution of 17-C (1 g, 3.93 mmol) in DCM (15 mL) was added HCl / dioxane (4 M, 2 mL) at 25 °C, and the mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure to give 17-D (0.72 g, 95% yield, HCl salt). MS: m / z = 155 (M + 1).

[0447] Step 4: 17-E To a mixture of 17-D (1.1 g, 7.13 mmol, HCl salt) in ethanol (50 mL) was added N-ethyl-N-isopropyl-propan-2-amine (1.38 g, 10.70 mmol) at 25 °C. After stirring for 3 minutes, Intermediate 2 (1.70 g, 7.13 mmol) was added to the mixture. The resulting mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated and purified by flash (30% ethyl acetate in petroleum ether) to give 17-E (1.5 g, 56% yield). MS: m / z = 375.3 (M + 1).

[0448] Process 5: 17-F To a solution of 17-E (450 mg, 1.20 mmol) and DIEA (465 mg, 3.61 mmol) in THF (5 mL), phenyl carbonochloridate (376 mg, 2.40 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give 17-F (590 mg, crude product). MS: m / z = 495, (M + 1).

[0449] Step 6: 17-G The crude product 17-F (590 mg, 1.2 mmol) was dissolved in 5 mL of pyridine, and 2,2-dimethoxyethanamine (379 mg, 3.61 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to give 17-G (3 g, crude product). MS: m / z = 506 (M + 1).

[0450] Step 7: 17-H A solution of crude product 17-G (3 g) in THF (5 mL) was treated with methanesulfonic acid (569 mg, 5.93 mmol). The solution was stirred at 60 °C for 2 h. After adjusting the pH to approximately 9 with aqueous KPO, BocO (388 mg, 1.78 mmol) was added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over sodium sulfate and concentrated to give a residue. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give 17-H (300 mg, 56.5% yield over three steps). MS: m / z = 442.1, (M + 1).

[0451] Step 8: 17-I To a solution of 17-H (300 mg, 679.5 μmol) and intermediate 1 in NMP (2 mL) was added N1,N2-dimethylcyclohexane-1,2-diamine (82 mg, 579.84 μmol), CuI (69 mg, 362.4 μmol), and K2CO3 (300 mg, 2.17 mmol), and the reaction mixture was heated at 130 °C for 3 h. The reaction mixture was diluted with 10 mL of ethyl acetate and washed with brine (10 mL x 5). The organic layer was dried, concentrated, and purified by column chromatography (PE / EA = 5 / 3) to give 17-I (320 mg, 75.9% yield). MS: m / z = 590.2, (M + 1).

[0452] Step 9: Intermediate 17 To a solution of 17-I (320 mg, 542.71 μmol) in DCM (4 mL) was added TFA (6.19 g, 54.27 mmol, 4.2 mL), and the reaction was stirred at 25 °C for 16 h. The solvent was removed, and the residue was treated with 5 mL of toluene and concentrated. This process was repeated three times to give intermediate 17 (250 mg, 89% yield, TFA salt). MS: m / z = 490.1 (M + 1).

[0453] Example 10 Synthesis of intermediate 18 TIFF2026035735000441.tif53128

[0454] Process 1: 18-B To a solution of 18-A (6 g, 28.27 mmol) in toluene (50 mL) was added benzyl alcohol (3.06 g, 28.27 mmol, 2.91 mL), DPPA (10.31 g, 42.41 mmol), and triethylamine (7.15 g, 70.68 mmol). The mixture was stirred at 90 °C for 20 h. The mixture was diluted with ethyl acetate (200 mL) and washed with aqueous NaHCO3 (100 mL x 2). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by chromatography (PE / EA = 2 / 1) to give 18-B (5.8 g, 58.18% yield). MS: m / z = 317.8 (M + 1).

[0455] Process 2: 18-C To a solution of 18-B (5 g, 15.75 mmol) in THF (50 mL) was added sodium borohydride (5.96 g, 157.54 mmol). The resulting mixture was stirred for 18 h, quenched with 100 mL of 1 M HCl, extracted with ethyl acetate (200 mL x 3), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to give 18-C (5.3 g, crude product). MS: m / z = 289.9 (M + 1).

[0456] Process 3: 18-D To a mixture of 18-C (1.5 g, 5.19 mmol), silver trifluoromethanesulfonate (2 g, 7.78 mmol), and DCM (22.5 mL) was added MeI (1.1 g, 7.78 mmol) dropwise at 0 °C. The reaction mixture was stirred for 3 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by combi-flash (PE / EA = 2 / 1) to give 18-D (323 mg, 20% yield). TIFF2026035735000442.tif19157

[0457] Step 4: Intermediate 18 A mixture of 18-D (323 mg, 1.06 mmol), Pd / C (40 mg), and methanol (10 mL) was stirred under H for 18 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 18 (190 mg, crude). MS: m / z = 170.2 (M + 1).

[0458] Example 11 Synthesis of intermediate 19 TIFF2026035735000443.tif89159

[0459] Process 1: 19-B To a solution of 19-A (5 g, 24.39 mmol), DEAD (5.10 g, 29.27 mmol), and tert-butyl N-(2-aminoethyl)carbamate (4.69 g, 29.27 mmol) in THF (50 mL) was added Ph3P (7.68 g, 29.27 mmol) over 0.5 h at 0 °C. The mixture was then stirred for 4 h, followed by the addition of MeOH (50 mL), water (12 mL), and NaOH (1.95 g, 48.78 mmol), which was then further stirred for 1 h. The mixture was concentrated, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The aqueous phase was acidified to pH 3 (1 M HCl), extracted with ethyl acetate (50 mL x 3), dried over sodium sulfate, filtered, and concentrated to give 19-B (8.1 g, 24.24 mmol, 99.4% yield).

[0460] Step 2: 19-C To a mixture of 19-B (8.1 g, 24.24 mmol), N-methoxymethanamine (1.48 g, 15.18 mmol, HCl salt) in DCM (100 mL) was added TEA (7.36 g, 72.72 mmol, 10.14 mL) and HATU (9.22 g, 24.24 mmol) at 30 °C. The reaction solution was stirred at 30 °C for 2 h. Ethyl acetate (100 mL) was then added, and the mixture was washed with HO (100 mL x 3), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 5 / 1 to 1 / 1) to give 19-C (7.7 g, 20.41 mmol, 84.21% yield).

[0461] Process 3: 19-D To a solution of 19-C (7 g, 18.56 mmol) in THF (50 mL) was added MeMgBr (1 M, 92.78 mL) at 0 °C. The mixture was then stirred at 25 °C for 2 h. The mixture was concentrated and purified by column chromatography (EA / PE = 1 / 10 to 1 / 1) to give 19-D (6 g, 18.06 mmol, 97.34% yield). MS: m / z = 232.0 (M + 1-100).

[0462] Step 4: 19-E To a mixture of 19-D (6 g, 18.06 mmol) in methanol (5 mL), HCl / dioxane (4 M, 40 mL) was added at 0 °C and stirred for 1 h. The reaction mixture was concentrated to give a white solid. DCM (40 mL) and TEA (18.28 g, 180.62 mmol, 25.17 mL) were then added, followed by NaBHCN (4.54 g, 72.25 mmol) at 0 °C and stirred for 2 h. The solution was concentrated and purified by silica gel chromatography (DCM / MeOH = 50 / 1 to 10 / 1, v / v) to give 19-E (3.1 g, 14.35 mmol, 79.43% yield).

[0463] Step 5: 19-F To a mixture of 19-E (3.1 g, 14.35 mmol) in HSO (40 mL) was added KNO (7.25 g, 71.73 mmol) at 0 °C. The reaction solution was stirred at 45 °C for 5 h. The solution was then poured into ice water (200 mL) to give a yellow solid, which was filtered. The solid was then dissolved in HCl / MeOH (4 M, 50 mL) and refluxed for 2 h. The mixture was concentrated to give 19-F (2 g, 7.66 mmol, 53.40% yield).

[0464] Step 6: 19-G To a mixture of 19-F (1.8 g, 6.89 mmol) and TEA (2.09 g, 20.68 mmol, 2.88 mL) in DCM (30 mL) was added BocO (1.81 g, 8.27 mmol) at 25 °C and stirred for 2 h. The solution was then concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1 to 4 / 1) to give 19-G (2.0 g, 5.54 mmol, 80.31% yield).

[0465] Step 7: 19-H To a mixture of 19-G (1.5 g, 4.15 mmol) and NH₄Cl (2.22 g, 41.53 mmol) in ethanol (50 mL) and water (50 mL) was added Zn (1.36 g, 20.76 mmol) at 25 °C. The mixture was stirred for 1 h, filtered, and concentrated. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1 to 2 / 1) to give 19-H (1.1 g, 3.32 mmol, 79.97% yield).

[0466] Step 8: 19-I To a mixture of 19-H (800 mg, 2.42 mmol) and bis(trichloromethyl)carbonate (2.15 g, 7.25 mmol) in DCM (10 mL) was added TEA (977.66 mg, 9.66 mmol, 1.35 mL) at -78 °C and stirred for 1 h. 2,2-Dimethoxyethanamine (1.27 g, 12.08 mmol, 1.32 mL) was added and stirred at 0 °C for 30 min. The mixture was concentrated to give a residue, which was dissolved in THF (20 mL), and trifluoromethanesulfonic acid (724.99 mg, 4.83 mmol, 423.97 μL) was added at 30 °C. The reaction solution was stirred at 70 °C for 2 h. BocO (1.05 g, 4.83 mmol, 1.11 mL) was added and stirred at 25 °C for 1 h. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (EA / PE = 1 / 1 to 1 / 0) to give 19-I (600 mg, 1.51 mmol, yield 62.37%).

[0467] Process 9: 19-J To a mixture of 19-I (68.91 mg, 173.03 μmol) and (4-fluoro-3,5-dimethylphenyl)boronic acid (37.78 mg, 224.94 μmol) in dioxane (4 mL) and HO (1 mL) was added Pd(dppf)Cl (12.66 mg, 17.30 μmol) and KCO (71.74 mg, 519.10 μmol) at 30 °C. The reaction solution was stirred at 100 °C for 2 h. The mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1 / 1 to 1 / 0) to give 19-J (70 mg, 158.55 μmol, 91.63% yield).

[0468] Step 10: 19-K A mixture of 19-J (70 mg, 158.55 μmol), Intermediate 1 (62.26 mg, 271.80 μmol), KCO (75.13 mg, 543.60 μmol), and CuI (17.25 mg, 90.60 μmol) in NMP (5 mL) was stirred at 80 °C for 6 h. The solution was then concentrated and purified by silica gel chromatography (PE / EA / TEA = 4 / 1 / 0.01 to 1 / 1:0.01) to give 19-K (68 mg, 115.33 μmol, 72.7% yield). MS: m / z = 590.4 (M + 1).

[0469] Step 11: Intermediate 19 19-K (50 mg, 84.80 μmol) was dissolved in HCl / dioxane (4 M, 2 mL) and stirred at 25° C. for 16 h. The reaction was then concentrated to give intermediate 19 (45 mg, 95% yield). MS: m / z = 490.1 (M + 1).

[0470] Example 12 Synthesis of intermediates 20-24 Intermediates 20-24 in Table 3 were made according to the procedure for Intermediate 19.

[0471] (Table 3) TIFF2026035735000444.tif217150

[0472] Example 13 Synthesis of intermediate 25 TIFF2026035735000445.tif69135

[0473] Process 1: 25-B To a solution of 25-A (an intermediate related to Intermediate 22, 0.26 g, 750.58 μmol) and DIEA (291 mg, 2.25 mmol) in THF (5 mL) was added phenyl carbonochloridate (153 mg, 975.76 μmol). The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was concentrated to give 25-B (0.4 g, crude product). MS: m / z = 467.1 (M + 1).

[0474] Process 2: 25-C To a solution of 25-B (0.4 g) in pyridine (8 mL) was added Intermediate 18 (290 mg, 1.71 mmol), and the reaction mixture was stirred at 20 °C for 15 h. The mixture was concentrated to give a residue, which was purified by silica gel column (PE / EA = 1 / 1) to give 25-C (0.33 g, 71% yield). MS: m / z = 542.2 (M + 1).

[0475] Process 3: 25-D To a solution of 25-C (0.3 g, 553.86 μmol) in dioxane (10 mL) was added 2-bromo-1,1-dimethoxyethane (2.8 g, 16.62 mmol, 2 mL), t-BuOK (620 mg, 5.54 mmol), and 18-crown-6 (586 mg, 2.22 mmol). The reaction mixture was sealed in a tube and heated at 120 °C for 36 h. The solvent was removed, and the residue was diluted with 20 mL of ethyl acetate. The organic layer was washed with water (5 mL x 2), dried over sodium sulfate, and concentrated to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 1 / 1) to give 25-D (0.18 g, 52% yield). MS: m / z = 630.4 (M + 1).

[0476] Step 4: Intermediate 25 To a solution of 25-D (0.18 g, 285.82 μmol) in ethyl acetate (2 mL) was added HCl (2 M, 1.4 mL). The reaction was stirred at 25 °C for 6 h. The reaction was concentrated to give a residue, which was purified by reverse phase column (55% MeCN in water) to give intermediate 25 (0.08 g, 56% yield). MS: m / z = 466.2 (M + 1).

[0477] Example 14 Synthesis of intermediates 19-P1 and 19-P2 TIFF2026035735000446.tif36142

[0478] Intermediate 19 (45 mg) was separated by SFC (column: Daicel CHIRALPAK OD-H 250 mm x 20 mm ID 5 μm; mobile phase: CO2 / MeOH (0.2% NH4 OH) = 65 / 35; flow rate: 50 g / min; wavelength: UV 214 nm; temperature: 35 °C) to give intermediate 19-P1 (23 mg) and intermediate 19-P2 (16 mg).

[0479] Example 15 Isolation of intermediates 17-P1, 17-P2, 20-P1, 20-P2, 22-P1, 22-P2, 23-P1, 23-P2, 24-P1, 24-P2, 25-P1, and 25-P2 The compounds in Table 4 were obtained by SFC separation similar to that of Intermediate 19-P1 and Intermediate 19-P2.

[0480] (Table 4) TIFF2026035735000447.tif181143TIFF2026035735000448.tif165143TIFF2026035735000449.tif165143

[0481] Example 16 Synthesis of intermediate 26 To a solution of TIFF2026035735000450.tif2112826-A (25 g, 195.05 mmol) in THF (250 mL) was added LDA (2 M, 117.03 mL) over 0.5 h at −70 °C. After stirring the mixture at −70 °C for 0.5 h, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (76.65 g, 214.56 mmol) in THF (250 mL) was added to the reaction mixture over 1 h at −60 °C. After the addition, the temperature was slowly raised to 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with aqueous NH4Cl (200 mL) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate and concentrated on a rotary evaporator to give Intermediate 26 (95 g, crude).

[0482] Example 17 Synthesis of intermediate 27 TIFF2026035735000451.tif66157

[0483] Process 1: 27-B To a solution of 27-A (25 g, 134.40 mmol) in DCM (100 mL) was added ethyl 2-(triphenylphosphanylidene)acetate (46.82 g, 134.40 mmol). The reaction mixture was stirred at 0 °C for 2 h. The solvent was removed under reduced pressure to give a solid, which was then washed with PE / EA = 10 / 1 (100 mL) to give the crude product. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1 to 5 / 1) to give 27-B (26.5 g, 77% yield). MS: m / z = 256.0 (M + 1, ESI).

[0484] Process 2: 27-C To a solution of 27-B (30 g, 117.14 mmol) in MeOH (300 mL) were added NaBH (5.32 g, 140.57 mmol) and NiCl (1.52 g, 11.71 mmol). The reaction mixture was stirred for 1 h. The mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 27-C (25 g, 82% yield). MS: m / z = 258.0 (M + 1).

[0485] Process 3: 27-D To a solution of 27-C (25 g, 96.86 mmol) in MeOH (200 mL) was added NH₃·H₂O (1.13 kg, 30%). The reaction mixture was stirred for 16 h. The solvent was removed under reduced pressure to give 27-D (20 g, 90% yield). MS: m / z = 229.0 (M + 1).

[0486] Step 4: 27-E To a solution of 27-D (20 g, 87.31 mmol) in dry dioxane (200 mL) was added TFAA (36.6 g, 174.62 mmol, 24.61 mL) and pyridine (17.2 g, 218.27 mmol, 17.65 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with HO (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash chromatography (PE / EA = 3 / 1) to give 27-E (16 g, 87% yield). MS: m / z = 211.0 (M + 1).

[0487] Process 5: 27-F To a solution of 27-E (15 g, 71.07 mmol) in MeCN (200 mL) was added ethyl 3-bromo-2-oxopropanoate (27.7 g, 142.14 mmol, 17.77 mL) and NaHCO (11.9 g, 142.14 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (PE / EA = 4 / 1) to give 27-F (1.0 g, 5% yield).

[0488] Step 6: 27-G A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (298 mg, 1.17 mmol), 27-F (300 mg, 976.75 μmol), Pd(dppf)Cl (71.47 mg, 97.67 μmol), and potassium acetate (192 mg, 1.95 mmol) in dioxane (5 mL) was stirred at 90 °C for 8 h. The mixture was concentrated under reduced pressure, and the residue was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, and concentrated to give 27-G (320 mg). MS: m / z = 355.1 (M + 1).

[0489] Step 7: 27-H A mixture of 27-G (320 mg, 903.43 μmol), Intermediate 26 (470 mg, 1.81 mmol), potassium carbonate (375 mg, 2.71 mmol), and Pd(dppf)Cl (66 mg, 90.34 μmol) in dioxane (3 mL) and water (1 mL) was stirred at 110 °C for 2 h. The mixture was concentrated, and the residue was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 8 / 1) to give 27-H (200 mg, 59% yield). MS: m / z = 339.1 (M + 1).

[0490] Step 8: 27-I To a solution of 27-H (150 mg, 443.26 μmol) in MeOH (3 mL) was added Pd / C (47 mg, 10%), and the mixture was stirred under H at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated to give 27-I (145 mg). MS: m / z = 341.1 (M + 1).

[0491] Step 9: Intermediate 27 To a solution of 27-I (180 mg, 528.77 μmol) in methanol (5 mL) was added sodium hydroxide solution (5 M, 1.06 mL) and stirred at 50 °C for 3 h. The reaction mixture was adjusted to pH ∼3 with HCl (1 M). The solution was extracted with ethyl acetate (10 mL × 3), and the combined organic layers were dried over sodium sulfate and concentrated to give a residue, which was purified by reverse-phase column (35% MeCN in HO) to give intermediate 27 (98 mg, 59% yield). MS: m / z = 313.2 (M + 1).

[0492] Example 18 Synthesis of intermediate 28 TIFF2026035735000452.tif30142

[0493] Process 1: 28-A To a solution of 27-I (330 mg, 969.40 μmol) and 1,3,2-dioxathiolane 2,2-dioxide (361 mg, 2.91 mmol) in DMPU (10 mL) was added dropwise KHMDS (1 M, 7.76 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Saturated NH4Cl solution (10 mL) was added to quench the reaction. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with aqueous LiCl solution (10 mL x 3), followed by brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by flash column chromatography (PE / EA = 1 / 1) to give 28-A (200 mg, 56% yield). MS: m / z = 367.2 (M + 1).

[0494] Step 2: Intermediate 28 To a solution of 28-A (81 mg, 221.04 μmol) in MeOH (3 mL) was added aqueous NaOH (2 M, 6 mL) and stirred at 50 °C for 2 h. The reaction mixture was extracted with ethyl acetate (10 mL x 2). The aqueous solution was then adjusted to pH 3 with HCl (1 M). The solution was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were dried over sodium sulfate and concentrated to give intermediate 28 (80 mg, crude product). MS: m / z = 339.1 (M + 1).

[0495] Example 19 Synthesis of intermediate 29 Intermediate 29 in Table 5 was made according to the procedure for Intermediate 28.

[0496] (Table 5) TIFF2026035735000453.tif32150

[0497] Example 20 Synthesis of intermediate 30 A solution of 30-A (300 mg, 881.28 μmol) and (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (122 mg, 881.28 μmol) in THF (5 mL) was added to a solution of 8HMDS (1 M, 7.05 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into aqueous NH4Cl (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate 30 (300 mg, 96% yield). MS: m / z = 353.1 (M + 1).

[0498] Example 21a Synthesis of intermediate 31 TIFF2026035735000455.tif61161

[0499] Process 1: 31-B To a solution of 31-A (15 g, 87.20 mmol, 10.34 mL) in MeCN (100 mL) were added sodium bicarbonate (14.65 g, 174.40 mmol) and ethyl 3-bromo-2-oxopropanoate (25.51 g, 130.80 mmol, 16.35 mL). The mixture was stirred at 90 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with HO (50 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by silica gel chromatography (PE / EA = 10 / 1) to give 31-B (2.6 g, 11% yield). MS: m / z = 268.1 (M + 1).

[0500] Process 2: 31-C A mixture of 31-B (2.43 g, 9.06 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.99 g, 11.78 mmol), KOAc (1.78 g, 18.13 mmol), and Pd(dppf)Cl (663 mg, 906.36 μmol) in dioxane (30 mL) was stirred at 90 °C for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 31-C (2.5 g, crude product). MS: m / z = 316.2 (M + 1).

[0501] Process 3: 31-D To a solution of 31-C (2.5 g, 7.93 mmol) in dioxane (20 mL) and water (5 mL), K2CO3 (2.19 g, 15.86 mmol), Pd(dppf)Cl2 (580 mg, 793.22 μmol), and Intermediate 26 (4.13 g, 15.86 mmol) were added, and the mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to give 31-D (2.1 g, 88% yield). MS: m / z = 300.1 (M + 1).

[0502] Step 4: 31-E To a solution of 31-D (1.3 g, 4.34 mmol) in methanol (30 mL) was added Pd / C (10%, 50% wet, 400 mg) under hydrogen. The reaction was stirred at 15 psi and 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give 31-E (1.2 g, 92% yield). MS: m / z = 302.1 (M + 1).

[0503] Process 5: 31-F To a mixture of 31-E (1.1 g, 3.65 mmol), 2-bromoacetonitrile (482 mg, 4.01 mmol, 279.99 μL), ferrous sulfate heptahydrate (508 mg, 1.82 mmol), and NaI (547 mg, 3.65 mmol) in DMSO (10 mL) was added hydrogen peroxide (1.88 mL, 30%) dropwise. The reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified on a silica gel column (PE / EA = 4 / 1) to give 31-F (530 mg, 43% yield). MS: m / z = 341.3 (M + 1).

[0504] Step 6: 31-G To a solution of 31-F (220 mg, 646.27 μmol) in DMPU (3 mL) was added 1,3,2-dioxathiolane 2,2-dioxide (241 mg, 1.94 mmol), and then LiHMDS (1 M, 5.82 mL) was slowly added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL x 10), dried over sodium sulfate, and concentrated to give a residue, which was purified by silica gel column chromatography (EA / PE = 1 / 5) to give 31-G (135 mg, 57% yield). MS: m / z = 367.1 (M + 1).

[0505] Step 7: Intermediate 31 To a solution of 31-G (135 mg, 368.40 μmol) in MeOH (2 mL) was added NaOH (5 M, 1.47 mL). The mixture was stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure, and the residue was added to HCl (1 M, 10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL×2), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate 31 (65 mg, 50% yield). MS: m / z = 339.1 (M + 1).

[0506] Example 21b Synthesis of intermediate 32 TIFF2026035735000456.tif30137

[0507] Process 1: 32-A To a solution of ethyl 27-F (10 mg, 32.56 μmol) in dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (9 mg, 32.56 μmol), Pd(dppf)Cl (3 mg, 3.2 μmol), and KCO (9 mg, 65.12 μmol). The mixture was stirred at 90 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was then diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EA = 2 / 1) to give 32-A (10 mg, 82% yield). MS: m / z = 374.1 (M + 1).

[0508] Step 2: Intermediate 32 To a solution of 32-A (10 mg, 26.79 μmol) in MeOH (1 mL) was added NaOH (5 M, 535.72 μL), and the reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated and adjusted to pH ∼5 with 1 N HCl. The mixture was filtered, and the filter cake was washed with HO (0.5 mL) and dried under vacuum to give intermediate 32 (8 mg, 87% yield). MS: m / z = 346.2 (M + 1).

[0509] Example 22 Synthesis of intermediate 33 TIFF2026035735000457.tif24157

[0510] Process 1: 33-A A three-neck flask was charged with LiHMDS (1M, 1.63 mL) and cooled to -40 °C. A solution of 27-F (100 mg, 325.58 μmol) and 1,3,2-dioxathiolane 2,2-dioxide (60 mg, 488.37 μmol) in THF (2 mL) was then added. The mixture was stirred at -40 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (PE / EA = 4 / 1) to give 33-A (20 mg, 18% yield). MS: m / z = 333.0 (M + 1).

[0511] Process 2: 33-B To a solution of 33-A (15 mg, 45.02 μmol) in dioxane (5 mL) and water (0.5 mL) was added K2CO3 (18 mg, 135.06 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (12 mg, 45.02 μmol), and Pd(dppf)Cl2 (32 mg, 45.02 μmol). The mixture was stirred at 90 °C for 2 h. Dioxane was removed under reduced pressure, and the crude product was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE / EA = 1 / 1) to give 33-B (15 mg, 83% yield). MS: m / z = 400.1 (M + 1).

[0512] Step 3: Intermediate 33 To a solution of 33-B (15 mg, 37.56 μmol) in THF (1 mL) and MeOH (1 mL) was added NaOH (6 M, 2.0 mL). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was concentrated and adjusted to pH ∼5 with 1 N HCl. The reaction mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate 33 (13 mg, 93% yield). MS: m / z = 372.0 (M + 1).

[0513] Example 23 Isolation of intermediate 27-P1 and intermediate 27-P2 TIFF2026035735000458.tif30132 Intermediate 27 (100 mg) was separated by SFC (column: Daicel CHIRALPAK AD-H 0.46 cm ID x 15 cm L, 5 μm; mobile phase: HEP / EtOH (0.1% DEA) = 60 / 40; flow rate: 0.5 mL; wavelength: UV 254 nm; temperature: 25 °C) to give intermediate 27-P1 (40 mg) and intermediate 27-P2 (40 mg).

[0514] Example 24 Synthesis and isolation of intermediates 28-P1, 28-P2, 30-P1, 30-P2, 30-P3, 30-P4, 31-P1, and 31-P2 The compounds in Table 6 were obtained by SFC separation as described in Intermediate 27-P1 and Intermediate 27-P2.

[0515] (Table 6) TIFF2026035735000459.tif74143TIFF2026035735000460.tif254143

[0516] Example 25 Synthesis of intermediate 34 TIFF2026035735000461.tif25141

[0517] Process 1: 34-B To a solution of 34-A (10 g, 37.30 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.84 g, 37.30 mmol) in dioxane (100 mL) and water (10 mL) was added K2CO3 (10.29 g, 74.60 mmol) and Pd(dppf)Cl2 (2.73 g, 3.73 mmol). The reaction was stirred at 90 °C for 4 h. The reaction was cooled and diluted with 200 mL of ethyl acetate and 100 mL of water. The solid was filtered, and the organic layer was dried over anhydrous sodium sulfate and concentrated to give a residue that was combined with the solid to give 34-B (6 g, 59% yield). MS: m / z = 272.2 (M + 1).

[0518] Step 2: Intermediate 34 To a solution of 34-B (5 g, 18.43 mmol) in DMF (25 mL) and MeOH (25 mL) was added Pd / C (10%, 50% wet, 1 g). The mixture was stirred under 15 psi of H for 4 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (PE / EA = 9 / 1) to give intermediate 34 (3.8 g, 72% yield). MS: m / z = 274.1 (M + 1).

[0519] Example 26 Synthesis of intermediates 35 and 36 Intermediates 35-36 in Table 7 were made according to the procedure for Intermediate 34.

[0520] (Table 7) TIFF2026035735000462.tif70143

[0521] Example 27 Synthesis of intermediate 37 TIFF2026035735000463.tif40128

[0522] Process 1: 37-A To a solution of 34-A (5.0 g, 18.65 mmol) in DMSO (50 mL) were added 2-fluorobenzonitrile (6.78 g, 55.95 mmol, 6.05 mL) and potassium tert-butoxide (6.28 g, 55.95 mmol). The mixture was stirred at 140 °C for 16 h. The mixture was cooled to 25 °C, poured into water, and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with water (30 mL x 2) and brine (30 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 20 / 1 to 10 / 1) to give 37-A (2.5 g, 36% yield). MS: m / z = 369 (M + 1).

[0523] Process 2: 37-B To a solution of 37-A (1.3 g, 3.52 mmol) in dioxane (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (887.62 mg, 4.23 mmol), Pd(dppf)Cl2 (257.39 mg, 352.10 μmol), sodium carbonate (559.78 mg, 5.28 mmol), and water (2 mL). The mixture was stirred at 90 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1) to give 37-B (1.22 g, 88% yield). MS: m / z = 373 (M + 1).

[0524] Step 3: 37-C To a solution of 37-B (600 mg, 1.52 mmol) in EtOH (10 mL) was added Pd / C (60 mg, 10%, 55% wet). The mixture was stirred under hydrogen at 25 °C for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 37-C (560 mg, crude). MS: m / z = 375 (M + 1).

[0525] Process 4: 37-D To a solution of 37-C (200 mg, 534.14 μmol) in DMSO (5 mL) was added hydroxylamine hydrochloride (185.59 mg, 2.67 mmol) and sodium bicarbonate (224.37 mg, 2.67 mmol). The mixture was stirred at 60° C. for 4 hours. The mixture was poured into water and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 37-D (200 mg, crude product). MS: m / z = 408 (M + 1).

[0526] Step 5: 37-E To a solution of 37-D (200 mg, 343.59 μmol) in DMSO (5 mL) were added di(imidazol-1-yl)methanone (111 mg, 687 μmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (104 mg, 687 μmol). The mixture was stirred at 25 °C for 3 h. The mixture was poured into water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, and concentrated to give 37-E (120 mg, crude product). MS: m / z = 434, (M + 1).

[0527] Step 6: Intermediate 37 To a solution of 37-E (120 mg, 229 μmol) in MeOH (5 mL) was added NaOH (2 M, 1.15 mL). The mixture was stirred at 60° C. for 1 hour. The mixture was concentrated, and water (10 mL) was added to the residue. The mixture was extracted with ethyl acetate (10 mL×2), and the aqueous phase was neutralized with aqueous HCl and extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give intermediate 37 (90 mg, 67% yield). MS: m / z = 406, (M + 1).

[0528] Example 28 Synthesis of intermediate 38 Intermediate 38 in Table 8 was made according to the procedure for Intermediate 37.

[0529] (Table 8) TIFF2026035735000464.tif55147

[0530] Example 29 Synthesis of intermediate 39 TIFF2026035735000465.tif36140

[0531] Process 1: 39-A To a solution of intermediate 34 (300 mg, 1.10 mmol) in DCM (6 mL) were added 4 Å molecular sieves (500 mg), (3-formylphenyl)boronic acid (247 mg, 1.65 mmol), DIEA (355 mg, 2.74 mmol, 477.94 μL), and Cu(OAc)2 (218 mg, 1.10 mmol). The mixture was stirred under oxygen at 35 °C for 16 h. Water (50 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (50 mL x 2), and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by silica gel chromatography (PE / EA = 20 / 1) to give 39-A (290 mg, 70% yield). MS: m / z = 400.1 (M + 23).

[0532] Step 2: Intermediate 39 To a solution of 39-A (290 mg, 768.35 μmol) in MeOH (6 mL) was added 2 M NaOH (2 mL) dropwise at 0 °C. The reaction solution was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue, which was then diluted with water (20 mL), adjusted to pH 3-4 with 6 M HCl at 0 °C, and extracted with ethyl acetate (20 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to give intermediate 39 (245 mg, 91% yield). MS: m / z = 350.2 (M + 1).

[0533] Example 30 Synthesis of intermediate 40 TIFF2026035735000466.tif69142

[0534] Process 1: 40-A To a solution of intermediate 36 (1.1 g, 3.92 mmol) in DMF (10 mL) was added potassium bis(trimethylsilyl)amide (0.5 M, 15.70 mL) in an ice-water bath, and the mixture was then stirred at 25 °C for 1 h. 2-Chloroacetonitrile (888.77 mg, 11.77 mmol, 740.64 μL) was added, and the resulting solution was stirred at 25 °C for 16 h. Saturated aqueous NH4Cl (50 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column (PE / EA = 2 / 1) to give 40-A (1.1 g, 87.78% yield). MS: m / z = 319.9 (M + 1).

[0535] Process 2: 40-B To a solution of 40-A (1.1 g, 3.44 mmol) in ethanol (15 mL) were added hydroxylamine hydrochloride (718.07 mg, 10.33 mmol) and DIPEA (1.34 g, 10.33 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE / EA = 1 / 1) to give 40-B (1.1 g, 90.63% yield). MS: m / z = 353.1 (M + 1).

[0536] Step 3: 40-C To a solution of 40-B (1.1 g, 3.12 mmol) in DMSO (10 mL) were added di(imidazol-1-yl)methanone (1.01 g, 6.24 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (950.44 mg, 6.24 mmol, 931.80 μL). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl (25 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 40-C (1 g, 84.66% yield). MS: m / z = 378.8 (M + 1).

[0537] Step 4: Intermediate 40 To a solution of 40-C (500 mg, 1.32 mmol) in water (5 mL), THF (5 mL), and methanol (5 mL) was added lithium hydroxide hydrate (277.26 mg, 6.61 mmol). The resulting solution was stirred at 25 °C for 16 h. Approximately half of the methanol was removed under reduced pressure, and HCl (1 M) was added to the residue until the pH reached approximately 5. The resulting mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give intermediate 40 (400 mg, 86.41% yield). MS: m / z = 351.1 (M + 1).

[0538] Example 31 Synthesis of intermediate 41 Intermediate 41 in Table 9 was made according to the procedure for Intermediate 40.

[0539] (Table 9) TIFF2026035735000467.tif46143

[0540] Example 32 Synthesis of intermediate 42 TIFF2026035735000468.tif65139

[0541] Process 1: 42-B To a mixture of 42-A (7.0 g, 26.71 mmol) in EtOH / HO (60 mL, 5 / 1) was added NaOH (2.14 g, 53.43 mmol). After stirring at 25 °C for 2 h, the volatile fractions were removed under reduced pressure. The residue was diluted with water (100 mL), and the pH was adjusted to approximately 5 with HCl (1 M). The mixture was extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 42-B (7.1 g, crude product). MS: m / z = 249.0 (M + 1).

[0542] Process 2: 42-C To a mixture of 42-B (7.00 g, 28.22 mmol) and 2-(trimethylsilyl)ethan-1-ol (4.00 g, 33.87 mmol) in DMF (70 mL) was added HOBT (4.58 g, 33.87 mmol), EDCI (6.50 g, 33.87 mmol), and DIPEA (10.94 g, 84.67 mmol). After stirring at 25 °C for 4 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (250 mL × 2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (PE / EA = 50 / 1) to give 42-C (7.3 g, 74.27% yield). TIFF2026035735000469.tif19161

[0543] Process 3: 42-D To a mixture of intermediate 35 (2.40 g, 7.96 mmol), 42-C (3.33 g, 9.56 mmol), and N,N'-dimethylethane-1,2-diamine (140.40 mg, 1.59 mmol) in dioxane (30 mL) was added CuI (151.66 mg, 0.80 mmol) and KPO (4.22 g, 19.91 mmol). The resulting mixture was stirred in a sealed tube at 110 °C for 40 h. After cooling to 25 °C, the reaction mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column (PE / EA = 20 / 1) to give 42-D (400 mg, 9.63% yield). MS: m / z = 522.3 (M +1).

[0544] Step 4: Intermediate 42 To a mixture of 42-D (400 mg, 0.77 mmol) in EtOH / HO (12 mL, 5 / 1) was added NaOH (61.60 mg, 1.54 mmol). After stirring at 25 °C for 2 h, the resulting mixture was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give intermediate 42 (190 mg, crude product). MS: m / z = 494.5 (M +1).

[0545] Example 33 Synthesis of intermediate 43 TIFF2026035735000470.tif27141

[0546] Process 1: 43-A To a solution of intermediate 41 (0.1 g, 291.26 μmol) in THF (10 mL) was added DIEA (188 mg, 1.46 mmol) and 2-(chloromethoxy)ethyl-trimethyl-silane (107 mg, 640.78 μmol). The reaction was stirred at 0 °C for 1 hour. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give 43-A (0.17 g, crude product). MS: m / z = 626.3 (M + 23).

[0547] Step 2: Intermediate 43 To a solution of 43-A (0.17 g, 281.53 μmol) in DMSO (5 mL) was added MgBr (518 mg, 2.82 mmol). The reaction was stirred at 40 °C for 8 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give intermediate 43 (0.12 g, 90% yield). MS: m / z = 496.2 (M + 23).

[0548] Example 34 Synthesis of intermediate 44 TIFF2026035735000471.tif52153

[0549] Process 1: 44-B To a solution of 44-A (4 g, 27.95 mmol) in DMF (5 mL) and acetonitrile (35 mL) was added potassium carbonate (7.73 g, 55.91 mmol, 3.37 mL). The reaction mixture was stirred at 25 °C for 15 min. Then, bromomethylbenzene (5.26 g, 30.75 mmol, 3.65 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated, diluted with water (15 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by FCC (gradient: 15–30% EA in PE) to give 44-B (4.72 g, 72% yield). MS: m / z = 234.1 (M + 1).

[0550] Process 2: 44-C To a solution of 44-B (3 g, 12.86 mmol) in MeOH (30 mL) was added sodium borohydride (973.31 mg, 25.73 mmol) slowly. The reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give 44-C (3.2 g, 97% yield). MS: m / z = 206.1 (M + 1).

[0551] Process 3: 44-D A solution of 44-C (856 mg, 4.17 mmol) in thionyl chloride (10 mL) was heated at 80 °C for 16 h. The reaction mixture was concentrated to dryness and extracted with ethyl acetate (5 mL x 3) from water (10 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by FCC (gradient: 5-10% EA in PE) to give 44-D (466 mg, 50% yield). MS: m / z = 224.1 (M + 1).

[0552] Step 4: 44-E To a solution of intermediate 35 (270 mg, 894.23 μmol) in DMF (5 mL) was added cesium carbonate (437 mg, 1.34 mmol) and stirred at 25° C. for 10 minutes. 44-D (200 mg, 894.23 μmol) was then added, and the reaction mixture was stirred at 60° C. for 5 hours. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (5 mL×3). The combined organic phases were washed with brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by FCC (gradient: 20% EA in PE) to give 44-E (414 mg, 95% yield). MS: m / z = 489.1 (M + 1).

[0553] Process 5: 44-F A solution of 44-E (414 mg, 847.36 μmol) in TFA (5 mL) was heated at 60° C. for 24 h. The reaction mixture was concentrated and purified by FCC (gradient: 30% EA in PE) to give 44-F (125 mg, 37% yield). MS: m / z = 399.1 (M + 1).

[0554] Step 6: Intermediate 44 To a solution of 44-F (125 mg, 313.71 μmol) in THF (3 mL) was added sodium hydroxide solution (25%, 30 μL). The reaction mixture was stirred at 25 °C for 16 h. After the reaction mixture was concentrated, water (5 mL) was added and the pH was adjusted to 2-3 with 2 M HCl. The aqueous phase was extracted with DCM (3 mL x 3). The combined organic phases were washed with brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by preparative TLC (gradient: 33.3% EA in PE with 1% HCOOH) to give intermediate 44 (62 mg, 54% yield). MS: m / z = 371.1 (M + 1).

[0555] Example 35 Synthesis of intermediate 45 TIFF2026035735000472.tif55157

[0556] Process 1: 45-B To a solution of 45-A (1 g, 5.19 mmol) in THF (10 mL), sodium thiomethoxide (730 mg, 10.42 mmol) was added and stirred overnight. The mixture was diluted with HO (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated. The crude product was purified on a silica gel column (PE / EA = 10 / 1) to give 45-B (200 mg, 18.87% yield). MS: m / z = 204.9 (M + 1).

[0557] Process 2: 45-C To a solution of 45-B (200 mg, 0.98 mmol) in THF (5 mL) was added LiAlH (44.6 mg, 1.17 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction was quenched with HO (10 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over MgSO, filtered, and concentrated to give 45-C (60 mg, crude product). MS: m / z = 163.0 (M + 1).

[0558] Process 3: 45-D To a solution of 45-C (60 mg, 0.37 mmol) in DCM (3 mL) were added methanesulfonyl chloride (32 mg, 0.28 mmol) and DMAP (67.78 mg, 0.56 mmol), and the mixture was stirred overnight. The reaction mixture was poured into HO (10 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over MgSO, filtered, and concentrated. The crude product was purified on a silica gel column (PE / EA = 10 / 1) to give 45-D (50 mg, 74.87% yield). MS: m / z = 180.8 (M + 1).

[0559] Process 4: 45-E To a solution of 45-D (50 mg, 0.28 mmol) and intermediate 35 (100 mg, 0.33 mmol) in MeCN (2 mL) was added cesium carbonate (180.34 mg, 0.55 mmol), and the mixture was stirred for 16 h. The mixture was filtered, and the filtrate was diluted with HO (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over MgSO, filtered, and concentrated. The crude product was purified on a silica gel column (PE / EA = 5 / 1) to give 45-E (80 mg, 65.05% yield). MS: m / z = 445.7 (M + 1).

[0560] Process 5: 45-F To a solution of 45-E (80 mg, 179.53 μmol) in DCM (2 mL) was added m-CPBA (91.12 mg, 448.84 μmol, 85% purity) and stirred for 16 h. The reaction was quenched with aqueous NaSO (3 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over MgSO, filtered, and concentrated. The crude product was purified on a silica gel column (PE / EA = 10 / 1) to give 45-F (40 mg, 46.65% yield). MS: m / z = 477.6 (M + 1).

[0561] Step 6: Intermediate 45 To a solution of 45-F (40 mg, 83.75 μmol) in THF (1 mL) was added aqueous lithium hydroxide (3 M, 0.1 mL) dropwise at 0° C. The mixture was stirred at 60° C. for 2 h. The mixture was filtered, and the filtrate was concentrated to give intermediate 45 (20 mg, crude product). MS: m / z = 387.7 (M + 1).

[0562] Example 36 Synthesis of intermediate 46 TIFF2026035735000473.tif85156

[0563] Process 1: 46-A To a mixture of 34-A (10 g, 37.30 mmol) in DMF (50 mL) was added sodium hydride (60% dispersion in mineral oil, 857.49 mg, 37.30 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 1 h, and then 2-chloroacetonitrile (2.82 g, 37.30 mmol) was added slowly. The resulting mixture was stirred for an additional 18 h. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (450 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatography (PE / EA = 5 / 1) to give 46-A (9 g, 78.56% yield). TIFF2026035735000474.tif19157

[0564] Process 2: 46-B A mixture of 46-A (7.2 g, 23.44 mmol) and 1,3,2-dioxathiolane 2,2-dioxide (7.27 g, 58.60 mmol) in THF (50 mL) was cooled to 5 °C under a nitrogen atmosphere, and then lithium bis(trimethylsilyl)amide (1 M, 23.44 mL) was added dropwise. The reaction mixture was stirred at this temperature for 0.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (300 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by column chromatography (PE / EA = 5 / 1) to give 46-B (4.5 g, 57.62% yield). MS: m / z = 332.9 (M + 1).

[0565] Process 3: 46-C A mixture of 46-B (2 g, 6.0 mmol), sodium bicarbonate (2.52 g, 30.01 mmol), and hydroxylamine hydrochloride (2.09 g, 30.01 mmol) in DMSO (50 mL) was heated at 50 °C for 3 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by column chromatography (PE / EA = 3 / 1) to give 46-C (2.0 g, 90.98% yield). MS: m / z = 365.8 (M + 1).

[0566] Process 4: 46-D To a mixture of 46-C (2.66 g, 7.26 mmol) in DMSO (30 mL) was added 1,1'-carbonyldiimidazole (2.36 g, 14.53 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.21 g, 14.53 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 46-D (2.2 g, 77.23% yield). MS: m / z = 391.6 (M + 1).

[0567] Step 5: 46-E A mixture of Intermediate 26 (2.6 g, 9.99 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.54 g, 9.99 mmol), and potassium acetate (1.96 g, 19.98 mmol) in dioxane (25 mL) was degassed for 15 minutes, and cyclopentyl(diphenyl)phosphane, dichloromethane, dichloropalladium, and iron (244.77 mg, 299.73 μmol) were added. The reaction mixture was degassed again for 15 minutes and then heated at 80° C. for 16 hours. The mixture was cooled, filtered, and washed with MTBE (10 mL×4). The organic extracts were combined and concentrated, and 2 M aqueous NaOH (26 mL) was added to the mixture in an ice bath. The basic aqueous solution was extracted with MTBE (10 mL x 3), and the organic extract was discarded. The aqueous phase was cooled and adjusted to pH 3-5 with concentrated HCl. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (0-15% EA in hexanes) to give 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 6.3 mmol).

[0568] A mixture of 2-(6,6-dimethyl-2,5-dihydropyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 6.3 mmol), Intermediate 46-D (2 g, 5.10 mmol), NaCO (1.08 g, 10.20 mmol), and Pd(dppf)Cl (416.43 mg, 509.94 μmol) in dioxane (15 mL) and water (5 mL) was heated at 90 °C for 16 h under a nitrogen atmosphere. The mixture was concentrated and purified by column chromatography (DCM / MeOH = 50 / 1) to give 46-E (2.5 g, crude product). MS: m / z = 423.8 (M + 1).

[0569] Process 6: 46-F A mixture of 46-E (2.5 g, 6.38 mmol) and Rh / C (1.5 g) in methanol (30 mL) was stirred at 25 °C under a H atmosphere (1 atm) for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Pd / C (1.5 g) was added to a methanol solution of the residue, and the mixture was stirred at 25 °C under a H atmosphere (1 atm) for 16 h. The mixture was filtered and concentrated to give a residue, which was purified by column chromatography (DCM / MeOH = 3 / 1) to give 46-F (700 mg, 28.63% yield). MS: m / z = 383.9 (M + 1).

[0570] Step 7: 46-G A mixture of 46-F (700 mg, 1.83 mmol), hydroxylamine hydrochloride (634.23 mg, 9.13 mmol), and TEA (1.85 g, 18.25 mmol) in ethanol (10 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 1 / 1) to give 46-G (450 mg, 61.71% yield). MS: m / z = 399.9 (M + 1).

[0571] Step 8: 46-H To a mixture of 46-G (450 mg, 1.13 mmol) in DMSO (5 mL) was added 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (342.98 mg, 2.25 mmol) and di(imidazol-1-yl)methanone (365.31 mg, 2.25 mmol). The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was cooled to 0 °C, quenched with saturated aqueous NH4Cl (15 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 46-H (440 mg, 91.80% yield). MS: m / z = 425.7 (M + 1).

[0572] Step 9: Intermediate 46 To a solution of 46-H (440 mg, 1.03 mmol) in methanol (2 mL), water (2 mL), and THF (2 mL) was added lithium hydroxide hydrate (216.98 mg, 5.17 mmol). The resulting solution was stirred at 50 °C for 16 h. The solvent was removed under reduced pressure, and the residue was diluted with water (15 mL) and adjusted to pH = 3-5 with HCl (1 M). The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give intermediate 46 (385 mg, 93.68% yield). MS: m / z = 419.8 (M + 23).

[0573] Example 37 Isolation of intermediate 35-P1 and intermediate 35-P2 TIFF2026035735000475.tif30142 Intermediate 35 (5.3 g) was separated by SFC (column: CHIRALPAK® IE 4.6×250 mm 5 μm; mobile phase: hexane / EtOH = 30 / 70; column temperature: 25° C.; flow rate: 1 mL / min) to give intermediate 35-P1 (Rt = 10.94 min) and intermediate 35-P2 (2.5 g, Rt = 21.33 min).

[0574] Example 38 Isolation of intermediates 46-P1 and 46-P2 The compounds in Table 10 were obtained by SFC separation similar to that of Intermediate 35-P1 and Intermediate 35-P2.

[0575] (Table 10) TIFF2026035735000476.tif80143

[0576] Example 39 Synthesis of intermediate 47 TIFF2026035735000477.tif83158

[0577] Process 1: 47-A To a solution of intermediate 35-P2 (1.5 g, 4.98 mmol) in methanol (20 mL) and water (10 mL) was added sodium hydroxide (597.21 mg, 14.93 mmol). The mixture was stirred at 60 °C for 3 hours. Approximately half of the methanol was removed under reduced pressure, and 1 M HCl was added to the residue until the pH was approximately 1. The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 47-A (1.30 g, 95.56% yield). MS: m / z = 274 (M + 1).

[0578] Process 2: 47-B To a solution of 47-A (1.30 g, 4.76 mmol) in DMA (30 mL) was added thionyl chloride (679.19 mg, 5.71 mmol) in an ice-water bath. After the addition, the resulting mixture was warmed to 25 °C and stirred for 3 h. To the resulting mixture in an ice-water bath, TEA (1.44 g, 14.27 mmol) and N-methylaniline (611.57 mg, 5.71 mmol) were added. The mixture was warmed to 25 °C and stirred for 16 h. Water (20 mL) was added to the reaction mixture. After filtration, the solid was collected, washed with water (10 mL), and dried under vacuum to give 47-B (1.52 g, 88.17% yield). MS: m / z = 363 (M + 1).

[0579] Step 3: 47-C To a suspension of sodium hydride (503.17 mg, 12.58 mmol, 60% dispersion in mineral oil) in 1,3-dimethylimidazolidin-2-one (40 mL) was added 47-B (1.52 g, 4.19 mmol) in an ice-water bath. After the addition, the resulting mixture was warmed to 25 °C and stirred for 1 h. 2-Chloroacetonitrile (474.90 mg, 6.29 mmol) was added, and the resulting solution was stirred at 25 °C for 16 h. Saturated aqueous NH4Cl (80 mL) was added to the resulting mixture, and the aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 47-C (1.68 g, crude product). MS: m / z = 402 (M + 1).

[0580] Process 4: 47-D To a solution of 47-C (1.68 g, 4.18 mmol), (4R)-4-methyl-1,3,2-dioxathiolane 2,2-dioxide (1.73 g, 12.55 mmol) in DMPU (20 mL) was added 1 M LiHMDS (33.47 mL) under ice-water cooling (<15 °C). The resulting solution was stirred at 15 °C for 4 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL), and the aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (20 mL), brine (15 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column (PE / EA = 3 / 1) to give 47-D (380 mg, 20.57% yield). MS: m / z = 442 (M + 1).

[0581] Step 5: 47-E To a solution of 47-D (380 mg, 860.58 μmol) and hydroxylamine hydrochloride (598.02 mg, 8.61 mmol) in DMSO (10 mL) was added sodium bicarbonate (722.89 mg, 8.61 mmol). The resulting mixture was heated at 60 °C for 5 h, and then ethyl acetate (70 mL) was added. The organic layer was separated, washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL), and CDI (279.08 mg, 1.72 mmol) and DBU (327.02 mg, 2.15 mmol) were added. The mixture was stirred at 25 °C for 4 h. Saturated aqueous NH4Cl (20 mL) was then added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (PE / EA = 1 / 1) to give 47-E (220 mg, yield 51.07%). TIFF2026035735000478.tif19160

[0582] Step 6: Intermediate 47 To a solution of 47-E (220.00 mg, 439.48 μmol) in methoxyethanol (3 mL) was added potassium hydroxide (246.57 mg, 4.39 mmol). The reaction mixture was heated at 100° C. for 3 h. After cooling, HCl (6 M) was added to the resulting mixture in an ice-water bath until the pH reached approximately 5. The reaction mixture was stirred at 25° C. for 10 min, and the aqueous layer was extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give Intermediate 47 (270 mg, crude product). MS: m / z = 412 (M + 1).

[0583] Example 40 Synthesis of intermediates 48 and 49 The compounds in Table 11 were made according to the procedure of Intermediate 47.

[0584] (Table 11) TIFF2026035735000479.tif83143

[0585] Example 41 Synthesis of intermediate 50 TIFF2026035735000480.tif25142

[0586] Process 1: 50-A To a solution of 37-C (1 g, 2.67 mmol) in THF (30 mL) was added NaOH (13.35 mmol, 10% aqueous solution), and the reaction was stirred at 20 °C for 16 h. Most of the solvent was evaporated, and the residue was diluted with 5 mL of water and concentrated HCl was added until the pH was approximately 3. The mixture was filtered, and the solid was dissolved in 10 mL of THF, dried over sodium sulfate, and concentrated to give 50-A (760 mg, 82% yield). MS: m / z = 347.1 (M + 1).

[0587] Step 2: Intermediate 50 To a solution of 50-A (380 mg, 1.10 mmol) in THF (5 mL), Dibal-H (1 M, 4.39 mL) was added and stirred at 20 °C for 48 h. The reaction mixture was poured into 5 mL of 1 M HCl and extracted with ethyl acetate (5 mL x 3). The organic layer was dried over sodium sulfate and concentrated to give a residue. The residue was purified by reverse phase (ACN:0.1% HCOOH in HO = 50:50) to give intermediate 50 (190 mg, 50% yield). MS: m / z = 350.2 (M + 1).

[0588] Example 42 Synthesis of intermediate 51-P1 and intermediate 51-P2 TIFF2026035735000481.tif59143

[0589] Process 1: 51-B To a solution of 51-A (1 g, 7.62 mmol) in THF (10 mL) was added n-BuLi (2.4 M, 6.35 mL) dropwise at −78°C. The reaction mixture was warmed to −60°C and stirred for 1 h. DMF (5.57 g, 76.21 mmol) was then added to the resulting mixture, and the mixture was stirred at −60°C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / DCM = 1 / 5) to give 51-B (1.1 g, 6.91 mmol, 90.65% yield). MS: m / z = 159.9 (M + 1).

[0590] Process 2: 51-C To a mixture of LiBH (276.33 mg, 12.56 mmol) in THF (10 mL) was added a solution of 51-B (1 g, 6.28 mmol) in THF (10 mL) dropwise at 25 °C. The resulting mixture was stirred for 18 h and then diluted with HCl (1 M, 1 mL). The mixture was adjusted to pH 8 with saturated aqueous NaHCO and extracted with DCM (10 mL x...

Claims

1. Formula (I): A compound of the formula teeth and The formula (I) is and During the ceremony, L is -CR 5 R 6 - and; R 1 is phenyl, wherein the phenyl is selected from the group consisting of halogen, CN, NO 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, NH 2 , NH-(C 1 ~C 6 alkyl), N(C 1 ~C 6 alkyl) 2 , O.H., C. 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, and C 3 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl; R 2 is heteroaryl, wherein the heteroaryl is Contains one or two five- or six-membered rings, containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; Halogen, CN, NO 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, NH 2 , NH-(C 1 ~C 6 alkyl), N(C 1 ~C 6 alkyl) 2 , O.H., C. 1 ~C 6 Alkoxy, and C 1 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy; and The C of the heteroaryl 1 ~C 6 The alkyl substituents are each C 1 ~C 6 optionally substituted with one or more substituents independently selected from alkoxy; Each R 3 are independently halogen, C 3 ~C 10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl; where Each C 3 ~C 10 cycloalkyl is pyrocycloalkyl, bridged cycloalkyl, or monocycloalkyl; each heterocyclyl independently contains one or two 3- to 6-membered rings; each heteroaryl independently contains one or two five- or six-membered rings; each heterocyclyl or heteroaryl contains 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and The C 3 ~C 10 Cycloalkyl, heterocyclyl, phenyl, or heteroaryl are each independently selected from halogen, CN, NO 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, NH 2 , NH-(C 1 ~C 6 alkyl), N(C 1 ~C 6 alkyl) 2 , O.H., C. 1 ~C 6 Alkoxy, and C 1 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy; R 4 CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, NH-(C 1 ~C 6 alkyl), N(C 1 ~C 6 alkyl) 2 , C 1 ~C 6 Alkoxy, or C 1 ~C 6 haloalkoxy; R 5 and R 6 together with the carbon atoms to which they are attached form halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, OH, C 1 ~C 6 Alkoxy, and C 1 ~C 6 C optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy 3 ~C 6 forming a cycloalkyl; and T is heteroaryl; wherein the heteroaryl is Contains one five- or six-membered ring, containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; Halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, OH, C 1 ~C 6 Alkoxy, and C 1 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy; and The C of the heteroaryl 1 ~C 6 The alkyl substituents are each C 1 ~C 6 optionally substituted with one or more substituents independently selected from alkoxy; however, (i) At least one R 3 is cycloalkyl, phenyl, heterocyclyl, or heteroaryl; and (ii) The compound of formula (I) is a compound selected from the group consisting of: or a pharmaceutically acceptable salt or tautomer thereof, compound, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. Formula (Ib1), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (Ib10), or (Ib11): A compound of the formula During the ceremony, Each R 7 are independently halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, OH C 1 ~C 6 Alkoxy, or C 1 ~C 6 haloalkoxy; and Each R 11 are independently halogens, CN, NO 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, NH 2 , NH-(C 1 ~C 6 alkyl), N(C 1 ~C 6 alkyl) 2 , O.H., C. 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, or C 3 ~C 6 is cycloalkyl, compound 2. The compound of claim 1, wherein:

3. Formula (Ib9):

2. The compound of claim 1, which is a compound of the formula:

4. R 1 is phenyl, wherein the phenyl is selected from the group consisting of halogen, C 1 ~C 6 Alkyl, and C 3 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl; 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

5. R 2 is heteroaryl, wherein the heteroaryl is containing two five- or six-membered rings; containing 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S; and Halogens and C 1 ~C 6 optionally substituted with one or more substituents independently selected from the group consisting of alkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. R 2 6. The compound of claim 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein is indazolyl.

7. The formula (I) is 2. The compound of claim 1, wherein:

8. The formula (I) is 2. The compound of claim 1, wherein:

9. The formula (I) is 2. The compound of claim 1, wherein:

10. R 4 But linear C 1 ~C 6 Alkyl or branched C 3 ~C 6 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

11. R 4 But CH 3 11. The compound of claim 10, wherein:

12. R 5 and R 6 and R 1 and R 2 together with the carbon atom to which they are attached form cyclopropyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

13. T, 2. The compound of claim 1, wherein:

14. A compound selected from the group consisting of:

2. The compound of claim 1, wherein:

15. A compound selected from the group consisting of:

2. The compound of claim 1, wherein:

16. A compound selected from the group consisting of:

2. The compound of claim 1, wherein:

17. 14. A pharmaceutical composition comprising the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

18. 14. A pharmaceutical composition for modulating the activity of the glucagon-like peptide-1 (GLP-1) receptor in a subject, comprising a therapeutically effective amount of a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

19. 16. A pharmaceutical composition comprising a compound of claim 14 or 15, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

20. 15. A pharmaceutical composition for modulating the activity of the glucagon-like peptide-1 (GLP-1) receptor in a subject, comprising a therapeutically effective amount of the compound of claim 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

21. 17. A pharmaceutical composition comprising the compound of claim 16, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, carrier, or excipient.

22. 17. A pharmaceutical composition for modulating the activity of the glucagon-like peptide-1 (GLP-1) receptor in a subject, comprising a therapeutically effective amount of the compound of claim 16, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

23. 19. The pharmaceutical composition of claim 18, wherein the subject has a GLP-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, liver disease, obesity, Parkinson's disease, and stroke.

24. 21. The pharmaceutical composition of claim 20, wherein the subject has a GLP-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, liver disease, obesity, Parkinson's disease, and stroke.

25. 23. The pharmaceutical composition of claim 22, wherein the subject has a GLP-1 receptor-mediated condition, disease, or disorder selected from the group consisting of Alzheimer's disease, atherosclerosis, arrhythmia, congestive heart failure, coronary heart disease, dementia, diabetes, diabetic kidney disease, hypercholesterolemia, hyperlipidemia, hypertension, hypertriglyceridemia, liver disease, obesity, Parkinson's disease, and stroke.

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